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COMPOUNDS AND THEIR USE

20230078576 · 2023-03-16

    Inventors

    Cpc classification

    International classification

    Abstract

    The specification generally relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, where A, U, V, W, X, Y, Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meanings defined herein. Such compounds are modulators of RXFP1 and may be useful as therapeutic agents. The specification also relates to the use of such compounds to treat or prevent diseases and conditions including heart failure, heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease and acute kidney injury. The specification further relates to compositions comprising such compounds, intermediates useful in processes for preparing such compounds, and processes for preparing such compounds using such intermediates.

    Claims

    1.-63. (canceled)

    64. A compound which is ##STR01349## or a pharmaceutically acceptable salt thereof.

    65.-75. (canceled)

    76. A pharmaceutical composition comprising the compound of claim 64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

    77.-98. (canceled)

    99. The compound of claim 64, which is ##STR01350##

    100. The compound of claim 64, which is a pharmaceutically acceptable salt of ##STR01351##

    101. A pharmaceutical composition comprising the compound of claim 99 and a pharmaceutically acceptable excipient.

    102. A pharmaceutical composition comprising the compound of claim 100 and a pharmaceutically acceptable excipient.

    Description

    LIST OF FIGURES

    [1728] The figures relate to solid forms of the compounds: Compound X, Compound Y or Compound Z.

    [1729] FIG. 1: X-Ray Powder Diffraction Pattern—Form A of Compound X

    [1730] FIG. 2: X-Ray Powder Diffraction Pattern—Form B of Compound X

    [1731] FIG. 3: X-Ray Powder Diffraction Pattern—Form D of Compound X

    [1732] FIG. 4: X-Ray Powder Diffraction Pattern—Form E of Compound X

    [1733] FIG. 5: X-Ray Powder Diffraction Pattern—Form A of Compound Y

    [1734] FIG. 6: X-Ray Powder Diffraction Pattern—Form B of Compound Y

    [1735] FIG. 7: X-Ray Powder Diffraction Pattern—Form A of Compound Z

    [1736] FIG. 8: X-Ray Powder Diffraction Pattern—Form B of Compound Z

    EXAMPLES

    [1737] The compounds described in this specification are further illustrated in the following Examples. These Examples are given by way of illustration only and are non-limiting.

    [1738] In the examples, high resolution mass spectra were recorded on a Micromass LCT mass spectrometer equipped with an electrospray interface (LC-HRMS).

    [1739] .sup.1H NMR measurements were performed on Bruker Avance III 300, 400, 500 and 600 spectrometers, operating at .sup.1H frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25° C. Chemical shifts are given in ppm with the solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therefore be missing. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet.

    [1740] Flash chromatography was performed using either normal phase silica FLASH+® (40M, 25M or 12M), Biotage® SNAP Cartridges KP-Sil (340, 100, 50 or 10), or Agela® Flash Column Silica-CS Cartridges (330, 180, 120, 80) unless otherwise stated.

    [1741] Reversed phase flash chromatography was performed using Agela® C-18 spherical 20-35 μm 100A cartridges unless otherwise stated.

    [1742] Purifications were performed by preparative HPLC, preparative SFC or reversed phase flash chromatography on a standard equipment, using MS or UV triggered fraction collection, and using one of the following methods; Method PrepAcidic-A The compound was purified by preparative HPLC on a XSelect CSH Prep C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H.sub.2O/FA (0.1%) buffer system; Method PrepAcidic-B The compound was purified by preparative HPLC on a Xselect CSH F-Phenyl OBD column (5 μm 250×19 mm ID) using a gradient of MeCN in a H.sub.2O/TFA (0.05%) buffer system; Method PrepAcidic-C The compound was purified by preparative HPLC on a XBridge Prep C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H.sub.2O/TFA (0.05%) buffer system; Method PrepAcidic-D The compound was purified by preparative HPLC on a XBridge Prep C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H.sub.2O/TFA (0.1%) buffer system; Method PrepAcidic-E The compound was purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H.sub.2O/FA (0.1%) buffer system; Method PrepAcidic-F The compound was purified by preparative HPLC on a Kromasil C18 column (10 μm 250×20 mm ID) using a gradient of MeCN in a H.sub.2O/MeCN/FA (95/5/0.2) buffer system; Method PrepAcidic-G The compound was purified by preparative HPLC on a XSelect CSH Prep C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H.sub.2O/TFA (0.05%) buffer system; Method PrepAcidic-H The compound was purified by preparative HPLC on a Kromasil C18 column (10 μm 250×20 mm ID) using a gradient of MeCN in a H.sub.2O/MeCN/Acetic acid (95/5/0.2) buffer system; Method PrepAcidic-I The compound was purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H.sub.2O/FA (0.1%) buffer system; Method PrepAcidic-J The compound was purified by preparative HPLC on a XSelect CSH Prep C18 OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H.sub.2O/TFA (0.5%) buffer system; Method PrepAcidic-K The compound was purified by preparative HPLC on a XSelect CSH Prep C18 OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H.sub.2O/TFA (0.05%) buffer system; Method PrepAcidic-L The compound was purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H.sub.2O/FA (0.05%) buffer system; Method PrepAcidic-M The compound was purified by preparative HPLC on a XSelect CSH OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H.sub.2O/TFA (0.10%) buffer system; Method PrepAcidic-N The compound was purified by preparative HPLC on a Xselect CSH F-Phenyl OBD column (5 μm 250×19 mm ID) using a gradient of MeCN in a H.sub.2O/TFA (0.1%) buffer system; Method PrepAcidic-O The compound was purified by preparative HPLC on a Phenomenex Luna C18 column (10 μm 50×100 mm ID) using a gradient of MeCN (40-70% over 25 min) in a H.sub.2O (0.05% HCl) buffer system; Method PrepAcidic-P The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 80-95% MeCN in a TFA (0.05%) buffer system as mobile phase; Method PrepBasic-A The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×19 mm ID) using a gradient of MeCN in a H.sub.2O/MeCN/NH.sub.3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-B The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 50×19 mm ID) using a gradient of MeCN in a H.sub.2O/MeCN/NH.sub.3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-C The compound was purified by preparative HPLC on a WatersSunfire C18 ODB column (5 μm 150×30 mm ID) using a gradient of MeCN in a H.sub.2O/MeCN/NH.sub.3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-D The compound was purified by preparative HPLC on a Xbridge C18 column (10 μm 250×19 mm ID) using a gradient of MeCN in a H.sub.2O/MeCN/NH.sub.3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-E The compound was purified by preparative HPLC on a Xbridge C18 ODB column (5 μm 150×19 mm ID) using a gradient of MeCN in a H.sub.2O/MeCN/NH.sub.3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-F The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 mm ID) using a gradient of MeCN in a H.sub.2O/MeCN/NH.sub.3 (95/5/0.2) buffer system at pH10 as mobile phase; Method PrepBasic-G The compound was purified by preparative HPLC on a Xbridge C18 OBD column (5 μm 150×19 mm ID) using a gradient of MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-H The compound was purified by preparative HPLC on a Xbridge C18 OBD column (5 μm 150×30 mm ID) using a gradient of MeCN in a H.sub.2O/NH.sub.3 (0.1)/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-I The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 20-90% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-J The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 50-70% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-K The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 70-90% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-L The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 30-45% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-M The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 20-70% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-N The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm 150×30 mm ID) using a gradient of 15-60% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-O The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 30-60% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-P The compound was purified by preparative HPLC on a Ultimate XB-C18 (11 μm 250×50 mm ID) using a gradient of 45-65% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-Q The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 40-65% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-R The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 50-70% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-S The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 25-60% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-T The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 65-75% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-U The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 40-90% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-V The compound was purified by preparative HPLC on a Ultimate XB-C18 column (11 μm 250×50 mm ID) using a gradient of 35-65% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase; Method PrepBasic-W The compound was purified by preparative HPLC on a XBridge C18 column (5 μm 150×30 mm ID) using a gradient of 10-50% MeCN in a H.sub.2O/NH.sub.3 (0.05%) buffer system as mobile phase; Method PrepBasic-X The compound was purified by preparative HPLC on a XBridge C18 column (5 μm 150×30 mm ID) using a gradient of 15-60% MeCN in a H.sub.2O/NH.sub.3 (0.05%) buffer system as mobile phase; Method PrepBasic-Y The compound was purified by preparative HPLC on a XBridge C18 column (5 μm 150×30 mm ID) using a gradient of 10-70% MeCN in a H.sub.2O/NH.sub.3 (0.05%) buffer system as mobile phase; Method SFC-A The compound was purified by preparative SFC on a Phenomenex Luna HILIC column (5 μm 250×30 ID mm) using MeOH/20 mM NH.sub.3 in CO.sub.2 as mobile phase; Method SFC-B The compound was purified by preparative SFC on a Waters BEH 2-EP column (5 μm 250×30 ID mm) using MeOH/20 mM NH.sub.3 in CO.sub.2 as mobile phase; Method SFC-C The compound was purified by preparative SFC on a Waters BEH 2-EP column (5 μm 250×30 ID mm) using MeOH/H.sub.2O (97/3)+50 mM NH.sub.3 in CO.sub.2 as mobile phase; Method SFC-D The compound was purified by preparative SFC on a Waters BEH column (5 μm 250×30 ID mm) using MeOH/20 mM NH.sub.3 in CO.sub.2 as mobile phase; Method SFC-E The compound was purified by preparative SFC on a Waters Acquity UPC2 BEH column (3.5 μm 250×30 mm ID) using MeOH/H.sub.2O (97/3)+50 mM NH.sub.3 in CO.sub.2 as mobile phase; Method SFC-F The compound was purified by preparative SFC on a Waters BEH column (5 μm 250×30 ID mm) using MeOH/H.sub.2O (97/3)+50 mM NH.sub.3 in CO.sub.2 as mobile phase; Method SFC-G The compound was purified by chiral preparative SFC on a Chiralpak IC column (5 μm 250×20 ID mm) using IPA in CO.sub.2 (g) as mobile phase; Method SFC-H The compound was purified by chiral preparative SFC on a Daicel Chiralpak AD column (10 μm 250×50 ID mm) using 55% 0.1% NH.sub.4OH (aq) and 45% IPA as the mobile phase; Method FlashAcid-A The compound was purified by preparative flash chromatography on a WelFlash C18, 120 g column using a gradient of 45-90% MeCN in a FA (0.05%) buffer system as mobile phase; Method FlashBasic-A The compound was purified by preparative flash chromatography on a WelFlash C18, 120 g column using a gradient of 30-80% MeCN in a H.sub.2O/NH.sub.4HCO.sub.3 (10 mM) buffer system as mobile phase;

    [1743] In general, all solvents used were commercially available and of analytical grade. Anhydrous solvents were routinely used for reactions.

    [1744] Phase Separators used in the examples are ISOLUTE® Phase Separator columns.

    [1745] The Intermediates and Examples named below were named using ChemDraw Professional version 19.0.0.22 from PerkinElmer.

    [1746] The following abbreviations were used [1747] Aq Aq [1748] AIBN 2,2′-Azobis(2-methylpropionitrile) [1749] APCI Atmospheric pressure chemical ionization [1750] Boc.sub.2O Di-tert-butyl dicarbonate [1751] B.sub.2Pin.sub.2 4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane [1752] BuOAc n-Butyl acetate [1753] BuOH Butanol [1754] Calcd Calculated [1755] Dba (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one [1756] DBAD Di-tert butyl azodicarboxylate [1757] DCM Dichloromethane [1758] DEA Diethylamine [1759] DIA Diisopropylamine [1760] DIAD Diisopropyl (E)-diazene-1,2-dicarboxylate [1761] DIPEA N-Ethyl-N-isopropyl-propan-2-amine [1762] DMA N,N-dimethylacetamide [1763] DMAP N,N-dimethylpyridin-4-amine [1764] DMF N,N-dimethylformamide [1765] DMSO Dimethylsulfoxide [1766] DPPA Diphenylphosphoryl azide [1767] Dppf 1,1′-bis(diphenylphosphino)ferrocene [1768] DTBBPY 4,4′-Di-tert-butyl-2,2′-dipyridyl [1769] Dtbpf 1,1′-Bis(di-tert-buthylphosphino)ferrocene [1770] EDC 3-(Ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine; hydrochloride [1771] ESI Electrospray ionization [1772] Et Ethyl [1773] Et.sub.2O Diethyl ether [1774] EtOAc Ethylacetate [1775] EtOH Ethanol [1776] FA Formic acid [1777] h/hr Hour(s) [1778] HATU (Dimethylamino)-N,N-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridinyl)methaniminium hexafluorophosphate [1779] HBTU 2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) [1780] HOAt 3H-1,2,3-Triazolo[4,5-b]pyridin-3-ol [1781] HOBt 1-Hydroxybenzotriazole; hydrate [1782] HPLC High performance liquid chromatography [1783] HRMS High resolution mass spectrometry [1784] IPA Isopropyl alcohol [1785] IPAC Isopropyl acetate [1786] [Ir(COD)OMe].sub.2 Bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) [1787] L Litre [1788] Me Methyl [1789] MeCN Acetonitrile [1790] mL Millilitre [1791] MeOH Methanol [1792] 2-Me-THF 2-Methyltetrahydrofuran [1793] Min Minutes [1794] MS Mass spectrometry [1795] MTBE Methyl tert-butyl ether [1796] NBS 1-Bromopyrrolidine-2,5-dione [1797] NMR Nuclear magnetic resonance [1798] OAc Acetate [1799] OTf Trifluoromethanesulfonate [1800] PE Petroleum ether [1801] Pd-C Palladium on charcoal [1802] Rt Room temperature [1803] Sat Saturated [1804] SM Starting material [1805] SFC Supercritical fluid chromatography [1806] T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide [1807] TBAF Tetra-n-butylammonium fluoride [1808] TCFH N-(Chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) [1809] TEA Triethylamine [1810] TFA Trifluoroacetic acid [1811] THF Tetrahydrofuran [1812] TLC Thin layer chromatography [1813] TCFH N-(Chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) [1814] Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

    Intermediates

    Intermediate 1: Ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate

    [1815] ##STR00095##

    [1816] A solution of DIA (576 mL, 413 g, 4.08 mol) in THF (3.50 L) was cooled to −50 to −40° C. and a solution of n-BuLi (2.5 M in hexane, 1.09 kg, 3.92 mol) was added over 3 h, maintaining the temperature between −50 to −40° C. The solution was stirred for 3 h at −50 to −40° C., followed by the addition of a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (700 g, 3.27 mol, 2.34 M in THF) over 2 h, maintaining the temperature between −50 to −40° C. The reaction mixture was stirred for 4 h at −50 to −40° C. before the addition of methyl iodide (603 g, 4.25 mol, 3.04 M in THF) over 3 h, maintaining the temperature between −50 to −30° C. The reaction mixture was further stirred for 2 h at −50 to −30° C. followed by the addition of aq NH.sub.4Cl (3.50 L, 20% w/w in H.sub.2O) over 1 h, maintaining the temperature <0° C. The solution was warmed to between 15 to 25° C., held for 0.5 h then the layers were separated and the organic layer washed with aq NH.sub.4Cl (2×3.50 L, 20% w/w in H.sub.2O). Exchange of the organic reaction solvent from THF to EtOH under reduced pressure, maintaining the temperature <45° C., gave the title compound as a 27% w/w solution in EtOH (2.51 kg, 2.91 mol, 89%). .sup.1H NMR for purified compound (400 MHz CDCl.sub.3) δ 1.18 (3H, s), 1.27-1.22 (3H, m), 1.47-1.35 (2H, m), 1.70-1.56 (4H, m), 2.13 (2H, d), 3.92 (4H, s), 4.14 (2H, q), MS (ESI): m/z [M+H]+ 229.2.

    Intermediate 2: 8-Methyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid

    [1817] ##STR00096##

    [1818] To a solution of Intermediate 1 (1.13 kg, 1.31 mol, 27% w/w in EtOH) was added EtOH (900 mL) followed by aq NaOH (2.63 L, 5.26 mol, 2 M in H.sub.2O) maintaining the temperature between 15 to 30° C. The solution was heated to between 50 to 60° C., then held for 6 h before cooling to 15 to 30° C. and concentration of the solution to between 1.8 to 2.4 L under reduced pressure. Hexane (1.50 L) was added and the layers separated. The aq layer was collected and the pH adjusted to between 3 to 4 by the addition of aq HCl (1.30 L, 5.2 mol, 4 M in H.sub.2O) maintaining the temperature <20° C. This aq solution was extracted with DCM (2×1.50 L) and the combined organic phases were concentrated under reduced pressure, maintaining the temperature <30° C. to give the title compound as a 17% w/w solution in DCM (1.43 kg, 1.24 mol, 94%). .sup.1H NMR for purified compound (500 MHz CDCl.sub.3) δ 1.25 (3H, s), 1.53 (2H, dt), 1.62-1.72 (4H, m), 2.05-2.19 (2H, m), 3.93 (4H, s). MS (ESI): m/z [M+Na].sup.+223.1.

    Intermediate 3: 1-Methyl-4-oxocyclohexane-1-carboxylic acid

    Method A

    [1819] ##STR00097##

    [1820] To a solution of Intermediate 2 (367 g, 250 mmol, 14% w/w in DCM) was added TFA (95.3 mL, 142 g, 1.25 mol). The reaction temperature was maintained between 25 to 35° C. for 20 h before cooling to between 0 to 10° C. H.sub.2O (250 mL) was added to the reaction solution and the pH of the aq phase adjusted to between 9 and 10 by the addition of aq NaOH (440 mL, 1.76 mol, 4 M in H.sub.2O). The layers were separated and the aq layer was retained and cooled to between 0 to 10° C. The pH was adjusted to between 2 and 3 by the addition of aq HCl (73.5 mL, 294 mmol, 4 M in H.sub.2O) then extracted with DCM (3×250 mL) and the combined DCM solutions concentrated to between 150 to 200 mL under reduced pressure. Exchange of the organic reaction solvent from DCM to MeCN under reduced pressure, maintaining the temperature <40° C., gave the title compound as a 30% w/w solution in MeCN (119 g, 227 mmol, 91%). .sup.1H NMR for purified compound (400 MHz CDCl3) δ 1.39 (3H, s), 1.73 (2H, td), 2.43 (6H, m). MS (ESI): m/z [M+H]+ 157.1.

    Method B

    [1821] To a solution of Intermediate 2 (6.17 kg, 3.83 mol, 12.4% in DCM) was added TFA (1.42 L, 2.18 kg, 19.13 mol). The reaction temperature was maintained between 25 to 35° C. for 20 h before cooling to between 0 to 10° C. A solution of aq NaOH (918 g, 22.96 mol dissolved in 7.66 L H.sub.2O) was added to the reaction solution and the pH of the aqueous phase was adjusted to between 9 and 11. The layers were separated and the aq layer was retained and cooled to between 0 to 10° C. Addition of DCM (3.83 L) followed by aq HCl (1.52 L, 6.08 mol, 4 M in H.sub.2O) adjusts the pH to between 3 and 4. The organic layer was retained and the aqueous extracted with DCM (2×3.83 L) and the combined organic phase was washed with brine (2.3 L, 15% w/w NaCl). The organic phase was concentrated under reduced pressure to 2.3 to 3.1 L. Exchange of the organic reaction solvent from DCM to MeCN under reduced pressure, maintaining the temperature <45° C., gave the title compound as a 18% solution in MeCN (2.85 kg, 3.32 mol, 87%). .sup.1H NMR for purified compound (400 MHz CDCl3) δ 1.39 (3H, s), 1.73 (2H, td), 2.43 (6H, m). MS (ESI): m/z [M+H].sup.+ 157.1.

    Intermediate 4: Naphthalen-1-ylmethyl 1-methyl-4-oxocyclohexane-1-carboxylate

    Method A

    [1822] ##STR00098##

    [1823] To a solution of Intermediate 3 (119 g, 192 mmol, 25% w/w in MeCN) was added 1-chloromethylnaphthalene (32.2 g, 183 mmol) followed by DIPEA (70.0 mL, 49.7 g, 384 mmol) and NaI (2.88 g, 19.2 mmol). The solution was heated to between 50 to 60° C. for 8 h before cooling to between 0 to 10° C. H.sub.2O (240 mL) was added and the pH of the reaction mixture adjusted to between 3 and 4 by the addition of aq HCl (55.0 mL, 220 mmol, 4 M in H.sub.2O). The reaction mixture was extracted with MTBE (2×150 mL) and the combined organic phases washed with aq NaHCO.sub.3(150 mL, 144 mmol, 8% w/w in H.sub.2O). The organic reaction solvent was exchanged from MTBE to IPA under reduced pressure, maintaining the temperature <40° C. The temperature of the reaction solution was lowered to between −10 to 3° C. and the solution stirred for 2 h, upon which a solid precipitate formed. The solids were filtered and dried under N.sub.2 for 15 h to give the title compound as a white solid (42.8 g, 144 mmol, 74%); .sup.1H NMR (500 MHz, CDCl.sub.3) 1.30 (3H, s), 1.65 (2H, td), 2.16-2.47 (6H, m), 5.66 (2H, s), 7.46 (1H, dd), 7.51-7.63 (3H, m), 7.78-7.93 (2H, m), 7.93-8.05 (1H, m). MS (ESI): m/z [M+Na].sup.+319.1.

    Method B

    [1824] To a solution of Intermediate 3 (2.66 kg, 3.09 mol, 18.2% in MeCN) was added 1-chloromethylnapthalene (535 g, 2.94 mol) followed by potassium carbonate (513 g, 3.71 mol) and a further portion of fresh MeCN (714 mL). The suspension was heated to between 50 to 60° C. for 17 h before cooling to 25 to 30° C. The solid was removed by filtration through a Celite pad, which was washed through with MeCN (2×967 mL). Concentrate the filtrates to 1.45 to 1.93 L under reduced pressure. The MeCN was exchanged to isopropanol under reduced pressure, maintaining the temperature <50° C. The temperature of the mixture was lowered to between 20 to 25° C., upon which a solid precipitate formed. The mixture was cooled further to -10 to 0° C., and the solids were then filtered, washed with isopropanol and dried under N.sub.2 to give the title compound as a white solid (752.6 g, 2.49 mol, 80.5%); .sup.1H NMR (500 MHz, CDCl.sub.3) 1.30 (3H, s), 1.65 (2H, td), 2.16-2.47 (6H, m), 5.66 (2H, s), 7.46 (1H, dd), 7.51-7.63 (3H, m), 7.78-7.93 (2H, m), 7.93-8.05 (1H, m). MS (ESI): m/z [M+Na].sup.+319.1.

    Intermediate 5: Methyl 5-(1,3,6,2-dioxazaborocan-2-yl)-4-fluoro-2-methoxybenzoate

    Method A

    [1825] ##STR00099##

    [1826] B.sub.2Pin.sub.2 (362 g, 1.43 mol) was added to 2-Me-THF (1.75 L) that had been degassed with N.sub.2 to <1% oxygen. The solution was held between 20 to 30° C. and methyl 4-fluoro-2-methoxybenzoate was added (250 g, 1.36 mol). DTBBPY (1.09 g, 4.10 mmol) was added and the reaction vessel evacuated and re-filled with N.sub.2 until the oxygen level was <0.5%. [Ir(COD)OMe].sub.2 (1.35 g, 2.04 mmol) was added and the reaction vessel evacuated and re-filled with N.sub.2 until the oxygen level was <0.5%. The reaction mixture was heated to between 80 to 85° C. and held at that temperature for a further 2 h. The reaction mixture was cooled to between 0 to 5° C. followed by the slow addition of diethanolamine (428 g, 4.07 mol, 10.9 M in IPA) over a period of 2.5 h, with the concurrent generation of H.sub.2 gas. The reaction mixture was stirred for 2.5 h between 0 to 5° C., followed by filtration and washing of the solids with 2-Me-THF (3×750 mL). The solid was dried under N.sub.2 for 10 h to give the title compound as a white solid (356 g, 1.20 mol, 88%); .sup.1H NMR (500 MHz, DMSO-d6) δ 2.81-2.89 (2H, m), 3.14 (2H, dq), 3.71 (2H, ddd), 3.74 (3H, s), 3.78 (3H, s), 3.84 (2H, td), 6.77 (1H, d), 7.10 (1H, s), 7.83 (1H, d). MS (ESI): m/z [M+H].sup.+ 297.1.

    Method B

    [1827] B.sub.2Pin.sub.2 (29.0 g, 114 mmol) and methyl 4-fluoro-2-methoxybenzoate (20.6 g, 109 mmol) were added to 2-Me-THF (140 mL) that had been degassed with N.sub.2 to <1% oxygen. The solution was held between 20 to 30° C. then DTBBPY (88 mg, 0.33 mmol) and [Ir(COD)OMe].sub.2 (108 mg, 0.16 mmol) were added and the reaction vessel evacuated and re-filled with N.sub.2 until the oxygen level was <0.5%. The reaction mixture was heated to between 80 to 85° C. and held at that temperature for a further 3 h. The reaction mixture was cooled to between 0 to 10° C. followed by the slow addition of isopropanol (12.4 mL, 218 mmol), with the concurrent generation of H.sub.2 gas. Addition of seed (100 mg of Intermediate 5) followed by addition of diethanolamine (22.84 g, 218 mmol) dissolved in IPA (20 mL) gave a mobile slurry. The slurry was warmed to 20 to 30° C. and the solid collect by filtration. It was then washed with 2-Me-THF (160 ml) and the solid was dried under N.sub.2 for 10 h to give the title compound as a white solid (29.1 g, 96 mol, 88%); .sup.1H NMR (500 MHz, DMSO-d6) δ 2.81-2.89 (2H, m), 3.14 (2H, dq), 3.71 (2H, ddd), 3.74 (3H, s), 3.78 (3H, s), 3.84 (2H, td), 6.77 (1H, d), 7.10 (1H, s), 7.83 (1H, d). MS (ESI): m/z [M+H].sup.+ 297.1.

    Intermediate 6: Methyl 4-fluoro-5-hydroxy-2-methoxybenzoate

    Method A

    [1828] ##STR00100##

    [1829] To a suspension of Intermediate 5 (350 g, 1.18 mol) in H.sub.2O (1.05 L) was added THF (1.75 L) and the reaction mixture stirred until a clear solution is obtained. (NH.sub.4).sub.2CO.sub.3 (136 g, 1.41 mol) was added and the heterogenous mixture cooled to between 0 to 10° C. NaBO.sub.3.4H.sub.2O (217 g, 1.41 mol) was added in 10 equal portions over a period of 2 h maintaining the reaction temperature between 0 to 30° C. The reaction temperature was adjusted to between 20 to 30° C. and held for 1 h. An aq solution of NaHSO.sub.3 (1.96 L, 942 mmol, 0.48 M in H.sub.2O) was added over 3 h and the reaction mixture stirred for an additional 0.5 h. The reaction mixture was filtered, the solids washed with ethylacetate (700 mL) and the filtrate and wash combined to give a biphasic solution. The solution was separated and the retained organic phase solvent exchanged from THF/ethylacetate to MeOH under reduced pressure, maintaining the temperature <40° C. H.sub.2O (3.50 L) was added drop-wise over a period of 4 h and the reaction mixture cooled to between 0 to 5° C. and held for 2 h. The reaction mixture was filtered, the collected solids washed with H.sub.2O (3×350 mL) and dried under hot air at <40° C. to give the title compound as a white solid (195 g, 974 mmol, 83% yield); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 3.82 (3H, s), 3.86 (3H, s), 6.72 (1H, d), 7.54 (1H, d). MS (ESI): m/z [M+H].sup.+ 201.0.

    Method B

    [1830] Intermediate 5 (32.41 g, 67.3 mmol) was dissolved in 2-Me-THF (100 mL) with acetic acid (12.13 g, 202 mmol) and cooled to between 0 to 10° C. Hydrogen peroxide solution (30% w/w, 9.16 g, 80.8 mmol) was added over 2 hours and then the reaction temperature was adjusted to between 20 to 30° C. and held for 18 hours. An aq solution of Na.sub.2S.sub.2O.sub.3.5H.sub.2O (20% w/w, 50 mL) quenches the mixture and gives a phase separation. The aqueous is discarded, and the organic washed twice with aq solution of Na.sub.2S.sub.2O.sub.3.5H.sub.2O (5% w/w, 100 mL). The organic phase was concentrated to 60 mL under reduced pressure followed by another 2 vacuum distillations with 2-Me-THF (100 mL) to give a dissolved solution at 35 to 45° C. Nucleation was controlled by addition of seed (100 mg of Intermediate 6) followed by slow addition of 300 mL n-heptane over 5 hours. The resulting slurry was adjusted to between 20 to 30° C. and stirred overnight prior to filtration. The collected solid was washed with n-heptane (2×60 mL) and dried to give the title compound as a white solid (12.5 g, 62.5 mmol, 93% yield); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 3.82 (3H, s), 3.86 (3H, s), 6.72 (1H, d), 7.54 (1H, d). MS (ESI): m/z [M+H].sup.+ 201.0.

    Intermediate 7: (1R,2R,3S,4S)-3-(Methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [1831] ##STR00101##

    [1832] To a solution of (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione (387 g, 2.36 mol) in toluene (4.64 L) was added quinidine (843 g, 2.60 mol) followed by toluene (774 mL). The reaction mixture was cooled to between −10 to −5° C. and MeOH (227 g, 286 mL, 7.08 mol) was added drop-wise over 1.5 h before holding at between −10 to −5° C. for 14 h. The reaction mixture was warmed to between -5 to 5° C., held for 2 h, then filtered. The solids were washed with toluene (3×387 mL), the filtrate and washes combined and cooled to between 0 to 10° C. In a separate vessel an aq solution of HCl (590 mL, 7.08 mol, 12 M in H.sub.2O) and NaCl (1.24 kg, 21.2 mol) were added to H.sub.2O (6.39 L) and the resulting solution added dropwise to the main reaction vessel, maintaining the reaction solution <10° C. The reaction mixture was warmed to between 10 to 20° C., held for 0.5 h then filtered. The solids were washed with toluene (1.94 L), the filtrate and wash combined, and the biphasic solution separated. The organic phase was washed with aq NaCl (3.87 L, 20% w/w in H.sub.2O) and stored at <5° C. to give the title compound as a 5.9% w/w solution in toluene (6.19 kg, 1.83 mol, 78%); .sup.1H NMR for purified compound (400 MHz DMSO-d.sub.6) δ 1.25-1.32 (1H, m), 1.95 (1H, d), 2.48-2.50 (2H, m), 2.93 (2H, s), 3.51 (3H, s), 6.15-6.22 (2H, m), 12.21 (1H, s). MS (ESI): m/z [M+Na]+219.1.

    Intermediate 8: Methyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

    [1833] ##STR00102##

    [1834] To a solution of Intermediate 7 in toluene (6.19 kg, 5.9% w/w, 1.85 mol) at between -5 to 5° C. was added TEA (307 mL, 223 g, 2.22 mol) followed by DPPA (538 g, 1.94 mol), maintaining the reaction solution <5° C. The reaction mixture was stirred for 4 h at between -5 to 5° C. then TEA was added (767 mL, 557 g, 5.55 mol) followed by citric acid (352 g, 1.85 mol). The reaction mixture was stirred for 6 h at between -5 to 5° C. then H.sub.2O (3.6 L) was added maintaining the reaction solution <10° C. The biphasic reaction solution was stirred for 0.5 h, the phases separated and the organic phase washed with H.sub.2O (3.6 L) and aq NaCl (3.6 L, 15% w/w in H.sub.2O) then stored between 2 to 8° C. to give methyl (1S,2S,3R,4R)-3-(azidocarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (Intermediate 9) as a solution in toluene that was used directly in the next step. Intermediate 9 as a solution in toluene at between 2 to 8° C. was added over 2 h to a reactor containing toluene (1.80 L) at between 70 to 80° C., maintaining the reaction temperature <80° C. The resulting solution was stirred for 1 h before cooling to between 20 to 30° C. Exchange of the organic reaction solvent from toluene to 1,4-dioxane under reduced pressure, maintaining the temperature <50° C., gave Methyl (1S,2S,3R,4R)-3-isocyanatobicyclo[2.2.1]hept-5-ene-2-carboxylate (Intermediate 10) as a solution in 1,4-dioxane that was used directly in the next step. To a solution of Intermediate 10 in 1,4-dioxane at between 10 to 20° C. was added HCl (420 mL, 1.68 mol, 4 M in 1,4-dioxane) followed by H.sub.2O (360 mL, 1.68 mol, 4.67 M in 1,4-dioxane). The reaction mixture was warmed to between 25 to 35° C. and held for 16 h. MTBE (1.65 L) was added drop-wise and the reaction mixture filtered, the solids washed with MTBE/1,4-dioxane (1:1, 660 mL) and MTBE (660 mL), then dried at between 30 to 40° C. under vacuum to give the title compound as a white solid (258 g, 1.27 mol, >99% ee, 75%); .sup.1H NMR (400 MHz, DMSO-d6) δ 1.45 (1H, d), 2.04 (1H, d), 2.52-2.67 (1H, m), 2.94-3.10 (2H, m), 3.19 (1H, d), 3.65 (3H, s), 6.21 (1H, m), 6.30 (1H, m), 8.34 (3H, s). MS (ESI): m/z [M+H].sup.+ 168.1.

    Intermediate 11: Naphthalen-1-ylmethyl (1r,4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate

    [1835] ##STR00103##

    Route A

    [1836] To a solution of Na.sub.2HPO.sub.4.12H.sub.2O (8.25 g, 23.0 mmol), NaH.sub.2PO.sub.4 (0.55 g, 4.48 mmol) and MgCl.sub.2 (0.11 g, 1.10 mmol) in H.sub.2O (550 mL) at 20 to 30° C. was added Intermediate 4 (50.0 g, 169 mmol) as a solution in IPA (450 mL). The pH of the reaction solution was adjusted to between 7.3 to 7.8 using 6 M HCl and NAD+ (0.66 g, 1.00 mmol) was added followed by ADH-230 (7.50 g, 0.15 wt %). ADH-230 is an alcohol dehydrogenase available from Johnson Matthey PLC, UK (catalogue no. ADH-230). The reaction mixture was then held at 33 to 37° C. for 18 h before concentration to between 300 and 400 mL under reduced pressure, maintaining the temperature <45° C. NaCl (150 g), Celite® (20.0 g, 0.4 wt %) and MTBE (500 mL) was added and the reaction held for 0.5 h. The mixture was filtered and the filter cake washed with MTBE (250 mL). The combined filtrate was separated and the aq phase extracted with MTBE (500 mL). The organic phases were combined and washed with H.sub.2O (250 mL) before solvent exchange to THF under reduced pressure, maintaining the temperature <45° C., gave the title compound (138 g, 33% w/w %, >99:1 trans:cis, <0.1% IPA, 92% yield) as a solution in THF that was used directly in the next step. .sup.1H NMR for purified compound (500 MHz, CDCl.sub.3) δ 1.21 (3H, s), 1.48-1.58 (2H, m), 1.62-1.77 (4H, m), 1.82-1.93 (2H, m), 3.74-3.77 (1H, m), 5.57 (2H, s), 7.41-7.48 (1H, m), 7.48-7.57 (3H, m), 7.85 (1H, d), 7.87-7.91 (1H, m), 7.98 (1H, d). MS (ESI): m/z [M+Na]+321.1.

    Route B

    [1837] A solution of lithium tri-sec-butylborohydride (1.06 g, 5.6 mmol) in THF (5 mL) was added dropwise to a stirred solution of Intermediate 4 (1.00 g, 3.37 mmol) in THF (10 mL) cooled to -78° C., over a period of 1 min under nitrogen. The resulting solution was stirred at −78° C. for 2 h. The reaction mixture was quenched with 0.1 M HCl (10 mL) at −78° C. and then extracted with EtOAc (3×50 mL). The organic layers were pooled and dried over Na.sub.2SO.sub.4 filtered and evaporated. The residue was purified by preparative TLC (EtOAc/PE, 1:3), to afford the title compound (0.488 g, 48.5%) as a pale yellow gum. The isolated material had a 3:100 cis/trans ratio. .sup.1H NMR (400 MHz, CDCl.sub.3) δ1.21-1.25 (s, 3H), 1.37-1.49 (m, 1H), 1.49-1.61 (m, 2H), 1.61-1.74 (m, 4H), 1.83-1.95 (m, 2H), 3.74-3.83 (dq, 1H), 5.57-5.61 (s, 2H), 7.43-7.54 (dd, 1H), 7.50-7.61 (m, 3H), 7.84-7.94 (m, 2H), 7.97-8.04 (m, 1H)). MS (ESI): m/z [M+Na].sup.+321.

    Intermediate 12: Methyl 4-fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [1838] ##STR00104##

    [1839] To a solution of Intermediate 11 in THF (736 g, 34% w/w, 839 mmol) was added THF (156 mL), PPh.sub.3 (248 g, 944 mmol) and Intermediate 6 (140 g, 699 mmol). The solution was heated to 30° C. prior to the drop-wise addition of DIAD (184 g, 909 mmol) over 1 h maintaining the reaction temperature <40° C. The solution was held at between 30 and 40° C. for 1 h before cooling to between 20 and 30° C. followed by the addition of an aq solution of NaCl (700 mL, 20% w/w in H.sub.2O). The layers were separated and the crude solution of the title compound in THF was used directly in the next step. .sup.1H NMR for purified compound (500 MHz, CDCl.sub.3) δ 1.17 (3H, s), 1.20-1.30 (2H, m), 1.58 (2H, qd), 1.88-1.98 (2H, m), 2.29 (2H, d), 3.84 (3H, s), 3.88 (3H, s), 4.05 (1H, tq), 5.61 (2H, s), 6.72 (1H, d), 7.43-7.58 (5H, m), 7.82-7.94 (2H, m), 8.00 (1H, d). MS (ESI): m/z [M+Na]+503.2.

    Intermediate 13: 4-Fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [1840] ##STR00105##

    [1841] To the crude solution of Intermediate 12 used directly from the previous step at between 0 and 5° C., was added a aq solution of LiOH.2H.sub.2O (88.0 g, 2.10 mol, in 525 mL of H.sub.2O) over 1 h maintaining the reaction temperature <10° C. The solution was warmed to between 15 and 30° C. and vigorously stirred for 16 h. IPAC (1.68 L) was added and the solution cooled to between 0 and 10° C. followed by the drop-wise addition of H.sub.3PO.sub.4 (1.26 L, 2.52 M, 2 M in H.sub.2O), maintaining the reaction temperature <10° C., to give a solution pH of between 4.0 and 5.0. The organic layer was separated and washed with of an aq solution of NaCl (700 mL, 20% w/w in H.sub.2O). The THF was removed under reduced pressure, maintaining the temperature <50° C. and IPAC (4.20 L) was added to give the title compound in IPAC that was used directly in the next step. .sup.1H NMR for purified compound (500 MHz, CDCl.sub.3) δ 1.18 (3H, s), 1.22-1.36 (2H, m), 1.58 (2H, qd), 1.95 (2H, dt), 2.29 (2H, d), 4.02 (3H, s), 4.19 (1H, td), 5.60 (2H, s), 6.82 (1H, d), 7.46 (1H, dd), 7.49-7.62 (3H, m), 7.78 (1H, d), 7.82-7.94 (2H, m), 7.99 (1H, d).

    Intermediate 14: 4-Fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate cyclohexanaminium salt

    [1842] ##STR00106##

    [1843] To a crude solution of Intermediate 13 in IPAC used directly from the previous step at between 50 and 55° C., was added a solution of cyclohexylamine (280 mL, 699 mmol, 2.5 M in IPAC) drop-wise over 3 h. The heterogenous slurry was stirred at between 50 and 55° C. for 0.5 h then at between 40 and 45° C. for a further 1 h. The reaction mixture was filtered and the solids washed with IPAC (3×0.98 L) pre warmed to between 40 and 45° C. and dried under a flow of N.sub.2 at 45° C. for 16 h. To the dried collected solids was added MeOH (3.64 L) and the mixture heated to between 55 and 56° C. H.sub.2O (1.58 L) was added drop-wise over 1 h then the mixture stirred for 1 h before cooling to between 0 and 5° C. over 3 h. The heterogenous slurry was held for a further 1 h then filtered, washed with 5:3 MeOH:H.sub.2O at 0° C. (2×750 mL) and the solids dried under N.sub.2 at 45° C. for 16 h to give the title compound as a white solid (332 g, 85% from methyl 4-fluoro-5-hydroxy-2-methoxybenzoate); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 0.96 (1H, ddt), 1.03-1.36 (6H, m), overlapping 1.14 (3H, S), 1.46-1.7 (5H, m), 1.91 (4H, dt), 2.26 (2H, d), 2.81 (1H, t), 3.76 (3H, s), 4.03 (1H, tt), 5.59 (2H, s), 6.65 (1H, d), 7.37-7.49 (2H, m), 7.49-7.6 (3H, m), 7.81-7.93 (2H, m), 7.98 (1H, d). MS (ESI): m/z [M+Na]+489.2.

    Intermediate 15: Methyl (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [1844] ##STR00107##

    [1845] To a solution of Intermediate 14 (149 g, 264 mmol) in DCM (750 mL) at between 15 and 30° C. was added H.sub.2O (450 mL) followed by the slow addition of HCL (300 mL, 1 M in H.sub.2O). The biphasic solution was stirred for 0.5 h then separated and the organic phased washed with HCl (750 mL, 0.2 M in H.sub.2O) then with H.sub.2O (3×750 mL). The organic solution was concentrated under reduced pressure, maintaining the temperature below 30° C., to dry to <0.1% H.sub.2O. The solution was diluted with DCM (450 mL) to bring the total volume to 750 mL before the addition of Intermediate 8 (59.3 g, 291 mmol) to give a heterogenous slurry. To this mixture was added DIPEA (137 g, 1.06 mol) followed by T3P (252 g, 397 mmol, 50% w/w in EtAOc) and the solution stirred for 1 h. The solution was cooled to between 0 and 10° C. followed by the addition of H.sub.2O (750 mL) and subsequently stirred for a further 0.5 h. The biphasic solution was separated and the organic phase washed with H.sub.2O (2×750 mL) before solvent exchange to THF under reduced pressure gave the title compound in THF that was used directly in the next step. .sup.1H NMR for purified compound (500 MHz, CDCl.sub.3) δ1.16 (3H, s), 1.25 (2H, td), 1.49-1.69 (3H, m), 1.92-2.01 (2H, m), 2.04-2.1 (1H, m), 2.28 (2H, d), 2.71 (1H, dd), 2.83 (1H, s), 2.92-3.05 (1H, m), 3.61 (3H, s), 3.93 (3H, s), 4.17 (1H, td), 4.46 (1H, td), 5.60 (2H, s), 6.25 (2H, ddd), 6.72 (1H, d), 7.46 (1H, dd), 7.48-7.6 (3H, m), 7.81-7.95 (3H, m), 7.99 (1H, d), 8.60 (1H, d). MS (ESI): m/z [M+H].sup.+ 616.3.

    Intermediate 16: (1S,2S,3R,4R)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [1846] ##STR00108##

    [1847] A crude solution of Intermediate 15 in THF (750 mL) from the previous step was cooled to between 0 and 5° C. An aq solution of LiOH.2H.sub.2O (27.7 g, 661 mmol, in 150 mL of H.sub.2O) was added and the solution held for 36 h. The pH of the solution was adjusted to 2 with the portion wise slow addition of HCl (0.5 M, 1.45 L, 2.90 mol) and held for 1 h between 0 and 5° C. The heterogenous slurry was filtered and the solids washed with 1:3 MeOH:H.sub.2O at 0° C. (600 mL) and the solids dried under N.sub.2 at 45° C. for 16 h to give crude title compound as a white solid (158 g, 99%). The crude (150 g) was slurried in IPAC (1.13 L) at between 60 and 65° C. for 0.5 h. The heterogenous mixture was cooled to between 0 and 5° C. over 3 h then further stirred for 1 h before filtration. The collected solids were with IPAC at between 0 and 5° C. (2×300 mL) then dried under N.sub.2 at 45° C. for 12 h to give the title compound as a white solid (127 g, 82% from Intermediate 14); .sup.1H NMR (500 MHz, CDCl.sub.3) δ1.16 (3H, s), 1.2-1.35 (2H, m), 1.50-1.69 (3H, m), 1.89-2.08 (3H, m), 2.27 (2H, ddd), 2.72 (1H, dd), 2.80 (1H, s), 3.06 (1H, s), 3.75 (3H, s), 4.15 (1H, tt), 4.43-4.54 (1H, m), 5.59 (2H, s), 6.24 (2H, ddd), 6.53 (1H, d), 7.45 (1H, dd), 7.47-7.58 (3H, m), 7.8-7.9 (3H, m), 7.94-8.05 (1H, m), 8.59 (1H, d). MS (ESI): m/z [M+H].sup.+ 602.3.

    Intermediate 17: Naphthalen-1-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1848] ##STR00109##

    [1849] To a solution of DIPEA (6.45 g, 49.9 mmol) in DCM (300 mL) at between 0 and 5° C. was added Intermediate 16 (30.6 g, 49.9 mmol) followed by (1-methylcyclobutyl)methanamine hydrochloride (8.63 g, 62.4 mmol). DIPEA (25.8 g, 200 mmol) was added drop-wise maintaining the temperature between 0 and 5° C., followed by the addition of T3P (50.8 g, 79.8 mmol, 50% w/w in EtAOc) over 0.5 h. The solution was warmed to between 15 and 25° C. and stirred for 1 h followed by the drop-wise addition of H.sub.2O (150 mL) maintaining the temperature below 30° C. The biphasic solution was separated and the organic phase washed with H.sub.2O (2×150 mL) then the solvent exchanged to EtOH under reduced pressure to give the title compound as a crude solution in EtOH (128 g, 26% w/w, 96% yield) that was used directly in the next step. .sup.1H NMR for purified compound (500 MHz, CDCl.sub.3) δ 0.98 (3H, s), 1.16 (3H, s), 1.21-1.29 (2H, m), 1.51-1.66 (5H, m), 1.66-1.76 (3H, m), 1.76-1.82 (1H, m), 1.88-2.02 (2H, m), 2.26 (3H, dd), 2.40 (1H, dd), 2.80 (1H, s), 3.00 (1H, s), 3.05 (1H, dd), 3.21 (1H, dd), 3.93 (3H, s), 4.06-4.2 (1H, m), 4.39 (1H, td), 5.60 (2H, s), 5.64 (1H, t), 6.19-6.38 (2H, m), 6.70 (1H, d), 7.46 (1H, dd), 7.49-7.62 (3H, m), 7.75-7.93 (3H, m), 8.00 (1H, d), 8.66 (1H, d). MS (ESI): m/z [M+H].sup.+ 683.3.

    Intermediate 19: (1S,2S,3R,4R)-3-((tert-Butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [1850] ##STR00110##

    [1851] A solution of (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid (0.90 g, 5.88 mmol) in H.sub.2O (15 mL) was added dropwise to a stirred solution of Boc.sub.2O (2.05 mL, 8.8 mmol) and Et.sub.3N (2.46 mL, 17.6 mmol) in 1,4-dioxane (20 mL) at 5° C., and under nitrogen atmosphere. The reaction mixture was stirred at 20° C. for 14 h, and then diluted with EtOAc (250 mL). The organic layer was washed sequentially with sat NaHCO.sub.3 (100 mL), H.sub.2O (100 mL), and sat brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was precipitated from EtOAc and PE to give the title compound (1.49 g, 100%) as a pale yellow solid; MS (ESI) m/z [M+Na].sup.+276

    Intermediate 20: tert-Butyl ((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamate

    [1852] ##STR00111##

    [1853] DIPEA (5.49 mL, 31.4 mmol) was added dropwise to a solution of Intermediate 19 (1.99 g, 7.86 mmol), (1-methylcyclobutyl)methanamine hydrochloride (1.07 g, 7.86 mmol), EDC (3.77 g, 19.64 mmol) and HOBt (3.01 g, 19.64 mmol) in DMF (60 mL) at 20° C. and under nitrogen atmosphere. The reaction mixture was stirred at 20° C. for 14 h and then diluted with EtOAc (125 mL). The organic layer was washed sequentially with sat NH.sub.4Cl (125 mL), H.sub.2O (125 mL), and sat brine (125 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by flash chromatography using a gradient of 0-12% EtOAc in PE as mobile phase, to give the title compound (2.5 g, 95%) as a pale yellow solid.

    Intermediate 21: (1S,2S,3R,4R)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [1854] ##STR00112##

    [1855] HCl (25 mL, 100 mmol, 4 M in 1,4-dioxane) was added dropwise to Intermediate 20 (2.5 g, 7.47 mmol) at 0° C., under nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure, and the crude product was purified by precipitation from EtOAc and diisopropyl ether to give the title compound (1.70 g, 84%) as a white solid.

    Intermediate 22: (1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [1856] ##STR00113##

    [1857] Pd-C (0.086 g, 0.81 mmol) was added to a solution of Intermediate 21 (1.1 g, 4.06 mmol) in MeOH (30 mL) and the reaction mixture was stirred under an atmosphere of hydrogen (1.5 atm) at 20° C. for 14 h. The reaction mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure to give the title compound (1.10 g, 99%); MS (ESI) m/z [M+H].sup.+ 237.

    Intermediate 23: Methyl 5-bromo-4-fluoro-2-((2-(trimethylsilyl)ethoxy)methoxy)benzoate

    [1858] ##STR00114##

    [1859] (2-(Chloromethoxy)ethyl)trimethylsilane (1.87 g, 11.2 mmol) was added dropwise to a solution of K.sub.2CO.sub.3 (3.11 g, 22.5 mmol) and methyl 5-bromo-4-fluoro-2-hydroxy-benzoate (2.8 g, 11.2 mmol) in DMF (25 mL) at 20° C. under a nitrogen atmosphere. The reaction mixture was heated at 80° C. for 14 h, and then cooled to rt and diluted with EtOAc (250 mL). The organic layer was washed with sat brine (3×150 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-3% EtOAc in PE as mobile phase, to give the title compound (3.0 g, 70%); MS (ESI) m/z [M+Na].sup.+401.4.

    Intermediate 24: Methyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)benzoate

    [1860] ##STR00115##

    [1861] Intermediate 23 (3.0 g, 7.91 mmol) was added to a suspension of B.sub.2Pin.sub.2 (3.01 g, 11.86 mmol), KOAc (2.33 g, 23.73 mmol) and PdCl.sub.2(dppf) (0.58 g, 0.79 mmol) in 1,4-dioxane (50 mL) and the reaction mixture was stirred at 60° C. for 14 h. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved in EtOAc (20 mL). The organic layer was washed with H.sub.2O (3×20 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-10% of EtOAc in PE as mobile phase, to give the title compound (2.5 g, 74%); MS (ESI) m/z [M+Na]+449.

    Intermediate 25: Methyl 4-fluoro-5-hydroxy-2-((2-(trimethylsilyl)ethoxy)methoxy)benzoate

    [1862] ##STR00116##

    [1863] A solution of sodium perborate (2.71 g, 17.59 mmol) in H.sub.2O (20 mL) was added slowly to a stirred solution of Intermediate 24 (2.5 g, 5.86 mmol) in THF (40 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 20° C. for 3 h, and then diluted with DCM (50 mL). The organic layer was washed with sat brine (3×50 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:PE, 1:3) to give the title compound (1.5 g, 81%); MS (ESI) m/z [M+Na].sup.+339.

    Intermediate 26: Methyl 4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-2-((2-(trimethylsilyl)ethoxy)methoxy)benzoate

    [1864] ##STR00117##

    [1865] A solution of DBAD (1.74 g, 7.54 mmol) in toluene (10 mL) was added dropwise to a stirred solution of Intermediate 11 (1.5 g, 5.03 mmol), Intermediate 25 (1.75 g, 5.53 mmol) and Ph.sub.3P (1.98 g, 7.54 mmol) in DCM (40 mL) at 20° C. and the reaction mixture was stirred at rt for 14 h. The reaction mixture was diluted with EtOAc (200 mL) and the organic layer was washed sequentially with sat NH.sub.4Cl (100 mL), sat NaHCO.sub.3 (100 mL) and sat brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:5) to give the title compound (2.50 g, 83%); MS (ESI) m/z [M+Na].sup.+619.

    Intermediate 27: Methyl 4-fluoro-2-hydroxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [1866] ##STR00118##

    [1867] HCl in 1.4-dioxane (1.27 mL, 4.2 M) was added dropwise to a stirred solution of Intermediate 26 (2.5 g, 4.19 mmol) in THF (40 mL) at 0° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 0° C. for 3 h. The solvent was removed under reduced pressure and the crude product was purified by precipitation from EtOAc and DCM to give the title compound (1.50 g, 77%); MS (ESI) m/z [M+Na].sup.+589.

    Intermediate 28: Methyl 4-fluoro-2-(fluoromethoxy)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [1868] ##STR00119##

    [1869] A solution of N-((fluoromethyl)(oxo)(phenyl)-λ.sup.6-sulfaneylidene)-4-methylbenzenesulfonamide (351 mg, 1.07 mmol) in DMSO (15 mL) was added dropwise to a stirred solution of Intermediate 27 (500 mg, 1.07 mmol) and NaH (50 mg, 1.25 mmol) in DMSO (10 mL) at 20° C. and under a nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 3 h, and then sat NH.sub.4Cl (10 mL) was added. The H.sub.2O phase was extracted with EtOAc (3×25 mL) and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated. The process described above was repeated two more times using in total 1.46 mmol of Intermediate 27. The crude products were combined and purified by preparative TLC (EtOAc:PE, 1:3) to give the title compound (0.52 g, 41%); MS (ESI) m/z [M+Na].sup.+521.

    Intermediate 29: 4-Fluoro-2-(fluoromethoxy)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [1870] ##STR00120##

    [1871] A solution of LiOH (14.4 mg, 0.60 mmol) in H.sub.2O (2.0 mL) was added dropwise to a stirred solution of Intermediate 28 (200 mg, 0.40 mmol) in THF (4 mL) and the reaction mixture was stirred at rt for 3 h. The process was repeated two more times using in total 0.64 mmol of Intermediate 28. The reaction mixtures were combined and pH adjusted to 3 with aq HCl (3 M). The reaction mixture was diluted with EtOAc (250 mL) and the organic layer was washed sequentially with sat brine (200 mL), H.sub.2O (200 mL) and sat brine (150 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated. The crude product was purified by preparative TLC (MeOH:DCM, 1:5) to give the title compound (310 mg, 60%); MS (ESI) m/z [M+Na].sup.+507.

    Intermediate 30: Naphthalen-1-ylmethyl (1S,4s)-4-(2-fluoro-4-(fluoromethoxy)-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1872] ##STR00121##

    [1873] DIPEA (0.56 mL, 3.20 mmol) was added dropwise to a solution of Intermediate 29 (310 mg, 0.64 mmol), Intermediate 22 (302 mg, 1.28 mmol), EDC (368 mg, 1.92 mmol) and HOBt (294 mg, 1.92 mmol) in DMF (10 mL) at 0° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (50 mL), and the organic layer was washed sequentially with sat NH.sub.4Cl (50 mL), sat NaHCO.sub.3(50 mL), and sat brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), to give the title compound (227 mg, 50%); MS (ESI) m/z [M+H].sup.+ 703.

    Intermediate 31: Methyl 4-fluoro-2-methyl-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [1874] ##STR00122##

    [1875] Intermediate 11 (1.10 g, 3.69 mmol), methyl 4-fluoro-5-hydroxy-2-methylbenzoate (1.02 g, 5.53 mmol), DIAD (1.43 mL, 7.37 mmol) and triphenylphosphine (1.45 g, 5.53 mmol) were dissolved in THF (20 mL) and the reaction mixture was heated at 60° C. for 5 h The reaction mixture was concentrated under reduced pressure and DCM (20 mL) was added to the crude product. The organic layer was washed with H.sub.2O (3×20 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated.

    [1876] The crude product was purified by reversed phase flash chromatography on a C18 column, using a gradient of 0-70% of MeCN in H.sub.2O as mobile phase, to give the title compound (1.50 g, 88%); MS (ESI) m/z [M+H].sup.+ 465.

    Intermediate 32: 4-Fluoro-2-methyl-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [1877] ##STR00123##

    [1878] Intermediate 31 (1.40 g, 3.01 mmol) and LiOH (217 mg, 9.04 mmol) was dissolved in a mixture of THF (12 mL) and H.sub.2O (3 mL), and the reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved in DCM (10 mL). The organic layer was washed with H.sub.2O (3×5 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc, 3:1), to give the title compound (800 mg, 59%); MS (ESI) m/z [M+H].sup.+ 299.

    Intermediate 33: Naphthalen-1-ylmethyl (1S,4s)-4-(2-fluoro-4-methyl-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1879] ##STR00124##

    [1880] Intermediate 32 (300 mg, 0.67 mmol), Intermediate 21 (156 mg, 0.67 mmol), HATU (380 mg, 1.00 mmol) and DIPEA (0.349 mL, 2.00 mmol) were dissolved in DMF (20 mL), and the reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved in DCM (10 mL). The organic layer was washed with H.sub.2O (3×5 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc, 3:1), to give the title compound (300 mg, 68%); MS (ESI) m/z [M+H].sup.+ 667.

    [1881] Intermediate 34: Benzyl (2RS,4r,6R)-6-hydroxyspiro[3.3]heptane-2-carboxylate

    ##STR00125##

    [1882] NaBH.sub.4 (46.5 mg, 1.23 mmol) was added slowly to a solution of benzyl 6-oxospiro[3.3]heptane-2-carboxylate (300 mg, 1.23 mmol) in MeOH (2 mL) cooled to 0° C. and under nitrogen. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL). The organic layer was washed with H.sub.2O (3×15 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by preparative TLC (PE:EtOAc, 2:1), to give the title compound (230 mg, 76%) as a colourless oil; MS (ESI) m/z [M+H].sup.+247.

    Intermediate 35: (1R,2S,3R,4S)-3-(4-Cyano-5-hydroxy-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [1883] ##STR00126##

    [1884] 4-Cyano-5-hydroxy-2-methoxybenzoic acid (500 mg, 2.59 mmol) was added to a solution of Intermediate 22 (847 mg, 3.11 mmol), EDC (744 mg, 3.88 mmol), HOBt (525 mg, 3.88 mmol) and DIPEA (1.0 g, 7.77 mmol) in DMF (20 mL) and the reaction mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (150 mL). The organic layer was washed sequentially with sat NaHCO.sub.3 (150 mL), H.sub.2O (150 mL), and sat brine (150 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated. The crude product was purified by preparative TLC (MeOH:DCM, 1:10), to give the title compound (360 mg, 34%); MS (ESI) m/z [M+H].sup.+ 412.3.

    Intermediate 36: Benzyl (2RS,4r,6R)-6-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylate

    [1885] ##STR00127##

    [1886] Intermediate 35 (350 mg, 0.85 mmol) was added to a solution of Intermediate 34 (314 mg, 1.28 mmol), Ph.sub.3P (335 mg, 1.28 mmol) and DBAD (294 mg, 1.28 mmol) in a mixture of toulene/DCM (16 mL, 1:1) at 20° C. The reaction mixture was stirred at 30° C. for 12 h and then cooled to rt and diluted with DCM (200 mL). The organic layer was washed sequentially with sat NH.sub.4Cl (200 mL), H.sub.2O (200 mL) and sat brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated. The crude product was purified by preparative TLC (PE:EtOAc, 3:1), to give the title compound (190 mg, 35%); MS (ESI) m/z [M+H].sup.+ 640.4.

    Intermediate 37: Benzyl (2R*,4r,6R)-6-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylate Isomer 1

    Intermediate 38: Benzyl (2R*,4r,6R)-6-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylate Isomer 2

    [1887] ##STR00128##

    [1888] The isomers of Intermediate 36 (200 mg, 0.31 mmol) were separated by preparative chiral HPLC on a Chiralpak IG column (5 μm, 250×20 mm ID) using 10% of EtOH in a hexane:DCM (5:1, 10 mM NH.sub.3 in MeOH) buffer system as mobile phase, to give the first eluting compound Isomer 1 Intermediate 37 (60 mg, 30%); MS (ESI) m/z [M+H].sup.+640.4, and the second eluting compound Isomer 2 Intermediate 38 (70 mg, 30%); MS (ESI) m/z [M+H].sup.+ 640.4.

    Intermediate 39: rac-Methyl (1R,2R,3S,4S)-3-isocyanato-7-oxabicyclo[2.2.1]heptane-2-carboxylate

    [1889] ##STR00129##

    Step A. Intermediate 40: rac-(1R,2R,3S,4S)-3-(Methoxycarbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

    [1890] Pd-C (0.107 g, 1.01 mmol, 10%) was added to a solution of rac-(1R,4S)-3-(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylic acid (2 g, 10.09 mmol) in MeOH (150 mL), and the reaction mixture was stirred under an atmosphere of hydrogen (1.5 atm) at rt for 5h. The reaction mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure to give the title compound (2 g, 99%). The crude product was used directly without further purification in the next step.

    Step B. rac-Methyl (1R,2R,3S,4S)-3-isocyanato-7-oxabicyclo[2.2.1]heptane-2-carboxylate

    [1891] Ethyl chloroformate (1.30 g, 12 mmol) was added dropwise to a solution of Intermediate 40 (2 g, 9.99 mmol) and TEA (1.52 g, 15.0 mmol) in acetone (20 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 30 min. A solution of NaN.sub.3 (0.97 g, 15.0 mmol) in H.sub.2O (10 mL) was added dropwise over a period of 15 min to the stirred reaction mixture at 0° C., and under a nitrogen atmosphere, and the reaction mixture was stirred at 0° C. overnight. The reaction mixture was diluted with toluene (150 mL), and washed sequentially with sat brine (250 mL), sat NaHCO.sub.3 (250 mL), and H.sub.2O (200 mL). The organic layer was dried over Na.sub.2SO.sub.4, and filtered. The filtrate was diluted with toluene (30 mL) and the reaction mixture was stirred at 110° C. overnight. The solvent was removed under reduced pressure to give the title compound (1.7 g, 88%) as a brown oil.

    Intermediate 41: rac-Methyl (1R,2R,3S,4S)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylate hydrochloride

    [1892] ##STR00130##

    [1893] A solution of HCl (2.6 mL, 86.2 mmol, 12 M, aq) in H.sub.2O (10 mL) was added to a solution of Intermediate 39 (1.7 g, 8.62 mmol) in THF (20 mL).The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure to give the title compound (1.75 g, 98%) as a crude product which was used without further purification.

    Intermediate 42: rac-Methyl (1R,2R,3S,4S)-3-((tert-butoxycarbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylate

    [1894] ##STR00131##

    [1895] Boc.sub.2O (3.91 mL, 16.8 mmol) and TEA (5.87 mL, 42.14 mmol) were added to a solution of Intermediate 41 (1.75 g, 8.43 mmol) in THF (20 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (50 mL), and washed with sat brine (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the title compound (2.1 g, 92%) as a crude product which was used without further purification.

    Intermediate 43: rac-(1R,2R,3S,4S)-3-((tert-Butoxycarbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

    [1896] ##STR00132##

    [1897] LiOH (0.556 g, 23.22 mmol) was added to a solution of Intermediate 42 (2.1 g, 7.74 mmol) in MeOH (8 mL) and H.sub.2O (4 mL) and the reaction mixture was stirred at rt for 5h. The reaction mixture was acidified with citric acid (0.5 M, aq), diluted with EtOAc (20 mL), and washed with sat brine (3×2 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the title compound Intermediate 43 (1.23 g, 62%) as yellow solid, which was used without further purification; MS (ESI) m/z [M+Na].sup.+280.

    Intermediate 44: tert-Butyl ((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate Isomer 1

    Intermediate 45: tert-Butyl ((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate Isomer 2

    [1898] ##STR00133##

    [1899] 4-Fluoro-3-(trifluoromethyl)aniline (1.028 g, 5.74 mmol), HATU (5.45 g, 14.34 mmol), DIPEA (2.472 g, 19.12 mmol) and Intermediate 43 (1.23 g, 4.78 mmol) were suspended in DMF (15 mL) and the reaction mixture was stirred at 80° C. for 5h. The reaction mixture was diluted with EtOAc (75 mL), and washed with sat brine (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by flash chromatography using a gradient of 0-40% PE in EtOAc as mobile phase, and then by preparative HPLC, Method PrepBasic-G, using decreasingly polar mixtures of the mobile phase. The enantiomers were separated by preparative chiral HPLC on a Chiralpak IA column (5 μm, 150×4.6 mm ID), using 20% IPA (0.1% DEA) in CO.sub.2(g) as mobile phase, to give the first eluting Isomer 1 Intermediate 44 (170 mg, 8.5%) as a white solid; MS (ESI) m/z [M+H].sup.+ 419, and the second eluting Isomer 2 Intermediate 45 (170 mg, 8.5%) as a white solid, MS (ESI) m/z [M+H].sup.+ 419.

    [1900] The stereochemistry of the two enantiomers were determined using VCD experiments. Experimental VCD spectra of both enantiomers were compared to the DFT calculated spectra. The assignment of the configuration was based of fits of 5 different regions of the spectrum.

    Intermediate 46: (1R,2R,3S,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide 2,2,2-trifluoroacetate

    [1901] ##STR00134##

    [1902] TFA (3 mL) was added to a solution of Intermediate 44 (50 mg, 0.12 mmol) in DCM (3 mL) and the reaction mixture was stirred at 20° C. for 2 h. The solvent was removed under reduced pressure to give the title compound (35 mg, 92%) as a white solid; MS (ESI) m/z [M+H].sup.+ 318.

    Intermediate 47: (1S,2S,3R,4R)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide 2,2,2-trifluoroacetate

    [1903] ##STR00135##

    [1904] The title compound was prepared from Intermediate 45 in an analogues way as described for Intermediate 46 to give the title compound (35 mg, 92%) as a white solid; MS (ESI) m/z [M+H].sup.+ 319.

    Intermediate 48: Benzyl ((1R,2S)-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclobutyl)carbamate

    [1905] ##STR00136##

    [1906] DIPEA (0.315 mL, 1.81 mmol) was added dropwise to a solution of (1S,2R)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid (150 mg, 0.60 mmol), 4-fluoro-3-(trifluoromethyl)aniline (129 mg, 0.72 mmol), and HATU (458 mg, 1.20 mmol) in DMF (10 mL) at 20° C. under a nitrogen atmosphere, and the reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat brine (150 mL), and H.sub.2O (125 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), to give the title compound (196 mg, 79%) as a pale yellow solid; MS (ESI) m/z [M+H].sup.+ 411.

    Intermediate 49: (1S,2R)-2-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)cyclobutane-1-carboxamide hydrobromide

    [1907] ##STR00137##

    [1908] Intermediate 48 (100 mg, 0.24 mmol) was added to a solution of HBr in glacial acetic acid (10 mL, 33%) at 0° C., and the reaction mixture was stirred at 0° C. for 2 h. The solvent was removed under reduced pressure to give the title compound (67 mg) which was used without further purification; MS (ESI) m/z [M+H].sup.+ 277.

    Intermediate 50: Methyl (R)-4-((1-phenylethyl)amino)-2,5-dihydrofuran-3-carboxylate

    [1909] ##STR00138##

    [1910] (R)-1-Phenylethan-1-amine (920 mg, 7.63 mmol) was added dropwise to a solution of methyl 4-oxotetrahydrofuran-3-carboxylate (1 g, 6.94 mmol), and Yb(OTf).sub.3 (0.129 g, 0.21 mmol) in toluene (50 mL) at 20° C. under a nitrogen atmosphere and the suspension was stirred at 110° C. for 42 h. The reaction mixture was filtered through Celite®, and the solvent was removed under reduced pressure to give the title compound (750 mg, 44%) as a pale yellow oil which solidified on standing.

    Intermediate 51: Methyl (3R,4S)-4-(((R)-1-phenylethyl)amino)tetrahydrofuran-3-carboxylate

    [1911] ##STR00139##

    [1912] NaBH.sub.4 (320 mg, 8.49 mmol) was added portion wise to acetic acid (25 mL) and the resulting suspension was stirred at 20° C. for 1 h, and then cooled to 0° C. A solution of Intermediate 50 (700 mg, 2.83 mmol) in MeCN (25 mL) was added to the mixture under a nitrogen atmosphere, and the resulting suspension was stirred at 0° C. for 2 h. The reaction mixture was quenched with H.sub.2O (125 mL), and concentrated under reduced pressure. The aq phase was extracted with EtOAc (3×150 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by flash chromatography, using a gradient of 0-30% EtOAc in PE as mobile phase, to give the title compound (410 mg, 58%) as a pale yellow oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 250.

    Intermediate 52: Methyl (3R,4S)-4-aminotetrahydrofuran-3-carboxylate

    [1913] ##STR00140##

    [1914] Pd-C (35 mg, 0.33 mmol) was added to a solution of Intermediate 51 (407 mg, 1.63 mmol) in MeOH (20 mL) and the reaction mixture was stirred under an atmosphere of hydrogen (1.5 atm) at 20° C. for 14 h. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure to give the title compound (237 mg, 100%) as a pale yellow solid.

    Intermediate 53: Methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-carboxylate

    [1915] ##STR00141##

    [1916] TEA (0.341 mL, 2.45 mmol) was added dropwise to a solution of Intermediate 52 (237 mg, 1.63 mmol) and Boc.sub.2O (0.46 mL, 1.96 mmol) in THF (20 mL) at 20° C. under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with sat brine (2×150 mL), H.sub.2O (150 mL), and sat NaHCO.sub.3 (150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the title compound (448 mg) as a yellow gum.

    Intermediate 54: (3RS,4S)-4-((tert-Butoxycarbonyl)amino)tetrahydrofuran-3-carboxylic acid

    [1917] ##STR00142##

    [1918] LiOH (219 mg, 9.13 mmol) was added portion wise to a solution of Intermediate 53 (448 mg, 1.83 mmol) in MeOH (10 mL) and H.sub.2O (10 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was acidified to pH-3 with citric acid (aq, 0.5 M). The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with sat brine (2×150 mL), H.sub.2O (125 mL), and sat NH.sub.4Cl (125 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to give a crude containing the title compound (350 mg, 83%) as a yellow gum. The crude product was used without further purification.

    Intermediate 55: tert-Butyl ((3S,4R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamate

    [1919] ##STR00143##

    [1920] DIPEA (0.79 mL, 4.54 mmol) was added dropwise to a solution of 4-fluoro-3-(trifluoromethyl)aniline (407 mg, 2.27 mmol), Intermediate 54 (350 mg, 1.51 mmol) and HATU (2.88 g, 7.57 mmol) in DMF (40 mL) and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat brine (100 mL), sat NaHCO.sub.3(100 mL), and H.sub.2O (100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:1), to give the title compound (240 mg, 40%) as a white solid; MS (ESI) m/z [M+H].sup.+ 393.

    Intermediate 56: (3R,4S)-4-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)tetrahydrofuran-3-carboxamide

    [1921] ##STR00144##

    [1922] The Boc-protecting group of Intermediate 55 (240 mg, 0.61 mmol) was partly deprotected upon standing and the mixture was purified by preparative chiral-HPLC, Method SFC-G, using an isocratic run of 15% of IPA as mobile phase, to give the title compound (40 mg, 22%) as a yellow solid; MS (ESI) m/z [M+Na].sup.+293.

    Intermediate 57: 2-Chloro-N-((1-methylcyclobutyl)methyl)-6-nitrobenzamide

    [1923] ##STR00145##

    [1924] DIPEA (0.65 mL, 3.72 mmol) was added dropwise to a solution of 2-chloro-6-nitrobenzoic acid (250 mg, 1.24 mmol), (1-methylcyclobutyl)methanamine hydrochloride (168 mg, 1.24 mmol), EDC (476 mg, 2.48 mmol), and HOBt (380 mg, 2.48 mmol) in DMF (5 mL) at 20° C. under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat NaHCO.sub.3 (100 mL), sat NH.sub.4Cl (150 mL), and sat brine (100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:3), to give the title compound (350 mg, 100%) as a white waxy solid; MS (ESI) m/z [M+H].sup.+ 283.

    Intermediate 58: 2-Amino-6-chloro-N-((1-methylcyclobutyl)methyl)benzamide

    [1925] ##STR00146##

    [1926] NH.sub.4Cl (662 mg, 12.38 mmol) was added portion wise to a suspension of Intermediate 57 (350 mg, 1.24 mmol) and Fe(s) (346 mg, 6.19 mmol) in H.sub.2O (2 mL) and EtOH (18 mL, 99.5%) at 20° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 80° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat NaHCO.sub.3 (75 mL), sat brine (75 mL), and H.sub.2O (75 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by precipitation from EtOAc and PE to give the title compound (290 mg, 93%) as a white waxy solid; MS (ESI) m/z [M+H].sup.+ 253.

    Intermediate 59: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((3-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [1927] ##STR00147##

    [1928] Intermediate 58 (250 mg, 0.99 mmol) was added to a solution of Intermediate 13 (692 mg, 1.48 mmol), T3P (5.9 mL, 9.89 mmol, 50% in EtOAc), and DIPEA (384 mg, 2.97 mmol) in BuOAc (10 mL) at 20° C., and the reaction was stirred at 120° C. for 12 h. The reaction mixture was concentrated and diluted with EtOAc (150 mL). The organic layer was washed sequentially with sat NH.sub.4Cl (250 mL), H.sub.2O (150 mL), and sat brine (250 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:3), to give the title compound (280 mg, 40%) as a yellow solid; MS (ESI) m/z [M+Na].sup.+723.3.

    Intermediate 60: Benzyl (1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate

    [1929] ##STR00148##

    [1930] TEA (18.2 mL, 130.8 mmol) was added to a solution of (1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (5.0 g, 21.8 mmol), phenylmethanol (3.54 g, 32.7 mmol), EDC (12.54 g, 65.42 mmol) and HOBt (10.02 g, 65.42 mmol) in DMF (50 mL) and the reaction mixture was stirred at 20° C. for 15 h. The reaction mixture was concentrated and diluted with EtOAc (125 mL), and washed sequentially with sat NaHCO.sub.3 (125 mL), H.sub.2O (3×125 mL), and sat brine (2×125 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by flash chromatography using a gradient of 10-15% in EtOAc in PE to give the title compound (5.0 g, 72%) as a white solid.

    Intermediate 61: Benzyl (1S,2R)-2-aminocyclopentane-1-carboxylate hydrochloride

    [1931] ##STR00149##

    [1932] HCl (10 mL, 40.0 mmol, 4 M in 1,4-dioxane) was added to a solution of Intermediate 60 (2 g, 6.26 mmol) in 1,4-dioxane (10 mL) at 20° C. The resulting suspension was stirred at 20° C. for 30 min. The solvent was removed under reduced pressure to give the title compound (2 g) as a yellow oil; MS (ESI) m/z [M+H].sup.+ 220.

    Intermediate 62: tert-Butyl (1S,4s)-4-(5-(((1R,2S)-2-((benzyloxy)carbonyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [1933] ##STR00150##

    [1934] DIPEA (2.28 mL, 13.1 mmol) was added dropwise to a solution of Intermediate 73 (1.0 g, 2.61 mmol), Intermediate 61 (0.67 g, 2.61 mmol) and HATU (2.98 g, 7.84 mmol) in DMF (20 mL) at 20° C. under a nitrogen atmosphere and the reaction mixture was stirred at 30° C. for 4 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with H.sub.2O (3×50 mL), sat NaHCO.sub.3 (50 mL), and sat brine (50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:3), to give the title compound (0.90 g, 59%) as a pale yellow oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 584.

    Intermediate 63: (1S,2R)-2-(5-(((1s,4S)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)cyclopentane-1-carboxylic acid

    [1935] ##STR00151##

    [1936] Pd-C (164 mg, 0.15 mmol) was added to a solution of Intermediate 62 (900 mg, 1.54 mmol) in MeOH (20 mL) and the reaction mixture was stirred at 20° C. under an atmosphere of hydrogen (1.3 atm) for 3 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give the title compound (700 mg, 92%) as a white solid; MS (ESI) m/z [M+H].sup.+ 494.

    Intermediate 64: Benzyl 5-(((1s,4s)-4-(tert-butoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

    [1937] ##STR00152##

    [1938] DIAD (1.46 mL, 7.53 mmol) was added dropwise to a solution of Intermediate 117 (1.39 g, 5.02 mmol), tert-butyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (1.2 g, 6.0 mmol) and PPh.sub.3 (1.97 g, 7.53 mmol) in THF (10 mL) at 60° C., and the reaction mixture was stirred at 60° C. for 3 h. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, using a gradient of 0-10% EtOAc in petroleum ether as mobile phase, to give the title compound (1.55 g, 67%) as a white solid; MS (ESI) m/z [M+Na].sup.+481.

    Intermediate 65: 5-(((1s,4s)-4-(tert-Butoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [1939] ##STR00153##

    [1940] Pd-C (0.67 g, 0.63 mmol, 10%) was added to a solution of Intermediate 64 (1.45 g, 3.16 mmol) in MeOH (50 mL) at 20° C. The reaction mixture was stirred at 20° C. for 4 h under an atmosphere of hydrogen The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give the title compound (1.10 g, 94%) as a white solid; MS (ESI) m/z [M+Na].sup.+368.

    Intermediate 66: Methyl (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(tert-butoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylate

    [1941] ##STR00154##

    [1942] DIPEA (2.61 mL, 14.93 mmol) was added dropwise to a solution of Intermediate 65 (1.1 g, 2.99 mmol), Intermediate 120 (2.8 g, 13.61 mmol) and HATU (3.41 g, 8.96 mmol) in DMF (20 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed with sat brine (3×25 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:EtOAc, 2:1), to give the title compound (0.56 g, 36%) as a brown yellow oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 520.

    Intermediate 67: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(tert-Butoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [1943] ##STR00155##

    [1944] LiOH (106 mg, 4.43 mmol) was added to a solution of Intermediate 66 (460 mg, 0.89 mmol) in MeOH (4 mL) and water (2 mL), and the reaction mixture was stirred at 20° C. for 5 h. The solvent was removed under reduced pressure. The reaction mixture was acidified with citric acid (0.5 M, aq) and the solids were filtered off to give the title compound (385 mg, 86%) as a white solid; MS (ESI) m/z [M+H].sup.+ 506.

    Intermediate 68: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-cyano-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [1945] ##STR00156##

    Step A. Intermediate 69: Methyl 4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [1946] ##STR00157##

    [1947] A solution of methyl 4-cyano-5-hydroxy-2-methoxybenzoate (1.4 g, 6.7 mmol), Intermediate 11 and PPh.sub.3 (2.6 g, 10.1 mmol) in THF (30 mL) was stirred at 60° C. for 10 min. After slow addition of DIAD (1.97 mL, 10.1 mmol), the reaction mixture was stirred at 60° C. for 14 h. The solvent was then removed under reduced pressure and the residue redissolved in EtOAc (150 mL), washed sequentially with NaHCO.sub.3 (sat, 200 mL), NH.sub.4Cl (sat, 250 mL) and brine (sat, 250 mL). The organic layer was separated and dried over Na.sub.2SO.sub.4, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-18% EtOAc in PE as mobile phase to give the title compound (3.25 g, 99%) as a white solid. MS (ESI): m/z [M+Na].sup.+510.3.

    Step B. Intermediate 70: 4-Cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [1948] ##STR00158##

    [1949] LiOH (1.6 g, 66.7 mmol) was added portionwise to a stirred solution of Intermediate 69 (3.25 g, 6.7 mmol) in H.sub.2O:THF 1:3 (80 mL) at 10° C. and the resulting suspension was stirred at 20° C. After 3 h, the pH of the reaction mixture was adjusted to pH 3 by the addition of HCl (2 M). The reaction mixture was diluted with EtOAc (350 mL), and washed sequentially with brine (sat, 350 mL), H.sub.2O (350 mL), and brine (350 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered and the solvent removed under reduced pressure. The crude product was purified by crystallisation from IPA/EtOAc to afford the title compound (3.16 g, 100%) as a white solid. MS (ESI): m/z [M+Na].sup.+ 496.3.

    Step C. Intermediate 71: Methyl (1S,2S,3R,4R)-3-(4-cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [1950] ##STR00159##

    [1951] DIPEA (3.5 mL, 20 mmol) was added to a solution of Intermediate 70 (3.16 g, 6.67 mmol), Intermediate 8 (1.291 g, 6.34 mmol), EDC (1.9 g, 10 mmol) and HOBt (1.533 g, 10.01 mmol) in DMF (60 mL) at 10° C. and the resulting suspension was stirred at rt for 13 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed sequentially with NH.sub.4Cl (sat, 200 mL), H.sub.2O (300 mL), and brine (sat, 250 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in PE as mobile phase to afford the title compound (2.6 g, 62%) as a white solid. MS (ESI): m/z [M+H].sup.+ 623.4.

    Step D. Intermediate 72: (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [1952] ##STR00160##

    [1953] Intermediate 71 (5.7 g, 9.15 mmol) and Pd/C (0.584 g, 0.55 mmol) in MeOH (100 mL) was stirred at 20° C. under an atmosphere of hydrogen (1.5 atm) for 14 h. The mixture was filtered through a Celite® pad and the solvent was removed under reduced pressure. The crude product was purified by crystallisation from EtOAc/EtOH to afford the title compound (5.1 g) as a pale yellow solid. MS (ESI): m/z [M+H].sup.+ 485.4.

    Step E. (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-cyano-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [1954] A solution of LiOH (50 mL, 52.6 mmol, 1.05 M in H.sub.2O) was added to a stirred solution of Intermediate 72 (5.1 g, 10.5 mmol) in THF (100 mL) at 10° C. The reaction mixture was allowed to warm to rt and stirred for 14 h, then acidified to pH 2 using HCl (1 M, aq). The reaction mixture was diluted with EtOAc (350 mL), and washed sequentially with brine (300 mL, sat), H.sub.2O (300 mL) and brine (300 mL, sat). The organic phase was separated and dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified by precipitation from EtOAc/Et.sub.2O followed by reversed phase flash chromatography on a C18 column using a gradient of 0-50% MeCN in HCl (0.4%, aq) as mobile phase to afford the title compound (4.00 g, 82%) as a white solid; .sup.1H NMR (400 MHz, DMSO-d6) δ 1.13 (s, 3H), 1.20 (s, 1H), 1.23 (s, 2H), 1.33 (t, 2H), 1.46 (q, 4H), 1.84 (d, 1H), 1.92 (d, 2H), 2.03-2.14 (m, 4H), 2.38 (d, 1H), 2.67 (d, 1H), 3.89 (s, 3H), 4.23 (t, 1H), 4.43 (dt, 1H), 7.54 (s, 1H), 7.59 (s, 1H), 8.67 (d, 1H), 12.30 (s, 2H). MS (ESI): m/z [M+H].sup.+ 471.3.

    Intermediate 73: 5-(((1s,4s)-4-(Tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [1955] ##STR00161##

    [1956] Pd(OH).sub.2/C (20 wt %, 78 mg, 0.11 mmol) was added to a solution of Intermediate 136 (527 mg, 1.12 mmol) in MeOH (11 mL). The reaction suspension was stirred at rt for 3 h under an atmosphere of hydrogen (2 atm). The reaction mixture was filtered through a pad of Celite® and the solvent removed under reduced pressure to afford the title compound (427 mg, 100%) as a colorless thick oil; MS (ESI): m/z [M−H].sup.− 381.2.

    Intermediate 74: tert-Butyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-(neopentylcarbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1957] ##STR00162##

    [1958] DIPEA (68 μL, 0.39 mmol) was added to a solution of Intermediate 73 (40 mg, 0.1 mmol) in DCM (0.4 mL). HATU (119 mg, 0.31 mmol) was added followed by 2-amino-N-(2,2-dimethylpropyl)benzamide (25.9 mg, 0.13 mmol) and the reaction mixture was stirred at rt overnight. Na.sub.2CO.sub.3 (sat) was added and the biphasic mixture stirred for 10 min before the two layers were separated. The aq phase was washed with DCM. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using a gradient of 5-95% EtOAc in heptane as mobile phase to afford the title compound (50.4 mg, 84%) as a white solid; .sup.1H NMR (400 MHz, DMSO-d6) δ 0.91 (s, 9H), 1.08 (s, 3H), 1.20-1.34 (m, 3H), 1.42 (s, 11H), 1.92 (d, 2H), 2.05 (d, 2H), 3.12 (d, 2H), 3.98 (s, 3H), 4.20 (t, 1H), 7.15-7.28 (m, 2H), 7.49 (t, 1H), 7.63 (d, 1H), 7.74 (d, 1H), 8.46-8.67 (m, 2H), 11.70 (s, 1H). MS (ESI): m/z [M−H].sup.− 569.3

    Intermediate 75: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [1959] ##STR00163##

    [1960] Palladium on carbon (7 mg, 0.07 mmol) was added to a solution of Intermediate 76 (400 mg, 0.66 mmol) in MeOH (30 mL). The reaction suspension was stirred at rt for 3 h under an atmosphere of hydrogen (1.3 atm). The suspension was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound (208 mg, 60.8%) as a white solid. MS (ESI): m/z [M+H].sup.+ 520.4.

    Intermediate 76: Benzyl (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [1961] ##STR00164##

    Step A. Intermediate 77: Benzyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

    [1962] ##STR00165##

    [1963] HCl (4 M in MeOH, 20 mL, 80 mmol) was added dropwise to a solution of Intermediate 108 (2.0 g, 5.82 mmol) in MeOH (10 mL) at 0° C. The resulting mixture was stirred at 20° C. for 16 h. The solvent was removed under reduced pressure to afford the title compound (1.6 g) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 1.48 (d, 1H), 2.06 (d, 1H), 2.65-2.71 (m, 1H), 2.98 (s, 1H), 3.06 (s, 1H), 3.24 (s, 1H), 5.09 (d, 1H), 5.22 (d, 1H), 6.24 (dd, 1H), 6.32 (dd, 1H), 7.29-7.47 (m, 5H), 8.22 (s, 3H).

    Step B. Benzyl (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [1964] DIPEA (5.1 mL, 29.4 mmol) was added dropwise to a solution of Intermediate 73 (2.25 g, 5.88 mmol), Intermediate 77 (1.88 g, 6.47 mmol) and HATU (6.71 g, 17.65 mmol) in DMF (20 mL) under nitrogen. The reaction mixture was stirred at rt for 14 h after which it was diluted with EtOAc and washed sequentially with NaHCO.sub.3(sat) and brine (sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduce pressure. The crude product was purified by flash silica chromatography using a gradient of 10-15% EtOAc in PE as mobile phase to afford 2.6 g the title compound as a pale yellow oil which solidified on standing. MS (ESI): m/z [M+H].sup.+ 608.4.

    Intermediate 78: Tert-butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-3-ethylpentan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate. Isomer 1

    Intermediate 79: Tert-butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-3-ethylpentan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate. Isomer 2

    [1965] ##STR00166##

    [1966] To a solution of Intermediate 75 (138 mg, 0.27 mmol) in DCM (2.7 mL) was added DIPEA (139 μL, 0.8 mmol) followed by HATU (303 mg, 0.8 mmol). 3-Ethylpentan-2-amine (66 μL, 0.4 mmol) was added to the solution and the reaction stirred at rt overnight. Na.sub.2CO.sub.3(sat) was added and the biphasic mixture stirred for 10 min. The organic layer was separated. The aq phase was washed with DCM twice. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using a gradient of 10-90% EtOAc in heptane as mobile phase to give the first eluting compound Intermediate 78, isomer 1 (67 mg, 41%); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.75 (d, 3H), 0.89 (td, 6H), 1.16-1.34 (m, 10H), 1.47 (s, 9H), 1.57 (d, 7H), 2.01 (dd, 3H), 2.21 (d, 3H), 2.42 (d, 1H), 2.54 (s, 1H), 3.93 (s, 4H), 4.06-4.23 (m, 1H), 4.41 (t, 1H), 5.40 (d, 1H), 6.71 (d, 1H), 7.88 (d, 1H), 8.53 (d, 1H); MS [ESI] m/z [M+H].sup.+ 617.5; and the second eluting compound Intermediate 79, isomer 2 (55 mg, 33%); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.61 (t, 3H), 0.68 (t, 3H), 0.86-0.92 (m, 2H), 1.04 (d, 4H), 1.25 (dd, 8H), 1.47 (s, 9H), 1.51-1.64 (m, 6H), 1.98 (d, 2H), 2.11 (d, 1H), 2.21 (d, 3H), 2.35 (d, 1H), 2.48 (s, 1H), 3.93 (s, 3H), 3.97-4.07 (m, 1H), 4.08-4.18 (m, 1H), 4.43 (t, 1H), 5.35 (d, 1H), 6.69 (d, 1H), 7.90 (d, 1H), 8.78 (d, 1H); MS [ESI] m/z [M+H].sup.+ 617.5.

    Intermediate 80: (1S,3s)-3-(2-Cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

    [1967] ##STR00167##

    Step A. Intermediate 81: Methyl 4-cyano-2-methoxy-5-((1s,3s)-3-(methoxycarbonyl)-3-methylcyclobutoxy)benzoate

    [1968] ##STR00168##

    [1969] Methyl (1r,3r)-3-hydroxy-1-methylcyclobutane-1-carboxylate (60 mg, 0.42 mmol) was added dropwise to a solution of DIAD (123 μL, 0.62 mmol), PPh.sub.3 (164 mg, 0.62 mmol) and methyl 4-cyano-5-hydroxy-2-methoxybenzoate (86 mg, 0.42 mmol) in THF (13.7 mL) at 50° C. under nitrogen. The resulting solution was stirred at the same temperature for 15 h. The reaction was allowed to cool to rt and it was diluted with EtOAc (150 mL). The organic phase was washed sequentially with H.sub.2O (2×50 mL) and brine (sat, 2×50 mL). The organic layer was separated, dried over a phase separator, filtered and the solvent removed under reduced pressure. The crude material was purified by Method PrepAcidic-F using a gradient of 15-55% followed by flash chromatography using a gradient from of 10-50% of EtOAc in heptane as mobile phase to afford the title compound (0.126 g, 91%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.48 (s, 3H), 2.47 (ddd, 2H), 2.73 (ddd, 2H), 3.74 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 4.77 (p, 1H), 7.15 (d, 2H). MS [ESI] m/z [M+H].sup.+ 334.3.

    Step B. Intermediate 82: 5-((1s,3s)-3-Carboxy-3-methylcyclobutoxy)-4-cyano-2-methoxybenzoic acid

    [1970] ##STR00169##

    [1971] Cesium hydroxide hydrate (21.9 mg, 0.15 mmol) was added in one portion to a solution of Intermediate 81 (126 mg, 0.38 mmol) in MeOH/H.sub.2O 1:1 (4 mL) at 20° C. The resulting suspension was stirred at 50° C. for 15 h. The reaction was allowed to cool to rt and it was acidified with HCl (aq, 3.8 M). The product was extracted with EtOAc (3×5 mL) and concentrated under reduced pressure to afford the title compound. The product was used in the next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.54 (s, 3H), 2.5-2.63 (m, 3H), 2.76 (ddq, 3H), 4.07 (s, 3H), 4.85 (p, 1H), 7.28 (s, 1H), 7.54 (s, 1H). MS (ESI): m/z [M−H].sup.− 304.3.

    Step C. (1S,3s)-3-(2-Cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

    [1972] Intermediate 82 (42 mg, 0.14 mmol) was dissolved in DCM (2.7 mL). DIPEA (28 μL, 0.16 mmol) was added to the solution, followed by HATU (157 mg, 0.41 mmol) and Intermediate 21 (69.6 mg, 0.14 mmol) and the reaction stirred at ambient temperature for 2 h. The reaction was queched with Na.sub.2CO.sub.3(sat) and the biphasic mixture stirred for 1 h. The organic layer was separated. The aq phase was washed with DCM. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude product was purified by Method PrepAcidic-F using a gradient of 15-55% to afford the title compound (17.5 mg, 24%) as a white solid; .sup.1H NMR (400 MHz, CD.sub.3OD) δ 1.08 (s, 3H), 1.45 (s, 3H), 1.51 (dt, 1H), 1.59-1.67 (m, 2H), 1.74-1.92 (m, 4H), 2.20 (dt, 1H), 2.42 (dd, 1H), 2.45-2.59 (m, 4H), 2.69 (d, 1H), 2.84 (s, 1H), 3.07 (dd, 1H), 3.21 (dd, 1H), 3.86 (s, 3H), 3.98 (td, 1H), 6.18-6.33 (m, 2H), 7.29 (s, 1H), 7.39 (s, 1H), 7.76 (d, 1H), 7.99 (t, 1H); MS (ESI): m/z [M+H].sup.+ 522.6.

    Intermediate 83: (1S,3s)-3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

    [1973] ##STR00170##

    Step A. Intermediate 84: Methyl 4-fluoro-2-methoxy-5-((1s,3s)-3-(methoxycarbonyl)-3-methylcyclobutoxy)benzoate

    [1974] ##STR00171##

    [1975] Methyl (1r,3r)-3-hydroxy-1-methylcyclobutane-1-carboxylate (60 mg, 0.42 mmol) was added dropwise to a solution of DIAD (123 μL, 0.62 mmol), PPh.sub.3 (164 mg, 0.62 mmol) and Intermediate 6 (83 mg, 0.42 mmol) in THF (13.7 mL) at 50° C. under nitrogen. The resulting solution was stirred at the same temperature for 6 h. The reaction was stirred at 30° C. over the weekend. The reaction was diluted with EtOAc (150 mL). The organic phase was washed sequentially with H.sub.2O (2×50 mL) and brine (sat, 2×50 mL). The organic layer was separated, dried over a phase separator, filtered and the solvent removed under reduced pressure. The crude material was purified by flash chromatography using a gradient from of 5-50% of EtOAc in heptane as mobile phase to afford the title compound (102 mg, 75%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.36 (s, 3H), 2.32 (ddd, 2H), 2.58 (ddd, 2H), 3.62 (s, 3H), 3.77 (d, 6H), 4.60 (p, 1H), 6.66 (d, 1H), 7.26 (d, 1H). MS [ESI] m/z [M+H].sup.+ 327.3.

    Step B. Intermediate 85: 5-((1s,3s)-3-Carboxy-3-methylcyclobutoxy)-4-fluoro-2-methoxybenzoic acid

    [1976] ##STR00172##

    [1977] Hydrolysis of Intermediate 84 (524 mg, 3.12 mmol) was carried out analogous to the procedure described for Intermediate 81 to afford the title compound. The product was used in the next step directly without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.51 (s, 3H), 2.51 (ddd, 2H), 2.72 (ddd, 2H), 4.04 (s, 3H), 4.79 (p, 1H), 6.86 (d, 1H), 7.62 (d, 1H). MS (ESI): m/z [M+H].sup.+ 299.3.

    Step C. (1S,3s)-3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)-methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

    [1978] Intermediate 85 (46.5 mg, 0.16 mmol) was dissolved in DCM (2.7 mL). DIPEA (28 μL, 0.16 mmol) was added to the solution, followed by HATU (178 mg, 0.47 mmol) and Intermediate 21 (69.6 mg, 0.14 mmol) and the reaction stirred at ambient temperature for 2 h. The reaction was queched with Na.sub.2CO.sub.3(sat) and the biphasic mixture stirred for 1 h. The organic layer was separated. The aq phase was washed with DCM. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude product was purified by Method PrepAcidic-F using a gradient of 25-65% to afford the title compound (17.7 mg, 22%) as a white solid; MS (ESI): m/z [M+H].sup.+ 515.6.

    Intermediate 86: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1979] ##STR00173##

    Step A. Intermediate 87: Tert-butyl (4-(((1-methylcyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate

    [1980] ##STR00174##

    [1981] 3-((tert-Butoxycarbonyl)amino)isonicotinic acid (84 mg, 0.35 mmol) and TCFH (124 mg, 0.44 mmol) were added to a solution of 1-methyl-1H-imidazole (82 μL, 1.03 mmol) and (1-methylcyclobutyl)methanamine hydrochloride (40 mg, 0.29 mmol) in MeCN (5.6 mL). The vial was sealed and the reaction was run at 120° C. for 80 min in a microwave reactor. The reaction mixture was then diluted with EtOAc (6 mL) and H.sub.2O (4 mL). The layers were separated, the aq layer was extracted with EtOAc (4 mL) and the combined organic layer was washed with H.sub.2O (4 mL) and passed through a phase separator. After removal of the solvent under reduced pressure, the title compound was progressed to the next step without further purification. MS (ESI): m/z [M+H].sup.+ 320.2.

    Step B. Intermediate 88: 3-Amino-N-((1-methylcyclobutyl)methyl)isonicotinamide hydrochloride

    [1982] ##STR00175##

    [1983] HCl in 1,4-dioxane (2.9 mL, 11.6 mmol) was added to a solution of Intermediate 87 (93 mg, 0.29 mmol) in 1,4-dioxane (2 mL). After 2 h, few drops of MeOH were added until a clear solution was achieved and the reaction was stirred for additional 5 h. The solvent was removed under reduced pressure and the title compound was progressed to the next step without further purification. MS (ESI): m/z [M+H].sup.+ 220.1.

    Step C. Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)-methyl)carbamoyl)pyridin-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1984] Intermediate 13 (176 mg, 0.38 mmol) and TCFH (122 mg, 0.44 mmol) were added to a microwave vial followed by a solution of 1-methyl-1H-imidazole (81 μL, 1.02 mmol) in MeCN. After stirring for 1 min, a solution of Intermediate 88 (74.2 mg, 0.29 mmol) in MeCN was added and the vial was sealed. The reaction was stirred at 120° C. for 80 min in a microwave reactor. The reaction was then diluted with EtOAc and H.sub.2O. The layers were separated, the aq layer was extracted with isopropyl acetate and the combined organic layers were washed with H.sub.2O, dried over a phase separator, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a gradient from of 10-60% of EtOAc in heptane as mobile phase to give the title compound (115 mg, 59%) as a white solid; MS (ESI): m/z [M+H].sup.+ 668.4. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.18 (d, 6H), 1.21-1.38 (m, 3H), 1.60 (q, 2H), 1.72-1.80 (m, 2H), 1.81-2.00 (m, 6H), 2.29 (d, 2H), 3.47 (d, 2H), 4.06 (s, 3H), 4.1-4.26 (m, 1H), 5.61 (s, 2H), 6.78 (d, 1H), 7.37-7.67 (m, 5H), 7.86 (d, 1H), 7.89 (d, 2H), 8.00 (d, 1H), 8.38 (d, 1H), 10.02 (s, 1H), 11.69 (s, 1H).

    Intermediate 89: Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1SR,2RS)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1985] ##STR00176##

    Step A. Intermediate 90: rac-tert-Butyl ((1R,2S)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamate

    [1986] ##STR00177##

    [1987] Rac-(1R,2S)-2-((tert-Butoxycarbonyl)amino)cyclooctane-1-carboxylic acid (96 mg, 0.35 mmol) and TCFH (124 mg, 0.44 mmol) were added to a microwave vial followed by a solution of 1-methyl-1H-imidazole (82 μL, 1.03 mmol) in MeCN (2.8 mL). After stirring for 1 min, a solution of (1-methylcyclobutyl)methanamine hydrochloride (40 mg, 0.29 mmol) in MeCN (2.8 mL) was added and the vial was sealed. The reaction was stirred at 120° C. for 80 min in a microwave reactor. The reaction was then diluted with EtOAc (6 mL) and H.sub.2O (4 mL). The layers were separated, the aq layer was extracted with iPrOAc and the combined organic layers were washed with H.sub.2O, dried over a phase separator, filtered and concentrated under reduced pressure to afford the title compound. The product was used in the next step without further purification. MS (ESI): m/z [M+H].sup.+ 353.3.

    Step B. Intermediate 91: rac-(1R,2S)-2-Amino-N-((1-methylcyclobutyl)methyl)cyclooctane-1-carboxamide

    [1988] ##STR00178##

    [1989] Intermediate 90 was dissolved in 1,4-dioxane (2 mL) and HCl (4 M in dioxane) was added. After stirring at rt for 12 h, the title compound was obtained. The product was used in the next step without further purification. MS (ESI): m/z [M+H].sup.+ 253.1.

    Step C. Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1SR,2RS)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclooctyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1990] Intermediate 91 was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86, to obtain the title compound (75%) as a white solid; MS (ESI): m/z [M+H].sup.+ 701.6.

    Intermediate 92: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-methyl-5-(((1-methylcyclobutyl)methyl)carbamoyl)isothiazol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1991] ##STR00179##

    Step A. Intermediate 93: tert-Butyl (3-methyl-5-(((1-methylcyclobutyl)methyl)carbamoyl)isothiazol-4-yl)carbamate

    [1992] ##STR00180##

    [1993] 4-((tert-Butoxycarbonyl)amino)-3-methylisothiazole-5-carboxylic acid was coupled with (1-methylcyclobutyl)methanamine hydrochloride in an analogous way to Intermediate 90 to afford the title compound. The product was used in the next step without further purification. MS (ESI): m/z [M+H].sup.+ 340.2.

    Step B. Intermediate 94: 4-Amino-3-methyl-N-((1-methylcyclobutyl)methyl)isothiazole-5-carboxamide

    [1994] ##STR00181##

    [1995] Hydrolysis of Intermediate 93 was carried out in an analogous way to Intermediate 91 to afford the title compound. The product was used in the next step without further purification.

    Step C. Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-methyl-5-(((1-methylcyclobutyl)methyl)carbamoyl)isothiazol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1996] Intermediate 94 was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86 to obtain the title compound (46%) as a white solid; .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.07 (s, 3H), 1.18 (s, 3H), 1.26 (t, 3H), 1.58-1.65 (m, 4H), 1.81 (d, 3H), 1.96 (d, 2H), 2.29 (d, 2H), 2.44 (s, 3H), 3.36 (d, 2H), 4.04 (s, 3H), 4.16 (d, 1H), 5.61 (s, 2H), 6.84 (d, 1H), 6.94 (s, 1H), 7.46 (t, 1H), 7.54 (dq, 3H), 7.83-7.91 (m, 3H), 8.00 (d, 1H), 9.84 (s, 1H). MS (ESI): m/z [M+H].sup.+ 688.3.

    Intermediate 95: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((5-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [1997] ##STR00182##

    [1998] 2-Amino-4-chloro-N-((1-methylcyclobutyl)methyl)benzamide was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86, to give the title compound (60%) as a white solid; .sup.1H NMR (400 MHz, DMSO-d6) δ 1.11 (s, 3H), 1.13 (s, 3H), 1.36 (dt, 4H), 1.53-1.66 (m, 2H), 1.72-2.03 (m, 6H), 2.09 (d, 2H), 3.98 (s, 3H), 4.21 (s, 1H), 5.62 (s, 2H), 7.21 (d, 1H), 7.28 (dd, 1H), 7.48-7.63 (m, 4H), 7.66 (d, 1H), 7.72 (d, 1H), 7.92-8.05 (m, 3H), 8.70 (d, 1H), 8.74 (t, 1H), 11.93 (s, 1H). MS (ESI): m/z [M+H].sup.+ 701.6.

    Intermediate 96: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-methyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [1999] ##STR00183##

    [2000] 2-Amino-3-methyl-N-((1-methylcyclobutyl)methyl)benzamide was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86, to give the title compound (62%) as a white solid; MS (ESI): m/z [M+H].sup.+ 681.7.

    Intermediate 97: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((4-chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2001] ##STR00184##

    [2002] 2-Amino-5-chloro-N-((1-methylcyclobutyl)methyl)benzamide was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86 to give the title compound (80%) as a white solid; MS (ESI): m/z [M+H].sup.+ 701.6. .sup.1H NMR (400 MHz, DMSO-d6) δ 1.10 (s, 3H), 1.12 (s, 3H), 1.36 (dt, 4H), 1.54-1.65 (m, 2H), 1.73-1.99 (m, 6H), 2.09 (d, 2H), 3.98 (s, 3H), 4.20 (s, 1H), 5.61 (s, 2H), 7.21 (d, 1H), 7.48-7.63 (m, 5H), 7.65 (dd, 1H), 7.72 (d, 1H), 7.86-8.07 (m, 3H), 8.57 (d, 1H), 8.78 (s, 1H), 11.74 (s, 1H).

    Intermediate 98: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)thiophen-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2003] ##STR00185##

    [2004] 3-Amino-N-((1-methylcyclobutyl)methyl)thiophene-2-carboxamide was coupled with Intermediate 13 in an analogous procedure for the synthesis of Intermediate 86 to give the title compound (96%) as a white solid; MS (ESI): m/z [M+H].sup.+ 673.6. .sup.1H NMR (400 MHz, DMSO-d6) δ 1.10 (s, 3H), 1.12 (s, 3H), 1.29-1.47 (m, 4H), 1.55-1.68 (m, 2H), 1.73-1.93 (m, 4H), 1.98 (td, 2H), 2.09 (d, 2H), 3.27 (d, 2H), 4.01 (s, 3H), 4.22 (s, 1H), 5.62 (s, 2H), 7.21 (d, 1H), 7.47-7.66 (m, 4H), 7.7-7.84 (m, 2H), 7.91-8.09 (m, 3H), 8.17-8.28 (m, 2H), 12.51 (s, 1H).

    Intermediate 99: ((1s,3s)-3-Methylcyclobutyl)methanamine

    [2005] ##STR00186##

    Step A. Intermediate 100: (1s,3s)-3-Methylcyclobutane-1-carboxylic acid

    [2006] ##STR00187##

    [2007] The title compound was obtained from 3-methylcyclobut-1-ene-1-carboxylic acid in 39% yield as colorless oil (Liebigs Ann. Chem. 1990, 411-414). .sup.1H NMR (400 MHz, CD.sub.3OD): δ 1.06 (dd, 3H), 1.79-1.86 (m, 2H), 2.28-2.39 (m, 3H), 2.89-2.98 (m, 1H).

    Step B. Intermediate 101: (1s,3s)-3-Methylcyclobutane-1-carboxamide

    [2008] ##STR00188##

    [2009] Intermediate 100 (35 g, 0.3 mol) was dissolved in anhydrous THF (500 mL) and N-methylmorpholine (37.2 g, 0.36 mol) was added. The resulting solution was cooled to 0° C. and isobutyl chloroformate (50 g, 0.36 mol) was added dropwise over 30 min. NH.sub.3 (g) was bubbled through the resulting solution during 30 min, then the resulting mixture was stirred at overnight. The reaction was diluted with HCl (1 M). The organic layer was separated and dried over MgSO.sub.4, filtered and the solvent removed under reduced pressure. The residue was recrystallized from PE and EtOAc to obtain the title compound (15 g, 35%) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 1.16 (d, 3H), 1.76-1.84 (m, 2H), 2.24-2.37 (m, 3H), 2.87-2.96 (m, 1H).

    Step C. ((1s,3s)-3-Methylcyclobutyl)methanamine

    [2010] Borane dimethylsulfide (30 g, 0.39 mol) was added to a solution of Intermediate 101 (15 g, 0.13 mol) in anhydrous THF (200 mL) at 0° C. After 30 min at rt, the reaction mixture was heated to 80° C. and stirred at the same temperature for 16 h. The reaction was quenched with MeOH at 0° C. and the solvent removed under reduced pressure. A mixture of HCl (4 M)/EtOAc was added and the resulting slurry stirred for 30 min. The solid was filtered and dried under reduced pressure to obtain the HCl salt of the title compound (9 g, 50%) as a white solid. MS (ESI): m/z [M+H].sup.+ 100.

    Intermediate 102: 4-Chloro-2-(4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)benzoic acid

    [2011] ##STR00189##

    Step A. Intermediate 103: Methyl 4-chloro-2-(4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)benzoate

    [2012] ##STR00190##

    [2013] Intermediate 70 (1.00 g, 2.09 mmol) was dissolved in MeCN (5.0 mL) and methyl 2-amino-4-chlorobenzoate (0.78 g, 4.18 mmol), was added followed by TCFH (0.89 g, 3.14 mmol) and 1-methyl-1H-imidazole (0.52 g, 6.27 mmol). The mixture was heated to 100° C. and stirred overnight at the same temperature. The reaction was then quenched with H.sub.2O and extracted with EtOAc. The crude material was purified by silica gel column with PE/EA (1:1) to obtain the title compound (187 mg, 13%) as alight yellow solid. MS (ESI): m/z [M+Na].sup.+663.1.

    Step B. 4-Chloro-2-(4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)benzoic acid

    [2014] LiOH (16.8 mg, 0.69 mmol) was added to a solution of Intermediate 103 (150 mg, 0.23 mol) in THF/H.sub.2O (10 mL) and the mixture was stirre overnight at rt. The mixture was extracted with EtOAc and the organic layer was purified by silica gel column chromatography with PE/EA (1:1) to give the title compound (128 mg, 78.4%) as a light yellow solid. MS (ESI): m/z [M+Na].sup.+649.1.

    Intermediate 104: 2-(4-Cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-4-methylbenzoic acid

    [2015] ##STR00191##

    Step A. Intermediate 105: Methyl 2-(4-cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-4-methylbenzoate

    [2016] ##STR00192##

    [2017] Intermediate 70 (1.00 g, 2.09 mmol) was dissolved in MeCN (5 mL) and methyl 2-amino-4-methylbenzoate (0.698 g, 4.18 mmol) was added followed by TCFH (0.889 g, 3.14 mmol) and 1-methyl-1H-imidazole (0.520 g, 6.27 mmol). The mixture was heated to 100° C. and stirred for 1 h under nitrogen atmosphere. The reaction was then quenched with H.sub.2O and extracted with EtOAc. The crude material was purified by silica gel column chromatography and elution with PE/EA (1:1) gave the title compound (220 mg, 14%) as a light yellow solid. MS (ESI): m/z [M+H].sup.+ 621.2.

    Step B. 2-(4-Cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-4-methylbenzoic acid

    [2018] LiOH (11 mg, 0.45 mmol) was added to a solution of Intermediate 105 (100 mg, 0.16 mol) in THF/H.sub.2O (2:1, 30 mL) and the mixture was stirred overnight at rt. The reaction was quenched with H.sub.2O and acidified with HCl. Extraction with EtOAc followed by purification by silica gel column chromatography and elution with PE/EA (1:1) gave the title compound (78 mg, 77%) as a yellow solid. MS (ESI): m/z [M+H].sup.+ 607.2

    Intermediate 106: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(Ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2019] ##STR00193##

    Step A. Intermediate 107: Methyl (1S,2S,3R,4R)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2020] ##STR00194##

    [2021] (Boc).sub.2O (22.8 mL, 98.2 mmol) was added to Intermediate 8 (10.0 g, 49.1 mmol) and TEA (34.2 mL, 245.5 mmol) in THF (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into brine (150 mL, sat), extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (13.0 g, 99%) as a yellow oil. The product was used in the next step directly without further purification.

    Step B. Intermediate 19 (1S,2S,3R,4R)-3-((tert-Butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [2022] ##STR00195##

    [2023] LiOH (6.5 g, 271.4 mmol) was added to Intermediate 107 (13.0 g, 48.63 mmol) in THF (40 mL), MeOH (10 mL) and H.sub.2O (10 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (300 mL), and acidified with 2 M HCl. The reaction mixture was extracted with EtOAc (3×125 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (12.0 g, 97%) as a colorless gum.

    Step C. Intermediate 108: Benzyl (1S,2S,3R,4R)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2024] ##STR00196##

    [2025] TEA (23.11 mL, 165.8 mmol) was added dropwise to Intermediate 19 (12.0 g, 47.38 mmol), phenylmethanol (7.68 g, 71.06 mmol) and EDC (19.98 g, 104.2 mmol), HOBt (15.96 g, 104.2 mmol) in DMF (60 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h. The mixture was poured into NaHCO.sub.3 (350 mL, sat), extracted with EtOAc (3×150 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a pale yellow oil. The crude product was purified by flash chromatography using a gradient of 0-5% EtOAc in heptane as mobile phase to give the title compound (15.0 g, 92%) as a colorless gum. MS (ESI): m/z [M+H-Boc].sup.+ 244.2.

    Step D. Intermediate 109: Benzyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2026] ##STR00197##

    [2027] TFA (6.06 mL, 78.6 mmol) was added to Intermediate 108 (5.4 g, 15.7 mmol) in DCM (60 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was diluted with EtOAc (250 mL), and washed with NaHCO.sub.3 (150 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to afford the title compound (3.80 g, 99%) as a pale yellow solid. The product was used in the next step directly without further purification. .sup.1H NMR (300 MHz, DMSO-d6): δ 1.44 (m, 1H), 2.00-2.08 (m, 1H), 2.56 (dd, 1H), 2.76 (d, 1H), 2.98 (d, 1H), 3.22 (dd, 1H), 5.06 (d, 1H), 5.19 (d, 1H), 6.05 (s, 2H), 6.16-6.29 (br s, 2H, NH.sub.2), 7.32-7.45 (m, 5H). MS (ESI): m/z [M+H].sup.+ 244.5.

    Step E. Intermediate 110: Benzyl (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2028] ##STR00198##

    [2029] HATU (4.88 g, 12.8 mmol) was added portion wise to Intermediate 111 (3.64 g, 10.69 mmol), Intermediate 109 (2.6 g, 10.7 mmol) and DIPEA (4.14 g, 32.06 mmol) in DMF (50 mL) at Rt. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into NaHCO.sub.3 (200 mL, sat), extracted with EtOAc (3×75 mL), the organic layer was washed with brine (2×100 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a brown oil. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as mobile phase to give the title compound (5.50 g, 91%) as a pale yellow gum. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 1.27-1.30 (m, 3H), 1.69 (dtt, 5H), 2.01 (td, 4H), 2.11 (dt, 1H), 2.41 (tt, 1H), 2.75-2.86 (m, 2H), 3.05 (s, 1H), 3.84 (s, 3H), 4.17 (dd, 2H), 4.45 (tt, 1H), 4.49-4.57 (m, 1H), 5.08 (s, 2H), 6.24 (dd, 1H), 6.30 (dd, 1H), 6.69 (d, 1H), 7.18-7.28 (m, 5H), 7.90 (d, 1H), 8.62 (d, 1H). MS (ESI): m/z [M+H].sup.+ 566.4.

    Step F. (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-(Ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2030] Pd-C (0.6 g, 5.6 mmol) was added to Intermediate 110 (5.5 g, 9.7 mmol) in MeOH (75 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h under an atmosphere of hydrogen. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to give the title compound (4.1 g, 88%) as a white solid. MS (ESI): m/z [M+H].sup.+ 478.4.

    Intermediate 111: 5-(((1s,4s)-4-(Ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2031] ##STR00199##

    Step A. Intermediate 112: 5-Bromo-4-fluoro-2-hydroxybenzoic acid

    [2032] ##STR00200##

    [2033] NBS (43.8 g, 246 mmol) was added portion wise to 4-fluoro-2-hydroxybenzoic acid (32 g, 205 mmol) in DMF (250 mL) at 0° C. The resulting solution was stirred at 20° C. for 20 h. The reaction mixture was poured into brine (1 L, sat), extracted with EtOAc (3×500 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (48.0 g, 100%) as a brown solid. The product was used in the next step directly without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 6.79 (d, 1H), 8.15 (d, 1H). (ESI): m/z [M−H].sup.+233.

    Step B. Intermediate 113: Methyl 5-bromo-4-fluoro-2-methoxybenzoate

    [2034] ##STR00201##

    [2035] Mel (77 mL, 1225.5 mmol) was added dropwise to Intermediate 112 (48 g, 204.2 mmol) and potassium carbonate (70.6 g, 510.6 mmol) in acetone (400 mL) at 20° C. over a period of 20 Min. The resulting suspension was stirred at 60° C. for 15 h. The reaction mixture was filtered through Celite®. The reaction mixture was diluted with EtOAc (750 mL), the organic layers was washed with brine (2×400 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a brown solid. The dried solid was triturated with EtOAc/PE (1/4) (50 mL) and filtered to afford the tile compound (37.0 g, 68.9%) as a pink solid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 3.90 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H), 8.06 (d, 1H). (ESI): m/z [M+H].sup.+ 262.9.

    Step C. Intermediate 114: 5-Bromo-4-fluoro-2-methoxybenzoic acid

    [2036] ##STR00202##

    [2037] A solution of NaOH (16.88 g, 421.95 mmol) in H.sub.2O (80 mL) was added slowly to a stirred solution of Intermediate 113 (37 g, 140.6 mmol) in MeOH (250 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into ice/H.sub.2O (2 L), extracted with DCM (3×500 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (34.0 g, 97%) as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 4.09 (s, 3H), 6.88 (d, 1H), 8.41 (d, 1H). (ESI): m/z [M+H].sup.+ 249.8.

    Step D. Intermediate 115: Benzyl 5-bromo-4-fluoro-2-methoxybenzoate

    [2038] ##STR00203##

    [2039] (Bromomethyl)benzene (15.76 mL, 132.51 mmol) was added slowly to Intermediate 114 (30 g, 120.5 mmol) and potassium carbonate (19.98 g, 144.56 mmol) in DMF (200 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h. The reaction mixture was poured into brine (1 L, sat), extracted with EtOAc (3×350 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (38.0 g, 93%) as an orange oil which solidified on standing. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 3.91 (s, 3H), 5.36 (s, 2H), 6.79 (d, 1H), 7.37-7.50 (m, 5H), 8.08 (dd, 1H). (ESI): m/z [M+H].sup.+ 341.3.

    Step E. Intermediate 116: Benzyl 4-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

    [2040] ##STR00204##

    [2041] PdCl.sub.2(Dppf)-CH.sub.2Cl.sub.2 Adduct (4.57 g, 5.60 mmol) was added to Intermediate 115 (38 g, 112.0 mmol), B.sub.2Pin.sub.2 (34.1 g, 134.4 mmol) and potassium acetate (27.5 g, 280.1 mmol) in 1,4-dioxane (240 mL) at 20° C. The resulting solution was stirred at 100° C. for 15 h under nitrogen. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as mobile phase to give the title compound (40.0 g, 92%) as a yellow oil which solidified on standing. .sup.1H NMR (300 MHz, 23.0° C., CDCl3): δ 1.37 (s, 12H), 3.93 (s, 3H), 5.37 (s, 2H), 6.63-6.70 (m, 1H), 7.36-7.43 (m, 3H), 7.46-7.51 (m, 2H), 8.29 (d, 1H). (ESI): m/z [M+H].sup.+ 387.4.

    Step F. Intermediate 117: Benzyl 4-fluoro-5-hydroxy-2-methoxybenzoate

    [2042] ##STR00205##

    [2043] H.sub.2O.sub.2 (30.0 mL, 30 weight %, 293.7 mmol) was added slowly to Intermediate 116 (44 g, 113.9 mmol) in MeOH (200 mL) at 20° C. The resulting solution was stirred at 25° C. for 5 h. The reaction mixture was poured into ice H.sub.2O. The precipitate was collected by filtration, and dried under vacuum to afford the title compound (20.00 g, 63.5%) as a pale yellow solid. (ESI): m/z [M+H].sup.+ 277.1.

    Step G. Intermediate 118: Benzyl 5-(((1s,4s)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

    [2044] ##STR00206##

    [2045] DIAD (12.67 mL, 65.16 mmol) was added dropwise to Intermediate 117 (15 g, 54.30 mmol), ethyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (9.35 g, 54.30 mmol) and triphenylphosphane (17.09 g, 65.16 mmol) in THF (35 mL) at 50° C. The resulting solution was stirred at 60° C. for 15 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-10% EtOAc in heptane as mobile phase to give the title compound (17.0 g, 72.7%) as a colorless oil which solidified on standing. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 1.30 (dd, 3H), 1.59-1.81 (m, 4H), 1.93-2.07 (m, 4H), 2.42 (tt, 1H), 3.88 (s, 3H), 4.15-4.23 (m, 2H), 4.36 (tt, 1H), 5.37 (s, 2H), 6.77 (d, 1H), 7.35-7.44 (m, 3H), 7.45-7.50 (m, 2H), 7.59 (d, 1H). (ESI): m/z [M+Na].sup.+453.3.

    [2046] Step H. 5-(((1s,4s)-4-(Ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid Pd-C (0.20 g, 1.88 mmol) was added to Intermediate 118 (0.5 g, 1.16 mmol) in MeOH (40 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h under an atmosphere of hydrogen. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound (0.300 g, 76%) as a white solid which was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, 3H), 1.67 (dt, 4H), 1.73-1.87 (m, 4H), 2.40-2.49 (m, 1H), 3.78 (s, 3H), 4.08 (2H, d), 4.42 (1H, d), 7.11 (1H, d), 7.46 (1H, d), 12.67 (1H, s). MS (ESI): m/z [M+H].sup.+ 341.

    Intermediate 119: (1R,2S,3R,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2047] ##STR00207##

    Step A. Intermediate 120: Methyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride

    [2048] ##STR00208##

    [2049] Pd-C (11.9 mg, 0.11 mmol) and Intermediate 8 (228 mg, 1.12 mmol) in MeOH (25 mL) was stirred under an atmosphere of hydrogen at 1.5 atm and 25° C. for 14 h. The mixture was filtered through a Celite® pad. The solvent was removed under reduced pressure to the title compound (230 mg, 100%) as a pale yellow solid. This was used in the next step without further purification.

    Step B. Intermediate 121: Methyl (1R,2S,3R,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptane-2-carboxylate

    [2050] ##STR00209##

    [2051] Boc.sub.2O (1.81 mL, 7.78 mmol) was added Intermediate 120 (1 g, 4.86 mmol) and TEA (2.71 mL, 19.45 mmol) in THF (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into brine (150 mL, sat), extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (1.20 g, 92%) as a yellow oil. The crude product was used in the next step directly without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 1.10-1.36 (m, 4H), 1.43 (s, 9H), 1.56-1.60 (m, 1H), 1.78-1.87 (m, 1H), 2.15 (d, 1H), 2.44 (dd, 1H), 2.64-2.79 (m, 1H), 3.65 (s, 3H), 3.97 (t, 1H), 5.01 (d, 1H).

    Step C. Intermediate 122: (1R,2S,3R,4S)-3-((tert-Butoxycarbonyl)amino)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2052] ##STR00210##

    [2053] LiOH (0.320 g, 13.37 mmol) was added to Intermediate 121 (1.2 g, 4.46 mmol) in THF (12 mL), MeOH (3 mL) and H.sub.2O (3 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL), the reaction mixture was acidified with 2 M HCl. The reaction mixture was extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (1.100 g, 97%) as a colorless gum. The crude product was used in the next step directly without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 1.18 (ddd, 2H), 1.47 (s, 9H), 1.50-1.69 (m, 3H), 1.98 (d, 1H), 2.17-2.22 (m, 1H), 2.51 (d, 1H), 2.61-2.72 (m, 1H), 3.93 (t, 1H), 6.99 (d, 1H).

    Step D. Intermediate 123: tert-Butyl ((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

    [2054] ##STR00211##

    [2055] HATU (0.357 g, 0.94 mmol) was added portion wise to 4-fluoro-3-(trifluoromethyl)aniline (0.140 g, 0.78 mmol), Intermediate 122 (0.2 g, 0.78 mmol) and DIPEA (0.304 g, 2.35 mmol) in DMF (10 mL). The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into sat NaHCO.sub.3 (200 mL), extracted with EtOAc (3×75 mL), the organic layer was washed with brine (2×100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a yellow oil. The residue was purified by preparative TLC (EtOAc/PE 1/5), to afford the title compound (0.260 g, 80%) as a yellow oil which solidified on standing. MS (ESI): m/z [M+H].sup.+ 417.

    Step E. (1R,2S,3R,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2056] TFA (0.241 mL, 3.12 mmol) was added to Intermediate 123 (0.26 g, 0.62 mmol) in DCM (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was diluted with EtOAc (150 mL), and washed with sat NaHCO.sub.3 (75 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to afford the title compound (0.180 g, 91%) as a yellow gum which was used in the next step without further purification. MS (ESI): m/z [M+H].sup.+ 317.

    Intermediate 124: (1R,2S,3R,4S)-3-Amino-N-phenylbicyclo[2.2.1]heptane-2-carboxamide

    [2057] ##STR00212##

    Step A. Intermediate 125: tert-butyl ((1S,2R,3S,4R)-3-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

    [2058] ##STR00213##

    [2059] Aniline (82 mg, 0.88 mmol), HATU (402 mg, 1.06 mmol), DIPEA (0.246 mL, 1.41 mmol) and DMAP (8.61 mg, 0.07 mmol) were added to a solution of Intermediate 122 (180 mg, 0.71 mmol) in DMF (5 mL). The reaction mixture was stirred at Rt for 1.5 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (3×10 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The residue was purified by preparative TLC (PE/EtOAc 1/1), to afford the title compound (187 mg, 80%) as a white solid. MS (ESI): m/z [M+Na].sup.+353.

    Step B. (1R,2S,3R,4S)-3-Amino-N-phenylbicyclo[2.2.1]heptane-2-carboxamide

    [2060] A solution of hydrogen chloride (21 mg, 0.57 mmol) was added to Intermediate 125 (187 mg, 0.57 mmol).The reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The product was used in the next step directly without further purification. MS (ESI): m/z [M+H].sup.+ 231.

    Intermediate 126: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-((4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexylidene)methyl)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2061] ##STR00214##

    Step A. Intermediate 127: Methyl (1R,2S,3R,4S)-3-(5-bromo-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylate

    [2062] ##STR00215##

    [2063] TEA (38.3 mL, 274.7 mmol) was added dropwise to Intermediate 8 (11.3 g, 54.9 mmol), Intermediate 114 (13.68 g, 54.94 mmol) and EDC (21.06 g, 109.88 mmol), HOBt (16.83 g, 109.88 mmol) in CHCl.sub.3 (200 mL) at 20° C. over a period of 1 min under air. The resulting suspension was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with (1×150 mL, sat), NaHCO.sub.3 (1×150 mL, sat), and H.sub.2O (1×150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The residue was purified by preparative TLC (PE/EtOAc 5/1), to afford the title compound (13.0 g, 59.1%) as a colorless oil which solidified on standing. MS (ESI): m/z [M+H].sup.+ 400.

    Step B. Intermediate 128: (1R,2S,3R,4S)-3-(5-Bromo-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2064] ##STR00216##

    [2065] A solution of LiOH (1.256 g, 52.47 mmol) in H.sub.2O (40.0 mL) was added dropwise to a stirred solution of Intermediate 127 (7 g, 17.5 mmol) in methanol (160 mL) cooled to 0° C., over a period of 1 minutes under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL). The H.sub.2O phase was acidified with 2 M HCl to pH 3, diluted with EtOAc (150 mL), and washed sequentially with sat NaHCO.sub.3 (1×150 mL), brine (1×125 mL), and H.sub.2O (1×150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (5.00 g, 74.0%). MS (ESI): m/z [M+H].sup.+ 386.

    Step C. Intermediate 129: Naphthalen-1-ylmethyl 1-methyl-4-methylenecyclohexane-1-carboxylate

    [2066] ##STR00217##

    [2067] Intermediate 4 (1.0 g, 3.37 mmol) was dissolved in THF (10.12 mL) under N.sub.2 atmosphere and cooled to 0° C. Tebbe reagent (6.75 mL, 3.37 mmol, 0.5 M in toluene) was added and the reaction was allowed to reach ambient temperature (50 min). Et2O (20 mL) was added followed by 20 drops of NaOH (0.1 M, aq). Gas evolution was observed. Filtered through a phase separator and evaporate the solvents. The crude product was purified by flash chromatography using a gradient of 10-50% EtOAc in heptane as mobile phase to give the title compound (0.479 g, 48.2%) as a yellowish oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.19 (s, 3H), 1.28-1.39 (m, 2H), 2.01-2.23 (m, 6H), 4.59 (s, 2H), 5.59 (s, 2H), 7.46 (dd, 1H), 7.49-7.58 (m, 3H), 7.82-7.93 (m, 2H), 7.96-8.03 (m, 1H).

    Step D. (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-((4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexylidene)methyl)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2068] Intermediate 128 (628 mg, 1.63 mmol), tetrabutylammonium chloride (45.2 mg, 0.16 mmol) and PdCl.sub.2(dtbpf) (105 mg, 0.16 mmol) was diluted in DMA (7.26 mL) and placed under an N.sub.2-atmosphere. Intermediate 129 (479 mg, 1.63 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.87 mL, 4.07 mmol) was dissolved in small amount of DMA and added to the reaction mixture and the reaction was heated to 80° C. over 2 days. An additional amount of PdCl.sub.2(dtbpf) (105 mg, 0.16 mmol) was added after 24 h. The reaction was diluted with H.sub.2O/1 M KHSO.sub.4 and EtOAc, rinsed with H.sub.2O/1 M KHSO.sub.4, filtered through phase separator. The organic phase was evaporated and the crude product was purified by Method PrepBasic-F to give the title compound (148 mg, 15%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.21 (d, 3H), 1.23-1.46 (m, 5H), 1.51-1.66 (m, 2H), 1.88 (d, 1H), 2.15 (d, 2H), 2.26 (dd, 4H), 2.35-2.46 (m, 1H), 2.54 (s, 1H), 2.81 (d, 1H), 3.78 (s, 3H), 4.46-4.63 (m, 1H), 5.53-5.7 (m, 2H), 6.03 (s, 1H), 6.42 (d, 1H), 7.41-7.6 (m, 4H), 7.87 (dd, 2H), 8.00 (dd, 2H), 8.38 (d, 1H). MS (ESI): m/z [M+H].sup.+ 231.

    Intermediate 130: (1S,2R,3S,4R)-3-(5-(((1s,4R)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2069] ##STR00218##

    Step A. Intermediate 131: tert-Butyl 4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexane-1-carboxylate

    [2070] ##STR00219##

    [2071] n-Butyllithium (28.6 mL, 71.5 mmol) was added dropwise to DIA (7.24 g, 71.5 mmol) in THF (100 mL) cooled to −78° C. under nitrogen. The resulting solution was stirred at −10° C. for 30 min and tert-butyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (15 g, 47.7 mmol) in THF (40 mL) was added dropwise to the former solution at −78° C. under nitrogen. The resulting solution was stirred at −78° C. for 3 h. Then Mel (4.17 mL, 66.8 mmol) in THF (40 mL) was added dropwise to the stirred mixture at −78° C. The resulting solution was stirred at −78° C. for 2 h. The reaction mixture was poured into NH.sub.4Cl (150 mL, sat), extracted with EtOAc (3×150 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to the title compound (15.50 g, 99%) as a pale yellow gum. .sup.1H NMR (300 MHz, DMSO-d6) δ 0.02 (d, 6H), 0.87 (d, 9H), 1.07 (d, 3H), 1.19 (m, 4H), 1.41 (d, 9H), 1.51 (d, 1H), 1.67 (d, 2H), 1.99 (d, 1H), 3.61 (m, 1H). (Major isomer).

    Step B. Intermediate 132: tert-Butyl 4-hydroxy-1-methylcyclohexane-1-carboxylate

    [2072] ##STR00220##

    [2073] TBAF (13.13 g, 50.22 mmol) was added in one portion to Intermediate 131 (15.0 g, 45.65 mmol) in THF (150 mL) at 20° C. over a period of min under air. The resulting solution was stirred at 20° C. for 20 h. The reaction mixture was evaporated to dryness and dissolved in EtOAc (200 mL), and washed sequentially with NH.sub.4Cl (1×100 mL, sat), brine (3×200 mL), and H.sub.2O (1×125 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by flash chromatography using a gradient of 0-10% EtOAc in PE as mobile phase to give the title compound (6.50 g, 66.4%) as a pale yellow gum. .sup.1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, 3H), 1.13 (m, 3H), 1.39 (d, 9H), 1.49 (d, 1H), 1.64 (t, 2H), 1.96 (d, 2H), 3.34 (m, 1H), 4.42 (dd, 1H). (Major isomer).

    Step C. Intermediate 133: 4-(tert-Butoxycarbonyl)-4-methylcyclohexyl 4-nitrobenzoate

    [2074] ##STR00221##

    [2075] DIAD (13.61 mL, 69.99 mmol) was added dropwise to Intermediate 132 (12 g, 56 mmol), 4-nitrobenzoic acid (12.17 g, 72.79 mmol) and triphenylphosphine (18.36 g, 69.99 mmol) in THF (50 mL) at 50° C. The resulting solution was stirred at 60° C. for 16 h. The reaction mixture was concentrated and diluted with EtOAc (125 mL), and washed sequentially with H.sub.2O (2×150 mL), and brine (3×150 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product. The crude product was purified by flash chromatography using a gradient of 5-10% EtOAc in PE as mobile phase to give the title compound (13.0 g, 63.9%) as a yellow solid.

    Step D. Intermediate 134: (1r,4r)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl 4-nitrobenzoate

    [2076] ##STR00222##

    [2077] Intermediate 133 (21 g, 57.8 mmol) was purified by preparative chiral-HPLC on a Chiralpak IB column, isocratic elution with 2% IPA in hexane (modified with 0.1% DEA) as eluent. The fractions containing the desired compound were evaporated to dryness to afford (1s,4s)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl 4-nitrobenzoate (2.30 g, 11.0%) as a yellow oil and Intermediate 134 (11.70 g, 55.7%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d6) δ 1.17 (s, 3H), 1.44 (s, 9H), 1.52-1.64 (m, 2H), 1.67-1.95 (m, 6H), 5.14 (s, 1H), 8.20-8.27 (m, 2H), 8.34-8.40 (m, 2H).

    Step E. Intermediate 135: tert-Butyl (1r,4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate

    [2078] ##STR00223##

    [2079] LiOH (2.313 g, 96.59 mmol) was added in one portion to Intermediate 134 (11.7 g, 32.20 mmol) in THF (80 mL) and H.sub.2O (40.0 mL) at 20° C. over a period of 1 min under air. The resulting suspension was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with brine (2×100 mL, sat), H.sub.2O (1×100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (6.60 g, 96%) as a yellow oil. .sup.1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 3H), 1.38 (s, 9H), 1.47 (dd, 6H), 1.62 (q, 2H), 3.57 (d, 1H), 4.38 (d, 1H).

    Step F. Intermediate 136: Benzyl 5-(((1s,4s)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

    [2080] ##STR00224##

    [2081] DIAD (8.98 mL, 46.20 mmol) was added to Intermediate 135 (6.6 g, 30.8 mmol), Intermediate 117 (8.51 g, 30.80 mmol) and triphenylphosphane (12.12 g, 46.20 mmol) in THF (150 mL) at 60° C. over a period of 5 min under nitrogen. The resulting solution was stirred at 60° C. for 15 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with H.sub.2O (2×150 mL) and brine (2×150 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by flash chromatography using a gradient of 5-10% EtOAc in PE as mobile phase to give the title compound (12.00 g, 82%) as a yellow solid. MS (ESI): m/z [M+Na].sup.+495.

    Step G. Intermediate 137: Benzyl (1R,2R,3S,4S)-3-(5-(((1s,4R)-4-(tert-butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2082] ##STR00225##

    [2083] DIPEA (6.17 mL, 35.30 mmol) was added to Intermediate 73 (2.7 g, 7.06 mmol), Intermediate 139 (3.1 g, 11.08 mmol) and HATU (8.05 g, 21.18 mmol) in DMF (150 mL) at 20° C. The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with H.sub.2O (3×100 mL), and brine (3×100 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product. The crude product was purified by flash chromatography using a gradient of 21-25% EtOAc in PE as mobile phase to give the title compound (3.50 g, 82%) as a yellow solid. MS (ESI): m/z [M+H].sup.+ 608.

    Step H. (1S,2R,3S,4R)-3-(5-(((1s,4R)-4-(tert-Butoxycarbonyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2084] Intermediate 137 (3.5 g, 5.76 mmol) and Pd-C (0.306 g, 0.29 mmol) in MeOH (150 mL) was stirred under an atmosphere of hydrogen at 1.5 atm and 20° C. for 1 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound (2.99 g, 100%) as a white solid. MS (ESI): m/z [M+H].sup.+ 520.

    Intermediate 138: tert-Butyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2085] ##STR00226##

    [2086] DIEA (2.52 mL, 14.4 mmol) was added dropwise to Intermediate 130 (2.50 g, 4.81 mmol), (1-methylcyclobutyl)methanamine hydrochloride (0.653 g, 4.81 mmol) and HATU (9.15 g, 24.1 mmol) in DMF (150 mL) cooled to 0° C. in 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (1.0 L) and sequentially washed with saturated NaHCO.sub.3 (250 mL), saturated brine (3×300 mL), and H.sub.2O (2×300 mL). The organic layers were combined and dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in petroleum ether. Pure fractions were pooled and evaporated to dryness to afford the crude title compound, 2.6 g, as a pale yellow solid. The crude product was further purified by C18-flash chromatography, elution gradient 0 to 85% MeCN in H.sub.2O. Fractions containing product were evaporated to dryness to afford 2.1 g of the title compound as a white solid. The material was further purified by preparative chiral SFC (CHIRALPAK IF 20×250 mm ID, 5 μm, 86445S90IF0SCJ-RA002 column) using 70% CO.sub.2 and 30% MeOH as mobile phase. Fractions containing the desired compound were pooled and evaporated to dryness to afford the title compound (1.50 g, 51.9%) as a white solid; MS (ESI): m/z, [M+H].sup.+=601.4.

    Intermediate 139: Benzyl (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

    [2087] ##STR00227##

    Step A. Intermediate 140: (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [2088] ##STR00228##

    [2089] MeOH (18.19 mL, 449.56 mmol) was added dropwise to (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione (24.6 g, 149.85 mmol) and quinine (48.6 g, 149.85 mmol) in toluene (150 mL) and CCl.sub.4 (150 mL) cooled to −55° C. over a period of 1 min under nitrogen. The resulting suspension was stirred at −55° C. for 100 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (1200 mL), and washed sequentially with 2 M HCl (3×500 mL), sat brine (1×500 mL), and H.sub.2O (1×500 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the desired product (25.7 g, 87%) as a white solid.

    Step B. Intermediate 141: Methyl (1R,2R,3S,4S)-3-(azidocarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2090] ##STR00229##

    [2091] Ethyl carbonochloridate (17.06 g, 157.18 mmol) was added dropwise to Intermediate 140 (25.7 g, 130.99 mmol) and TEA (19.88 g, 196.48 mmol) in acetone (450 mL) at 0° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 0° C. for 2 h. A solution of sodium azide (12.77 g, 196.48 mmol) in H.sub.2O (150 mL) was added dropwise to the stirred suspension of above at 0° C., over a period of 15 min under nitrogen. The resulting solution was stirred at 0° C. for 2 h followed by 14 h at 20° C. The reaction mixture was diluted with toluene (500 mL), and washed sequentially with brine (2×250 mL, sat), NaHCO.sub.3 (2×250 mL, sat), and H.sub.2O (2×200 mL). The organic layer was dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the solution was used in next step without any purification.

    Step C. Intermediate 142: Methyl (1R,2R,3S,4S)-3-isocyanatobicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2092] ##STR00230##

    [2093] Intermediate 141 (29 g, 131.1 mmol) was added to toluene (500 mL) at 25° C. over a period of 1 min under air. The resulting solution was stirred at 100° C. for 1 h. The solvent was removed under reduced pressure to afford the title compound (25.3 g, 100%) as a yellow oil which was used in next step without further purification.

    Step D. Intermediate 143: Methyl (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

    [2094] ##STR00231##

    [2095] A solution of hydrogen chloride (26.4 g, 724.63 mmol) in H.sub.2O (100 mL) was added dropwise to a stirred solution of Intermediate 142 (28 g, 144.93 mmol) in THF (250 mL) at 0° C., over a period of 5 min under air. The resulting solution was stirred at 25° C. for 14 h. The solvent was removed under reduced pressure to afford the title compound (30.0 g, 102%) as a beige oil, which solidified on standing.

    Step E. Intermediate 144: Methyl (1R,2R,3S,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2096] ##STR00232##

    [2097] TEA (54.8 mL, 393.3 mmol) was added dropwise to Boc.sub.2O (45.7 mL, 196.65 mmol), and Intermediate 143 (26.7 g, 131.1 mmol) in THF (400 mL) at 0° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (500 mL), and washed sequentially with brine (1×250 mL, sat), H.sub.2O (1×200 mL), and NaHCO.sub.3 (1×250 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated and the residue was crystallized from EtOAc/Et.sub.2O to afford crude title compound (42 g) as a white solid which was used without further purification.

    Step F. Intermediate 145: (1R,2R,3S,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [2098] ##STR00233##

    [2099] LiOH (9.41 g, 392.78 mmol) in H.sub.2O (180 mL) was added dropwise to Intermediate 144 (42.0 g, 157.11 mmol) in MeOH (360 mL) at 20° C. over a period of 10 min under air. The resulting suspension was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure. The reaction mixture was adjusted to pH 2 by 0.5 M citric acid. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with brine (1×150 mL, sat), sat NaHCO.sub.3 (1×150 mL), and H.sub.2O (1×150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford pure product. The crude product was purified by crystallization from EtOAc/PE to afford the title compound (21.00 g, 52.8%) as a white solid.

    Step G. Intermediate 146: Benzyl (1R,2R,3S,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2100] ##STR00234##

    [2101] TEA (9.63 mL, 69.1 mmol) was added dropwise to Intermediate 145 (5.0 g, 19.7 mmol), phenylmethanol (3.20 g, 29.61 mmol), EDC (8.33 g, 43.43 mmol) and HOBt (6.65 g, 43.43 mmol) in DMF (100 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h. The reaction mixture was poured into sat NaHCO.sub.3 (350 mL), extracted with EtOAc (3×150 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford pale yellow oil. The crude product was purified by flash chromatography using a gradient of 0-5% EtOAc in PE as mobile phase to give the title compound (4.50 g, 66%) as a colorless gum. MS (ESI): m/z [M+Na].sup.+ 366.

    Step H. Benzyl (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride

    [2102] Intermediate 146 (3.8 g, 11.07 mmol) was added dropwise to HCl (1.34 mL, 44 mmol) in 1,4-dioxane (100 mL) at 0° C. over a period of 1 min under air. The resulting solution was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure. The crude product was purified by crystallization from EtOAc/PE to afford the title compound (3.10 g, 100%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 1.42-1.52 (m, 1H), 2.03-2.10 (m, 1H), 2.63-2.71 (dd, 1H), 2.95-3.01 (d, 1H), 3.04-3.09 (s, 1H), 3.21-3.26 (s, 1H), 5.04-5.11 (d, 1H), 5.19-5.26 (d, 1H), 6.19-6.27 (dd, 1H), 6.29-6.36 (dd, 1H), 7.29-7.47 (m, 5H), 8.21-8.26 (s, 3H). MS (ESI): m/z [M+H].sup.+ 244.

    Intermediate 147: 2-(Difluoromethoxy)-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2103] ##STR00235##

    Step A. Intermediate 148: Methyl 5-bromo-4-fluoro-2-hydroxybenzoate

    [2104] ##STR00236##

    [2105] Intermediate 112 (3 g, 12.77 mmol) was added portion wise to HCl (7.29 mL, 240 mmol) in MeOH (60 mL) at 20° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 78° C. for 48 h. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography using a gradient of 0-7% EtOAc in PE as mobile phase to give the title compound (1.50 g, 47.2%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d6) δ 3.87 (s, 3H), 7.05 (d, 1H), 7.99 (d, 1H), 10.81 (s, 1H).

    Step B. Intermediate 149: Methyl 5-bromo-2-(difluoromethoxy)-4-fluorobenzoate

    [2106] ##STR00237##

    [2107] (Bromodifluoromethyl)trimethylsilane (3.26 g, 16.06 mmol) in DCM (12 mL) was added slowly to Intermediate 148 (1 g, 4.02 mmol) and KOH (2.253 g, 40.15 mmol) in H.sub.2O (12 mL) at 0° C. over a period of 1 min under nitrogen. The resulting suspension was stirred at 0° C. for 2 h. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with NaHCO.sub.3 (1×100 mL, sat), brine (1×100 mL, sat), and H.sub.2O (1×100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the desired product (1.201 g, 100%) as a pale yellow residue. The product was used in the next step directly without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 7.40 (t, 1H), 7.52 (d, 1H), 8.18 (d, 1H).

    Step C. Intermediate 150: Methyl 2-(difluoromethoxy)-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

    [2108] ##STR00238##

    [2109] Potassium acetate (0.985 g, 10.03 mmol) was added slowly to Intermediate 149 (1.2 g, 4.01 mmol)), PdCl.sub.2(dppf)-DCM adduct (0.328 g, 0.40 mmol) and B.sub.2Pin.sub.2 (2.038 g, 8.03 mmol) in 1,4-dioxane (30 mL) at 20° C. over a period of 1 min under nitrogen. The resulting suspension was stirred at 60° C. for 14 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (3×75 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by preparative TLC (EtOAc/PE1/4), to afford the title compound (0.587 g, 42.3%) as a pale yellow gum.

    Step D. Intermediate 151: Methyl 2-(difluoromethoxy)-4-fluoro-5-hydroxybenzoate

    [2110] ##STR00239##

    [2111] NaBO.sub.3×4 H.sub.2O (907 mg, 5.89 mmol) was added slowly to Intermediate 150 (510 mg, 1.47 mmol) in THF (20 mL) at 0° C. over a period of 1 min under air. The resulting solution was stirred at 20° C. for 12 h. A solution of ammonium chloride (788 mg, 14.74 mmol) in H.sub.2O (10 mL) was added slowly to the stirred solution obtained above at 0° C., over a period of 1 min under air. The resulting solution was stirred at 20° C. for 4 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (3×75 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc/PE 1/3), to afford the title compound (180 mg, 51.7%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 7.01 (t, 1H), 7.22 (d, 1H), 7.43 (d, 1H), 10.47 (s, 1H).

    Step E. Intermediate 152: Methyl 2-(difluoromethoxy)-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [2112] ##STR00240##

    [2113] A solution of DBAD (280 mg, 1.22 mmol) in toluene (3 mL) was added dropwise to a stirred solution of triphenylphosphane (287 mg, 1.10 mmol), Intermediate 151 (115 mg, 0.49 mmol) and Intermediate 11 (153 mg, 0.51 mmol) in DCM (3 mL) cooled to 10° C., over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with brine (1×150 mL, sat), NaHCO.sub.3 (1×150 mL, sat), and H.sub.2O (1×150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. which was purified by preparative TLC (EtOAc/PE 1/4), to afford the title compound (200 mg, 80%) as a pale yellow solid. MS (ESI): m/z [M+Na].sup.+539.

    Step F. 2-(Difluoromethoxy)-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2114] A solution of LiOH (46.4 mg, 1.94 mmol) in H.sub.2O (8 mL) was added dropwise to a stirred solution of Intermediate 152 (200 mg, 0.39 mmol) in THF (10 mL) cooled to 0° C., over a period of 1 min under nitrogen. The resulting solution was stirred at ambient temperature for 2 h. The reaction mixture was adjusted to pH=3 by 0.1 M HCl, diluted with EtOAc (200 mL) and washed sequentially with NH.sub.4Cl (1×150 mL, sat), H.sub.2O (1×200). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (195 mg, 100%) as a pale yellow solid. MS (ESI): m/z [M+H].sup.+ 503.

    Intermediate 153: (1R,2S,3R,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2115] ##STR00241##

    Step A. Intermediate 154: tert-Butyl ((1R,2R,3S,4S)-3-((3-((trifluoromethyl)thio)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamate

    [2116] ##STR00242##

    [2117] DIPEA (5.52 mL, 31.6 mmol) was added dropwise to Intermediate 19 (4.0 g, 15.8 mmol), 3-((trifluoromethyl)thio)aniline (3.05 g, 15.79 mmol) and T3P (30.1 g, 47.38 mmol) in butyl acetate (100 mL) at 20° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 120° C. for 5 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with brine (1×200 mL, sat), NaHCO.sub.3 (1×100 mL, sat), and H.sub.2O (1×100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc/PE 1/1), to afford the title compound (3.20 g, 47.3%) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 1.12 (s, 9H), 1.40 (d, 1H), 2.29 (d, 1H), 2.60 (d, 2H), 2.86 (s, 1H), 3.82 (1H, t), 6.21-6.31 (m, 2H), 6.64 d, (1H), 7.34 (d, 1H), 7.42 (t, 1H), 7.68 (m, 1H), 8.12 (s, 1H), 10.10 (s, 1H).

    Step B. Intermediate 155: tert-Butyl ((1S,2R,3S,4R)-3-((3-((trifluoromethyl)thio)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

    [2118] ##STR00243##

    [2119] Intermediate 154 (1.8 g, 4.20 mmol) and Pd-C (2.235 g, 2.10 mmol) in MeOH (50 mL) was stirred under an atmosphere of hydrogen at 1.5 atm and 30° C. for 14 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound (1.808 g, 100%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07-1.12 (s, 9H), 1.12-1.20 (m, 3H), 1.32-1.39 (m, 1H), 1.42-1.47 (m, 1H), 1.50-1.55 (m, 1H), 2.02 (s, 1H), 2.12 (d, 1H), 2.31-2.36 (m, 1H), 3.86 (t, 1H), 6.62 (d, 1H), 7.32 (d, 1H), 7.42 (t, 1H), 7.66 (d, 1H), 8.08-8.14 (m, 1H), 10.04 (s, 1H). MS (ESI): m/z [M+Na].sup.+ 453.

    Step C. Intermediate 156: tert-Butyl ((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

    [2120] ##STR00244##

    [2121] Sodium periodate (1.789 g, 8.36 mmol) was added portion wise to Intermediate 155 (1.8 g, 4.18 mmol) and ruthenium(III) chloride (0.087 g, 0.42 mmol) in MeCN (15 mL) and H.sub.2O (5.00 mL) at 20° C. over a period of 1 min under air. The resulting suspension was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with brine (3×25 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by C18 flash chromatography using a gradient of 0-90% H.sub.2O in MeCN as mobile phase to give the title compound (1.93 g, 100%) as a yellow solid.

    Step D. (1R,2S,3R,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2122] TFA (0.045 mL, 0.58 mmol) was added dropwise to Intermediate 156 (180 mg, 0.39 mmol) in DCM (25 mL) at 20° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with (1×125 mL, sat), NaHCO.sub.3 (1×125 mL, sat), and H.sub.2O (1×125 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to the title compound (141 mg, 100%). MS (ESI): m/z [M+H].sup.+ 363.

    Intermediate 157: (1R,2S,3R,4S)-3-(4′-(Ethoxycarbonyl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2123] ##STR00245##

    Step A. Intermediate 158: 3-Benzyl 4′-ethyl 6-fluoro-4-methoxy-[1,1′-biphenyl]-3,4′-dicarboxylate

    [2124] ##STR00246##

    [2125] PdCl.sub.2(dppf)-DCM adduct (1.743 g, 2.13 mmol) was added to Intermediate 115 (3.62 g, 10.67 mmol), (4-(ethoxycarbonyl)phenyl)boronic acid (2.485 g, 12.81 mmol) and K.sub.2CO.sub.3 (3.69 g, 26.68 mmol) in 1,4-dioxane (30 mL) and H.sub.2O (7.50 mL). The resulting mixture was stirred at 70° C. for 1.5 h under nitrogen. The reaction mixture was diluted with EtOAc (1 L), and washed sequentially with brine (3×200 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product which was purified by flash chromatography using a gradient of 0-30% EtOAc in PE as mobile phase to give the title compound (4.20 g, 96%) as a brown oil which solidified on standing. .sup.1H NMR (300 MHz, DMSO-d6) δ 1.33 (t, 3H), 3.91 (s, 3H), 4.34 (q, 2H), 5.34 (s, 2H), 7.26 (d, 1H), 7.32-7.50 (m, 5H), 7.68 (d, 2H), 7.92 (d, 1H), 8.04 (d, J=8.4 Hz, 2H). MS (ESI): m/z [M+H].sup.+ 409.

    Step B. Intermediate 159: 4′-(Ethoxycarbonyl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxylic acid

    [2126] ##STR00247##

    [2127] Pd-C (10 mg, 0.09 mmol) was added to Intermediate 158 (4.1 g, 10.04 mmol) in MeOH (150 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure and the product (0.9 g, 28%) was used in the next step without further purification. MS (ESI): m/z [M+H].sup.+ 319.

    Step C. Intermediate 160: Benzyl (1S,2S,3R,4R)-3-(4′-(ethoxycarbonyl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [2128] ##STR00248##

    [2129] HATU (1.22 g, 3.20 mmol) was added portion wise to Intermediate 109 (0.715 mg, 2.94 mmol), Intermediate 159 (0.850 g, 2.67 mmol) and DIPEA (0.518 g, 4.01 mmol) in DMF (10 mL) at Rt. The resulting solution was stirred at 60° C. for 1.5 h. The reaction mixture was extracted with EtOAc (3×75 mL), the organic layer was washed with brine (2×100 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to the title compound (3.30 g) as a brown oil. The crude product was used in the next step directly without further purification. MS (ESI): m/z [M+H].sup.+ 544.

    Step D. (1R,2S,3R,4S)-3-(4′-(Ethoxycarbonyl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2130] Pd-C (0.626 g, 5.89 mmol) was added to Intermediate 160 (3.2 g, 5.89 mmol) in MeOH (150 mL).The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was filtered through Celite®. The solvent was removed under reduced pressure to afford the title compound in mixture with the corresponding methyl ester due to some transesterification from the solvent.The crude product was used in the next step directly without purification. MS (ESI): m/z [M+H].sup.+ 456.3 (ethyl ester) and MS (ESI): m/z [M+H].sup.+ 442.3 (methyl ester).

    Intermediate 161: 2-Amino-3,5-dimethyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride

    [2131] ##STR00249##

    Step A. Intermediate 162: tert-Butyl (2,4-dimethyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamate

    [2132] ##STR00250##

    [2133] 2-((tert-Butoxycarbonyl)amino)-3,5-dimethylbenzoic acid (106 mg, 0.4 mmol) and HATU (304 mg, 0.80 mmol) was diluted in DCM (1.79 mL). DIPEA (210 μL, 1.20 mmol) and (1-methylcyclobutyl)methanamine hydrochloride (65.1 mg, 0.48 mmol) was added and the reaction was stirred overnight. DCM (1.79 mL) and NaHCO.sub.3 (aq) was added and the phases was separated and the organic phase was evaporated. The crude product which was purified by flash chromatography using a gradient of 5-50% EtOAc in heptane as mobile phase to give the title compound (100 mg, 72.2%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.17 (s, 3H), 1.47 (s, 9H), 1.69-1.77 (m, 2H), 1.85-1.96 (m, 4H), 2.27 (s, 3H), 2.31 (s, 3H), 3.41 (d, 2H), 6.16 (s, 1H), 7.07 (s, 1H), 7.12 (s, 1H), 7.36 (s, 1H). MS (ESI): m/z [M+H].sup.+ 347.4.

    Step B. 2-Amino-3,5-dimethyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride Intermediate 162

    [2134] (100 mg, 0.29 mmol) was diluted in dioxane (1 mL). 4 M HCl in dioxane (1 mL, 4.00 mmol) was added and the reaction was stirred at ambient temperature for 2 h, an additional 4 M HCl in Dioxane (1 mL, 4.00 mmol) was added and the stirring was continued for 2 h. The solvent and excess HCl was evaporated and the crude product was used as such in the next step. MS (ESI): m/z [M+H].sup.+ 247.3.

    Intermediate 163: 2-Amino-4,5-dimethyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride

    [2135] ##STR00251##

    Step A. Intermediate 164: tert-Butyl (4,5-dimethyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamate

    [2136] ##STR00252##

    [2137] 2-((tert-Butoxycarbonyl)amino)-4,5-dimethylbenzoic acid (106 mg, 0.4 mmol) and HATU (304 mg, 0.80 mmol) was diluted in DCM (1790 μL). DIPEA (210 μL, 1.20 mmol and (1-methylcyclobutyl)methanamine hydrochloride (65.1 mg, 0.48 mmol) was added and the reaction was stirred overnight. Diluted with DCM and NaHCO.sub.3 (aq) separated the phases and evaporated the organic phase. The crude product was purified by flash chromatography using a gradient of 5-50% EtOAc in heptane as mobile phase to give the title compound (102 mg, 73.6%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.20 (s, 3H), 1.51 (s, 9H), 1.73-1.8 (m, 2H), 1.93 (ddt, 4H), 2.23 (s, 3H), 2.29 (s, 3H), 3.43 (d, 2H), 6.09 (s, 1H), 7.13 (s, 1H), 8.17 (s, 1H), 10.06 (s, 1H). MS (ESI): m/z [M+H].sup.+ 347.4.

    Step B. 2-Amino-4,5-dimethyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride Intermediate 164

    [2138] (102 mg, 0.29 mmol) was diluted in dioxane (1 mL). 4 M HCl in Dioxane (1 mL, 4.00 mmol) was added and the reaction was stirred at ambient temperature for 4 h, evaporated with a stream of N.sub.2. The solvent and excess HCl was evaporated and the crude product was used as such in the next step. MS (ESI): m/z [M+H].sup.+ 247.3.

    Intermediate 165: Ethyl (1s,4s)-4-(5-carbamoyl-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2139] ##STR00253##

    [2140] EDC (1.239 g, 6.46 mmol) was added slowly to Intermediate 111 (1 g, 2.94 mmol), NH.sub.4Cl (1.572 g, 29.38 mmol), HOBt (0.990 g, 6.46 mmol) and TEA (8.19 mL, 58.76 mmol) in DMF (20 mL) at 20° C. The resulting solution was stirred at 60° C. for 14 h. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with brine (2×150 mL, sat), NaHCO.sub.3 (1×150 mL, sat), and H.sub.2O (1×150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (0.900 g, 90%) as a yellow oil which solidified on standing. MS (ESI): m/z [M+H].sup.+ 340.2.

    Intermediate 166: 2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl trifluoromethanesulfonate

    [2141] ##STR00254##

    Step A. Intermediate 167: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-hydroxycyclohex-1-ene-1-carboxamide

    [2142] ##STR00255##

    [2143] DMAP (0.108 g, 0.88 mmol) was added to 4-fluoro-3-(trifluoromethyl)aniline (1.315 g, 7.34 mmol) and ethyl 2-oxocyclohexane-1-carboxylate (0.5 g, 2.94 mmol) in toluene (20 mL) at 20° C. The resulting solution was stirred at 130° C. for 15 h. The reaction mixture was poured into 2 M HCl (200 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product as a yellow oil. The residue was purified by preparative TLC (EtOAc/PE 1/2), to afford the title compound (0.500 g, 56.1%) as a yellow gum. MS (ESI): m/z [M+H].sup.+ 304.1.

    Step B. 2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl trifluoromethanesulfonate

    [2144] A solution of trifluoromethanesulfonic anhydride (4.23 g, 15.00 mmol) in DCM (10 mL) was added slowly to a stirred solution of Intermediate 167 (3.5 g, 11.54 mmol) and TEA (5.63 mL, 40.39 mmol) in DCM (10 mL) cooled to −78° C. under nitrogen. The resulting solution was stirred at −78° C. for 30 min. The temperature was increased to Rt and stirred overnight. The reaction mixture was poured into brine (200 mL, sat), extracted with EtOAc (3×75 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product as a yellow oil. The crude product which was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as mobile phase to give the title compound (1.500 g, 29.9%) as an orange oil which solidified on standing. .sup.1HNMR (300 MHz, CDCl.sub.3): δ 1.68-1.91 (m, 4H), 2.54 (m, 4H), 7.19 (d, 1H), 7.76 (dd, 1H), 7.82-7.86 (m, 1H). MS (ESI): m/z [M+H].sup.+ 436.3.

    Intermediate 168: 2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl trifluoromethanesulfonate

    [2145] ##STR00256##

    Step A. Intermediate 169: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-hydroxycyclopent-1-ene-1-carboxamide

    [2146] ##STR00257##

    [2147] DMAP (0.469 g, 3.84 mmol) was added to 4-fluoro-3-(trifluoromethyl)aniline (5.73 g, 32.01 mmol) and ethyl 2-oxocyclopentane-1-carboxylate (2 g, 12.81 mmol) in toluene (25 mL) under nitrogen. The resulting solution was stirred at 130° C. for 18 h. The reaction mixture was poured into 2 M HCl (200 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (3.50 g, 94%) as a yellow gum. The product was used in the next step directly without further purification. MS (ESI): m/z [M+H].sup.+ 290.1.

    Step B. 2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl trifluoromethanesulfonate

    [2148] A solution of trifluoromethanesulfonic anhydride (4.10 g, 14.52 mmol) in DCM (10 mL) was added slowly to a stirred solution of Intermediate 169 (3.5 g, 12.10 mmol) and TEA (5.06 mL, 36.30 mmol) in DCM (20 mL) cooled to −78° C. under nitrogen. The resulting solution was stirred at −78° C. for 30 min. The temperature was increased to room temperature. The reaction mixture was poured into brine (200 mL, sat), extracted with EtOAc (3×75 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a yellow oil. The crude product which was purified by flash chromatography using a gradient of 0-20% EtOAc in heptane as mobile phase to give the title compound (1.20 g, 24%) as a pale yellow oil which solidified on standing. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 2.08-2.16 (m, 2H), 2.83 (m, 2H), 2.90 (m, 2H), 7.20 (t, 1H), 7.70-7.76 (m, 1H), 7.78 (s, 1H), 7.87 (dd, 1H). MS (ESI): m/z [M+H].sup.+ 422.0.

    Intermediate 170: 3-Amino-N-((1-methylcyclobutyl)methyl)-2-naphthamide 2,2,2-trifluoroacetate

    [2149] ##STR00258##

    Step A. Intermediate 171: tert-Butyl (3-(((1-methylcyclobutyl)methyl)carbamoyl)naphthalen-2-yl)carbamate

    [2150] ##STR00259##

    [2151] DIPEA (1.277 mL, 7.31 mmol) was added dropwise to 3-((tert-butoxycarbonyl)amino)-2-naphthoic acid (0.70 g, 2.44 mmol), (1-methylcyclobutyl)methanamine hydrochloride (0.330 g, 2.44 mmol) and HATU (2.78 g, 7.31 mmol) in DMF (20 mL) at 0° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (1×100 mL, sat), NH.sub.4Cl (1×100 mL, sat) and brine (1×100 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc/PE 1/3), to afford the title compound (0.350 g, 39%) as a white solid. MS (ESI): m/z [M+H].sup.+ 369.3.

    Step B. 3-Amino-N-((1-methylcyclobutyl)methyl)-2-naphthamide 2,2,2-trifluoroacetate

    [2152] TFA (0.732 mL, 9.50 mmol) was added dropwise to Intermediate 171 (0.35 g, 0.95 mmol) in DCM (20 mL) at 10° C., over a period of 1 second under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure. The crude product was purified by crystallization from EtOAc/EtOH to afford the title compound (0.385 g) as a pale yellow solid. MS (ESI): m/z [M+H].sup.+ 269.3.

    Intermediate 172: 2-Amino-5-methyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride

    [2153] ##STR00260##

    Step A. Intermediate 173: tert-Butyl (4-methyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamate

    [2154] ##STR00261##

    [2155] 2-((tert-Butoxycarbonyl)amino)-5-methylbenzoic acid (300 mg, 1.19 mmol) was added to (1-methylcyclobutyl)methanamine (178 mg, 1.79 mmol), EDC (343 mg, 1.79 mmol), HOBt (242 mg, 1.79 mmol) and DIPEA (463 mg, 3.58 mmol) in DMF (10 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was concentrated, diluted with EtOAc (150 mL) and washed sequentially with NaHCO.sub.3 (1×150 mL, sat), H.sub.2O (1×200 mL), and brine (1×200 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The residue was purified by preparative TLC (EtOAc/PE=1/3), to afford the title compound (260 mg, 65%) as a yellow solid. MS (ESI): m/z [M+H].sup.+ 333.3.

    Step B. 2-Amino-5-methyl-N-((1-methylcyclobutyl)methyl)benzamide hydrochloride

    [2156] Hydrogen chloride (384 mg, 10.53 mmol) was added to Intermediate 173 (350 mg, 1.05 mmol) in MeOH (6 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The solvent was removed by distillation under vacuum and the residue was purified by preparative TLC (PE/EtOAc 3/1), to afford the title compound (210 mg, 74%) as a yellow solid. MS (ESI): m/z [M+H].sup.+ 233.3.

    Intermediate 174: 2-Amino-N-((1-methylcyclobutyl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride

    [2157] ##STR00262##

    Step A. Intermediate 175: tert-Butyl (3-(((1-methylcyclobutyl)methyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate

    [2158] ##STR00263##

    [2159] 2-((tert-Butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (300 mg, 1.08 mmol) was added to (1-methylcyclobutyl)methanamine (160 mg, 1.62 mmol), EDC (310 mg, 1.62 mmol, HOBt (219 mg, 1.62 mmol) and DIPEA (418 mg, 3.23 mmol) in DMF (10 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with NaHCO.sub.3 (1×200 mL, sat), H.sub.2O (1×200 mL) and brine (1×200 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by preparative TLC (PE/EtOAc 3/1), to afford the title compound (280 mg, 72%) as a yellow solid. MS (ESI): m/z [M+H].sup.+ 360.4.

    Step B. 2-Amino-N-((1-methylcyclobutyl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride

    [2160] Hydrogen chloride (203 mg, 5.56 mmol) was added to Intermediate 175 (200 mg, 0.56 mmol) in MeOH (6 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with H.sub.2O (1×200 mL), brine (1×200 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc/PE 1/1), to afford the title compound (130 mg, 79%) as a yellow solid. MS (ESI): m/z [M+H].sup.+ 260.3.

    Intermediate 176: rac-(1R,2R,3S,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

    [2161] ##STR00264##

    Step A: Intermediate 177: rac-Methyl (1R,2R,3S,4S)-3-(((benzyloxy)carbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylate

    [2162] ##STR00265##

    [2163] DIPEA (1.17 mL, 6.74 mmol) was added to a solution of rac-(1R,2R,3S,4S)-3-(methoxycarbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (900 mg, 4.50 mmol) in toluene and DPPA (1.16 mL, 5.40 mmol) was added dropwise, then the reaction mixture was stirred at rt for 1 hr. The reaction mixture was stirred at 90° C. for 10 min, then benzyl alcohol (0.56 mL, 5.39 mmol) was added and the reaction mixture was stirred for 1.5 hr. The reaction mixture was diluted with EtOAc and washed with H.sub.2O, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-35% EtOAc in hexane as mobile phase to give the title compound (1.33 g, 97%). MS (ESI) m/z 306.1 [M+H].sup.+

    Step B: Intermediate 178: rac-(1R,2R,3S,4S)-3-(((Benzyloxy)carbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

    [2164] ##STR00266##

    [2165] Intermediate 177 was dissolved in THF (11 mL) and H.sub.2O (5.5 mL), then the mixture was cooled to 0° C. LiOH was added and the reaction mixture was stirred at 0° C. for 1 h and rt for 3 hr. 1 M aq HCl was added to the reaction mixture until pH<2, then the reaction mixture was extracted with CHCl.sub.3 twice and the combined organic layer was concentrated in vacuo to give titled compound which was used without further purification.

    Step C: Intermediate 179: rac-Benzyl ((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [2166] ##STR00267##

    [2167] HATU (1.82 g, 4.79 mmol) was added to a solution of Intermediate 178 (1.27 g, 4.35 mmol), (1-methylcyclobutyl)methylamine hydrochloride (708 mg, 5.220 mmol) and DIPEA (1.69 g, 13.05 mmol) in DMF (11 mL) and the reaction mixture was stirred at rt for 1 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc/Hexane (2/1), then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the title compound (671 mg, 41%). MS (ESI) m/z 373.1 [M+H].sup.+

    Step D: rac-(1R,2R,3S,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

    [2168] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 100 mg) was added to a solution of Intermediate 179 (661 mg, 1.77 mmol) in MeOH (8.9 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 4 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®. The filtrate was concentrated in vacuo to give titled compound (524 mg, 100%). MS (ESI) m/z 239.2 [M+H].sup.+

    Intermediate 180: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2169] ##STR00268##

    Step A: Intermediate 181: rac-tert-Butyl ((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [2170] ##STR00269##

    [2171] EDC (121 mg, 0.63 mmol) and HOAt (86 mg, 0.63 mmol) were added to a solution of rac-(1R,2S,3R,4S)-3-((tert-butoxycarbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (125 mg, 0.486 mmol), (1-methylcyclobutyl)methylamine hydrochloride (86 mg, 0.634 mmol) and DIPEA (160 mg, 1.20 mmol) in DMF (5 mL) and the reaction mixture was stirred at rt for 12 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo to give the title compound (169 mg, 100%). MS (ESI) m/z 339.1 [M+H].sup.+

    Step B: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2172] ##STR00270##

    [2173] A solution of Intermediate 181 in 4 M HCl in EtOH (2 mL) was stirred at rt for 12 h and the reaction mixture was concentrated in vacuo to give titled compound (144 mg, 100%). MS (ESI) m/z 239.3 [M+H].sup.+

    Intermediate 182: rac-tert-Butyl (1R,2R,3S,4S)-2-amino-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

    [2174] ##STR00271##

    [2175] The titled compound was prepared analogous to Intermediate 176, using rac-(1R,2R,3S,4S)-7-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid instead of rac-(1R,2R,3S,4S)-3-methoxycarbonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid. MS (ESI) m/z 338.2 [M+H].sup.+

    Intermediate 183: rac-(1R,2S)-2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclobutane-1-carboxamide

    [2176] ##STR00272##

    [2177] The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid instead of Intermediate 178 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 184: rac-(1R,2S)-2-Amino-N-neopentylcyclobutane-1-carboxamide

    [2178] ##STR00273##

    [2179] The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid instead of Intermediate 178 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 185: rac-(1R,2S)-2-Amino-N-(4-fluoro-3-(pentafluoro-46-sulfaneyl)phenyl)cyclobutane-1-carboxamide

    [2180] ##STR00274##

    [2181] The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid instead of Intermediate 178 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 335.0 [M+H].sup.+

    Intermediate 186: rac-(1R,2S)-2-Amino-N-((1-methylcyclobutyl)methyl)cyclobutane-1-carboxamide

    [2182] ##STR00275##

    [2183] The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S)-2-(((benzyloxy)carbonyl)amino)cyclobutane-1-carboxylic acid instead of Intermediate 178.

    Intermediate 187: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.2]oct-5-ene-2-carboxamide hydrochloride

    [2184] ##STR00276##

    Step A: Intermediate 188: rac-tert-Butyl ((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamate

    [2185] ##STR00277##

    [2186] HATU (1.91 g, 5.02 mmol) was added to a solution of rac-(1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid (Compound 1) (1.22 g, 4.56 mmol), (1-methylcyclobutyl)methylamine hydrochloride (681 mg, 5.02 mmol) and DIPEA (2.37 g, 13.69 mmol) in DMF (11 mL) and the reaction mixture was stirred at rt for 10 min. H.sub.2O was added to the reaction mixture and the reaction mixture was stirred vigorously. The precipitate was collected by filtration and the crude material was dried under air to give titled compound (1.56 g, 98%). MS (ESI) m/z 349.3 [M+H].sup.+

    Step B: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.2]oct-5-ene-2-carboxamide hydrochloride

    [2187] A solution of Intermediate 188 in 4 M HCl in cyclopentyl methyl ether (11 mL) was stirred at rt for 30 min and the reaction mixture was concentrated in vacuo to give titled compound (1.25 g, 98%). MS (ESI) m/z 249.2 [M+H].sup.30

    Intermediate 189: (1S,2R)-2-Amino-N-((1-methylcyclobutyl)methyl)cyclohexane-1-carboxamide hydrochloride

    [2188] ##STR00278##

    [2189] The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclohexane-1-carboxylic acid instead of Compound 1. MS (ESI) m/z 225.3 [M+H].sup.+.

    Intermediate 190: (1S,2R)-2-Amino-N-((1-methylcyclobutyl)methyl)cyclopentane-1-carboxamide hydrochloride

    [2190] ##STR00279##

    [2191] The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1. MS (ESI) m/z 211.3 [M+H].sup.+.

    Intermediate 191: rac-(1R,2S,4R)-2-Amino-4-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

    [2192] ##STR00280##

    Step A: Intermediate 192: rac-Methyl (1R,2S,4R)-2-(((benzyloxy)carbonyl)amino)-4-methoxycyclopentane-1-carboxylate

    [2193] ##STR00281##

    [2194] AgO (231 mg, 1.00 mmol) and iodomethane (0.09 mL, 1.36 mmol) were added to a solution of rac-methyl (1S,2R,4S)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-cyclopentanecarboxylate (Compound 2) (132 mg, 0.453 mmol) in MeCN (5 mL) and the reaction mixture was stirred at 50° C. for 3 hr. Iodomethane (0.38 mL, 6.07 mmol) was added and the reaction mixture was stirred at 40° C. for 20 hr. The reaction mixture was cooled at ambient temperature and filtered with Celite®, then the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 30-60% EtOAc in hexane as mobile phase to give the title compound (130 mg, 91%). MS (ESI) m/z 308.3 [M+H].sup.+.

    Step B: Intermediate 193: rac-(1R,2S,4R)-2-(((Benzyloxy)carbonyl)amino)-4-methoxycyclopentane-1-carboxylic acid

    [2195] ##STR00282##

    [2196] LiOH (51 mg, 2.11 mmol) was added to a solution of Intermediate 192 (130 mg, 0.42 mmol) in THF (3 mL) and H.sub.2O (1 mL), then the reaction mixture was stirred at rt for 19 hr. 1 M aq HCl was added to a reaction mixture to neutralize and the mixture was extracted with EtOAc three times, then the combined organic layer was concentrated in vacuo to give titled compound (125 mg, 100%). MS (ESI) m/z 294.1 [M+H].sup.+.

    Step C: Intermediate 194: rac-Benzyl ((1R,2S,4S)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate

    [2197] ##STR00283##

    [2198] T3P (1.7 M in EtOAc, 0.54 mL, 0.91 mmol) and DIPEA (0.20 mL, 1.13 mmol) were added to a solution of Intermediate 193 (122 mg, 0.42 mmol) and 3-((trifluoromethyl)sulfonyl)aniline (85 mg, 0.38 mmol) in MeCN (4 mL), then the reaction mixture was stirred at rt for 20 hr. Sat aq NaHCO.sub.3 was added to a reaction mixture and the mixture was extracted with EtOAc three times, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-2% MeOH in CHCl.sub.3 as mobile phase to give the title compound (133 mg, 71%). MS (ESI) m/z 501.1 [M+H].sup.+.

    Step D: rac-(1R,2S,4R)-2-Amino-4-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

    [2199] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 38 mg) was added to a solution of Intermediate 194 (130 mg, 0.26 mmol) in MeOH (3 mL) and THF (6 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 5 hr. The hydrogen in the reaction vessel was replaced with argon, and the reaction mixture was filtered with Celite®, then the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% MeOH in CHCl.sub.3 as mobile phase to give the title compound (46 mg, 48%). MS (ESI) m/z 367.1 [M+H].sup.+.

    Intermediate 195: rac-(1R,2S,4S)-2-Amino-4-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

    [2200] ##STR00284##

    [2201] The titled compound was prepared analogous to Intermediate 191, using rac-methyl (1S,2R,4R)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-cyclopentanecarboxylate instead of Compound 2. MS (ESI) m/z 367.4 [M+H].sup.+.

    Intermediate 196: rac-(1R,2R)-2-Amino-1-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

    [2202] ##STR00285##

    Step A: Intermediate 197: Methyl (1R,2R)-2-(benzyl((R)-1-phenylethyl)amino)-1-fluorocyclopentane-1-carboxylate

    [2203] ##STR00286##

    [2204] n-BuLi (2.6 M in Hexane, 0.73 mL, 1.90 mmol) was added dropwise to −78° C. cooled solution of (1R)-N-benzyl-1-phenyl-ethanamine (502 mg, 2.38 mmol) in THF (4 mL) and the reaction mixture was stirred at −78° C. for 20 min. Methyl cyclopentene-1-carboxylate (200 mg, 1.59 mmol) was added dropwise to a reaction mixture was stirred at −78° C. for 30 min. N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (1.0 g, 3.17 mmol) in THF (4 mL) was added to a reaction mixture and the mixture was stirred at rt for 30 min. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give the title compound (210 mg, 37%). MS (ESI) m/z 356.2 [M+H].sup.+.

    Step B: Intermediate 198: (1R,2R)-2-(Benzyl((R)-1-phenylethyl)amino)-1-fluorocyclopentane-1-carboxylic acid

    [2205] ##STR00287##

    [2206] LiOH (142 mg, 5.91 mmol) was added to a solution of Intermediate 197 (210 mg, 0.59 mmol) in THF (3 mL) and H.sub.2O (1.5 mL), then the reaction mixture was stirred at rt for 7 days. 1 M aq HCl was added to a reaction mixture to neutralize and the mixture was extracted with CHCl.sub.3 twice, then the combined organic layer was concentrated in vacuo give titled compound (60 mg, 30%) which was used without further purification.

    Step C: Intermediate 199: (1R,2R)-2-(Benzyl((R)-1-phenylethyl)amino)-1-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

    [2207] ##STR00288##

    [2208] HATU (73 mg, 0.19 mmol) and DIPEA (0.09 mL, 0.53 mmol) were added to a solution of Intermediate 198 (60 mg, 0.18 mmol) and 3-((trifluoromethyl)sulfonyl)aniline (44 mg, 0.19 mmol) in DMF (1 mL), then the reaction mixture was stirred at rt for 24 hr. H.sub.2O was added to a reaction mixture and the mixture was extracted with CHCl.sub.3 twice, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-25% EtOAc in hexane as mobile phase to give the title compound (43 mg, 45%). MS (ESI) m/z 549.5 [M+H].sup.+.

    Step D: rac-(1R,2R)-2-Amino-1-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

    [2209] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 10 mg) was added to a solution of Intermediate 199 (43 mg, 0.078 mmol) in MeOH (1.5 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 20 hr. The hydrogen in the reaction vessel was replaced with argon, and the reaction mixture was filtered with Celite®, then the filtrate was concentrated in vacuo to give titled compound (27 mg, 97%). MS (ESI) m/z 355.3 [M+H].sup.+.

    Intermediate 200: rac-(1R,2R,3S)-2-Amino-3-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2210] ##STR00289##

    Step A: Intermediate 201: rac-Benzyl (3aR,4R,6R,6aR)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-4-carboxylate

    [2211] ##STR00290##

    [2212] NBS (336 mg, 1.89 mmol) was added to a solution of rac-benzyl (1S,2R)-2-(tert-butoxycarbonylamino)cyclopent-3-ene-1-carboxylate (500 mg, 1.58 mmol) in THF (7.9 mL) and H.sub.2O (0.79 mL), and the reaction mixture was stirred at rt for 3 days. H.sub.2O was added to the reaction mixture and the mixture was extracted with CHCl.sub.3 twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the title compound (361 mg, 67%). MS (ESI) m/z 340.2/342.2 [M+H].sup.+.

    Step B: Intermediate 202: rac-Benzyl (3aR,4R,6aS)-2-oxohexahydro-2H-cyclopenta[d]oxazole-4-carboxylate

    [2213] ##STR00291##

    [2214] AIBN (17 mg, 0.11 mmol) was added to a solution of Intermediate 201 (359 mg, 1.05 mmol) and tributylstannane (338 mg, 1.16 mmol) in toluene (3 mL), then the reaction mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (216 mg, 78%). MS (ESI) m/z 262.1 [M+H].sup.+.

    Step C: Intermediate 203: rac-4-Benzyl 3-(tert-butyl) (3aR,4R,6aS)-2-oxotetrahydro-2H-cyclopenta[d]oxazole-3,4(3aH)-dicarboxylate

    [2215] ##STR00292##

    [2216] Boc.sub.2O (193 mg, 0.88 mmol) and 4-(dimethylamino)pyridine (10 mg, 0.08 mmol) were added to a solution of Intermediate 202 (210 mg, 0.80 mmol) in MeCN (4 mL), then the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo to give titled compound (310 mg, 107%) which was used without further purification.

    Step D: Intermediate 204: rac-(3aR,4R,6aS)-3-(tert-Butoxycarbonyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-4-carboxylic acid

    [2217] ##STR00293##

    [2218] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 30 mg) was added to a solution of Intermediate 203 (262 mg, 0.73 mmol) in MeOH (3.6 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 4 hr. The hydrogen in the reaction vessel was replaced with argon, and CHCl.sub.3 and MeOH were added to the reaction mixture to dissolve precipitated product. The reaction mixture was filtered with Celite®, then the filtrate was concentrated in vacuo to give titled compound (196 mg, 100%). MS (ESI) m/z 270.3 [M−H]−

    Step E: Intermediate 205: rac-tert-Butyl (3aR,4R,6aS)-2-oxo-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-cyclopenta[d]oxazole-3(3aH)-carboxylate

    [2219] ##STR00294##

    [2220] T3P (1.7 M in EtOAc, 910 mg, 1.43 mmol) and pyridine (113 mg, 1.43 mmol) were added to a solution of Intermediate 204 (194 mg, 0.72 mmol) and 3-((trifluoromethyl)sulfonyl)aniline (177 mg, 0.79 mmol) in EtOAc (1.8 mL), then the reaction mixture was stirred at rt for 15 h. CHCl.sub.3 and H.sub.2O were added to a reaction mixture and the mixture was extracted with EtOAc twice, then the combined organic layer was concentrated in vacuo. The crude product was triturated with IPA to give titled compound (164 mg, 48%). MS (ESI) m/z 477.4 [M−H]−

    Step F: Intermediate 206: rac-tert-Butyl ((1R,2S,5R)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate hydrochloride

    [2221] ##STR00295##

    [2222] LiOH (80 mg, 3.34 mmol) was added to a solution of Intermediate 205 (160 mg, 0.33 mmol) in THF (3.3 mL) and H.sub.2O (0.84 mL), and the reaction mixture was stirred at rt for 3 hr. H.sub.2O was added to the reaction mixture and the reaction mixture was extracted with EtOAc twice and the combined organic layer was concentrated in vacuo to give titled compound (116 mg, 77%). MS (ESI) m/z 451.3 [M−H]−

    Step G: rac-(1R,2R,3S)-2-Amino-3-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2223] Intermediate 206 (70 mg, 0.15 mmol) was dissolved in 2 M HCl in EtOH (1.6 mL) and the reaction mixture was stirred at rt for 5 hr. The reaction mixture was concentrated in vacuo to give titled compound (62 mg, 103%). MS (ESI) m/z 353.1 [M+H].sup.+.

    Intermediate 207: rac-(1R,2R,3R)-2-Amino-3-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2224] ##STR00296##

    Step A: Intermediate 208: rac-tert-Butyl ((1R,2S,3S,5S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)-6-oxabicyclo[3.1.0]hexan-2-yl)carbamate

    [2225] ##STR00297##

    [2226] 3-((Trifluoromethyl)sulfonyl)aniline (1.33 g, 5.91 mmol) was added to a suspension of NaH (60% in oil suspension, 236 mg, 5.91 mmol) in THF (7.9 mL), then the reaction mixture was stirred at rt for 10 min. The reaction mixture was cooled to 0° C. and rac-tert-butyl (1R,2S,4R,6R)-7-oxo-3-oxa-8-azatricyclo[4.2.0.02,4]octane-8-carboxylate (888 mg, 3.94 mmol) in THF (4 mL) was added to the reaction mixture and the reaction mixture was stirred at rt for 3 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was filtered to give titled compound (809 mg, 46%). The filtrate was extracted with EtOAc twice and the combined organic layer was concentrated in vacuo. The crude product was triturated with IPA to give additional titled compound (549 mg, 31%). MS (ESI) m/z 449.4 [M−H]−

    Step B: Intermediate 209: rac-tert-Butyl ((1R,2S,3S,5R)-3-bromo-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate

    [2227] ##STR00298##

    [2228] Lithium bromide (289 mg, 3.33 mmol) was added to a solution of Intermediate 208 (300 mg, 0.67 mmol) in acetic acid (4.2 mL) at 0° C., then the reaction mixture was stirred at 0° C. for 1 h and rt for 5 hr. H.sub.2O was added to the reaction mixture and filtered to give titled compound (218 mg, 62%). MS (ESI) m/z 529.2/531.2 [M−H]−

    Step C: Intermediate 210: rac-tert-Butyl ((1R,2R,5R)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate

    [2229] ##STR00299##

    [2230] AIBN (14 mg, 0.09 mmol) was added to a solution of Intermediate 209 (455 mg, 0.86 mmol) and tributylstannane (300 mg, 1.03 mmol) in toluene (1.7 mL), then the reaction mixture was stirred at 90° C. for 4 hr. Additional tributylstannane (150 mg, 0.51 mmol) and AIBN (14 mg, 0.09 mmol) was added to the reaction mixture, then the reaction mixture was stirred at 90° C. for 1.5 hr. The reaction precipitate was collected by filtration and washed with toluene to give titled compound (335 mg, 87%). MS (ESI) m/z 451.2 [M−H]−

    Step D: rac-(1R,2R,3R)-2-Amino-3-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2231] Intermediate 210 (120 mg, 0.27 mmol) was dissolved in 2 M HCl in EtOH (3 mL) and the reaction mixture was stirred at rt for 5 hr. The reaction mixture was concentrated in vacuo to give titled compound (107 mg, 103%). MS (ESI) m/z 353.1 [M+H].sup.+.

    Intermediate 211: rac-(1R,2R,3R)-2-Amino-3-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2232] ##STR00300##

    Step A: Intermediate 212: rac-tert-Butyl ((1R,2R,5R)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamate

    [2233] ##STR00301##

    [2234] Silver oxide (131 mg, 0.57 mmol) and iodomethane (0.26 mL, 4.23 mmol) were added to a solution of Intermediate 210 (137 mg, 0.26 mmol) in MeCN (2.6 mL), then the reaction mixture was stirred at 50° C. for 6 hr. Additional silver oxide (48 mg, 0.21 mmol) and iodomethane (0.06 mL, 0.93 mmol) were added to the reaction mixture, then the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The crude product was triturated with Et.sub.2O to give titled compound (65 mg, 43%).

    [2235] The filtrate was concentrated in vacuo and the residual powder was triturated with THF-hexane to give additional titled compound (50 mg, 33%). MS (ESI) m/z 465.3 [M−H]−

    Step B: rac-(1R,2R,3R)-2-Amino-3-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2236] Intermediate 212 (115 mg, 0.20 mmol) was dissolved in 2 M HCl in EtOH (3 mL) and the reaction mixture was stirred at rt for 18 hr. The reaction mixture was concentrated in vacuo and the crude product was triturated with IPA to give titled compound (79 mg, 89%). MS (ESI) m/z 367.2 [M+H].sup.+.

    Intermediate 213: rac-(1R,2R,3S,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [2237] ##STR00302##

    [2238] The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 361.2 [M+H].sup.+.

    Intermediate 214: rac-(1R,2R,3S,4S)-3-Amino-N-(4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [2239] ##STR00303##

    [2240] The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 379.0 [M+H].sup.+.

    Intermediate 215: rac-(1R,2R,3S,4S)-3-Amino-N-(3-fluoro-5-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [2241] ##STR00304##

    [2242] The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 3-fluoro-5-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 373.2 [M+H].sup.+.

    Intermediate 216: rac-(1R,2S)-2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2243] ##STR00305##

    [2244] The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 337.0 [M+H].sup.+.

    Intermediate 217: (1S,2R)-2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2245] ##STR00306##

    [2246] The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 337.2 [M+H].sup.+.

    Intermediate 218: (1S,2R)-2-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2247] ##STR00307##

    [2248] The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 349.1 [M+H].sup.+.

    Intermediate 219: (1R,2S,3R,4S)-3-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2249] ##STR00308##

    [2250] The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 375.1 [M+H].sup.+.

    Intermediate 220: (1R,2S,3R,4S)-3-Amino-N-((1-(trifluoromethyl)cyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2251] ##STR00309##

    [2252] The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using (1-trifluoromethylcyclobutyl)methylamine hydrochloride instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 221: (1S,2S,3R,4R)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2253] ##STR00310##

    [2254] The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1.

    Intermediate 222: (1S,2S,3R,4R)-3-Amino-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2255] ##STR00311##

    [2256] The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 223: (1R,2S,3R,4S)-3-Amino-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2257] ##STR00312##

    [2258] The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 239.2 [M+H].sup.+.

    Intermediate 224: (1R,2S,3R,4S)-3-Amino-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2259] ##STR00313##

    [2260] The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 225.3 [M+H].sup.+.

    Intermediate 225: (1R,2S,3R,4S)-3-Amino-N-(3,3,3-trifluoro-2,2-dimethylpropyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2261] ##STR00314##

    [2262] The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-methyl-3-trifluoromethylpropylamine instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 279.2 [M+H].sup.+.

    Intermediate 226: (1R,2S,3R,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2263] ##STR00315##

    [2264] The titled compound was prepared analogous to Intermediate 187, using (1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 363.2 [M+H].sup.+.

    Intermediate 227: (1S,2S,3R,4R)-3-Amino-N-(4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [2265] ##STR00316##

    [2266] The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 379.0 [M+H].sup.+.

    Intermediate 228: (1S,2R)-2-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2267] ##STR00317##

    [2268] The titled compound was prepared analogous to Intermediate 187, using (1S,2R)-2-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 291.0 [M+H].sup.+.

    Intermediate 229: (1S,2S,3R,4R)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [2269] ##STR00318##

    [2270] The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 315.0 [M+H].sup.+.

    Intermediate 230: (1R,2R,3S,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [2271] ##STR00319##

    [2272] The titled compound was prepared analogous to Intermediate 187, using (1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 315.1 [M+H].sup.+.

    Intermediate 231: rac-(1R,2R,3S,4S)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2273] ##STR00320##

    [2274] The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 363.1 [M+H].sup.+.

    Intermediate 232: (1S,2S,3R,4R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2275] ##STR00321##

    [2276] The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 363.1 [M+H].sup.+.

    Intermediate 233: rac-(1R,2R,3S,4S)-3-Amino-N-(3-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2277] ##STR00322##

    [2278] The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (APCI) m/z 357.0 [M+H].sup.+.

    Intermediate 234: (1S,2S,3R,4R)-3-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [2279] ##STR00323##

    [2280] The titled compound was prepared analogous to Intermediate 187, using (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 373.1 [M+H].sup.+.

    Intermediate 235: rac-(1R,2R,3S,4S)-3-Amino-N-(4-fluoro-3-(pentafluoro-6-sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2281] ##STR00324##

    [2282] The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 375.1 [M+H].sup.+.

    Intermediate 236: rac-(3R,4R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydro-2H-pyran-4-carboxamide hydrochloride

    [2283] ##STR00325##

    [2284] The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 353.3 [M+H].sup.+.

    Intermediate 237: rac-(3R,4R)-3-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)tetrahydro-2H-pyran-4-carboxamide hydrochloride

    [2285] ##STR00326##

    [2286] The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 238: (2S,3R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydro-2H-pyran-2-carboxamide hydrochloride

    [2287] ##STR00327##

    Step A: (2S,3R)-3-((tert-Butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid

    [2288] ##STR00328##

    [2289] The titled compound was prepared analogous to Intermediate 196 Step B, using methyl (2S,3R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate instead of Intermediate 197.

    Step B: (2S,3R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydro-2H-pyran-2-carboxamide hydrochloride

    [2290] The titled compound was prepared analogous to Intermediate 187, using (2S,3R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 239: rac-(1R,2S)-2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)cycloheptane-1-carboxamide hydrochloride

    [2291] ##STR00329##

    [2292] The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2S)-2-(tert-butoxycarbonylamino)cycloheptane-1-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 240: rac-(3R,4R)-4-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydro-2H-pyran-3-carboxamide hydrochloride

    [2293] ##STR00330##

    [2294] The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4R)-4-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-3-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 241: (2S,3R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydrofuran-2-carboxamide hydrochloride

    [2295] ##STR00331##

    [2296] The titled compound was prepared analogous to Intermediate 187, using (2S,3R)-3-(tert-butoxycarbonylamino)tetrahydrofuran-2-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 242: rac-(3R,4S)-4-Amino-N-((1-methylcyclobutyl)methyl)tetrahydrofuran-3-carboxamide hydrochloride

    [2297] ##STR00332##

    [2298] The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4S)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid instead of Compound 1. MS (ESI) m/z 213.2 [M+H].sup.+.

    Intermediate 243: rac-(3R,4S)-4-Amino-N-neopentyltetrahydrofuran-3-carboxamide hydrochloride

    [2299] ##STR00333##

    [2300] The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4S)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 244: rac-(3R,4S)-4-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)tetrahydrofuran-3-carboxamide hydrochloride

    [2301] ##STR00334##

    [2302] The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4S)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid instead of Compound 1 and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 245: rac-(3R,4S)-4-Amino-N-(4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)tetrahydrofuran-3-carboxamide hydrochloride

    [2303] ##STR00335##

    [2304] The titled compound was prepared analogous to Intermediate 187, using rac-(3R,4S)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid instead of Compound 1 and using 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 246: rac-(1R,2S,4S)-2-Amino-4-hydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide

    [2305] ##STR00336##

    [2306] The titled compound was prepared analogous to Intermediate 176 Step B-D, using rac-methyl (1S,2R,4R)-2-(((benzyloxy)carbonyl)amino)-4-hydroxycyclopentane-1-carboxylate instead of rac-methyl (1R,2R,3S,4S)-3-(((benzyloxy)carbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylate and using 3-((trifluoromethyl)sulfonyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 247: rac-(1R,2S,4R)-2-Amino-4-methoxy-N-neopentylcyclopentane-1-carboxamide

    [2307] ##STR00337##

    [2308] The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S,4R)-2-(((benzyloxy)carbonyl)amino)-4-methoxycyclopentane-1-carboxylic acid instead of Intermediate 178 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 248: rac-(1R,2S,4R)-2-Amino-4-methoxy-N-((1-methylcyclobutyl)methyl)cyclopentane-1-carboxamide

    [2309] ##STR00338##

    [2310] The titled compound was prepared analogous to Intermediate 176 Step C and D, using rac-(1R,2S,4R)-2-(((benzyloxy)carbonyl)amino)-4-methoxycyclopentane-1-carboxylic acid instead of Intermediate 178. MS (ESI) m/z 241.2 [M+H].sup.+.

    Intermediate 249: (1R,2S,3R,4S,5S,6R)-3-Amino-5,6-dihydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2311] ##STR00339##

    Step A: Intermediate 250: tert-Butyl ((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamate

    [2312] ##STR00340##

    [2313] T3P (1.7 M in EtOAc, 2.30 mL, 3.90 mmol) and DIPEA (1.02 mL, 5.90 mmol) were added to a solution of (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (500 mg, 1.97 mmol) and 3-((trifluoromethyl)sulfonyl)aniline (489 mg, 2.17 mmol) in EtOAc (5 mL), then the reaction mixture was stirred at rt for 7 hr. Sat aq NaHCO.sub.3 was added to a reaction mixture and the mixture was extracted with EtOAc three times, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using CHCl.sub.3 as mobile phase to give the title compound (493 mg, 54%). MS (ESI) m/z 405.1 [M+H-tBuH]+

    Step B: Intermediate 251: tert-Butyl ((1S,2R,3S,4R,5R,6S)-5,6-dihydroxy-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

    [2314] ##STR00341##

    [2315] OsO4 (microcapsulated, 273 mg, 0.107 mmol) and N-methylmorpholine N-oxide (0.9 mL, 4.40 mmol) were added to a solution of Intermediate 250 (493 mg, 1.07 mmol) in MeCN (3 mL) and acetone (3 mL), and the reaction mixture was stirred at rt for 24 hr. Iodomethane (0.38 mL, 6.07 mmol) was added and the reaction mixture was stirred at 40° C. for 20 hr. The reaction mixture was filtered with Celite®, then the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in CHCl.sub.3 as mobile phase to give the title compound (498 mg, 94%). MS (ESI) m/z 439.1 [M+H-tBuH]+

    Step C: (1R,2S,3R,4S,5S,6R)-3-Amino-5,6-dihydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2316] 4 M HCl in EtOAc (3 mL) was added to a solution of Intermediate 251 (498 mg, 1.00 mmol) in MeOH (2 mL), and the reaction mixture was stirred at rt for 18 hr. The reaction mixture was concentrated in vacuo to give titled compound (434 mg, 100%).

    Intermediate 252: rac-(1R,2R,3S,4R)-2-Amino-3,4-dihydroxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2317] ##STR00342##

    [2318] The titled compound was prepared analogous to Intermediate 249, using rac-(1S,2R)-2-(tert-butoxycarbonylamino)cyclopent-3-ene-1-carboxylic acid instead of (1S,2S,3R,4R)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid.

    Intermediate 253: rac-(1R,2S)-2-Amino-4,4-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopentane-1-carboxamide hydrochloride

    [2319] ##STR00343##

    [2320] The titled compound was prepared analogous to Intermediate 187, using rac-(1S,2R)-2-(tert-butoxycarbonylamino)-4,4-difluoro-cyclopentanecarboxylic acid instead of Compound 1 and using 4-fluoro-3-(trifluoromethyl)aniline instead of (1-methylcyclobutyl)methylamine hydrochloride.

    Intermediate 254: rac-(1R,2S,3R,4S)-3-Amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2321] ##STR00344##

    [2322] The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2S,3R,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1. MS (ESI) m/z 237.2 [M+H].sup.+.

    Intermediate 255: rac-(1R,2R,3S,4S)-3-Amino-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide hydrochloride

    [2323] ##STR00345##

    [2324] The titled compound was prepared analogous to Intermediate 187, using rac-(1R,2R,3S,4S)-3-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid instead of Compound 1 and using neopentylamine instead of (1-methylcyclobutyl)methylamine hydrochloride. MS (ESI) m/z 237.2 [M+H].sup.+.

    Intermediate 256: (1S,2S,3R,4R)-3-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide hydrochloride

    [2325] ##STR00346##

    [2326] The titled compound was prepared analogous to Intermediate 207 Step D, using Intermediate 250 instead of Intermediate 210. MS (APCI) m/z 361.0 [M+H].sup.+.

    Intermediate 257: Ethyl 1-(cyanomethyl)-4-hydroxycyclohexane-1-carboxylate

    [2327] ##STR00347##

    Step A: Intermediate 258: Ethyl 8-(cyanomethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate

    [2328] ##STR00348##

    [2329] n-BuLi (2.6 M in hexane, 3.87 mL, 10.3 mmol) was added dropwise to 0° C. cooled solution of DIA (1.14 g, 11.2 mmol) in THF (12 mL) and the reaction mixture was stirred at 0° C. for 30 min. Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (2 g, 9.33 mmol) in THF (3 mL) was added dropwise to a reaction mixture was stirred at −78° C. for 1 hr. 2-Bromoacetonitrile (1.68 g, 14.0 mmol) was added to a reaction mixture and the mixture was stirred at rt for 4 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-35% EtOAc in hexane as mobile phase to give the title compound (900 mg, 38%). MS (ESI) m/z 254.1 [M+H].sup.+.

    Step B: Ethyl 1-(cyanomethyl)-4-hydroxycyclohexane-1-carboxylate

    [2330] 2 M aq HCl (5 mL) was added to a solution of Intermediate 258 (900 mg, 3.55 mmol) in acetone (5 mL) and the reaction mixture was stirred at rt for 20 hr. The reaction mixture was concentrated in vacuo, and H.sub.2O and EtOAc were added and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was dissolved in EtOH (7 mL) and NaBH.sub.4 (161 mg, 4.26 mmol) was added portionwise to 0° C. cooled solution of mixture. The reaction mixture was stirred at 0° C. for 1 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10-60% EtOAc in hexane as mobile phase to give the title compound (649 mg, 87%) as cis/trans mixture. MS (ESI) m/z 194.1 [M+H-H.sub.2O]+

    Intermediate 259: tert-Butyl (1s,4s)-4-hydroxy-1-(trifluoromethyl)cyclohexane-1-carboxylate

    [2331] ##STR00349##

    Step A: Intermediate 260: tert-Butyl 4-oxo-1-(trifluoromethyl)cyclohexane-1-carboxylate

    [2332] ##STR00350##

    [2333] A mixture of tert-butyl 2-(trifluoromethyl)prop-2-enoate and trimethyl(1-methyleneallyloxy)silane was stirred at 140° C. for 6 hr. THF (5 mL) and 0.1 M aq HCl (5 mL) were added to the reaction mixture and the mixture was stirred at rt for 16 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was washed with sat aq NaHCO.sub.3 and was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (880 mg, 65%).

    Step B: Intermediate 261: tert-Butyl (1r,4r)-4-hydroxy-1-(trifluoromethyl)cyclohexane-1-carboxylate

    [2334] ##STR00351##

    [2335] NaBH.sub.4 (150 mg, 3.97 mmol) was added portionwise to 0° C. cooled solution of Intermediate 260 (880 mg, 3.30 mmol) in EtOH (5 mL). The reaction mixture was stirred at 0° C. for 1 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-35% EtOAc in hexane as mobile phase to give the title compound (869 mg, 98%).

    Step C: tert-Butyl (1s,4s)-4-hydroxy-1-(trifluoromethyl)cyclohexane-1-carboxylate

    [2336] Di-2-methoxyethyl azodicarboxylate (869 mg, 4.86 mmol) in THF (10 mL) was added dropwise to a solution of p-nitrobenzoic acid (812 mg, 4.86 mmol), Intermediate 261 (869 mg, 3.24 mmol) and triphenylphosphine (1.27 g, 4.84 mmol) at 0° C., and the reaction mixture was stirred at rt for 7 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo to give crude p-nitrobenzoate derivative. Potassium carbonate (1.04 g, 7.52 mmol) in H.sub.2O (2 mL) was added to a mixture of above crude product in MeOH (8 mL) and the reaction mixture was stirred at reflux for 3 hr. After being concentrated the solvent, H.sub.2O was added to the reaction mixture and then the mixture was extracted with CHCl.sub.3, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give the title compound (630 mg, 72%).

    Intermediate 262: Benzyl (1s,4s)-4-hydroxy-1-methoxycyclohexane-1-carboxylate

    [2337] ##STR00352##

    [2338] NaBH.sub.4 (204 mg, 5.39 mmol) was added portionwise to −78° C. cooled solution of benzyl 1-methoxy-4-oxo-cyclohexane-1-carboxylate (705 mg, 2.69 mmol) in EtOH (5 mL). The reaction mixture was stirred at 0° C. for 4 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-60% EtOAc in hexane as mobile phase to give the title compound (536 mg, 75%). MS (ESI) m/z 265 [M+H].sup.+.

    Intermediate 263: Benzyl (1r,4r)-1-((benzyloxy)methyl)-4-hydroxycyclohexane-1-carboxylate

    [2339] ##STR00353##

    Step A: Intermediate 264: Benzyl 8-((benzyloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate

    [2340] ##STR00354##

    [2341] 4 M aq NaOH (13.2 mL, 52.8 mmol) was added to a solution of ethyl 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (5.89 g, 17.6 mmol) in MeOH (15 mL). The reaction mixture was stirred at reflux for 6 hr. The reaction mixture was concentrated in vacuo and 6 M aq HCl was added to the mixture, and the mixture was extracted with CHCl.sub.3 twice. The combined organic layer was concentrated in vacuo. The crude product was dissolved in DMF (20 mL). Potassium carbonate (3.65 g, 26.4 mmol) and benzyl bromide (2.20 mL, 18.5 mmol) were added to mixture, and the mixture was stirred at rt for 3 hr. H.sub.2O was added to the mixture and the mixture was extracted with Et2O twice. The combined organic layer was washed with H.sub.2O twice and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in hexane as mobile phase to give the title compound (6.92 g, 99%). MS (ESI) m/z 397.5 [M+H].sup.+.

    Step B: Intermediate 265: Benzyl (1s,4s)-1-((benzyloxy)methyl)-4-hydroxycyclohexane-1-carboxylate

    [2342] ##STR00355##

    [2343] 2 M aq HCl (70 mL) was added to a solution of Intermediate 264 (6.92 g, 17.5 mmol) in acetone (20 mL) and the reaction mixture was stirred at rt for 8 hr. The reaction mixture was concentrated in vacuo, and H.sub.2O and EtOAc were added and the mixture was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was dissolved in MeOH (10 mL) and THF (10 mL), and NaBH.sub.4 (1.98 g, 52.3 mmol) was added portionwise to −78° C. cooled solution of mixture. The reaction mixture was stirred at −40° C. for 2 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with CHCl.sub.3 twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10-50% EtOAc in hexane as mobile phase to give the title compound (5.22 g, 84%). MS (ESI) m/z 355.4 [M+H].sup.+.

    Step C: Benzyl (1r,4r)-1-((benzyloxy)methyl)-4-hydroxycyclohexane-1-carboxylate

    [2344] Di-2-methoxyethyl azodicarboxylate (5.17 g, 22.1 mmol) in THF (20 mL) was added dropwise to a solution of p-nitrobenzoic acid (3.69 g, 22.1 mmol), Intermediate 265 (5.22 g, 14.7 mmol) and triphenylphosphine (5.79 g, 22.1 mmol) in THF (10 mL) at 0° C., and the reaction mixture was stirred at rt for 3 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo to give crude p-nitrobenzoate derivative.

    [2345] 2 M aq LiOH (22.0 mL, 44.0 mmol) was added to a mixture of above crude product in DME (40 mL) and the reaction mixture was stirred at rt for 24 hr. H.sub.2O was added to the reaction mixture and then the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 5-50% EtOAc in hexane as mobile phase to give the title compound (2.49 g, 48%). MS (ESI) m/z 355.4 [M+H].sup.+.

    Intermediate 266: Naphthalen-1-ylmethyl 3-hydroxy-1-methylcyclobutane-1-carboxylate

    [2346] ##STR00356##

    Step A: Intermediate 267: Naphthalen-1-ylmethyl 1-methyl-3-oxocyclobutane-1-carboxylate

    [2347] ##STR00357##

    [2348] Lithium iodide (3.1 g, 23 mmol) and potassium carbonate (6.7 g, 49 mmol) were added to a solution of 1-methyl-3-oxocyclobutane-1-carboxylic acid (2.5 g, 20 mmol) in DMF (50 mL), then 1-(chloromethyl)naphthalene (3.8 g, 21 mmol) was added dropwise to a reaction mixture and the mixture was stirred at rt for overnight. The mixture was added H.sub.2O and extracted with EtOAc twice and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% EtOAc in hexane as mobile phase to give the title compound (5.18 g, 99%).

    Step B: Naphthalen-1-ylmethyl 3-hydroxy-1-methylcyclobutane-1-carboxylate

    [2349] NaBH.sub.4 (630 mg, 17 mmol) was added portionwise to −78° C. cooled solution of Intermediate 267 (1.5 g, 5.60 mmol) in MeOH (15 mL). The reaction mixture was stirred at −78° C. for 2 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was concentrated in vacuo. The residue was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 30-50% EtOAc in hexane as mobile phase to give the title compound (1.51 g, 100%) as cis/trans mixture.

    Intermediate 268: rac-Benzyl (2R,5S)-5-(tosyloxy)tetrahydro-2H-pyran-2-carboxylate

    [2350] ##STR00358##

    Step A: Intermediate 269: rac-Benzyl (2R,5S)-5-hydroxytetrahydro-2H-pyran-2-carboxylate

    [2351] ##STR00359##

    [2352] BH.sub.3-THF complex (1.0 M in THF, 4.1 mL, 4.10 mmol) was added to −78° C. cooled solution of benzyl 3,4-dihydro-2H-pyran-2-carboxylate (690 mg, 3.16 mmol) in THF (16 mL) and the mixture was stirred for 30 min and rt for 6 hr. Sodium acetate (285 mg, 3.48 mmol), H.sub.2O.sub.2 (30% in H.sub.2O, 0.72 mL, 6.32 mmol) and H.sub.2O (5.27 mL) were added to a reaction mixture and the mixture was stirred at rt for 16 hr. The mixture was extracted with CHCl.sub.3 twice and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-65% EtOAc in hexane as mobile phase to give the title compound (203 mg, 27%). MS (ESI) m/z 237.2 [M+H].sup.+.

    Step B: rac-Benzyl (2R,5S)-5-(tosyloxy)tetrahydro-2H-pyran-2-carboxylate

    [2353] p-Toluenesulfonyl chloride (61 mg, 0.32 mmol) and trimethylamine hydrochloride (3 mg, 0.031 mmol) were added to a mixture of Intermediate 269 (50 mg, 0.212 mmol), TEA (64 mg, 0.635 mmol) and 4-dimethylaminopyridine (2.6 mg, 0.021 mmol) in CH.sub.2Cl.sub.2 (1 mL) and the reaction mixture was stirred at rt for 5 hr. H.sub.2O was added to a reaction mixture and the mixture was extracted with CHCl.sub.3, and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 5-20% EtOAc in hexane as mobile phase to give the title compound (37 mg, 45%).

    Intermediate 270: 4-Hydroxy-N-(4-methoxybenzyl)cyclohexane-1-sulfonamide

    [2354] ##STR00360##

    [2355] NaBH.sub.4 (35 mg, 0.93 mmol) was added portionwise to 0° C. cooled solution of N-(4-methoxybenzyl)-4-oxocyclohexane-1-sulfonamide (185 mg, 0.62 mmol) in MeOH (3 mL) and THF (2 mL). The reaction mixture was stirred at 0° C. for 1 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was concentrated in vacuo. The residue was extracted with EtOAc twice. The combined organic layer was concentrated in vacuo to give titled compound which was used without further purification.

    Intermediate 271: Naphthalen-1-ylmethyl (1s,4s)-1,4-dihydroxycyclohexane-1-carboxylate

    [2356] ##STR00361##

    [2357] The titled compound was prepared analogous to Intermediate 266 Step A, using (1s,4s)-1,4-dihydroxycyclohexane-1-carboxylic acid instead of 1-methyl-3-oxocyclobutane-1-carboxylic acid.

    Intermediate 272: rac-Benzyl (1R,3S)-3-((methylsulfonyl)oxy)cyclohexane-1-carboxylate and rac-benzyl (1R,3R)-3-((methylsulfonyl)oxy)cyclohexane-1-carboxylate

    [2358] ##STR00362##

    Step A: rac-Benzyl (1R,3S)-3-hydroxycyclohexane-1-carboxylate and rac-benzyl (1R,3R)-3-hydroxycyclohexane-1-carboxylate

    [2359] ##STR00363##

    [2360] NaBH.sub.4 (326 mg, 8.61 mmol) was added portionwise to 0° C. cooled solution of rac-benzyl 3-oxocyclohexane-1-carboxylate (1 g, 4.305 mmol) in THF (15 mL). The reaction mixture was stirred at rt for 4 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 30-50% EtOAc in hexane as mobile phase to give the first eluting compound Isomer 1: (110 mg, 11%), and the second eluting compound Isomer 2: (225 mg, 22%).

    Step B: rac-Benzyl (1R,3S)-3-((methylsulfonyl)oxy)cyclohexane-1-carboxylate and rac-benzyl (1R,3R)-3-((methylsulfonyl)oxy)cyclohexane-1-carboxylate

    [2361] Methanesulfonyl chloride (64 mg, 0.56 mmol) was added to a solution of the first eluting compound Isomer 1 (110 mg, 0.47 mmol), obtained from Step A, and TEA (71 mg, 0.70 mmol) in CHCl.sub.3 (2 mL), and the reaction mixture was stirred at rt for 12 hr. Sat aq NaHCO.sub.3 was added, then the mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo to give mesylated product (146 mg, 99%).

    [2362] Methanesulfonyl chloride (132 mg, 1.15 mmol) was added to a solution of the second eluting compound Isomer 2 (225 mg, 0.96 mmol), obtained from Step A, and TEA (146 mg, 1.44 mmol) in CHCl.sub.3 (2 mL), and the reaction mixture was stirred at rt for 12 hr. Sat aq NaHCO.sub.3 was added, then the mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo to give mesylated product (299 mg, 99%).

    Intermediate 273: 1-(tert-Butyl) 1-methyl (1r,4r)-4-hydroxycyclohexane-1,1-dicarboxylate

    [2363] ##STR00364##

    Step A: Intermediate 274: (1r,4r)-4-(tert-Butoxycarbonyl)-4-(methoxymethyl)cyclohexyl 4-nitrobenzoate

    [2364] ##STR00365##

    [2365] Di-2-methoxyethyl azodicarboxylate (2.59 g, 11.1 mmol) in THF (10 mL) was added dropwise to a solution of p-nitrobenzoic acid (1.85 g, 11.1 mmol), tert-butyl (1s,4s)-4-hydroxy-1-(methoxymethyl)cyclohexane-1-carboxylate (1.80 g, 7.37 mmol) and triphenylphosphine (2.9 g, 11.1 mmol) in THF (10 mL) at 0° C., and the reaction mixture was stirred at rt for 24 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was triturated with IPA to give title compound (2.16 g, 75%).

    Step B: Intermediate 275: 1-(tert-Butyl) 1-methyl (1r,4r)-4-((4-nitrobenzoyl)oxy)cyclohexane-1,1-dicarboxylate

    [2366] ##STR00366##

    [2367] Sodium periodate (784 mg, 3.67 mmol) and trichlororuthenium hydrate (82 mg, 0.367 mmol) were added to a mixture of Intermediate 274 (721 mg, 1.83 mmol) in CCl.sub.4 (4.6 mL), MeCN (4.6 mL) and H.sub.2O (6.1 mL), and the reaction mixture was stirred at rt for 10 hr. Sodium periodate (392 mg, 1.83 mmol) and trichlororuthenium hydrate (41 mg, 0.183 mmol) were added to a mixture and the mixture was stirred at rt for additional 12 hr. The reaction mixture was diluted with H.sub.2O and extracted with CHCl.sub.3, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-15% EtOAc in hexane as mobile phase to give the title compound (530 mg, 71%).

    Step C: 1-(tert-Butyl) 1-methyl (1r,4r)-4-hydroxycyclohexane-1,1-dicarboxylate

    [2368] Sodium methoxide (28% in MeOH, 50 mg, 0.259 mmol) was added to a mixture of Intermediate 275 (528 mg, 1.30 mmol) in MeOH (3.2 mL) and the reaction mixture was stirred at rt for 1 hr. The reaction mixture was neutralized with 1 M aq HCl, then the mixture was extracted with CHCl.sub.3, and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (308 mg, 92%).

    Intermediate 276: Naphthalen-1-ylmethyl (1r,4r)-1-ethyl-4-hydroxycyclohexane-1-carboxylate

    [2369] ##STR00367##

    Step A: Intermediate 277: Naphthalen-1-ylmethyl (1s,4s)-1-ethyl-4-hydroxycyclohexane-1-carboxylate

    [2370] ##STR00368##

    [2371] The titled compound was prepared analogous to Intermediate 266 Step A and B, using 1-ethyl-4-oxocyclohexane-1-carboxylic acid instead of 1-methyl-3-oxocyclobutane-1-carboxylic acid.

    Step B: Intermediate 278: (1r,4r)-4-Ethyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl 4-nitrobenzoate

    [2372] ##STR00369##

    [2373] The titled compound was prepared analogous to Intermediate 273 Step A, using Intermediate 277 instead of tert-butyl (1s,4s)-4-hydroxy-1-(methoxymethyl)cyclohexane-1-carboxylate.

    Step C: Naphthalen-1-ylmethyl (1r,4r)-1-ethyl-4-hydroxycyclohexane-1-carboxylate

    [2374] Potassium carbonate (2.39 g, 17.3 mmol) was added to a mixture of Intermediate 278 (2.66 g, 5.77 mmol) in MeOH (8 mL) and H.sub.2O (2 mL), then the reaction mixture was stirred at reflux for 2 hr. The reaction mixture was cooled to rt and CHCl.sub.3 was added to the mixture, and the mixture was extracted with CHCl.sub.3, and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the title compound (860 mg, 48%).

    Intermediate 279: Ethyl 2-(4-hydroxy-1-methylcyclohexyl)acetate

    [2375] ##STR00370##

    [2376] The titled compound was prepared analogous to Intermediate 266 Step B, using ethyl 2-(1-methyl-4-oxocyclohexyl)acetate instead of Intermediate 267.

    Intermediate 280: Methyl 5-hydroxy-2-methoxy-6-methylnicotinate

    [2377] ##STR00371##

    [2378] Bis(pinacolato)diboron (440 mg, 1.73 mmol), PdCl.sub.2(dppf).sub.2.CH.sub.2Cl.sub.2 (50.5 mg, 0.062 mmol) and potassium acetate (243 mg, 2.48 mmol) were added to a solution of methyl 5-bromo-2-methoxy-6-methylnicotinate (Compound 3) (322 mg, 1.24 mmol) in cyclopentyl methyl ether (5 mL) and the reaction mixture was stirred at reflux temperature for 3 hr. H.sub.2O and EtOAc were added to a reaction mixture and the mixture was stirred vigorously. The reaction mixture was separated, and the organic layer was concentrated in vacuo.

    [2379] Ammonium hydrogen carbonate (117 mg, 1.48 mmol) and H.sub.2O (0.32 mL, 3.09 mmol) were added to a solution of crude product in MeCN (5 mL) and the mixture was stirred at rt for 2 hr. 1 M aq HCl was added to a reaction mixture and the mixture was extracted with EtOAc twice, and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 5-35% EtOAc in hexane as mobile phase to give the title compound (222 mg, 91%). MS (ESI) m/z 198.0 [M+H].sup.+.

    Intermediate 281: Methyl 5-hydroxy-2-methoxy-4-(trifluoromethyl)benzoate

    [2380] ##STR00372##

    [2381] The titled compound was prepared analogous to Intermediate 280, using methyl 5-bromo-2-methoxy-4-(trifluoromethyl)benzoate instead of Compound 3. MS (ESI) m/z 251.1 [M+H].sup.+.

    Intermediate 282: Ethyl 5-hydroxy-2,3-dihydrobenzofuran-7-carboxylate

    [2382] ##STR00373##

    [2383] The titled compound was prepared analogous to Intermediate 280, using ethyl 5-bromo-2,3-dihydrobenzofuran-7-carboxylate instead of Compound 3. MS (ESI) m/z 209.1 [M+H].sup.+.

    Intermediate 283: Methyl 4-fluoro-5-hydroxy-2-isopropoxybenzoate

    [2384] ##STR00374##

    Step A: Intermediate 284: Methyl 5-bromo-4-fluoro-2-isopropoxybenzoate

    [2385] ##STR00375##

    [2386] Potassium carbonate (3.55 g, 25.7 mmol) and 2-iodopropane (2.40 g, 14.1 mmol) were added to a solution of methyl 5-bromo-4-fluoro-2-hydroxybenzoate (322 mg, 1.24 mmol) in DMF (21 mL) and the reaction mixture was stirred at rt for 2 h and 50° C. for 2 hr. H.sub.2O was added to a reaction mixture and the mixture was extracted with EtOAc, and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 10% EtOAc in hexane as mobile phase to give the title compound (2.86 g, 76%). MS (ESI) m/z 291.0/293.0 [M+H].sup.+.

    Step B: Methyl 4-fluoro-5-hydroxy-2-isopropoxybenzoate

    [2387] The titled compound was prepared analogous to Intermediate 280, using Intermediate 284 instead of Compound 3. MS (ESI) m/z 229.1 [M+H].sup.+.

    Intermediate 285: Methyl 3-fluoro-5-hydroxy-2-methoxybenzoate

    [2388] ##STR00376##

    [2389] The titled compound was prepared analogous to Intermediate 280, using methyl 5-bromo-3-fluoro-2-methoxybenzoate instead of Compound 3. MS (ESI) m/z 197.1 [M+H].sup.+.

    Intermediate 286: Methyl 3-chloro-5-hydroxy-2-methoxybenzoate

    [2390] ##STR00377##

    [2391] The titled compound was prepared analogous to Intermediate 280, using methyl 5-bromo-3-chloro-2-methoxybenzoate instead of Compound 3. MS (ESI) m/z 217.0/219.0 [M+H].sup.+.

    Intermediate 287: Methyl 5-hydroxy-2-methoxy-4-(methoxymethyl)benzoate

    [2392] ##STR00378##

    [2393] The titled compound was prepared analogous to Intermediate 280, using methyl 5-bromo-4-methoxymethyl-2-methoxybenzoate instead of Compound 3. MS (ESI) m/z 227.1 [M+H].sup.+.

    Intermediate 288: Methyl 4-fluoro-5-hydroxy-2-(methoxymethyl)benzoate

    [2394] ##STR00379##

    Step A: Intermediate 289: Methyl 5-bromo-4-fluoro-2-(methoxymethyl)benzoate

    [2395] ##STR00380##

    [2396] Sodium methoxide (28% in MeOH, 1.78 mL, 8.71 mmol) was added to a solution of methyl 5-bromo-4-fluoro-2-(hydroxymethyl)benzoate (1.42 g, 4.36 mmol) in MeOH (10 mL) and the reaction mixture was stirred at rt for 30 min and 80° C. for 30 min. The mixture was cooled to ambient temperature and 1 M aq HCl was added to adjust pH-2, then the mixture was extracted with EtOAc, and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-10% EtOAc in hexane as mobile phase to give the title compound (254 mg, 21%). MS (ESI) m/z 277.0/279.0 [M+H].sup.+.

    Step B: Methyl 4-fluoro-5-hydroxy-2-(methoxymethyl)benzoate

    [2397] The titled compound was prepared analogous to Intermediate 280, using Intermediate 289 instead of Compound 3. MS (ESI) m/z 213.1 [M−H]−

    Intermediate 290: Methyl 2-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-4-fluoro-5-hydroxybenzoate

    [2398] ##STR00381##

    Step A: Intermediate 291: Methyl 5-bromo-2-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-4-fluorobenzoate

    [2399] ##STR00382##

    [2400] Di-2-methoxyethyl azodicarboxylate (451 mg, 1.93 mmol) in THF (15 mL) was added dropwise to a solution of methyl 5-bromo-4-fluoro-2-hydroxybenzoate (400 mg, 1.61 mmol), 2-((tert-butyldiphenylsilyl)oxy)ethan-1-ol (579 mg, 1.93 mmol) and triphenylphosphine (505 mg, 1.93 mmol) in THF (15 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 12 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% EtOAc in hexane as mobile phase to give the title compound (854 mg, 100%).

    Step B: Methyl 2-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-4-fluoro-5-hydroxybenzoate

    [2401] The titled compound was prepared analogous to Intermediate 280, using Intermediate 291 instead of Compound 3. MS (ESI) m/z 467.2[M−H]−

    Intermediate 292: Benzyl 2,4-difluoro-5-hydroxybenzoate

    [2402] ##STR00383##

    Step A: Intermediate 293: Benzyl 5-bromo-2,4-difluorobenzoate

    [2403] ##STR00384##

    [2404] Potassium carbonate (1.30 g, 9.39 mmol) and benzyl bromide (835 mg, 4.88 mmol) were added to a solution of 5-bromo-2,4-difluorobenzoic acid (890 mg, 3.76 mmol) in DMF (10 mL) and the reaction mixture was stirred at rt for 12 h. H.sub.2O was added to a reaction mixture and the mixture was extracted with EtOAc, and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-5% EtOAc in hexane as mobile phase to give the title compound (1.22 g, 100%).

    Step B: Benzyl 2,4-difluoro-5-hydroxybenzoate

    [2405] The titled compound was prepared analogous to Intermediate 280, using Intermediate 293 instead of Compound 3. MS (ESI) m/z 263.1 [M−H]−

    Intermediate 294: tert-Butyl 4-cyano-5-hydroxy-2-methoxybenzoate

    [2406] ##STR00385##

    [2407] 1,1-Di-tert-butoxy-N,N-dimethyl-methylamine (4.20 g, 20.9 mmol) was added to a mixture of 4-cyano-5-hydroxy-2-methoxybenzoic acid (767 mg, 3.97 mmol) in toluene (4 mL) and the reaction mixture was stirred at 80° C. for 18 hr. The mixture was cooled to ambient temperature and sat aq NaHCO.sub.3 was added, then the mixture was extracted with EtOAc, and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-20% EtOAc in hexane as mobile phase to give the title compound (252 mg, 25%). MS (ESI) m/z 248.1 [M−H]−

    Intermediate 295: 4-(Difluoromethyl)-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2408] ##STR00386##

    [2409] Di-2-methoxyethyl azodicarboxylate (328 mg, 1.40 mmol) in THF (5 mL) was added dropwise to a solution of methyl 4-(difluoromethyl)-5-hydroxy-2-methoxybenzoate (Compound 4) (250 mg, 1.08 mmol), Intermediate 11 (418 mg, 1.40 mmol) and triphenylphosphine (367 mg, 1.40 mmol) in THF (5 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10-30% EtOAc in hexane as mobile phase to give methyl 4-(difluoromethyl)-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate (432 mg, 78%).

    [2410] 2 M aq LiOH (1.26 mL, 2.53 mmol) was added to a solution of methyl 4-(difluoromethyl)-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate (432 mg, 0.843 mmol) in DME (10 mL), and the reaction mixture was stirred at rt for 6 hr. 1 M aq HCl was added to the reaction mixture until pH<2, the reaction mixture was extracted with EtOAc twice and the combined organic layer was concentrated in vacuo to give titled compound (381 mg, 91%). MS (ESI) m/z 497.2 [M−H]−

    Intermediate 296: 3-Fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2411] ##STR00387##

    [2412] The titled compound was prepared analogous to Intermediate 295, using Intermediate 285 instead of Compound 4. MS (ESI) m/z 465.2 [M−H]−

    Intermediate 297: 3-Chloro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2413] ##STR00388##

    [2414] The titled compound was prepared analogous to Intermediate 295, using Intermediate 286 instead Compound 4. MS (ESI) m/z 481.2/483.2 [M−H]−

    Intermediate 298: 2-Methoxy-3-methyl-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2415] ##STR00389##

    [2416] The titled compound was prepared analogous to Intermediate 295, using methyl 3-methyl-5-hydroxy-2-methoxybenzoate instead of Compound 4. MS (ESI) m/z 477.3 [M+H].sup.+.

    Intermediate 299: 2-Methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-4-(trifluoromethyl)benzoic acid

    [2417] ##STR00390##

    [2418] The titled compound was prepared analogous to Intermediate 295, using Intermediate 281 instead of Compound 4.

    Intermediate 300: 2-Chloro-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2419] ##STR00391##

    [2420] The titled compound was prepared analogous to Intermediate 295, using methyl 2-chloro-4-fluoro-5-hydroxybenzoate instead of Compound 4. MS (ESI) m/z 469.2/471.2 [M−H]−

    Intermediate 301: 4-Chloro-2-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2421] ##STR00392##

    [2422] The titled compound was prepared analogous to Intermediate 295, using methyl 4-chloro-2-fluoro-5-hydroxybenzoate instead of Compound 4. MS (ESI) m/z 469.1/471.2 [M−H]−

    Intermediate 302: 4-Cyano-2-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2423] ##STR00393##

    [2424] The titled compound was prepared analogous to Intermediate 295, using methyl 4-cyano-2-fluoro-5-hydroxybenzoate instead of Compound 4. MS (ESI) m/z 460.2 [M−H]−

    Intermediate 303: 4-Fluoro-3-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2425] ##STR00394##

    [2426] The titled compound was prepared analogous to Intermediate 295, using methyl 4-fluoro-3-hydroxy-benzoate instead of Compound 4.

    Intermediate 304: 2-Methoxy-4-(methoxymethyl)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2427] ##STR00395##

    [2428] The titled compound was prepared analogous to Intermediate 295, using Intermediate 287 instead of Compound 4. MS (ESI) m/z 507.3 [M+H].sup.+.

    Intermediate 305: 2-Cyano-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2429] ##STR00396##

    [2430] The titled compound was prepared analogous to Intermediate 295, using methyl 2-cyano-4-fluoro-5-hydroxybenzoate instead of Compound 4. MS (ESI) m/z 460.7 [M−H]−

    Intermediate 306: 1-Methyl-7-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-1H-indazole-5-carboxylic acid

    [2431] ##STR00397##

    [2432] The titled compound was prepared analogous to Intermediate 295, using methyl 1-methyl-7-hydroxy-1H-indazole-5-carboxylate instead of Compound 4. MS (ESI) m/z 473.3 [M+H].sup.+.

    Intermediate 307: 1-Methyl-4-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-1H-indazole-6-carboxylic acid

    [2433] ##STR00398##

    [2434] The titled compound was prepared analogous to Intermediate 295, using methyl 1-methyl-4-hydroxy-1H-indazole-6-carboxylate instead of Compound 4. MS (ESI) m/z 473.3 [M+H].sup.+.

    Intermediate 308: 4-Fluoro-2-(methoxymethyl)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2435] ##STR00399##

    [2436] The titled compound was prepared analogous to Intermediate 295, using Intermediate 288 instead of Compound 4. MS (ESI) m/z 479.7 [M−H]−

    Intermediate 309: 2-Ethoxy-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2437] ##STR00400##

    [2438] The titled compound was prepared analogous to Intermediate 295, using methyl 2-ethoxy-4-fluoro-5-hydroxybenzoate instead of Compound 4. MS (ESI) m/z 481.3 [M+H].sup.+.

    Intermediate 310: 5-(((1s,4s)-4-Methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-carboxylic acid

    [2439] ##STR00401##

    [2440] The titled compound was prepared analogous to Intermediate 295, using Intermediate 282 instead of Compound 4. MS (ESI) m/z 461.3 [M+H].sup.+.

    Intermediate 311: 6-(((1s,4s)-4-Methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)quinoline-8-carboxylic acid

    [2441] ##STR00402##

    [2442] The titled compound was prepared analogous to Intermediate 295, using methyl 6-hydroxyquinoline-8-carboxylate instead of Compound 4. MS (ESI) m/z 470.3 [M+H].sup.+.

    Intermediate 312: 4-Chloro-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2443] ##STR00403##

    [2444] The titled compound was prepared analogous to Intermediate 295, using methyl 4-chloro-5-hydroxy-2-methoxybenzoate instead of Compound 4. MS (ESI) m/z 481.2/483.2 [M−H]−.

    Intermediate 313: 3-Cyano-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2445] ##STR00404##

    [2446] The titled compound was prepared analogous to Intermediate 295, using methyl 3-cyano-5-hydroxy-2-methoxybenzoate instead of Compound 4. MS (ESI) m/z 472.2 [M−H]−.

    Intermediate 314: 4-Bromo-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2447] ##STR00405##

    Step A: Intermediate 315: Methyl 4-bromo-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [2448] ##STR00406##

    [2449] Di-2-methoxyethyl azodicarboxylate (460 mg, 1.97 mmol) in THF (5 mL) was added dropwise to a solution of methyl 4-bromo-5-hydroxy-2-methoxybenzoate (341 mg, 1.31 mmol), Intermediate 11 (456 mg, 1.45 mmol) and triphenylphosphine (514 mg, 1.96 mmol) in THF (10 mL) at 40° C., and the reaction mixture was stirred at 40° C. for 1 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give titled compound (707 mg, 99%). MS (ESI) m/z 541.2/543.2 [M+H].sup.+.

    Step B: 4-Bromo-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2450] 2 M aq LiOH (0.28 mL, 0.55 mmol) was added to a solution of Intermediate 315 (100 mg, 0.185 mmol) in THF (0.5 mL), and the reaction mixture was stirred at rt for 6 hr. 1 M aq HCl was added to the reaction mixture until pH<2, the reaction mixture was extracted with EtOAc twice and the combined organic layer was concentrated in vacuo to give titled compound (94 mg, 97%). MS (ESI) m/z 527.1/529.1 [M+H].sup.+.

    Intermediate 316: 2-Methoxy-4-methyl-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2451] ##STR00407##

    Step A: Intermediate 317: Methyl 2-methoxy-4-methyl-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [2452] ##STR00408##

    [2453] PdCl.sub.2(dppf).sub.2.CH.sub.2Cl.sub.2 (33 mg, 0.040 mmol) was added to the mixture of Intermediate 315 (201 mg, 0.371 mmol) and trimethylboroxine (72 mg, 0.572 mmol) in potassium carbonate (157 mg, 1.138 mmol) and DME (3.7 mL), and the mixture was stirred at reflux for 1 hr. The mixture was cooled to ambient temperature and extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-30% EtOAc in hexane as mobile phase to give the title compound (127 mg, 72%). MS (ESI) m/z 477.3 [M+H].sup.+.

    Step B: 2-Methoxy-4-methyl-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2454] The titled compound was prepared analogous to Intermediate 314 step B, using Intermediate 317 instead of Intermediate 315. MS (ESI) m/z 463.3 [M+H].sup.+.

    Intermediate 318: 4-Ethyl-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2455] ##STR00409##

    Step A: Intermediate 319: Methyl 4-ethyl-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [2456] ##STR00410##

    [2457] The titled compound was prepared analogous to Intermediate 316 step A, using ethylboronic acid instead of trimethylboroxine. MS (ESI) m/z 491.3 [M+H].sup.+.

    Step B: 4-Ethyl-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2458] The titled compound was prepared analogous to Intermediate 314 step B, using Intermediate 319 instead of Intermediate 315. MS (ESI) m/z 475.2 [M+H].sup.+.

    Intermediate 320: 4-Cyclopropyl-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2459] ##STR00411##

    Step A: Intermediate 321: Methyl 4-cyclopropyl-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [2460] ##STR00412##

    [2461] The titled compound was prepared analogous to Intermediate 316 step A, using 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of trimethylboroxine. MS (ESI) m/z 503.3 [M+H].sup.+.

    Step B: 4-Cyclopropyl-2-methoxy-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2462] The titled compound was prepared analogous to Intermediate 314 step B, using Intermediate 321 instead of Intermediate 315. MS (ESI) m/z 489.3 [M+H].sup.+.

    Intermediate 322: 5-(((1r,4r)-4-(cyanomethyl)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2463] ##STR00413##

    Step A: Intermediate 323: Benzyl 5-(((1r,4r)-4-(cyanomethyl)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoate and Intermediate 324: Benzyl 5-(((1s,4s)-4-(cyanomethyl)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

    [2464] ##STR00414##

    [2465] Di-2-methoxyethyl azodicarboxylate (918 mg, 3.92 mmol) in THF (5 mL) was added dropwise to a solution of benzyl 4-fluoro-5-hydroxy-2-methoxybenzoate (722 mg, 2.61 mmol), Intermediate 257 (648 mg, 3.07 mmol) and triphenylphosphine (1030 mg, 3.93 mmol) in THF (5 mL) at 0° C., and the reaction mixture was stirred at rt for 5 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give the first eluting compound Isomer 1: Intermediate 323 (409 mg, 33%); MS (ESI) m/z 470.2 [M+H].sup.+, and the second eluting compound Isomer 2: Intermediate 324 (159 mg, 13%); MS (ESI) m/z 470.2 [M+H].sup.+.

    Step B: 5-(((1r,4r)-4-(Cyanomethyl)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2466] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 88 mg) was added to a solution of Intermediate 323 (409 mg, 0.871 mmol) in EtOH (5 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 4 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®. After the filtrate was concentrated in vacuo, the crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give titled compound (265 mg, 80%). MS (ESI) m/z 380.4 [M+H].sup.+.

    Intermediate 325: 5-(((1s,4s)-4-(Cyanomethyl)-4-(ethoxycarbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2467] ##STR00415##

    [2468] The titled compound was prepared analogous to Intermediate 322 Step B, using Intermediate 324 of Intermediate 323. MS (ESI) m/z 380.1 [M+H].sup.+.

    Intermediate 326: 5-((1s,3s)-3-Carboxy-3-methylcyclobutoxy)-4-fluoro-2-methoxybenzoic acid

    [2469] ##STR00416##

    Step A: Intermediate 327: Methyl 4-fluoro-2-methoxy-5-((1r,3r)-3-methyl-3-((naphthalen-1-ylmethoxy)carbonyl)cyclobutoxy)benzoate and Intermediate 328: Methyl 4-fluoro-2-methoxy-5-((1s,3s)-3-methyl-3-((naphthalen-1-ylmethoxy)carbonyl)cyclobutoxy)benzoate

    [2470] ##STR00417##

    [2471] Di-2-methoxyethyl azodicarboxylate (790 mg, 3.37 mmol) in THF (10 mL) was added dropwise to a solution of Intermediate 6 (450 mg, 2.25 mmol), Intermediate 266 (699 mg, 2.59 mmol) and triphenylphosphine (885 mg, 3.37 mmol) in THF (5 mL) at 0° C., and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 5-30% EtOAc in hexane as mobile phase to give the first eluting compound Isomer 1: Intermediate 327 (232 mg, 23%); MS (ESI) m/z 453.4 [M+H].sup.+, and the second eluting compound Isomer 2: Intermediate 328 (215 mg, 21%); MS (ESI) m/z 453.2 [M+H].sup.+.

    Step B: 5-((1s,3s)-3-Carboxy-3-methylcyclobutoxy)-4-fluoro-2-methoxybenzoic acid

    [2472] The titled compound was prepared analogous to Intermediate 314 Step B, using Intermediate 328 instead of Intermediate 315. MS (ESI) m/z 299.0 [M+H].sup.+.

    Intermediate 329: 5-(((1r,4r)-4-Carboxy-4-methoxycyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2473] ##STR00418##

    Step A: Intermediate 330: Methyl 5-(((1r,4r)-4-((benzyloxy)carbonyl)-4-methoxycyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

    [2474] ##STR00419##

    [2475] Di-2-methoxyethyl azodicarboxylate (690 mg, 2.94 mmol) in THF (5 mL) was added dropwise to a solution of Intermediate 6 (393 mg, 1.96 mmol), Intermediate 262 (535 mg, 2.03 mmol) and triphenylphosphine (773 mg, 2.95 mmol) in THF (10 mL) at 0° C., and the reaction mixture was stirred at rt for 3 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give titled compound (540 mg, 62%). MS (ESI) m/z 447.4 [M+H].sup.+.

    Step B: 5-(((1r,4r)-4-Carboxy-4-methoxycyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2476] The titled compound was prepared analogous to Intermediate 314 Step B, using Intermediate 330 instead of Intermediate 315. MS (ESI) m/z 343.3 [M+H].sup.+.

    Intermediate 331: 5-(((1R,3r,5S,6s)-6-(Ethoxycarbonyl)bicyclo[3.1.0]hexan-3-yl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2477] ##STR00420##

    Step A: Intermediate 332: Ethyl (1R,3r,5S,6s)-3-(5-((benzyloxy)carbonyl)-2-fluoro-4-methoxyphenoxy)bicyclo[3.1.0]hexane-6-carboxylate and Intermediate 333: Ethyl (1R,3r,5S,6r)-3-(5-((benzyloxy)carbonyl)-2-fluoro-4-methoxyphenoxy)bicyclo[3.1.0]hexane-6-carboxylate

    [2478] ##STR00421##

    [2479] Di-2-methoxyethyl azodicarboxylate (420 mg, 1.79 mmol) in THF (4 mL) was added dropwise to a solution of Intermediate 6 (330 mg, 1.19 mmol), ethyl 3-hydroxybicyclo[3.1.0]hexane-6-carboxylate (250 mg, 1.47 mmol) and triphenylphosphine (470 mg, 1.79 mmol) in THF (4 mL) at 0° C., and the reaction mixture was stirred at rt for 4 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in hexane as mobile phase to give the first eluting compound Isomer 1: Intermediate 332 (87 mg, 17%); MS (ESI) m/z 429.2 [M+H].sup.+, and the second eluting compound Isomer 2: Intermediate 333 (199 mg, 39%); MS (ESI) m/z 429.2 [M+H].sup.+.

    Step B: 5-(((1R,3r,5S,6s)-6-(Ethoxycarbonyl)bicyclo[3.1.0]hexan-3-yl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2480] The titled compound was prepared analogous to Intermediate 322 Step B, using Intermediate 332 instead of Intermediate 323. MS (ESI) m/z 339.1 [M+H].sup.+

    Intermediate 334: 5-(((1R,3r,5S,6r)-6-(Ethoxycarbonyl)bicyclo[3.1.0]hexan-3-yl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2481] ##STR00422##

    [2482] The titled compound was prepared analogous to Intermediate 322 Step B, using Intermediate 333 instead of Intermediate 323. MS (ESI) m/z 339.1 [M+H].sup.+

    Intermediate 335: 5-(((1r,4r)-4-(tert-Butoxycarbonyl)-4-fluorocyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2483] ##STR00423##

    [2484] The titled compound was prepared analogous to Intermediate 329 Step A and B, using tert-butyl (1s,4s)-1-fluoro-4-hydroxycyclohexane-1-carboxylate instead of Intermediate 262. MS (ESI) m/z 331.2 [M+H-tBu+H]+

    Intermediate 336: 5-(((1r,4r)-4-(tert-Butoxycarbonyl)-4-(trifluoromethyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2485] ##STR00424##

    [2486] The titled compound was prepared analogous to Intermediate 329 Step A and B, using Intermediate 259 instead of Intermediate 262. MS (ESI) m/z 381.1 [M+H-tBu+H]+

    Intermediate 337: 5-(((1r,4r)-4-(tert-Butoxycarbonyl)-4-hydroxycyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2487] ##STR00425##

    [2488] The titled compound was prepared analogous to Intermediate 329 Step A and B, using tert-butyl (1s,4s)-1,4-dihydroxycyclohexane-1-carboxylate instead of Intermediate 262. MS (ESI) m/z 329.0 [M+H-tBu+H]+

    Intermediate 338: 4-Fluoro-2-methoxy-5-((4-(N-(4-methoxybenzyl)sulfamoyl)cyclohexyl)oxy)benzoic acid

    [2489] ##STR00426##

    [2490] The titled compound was prepared analogous to Intermediate 329 Step A and B, using Intermediate 270 instead of Intermediate 262. MS (ESI) m/z 482.1 [M+H].sup.+.

    Intermediate 339: 5-((3-(tert-Butoxycarbonyl)cyclobutyl)methoxy)-4-fluoro-2-methoxybenzoic acid

    [2491] ##STR00427##

    [2492] The titled compound was prepared analogous to Intermediate 329 Step A and B, using tert-butyl 3-(hydroxymethyl)cyclobutane-1-carboxylate instead of Intermediate 262. MS (ESI) m/z 299.2 [M+H-tBu]+

    Intermediate 340: 4-Fluoro-2-methoxy-5-(3-(2-methoxy-2-oxoethyl)cyclobutoxy)benzoic acid

    [2493] ##STR00428##

    [2494] The titled compound (3:2 trans:cis) was prepared analogous to Intermediate 329 Step A and B, using methyl 2-(3-hydroxycyclobutyl)acetate instead of Intermediate 262. MS (ESI) m/z 313.1 [M+H].sup.+.

    Intermediate 341: 5-((4-(2-Ethoxy-2-oxoethyl)-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2495] ##STR00429##

    [2496] The titled compound was prepared analogous to Intermediate 329 Step A and B, using Intermediate 279 instead of Intermediate 262. MS (ESI) m/z 369.4 [M+H].sup.+.

    Intermediate 342: 5-(((1s,4s)-4-((Benzyloxy)methyl)-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2497] ##STR00430##

    [2498] The titled compound was prepared analogous to Intermediate 329 Step A and B, using Intermediate 265 instead of Intermediate 262. MS (ESI) m/z 573.1 [M+H].sup.+.

    Intermediate 343: 5-(((1s,4s)-4-Ethyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2499] ##STR00431##

    [2500] The titled compound was prepared analogous to Intermediate 329 Step A and B, using Intermediate 276 instead of Intermediate 262. MS (ESI) m/z 481.5 [M+H].sup.+.

    Intermediate 344: 4-Cyano-2-methoxy-5-((5-methoxy-4,4-dimethyl-5-oxopentyl)oxy)benzoic acid

    [2501] ##STR00432##

    Step A: Intermediate 345: tert-Butyl 4-cyano-2-methoxy-5-((5-methoxy-4,4-dimethyl-5-oxopentyl)oxy)benzoate

    [2502] ##STR00433##

    [2503] Methyl 5-bromo-2,2-dimethylpentanoate (340 mg, 1.52 mmol) was added to a mixture of Intermediate 294 (249 mg, 1.00 mmol) and potassium carbonate (279 mg, 2.02 mmol) in DMF (2 mL), then the mixture was stirred at 70 C for 1 hr. 1 M aq HCl was added to a mixture and the mixture was extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-25% EtOAc in hexane as mobile phase to give the title compound (366 mg, 94%). MS (ESI) m/z 336.2 [M-tBu]+

    Step B: 4-Cyano-2-methoxy-5-((5-methoxy-4,4-dimethyl-5-oxopentyl)oxy)benzoic acid

    [2504] TFA (0.5 mL) was added to a mixture of Intermediate 345 (363 mg, 0.928 mmol) in CHCl.sub.3 (2 mL). The reaction mixture was stirred at rt for 4 hr. The reaction mixture was concentrated, and the crude product was triturated with EtOAc-hexane to give the title compound (45 mg, 92%). MS (ESI) m/z 336.2 [M+H].sup.+.

    Intermediate 346: 2,4-Difluoro-5-(((1s,4s)-4-(methoxycarbonyl)cyclohexyl)oxy)benzoic acid

    [2505] ##STR00434##

    Step A: Intermediate 347: Benzyl 2,4-difluoro-5-(((1s,4s)-4-(methoxycarbonyl)cyclohexyl)oxy)benzoate

    [2506] ##STR00435##

    [2507] Trans-methyl 4-methylsulfonyloxycyclohexane-1-carboxylate (134 mg, 0.567 mmol) was added to a mixture of Intermediate 292 (100 mg, 0.379 mmol) and potassium carbonate (105 mg, 0.757 mmol) in DMF (5 mL), then the mixture was stirred at 80° C. for 12 hr. H.sub.2O was added to a mixture and the mixture was extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 10-40% EtOAc in hexane as mobile phase to give the title compound (53 mg, 35%).

    Step B: 2,4-Difluoro-5-(((1s,4s)-4-(methoxycarbonyl)cyclohexyl)oxy)benzoic acid

    [2508] The titled compound was prepared analogous to Intermediate 322 Step B, using Intermediate 347 instead of Intermediate 323.

    Intermediate 348: 4-Fluoro-2-methoxy-5-(((1s,4s)-4-(methoxycarbonyl)cyclohexyl)oxy)benzoic acid

    [2509] ##STR00436##

    [2510] The titled compound was prepared analogous to Intermediate 346, using benzyl 4-fluoro-2-methoxy-5-hydroxybenzoate instead of Intermediate 292.

    Intermediate 349: 5-(((1s,4s)-4-(tert-Butoxycarbonyl)-4-(methoxymethyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2511] ##STR00437##

    [2512] The titled compound was prepared analogous to Intermediate 329 step A and B, using tert-butyl (1r,4r)-4-hydroxy-1-(methoxymethyl)cyclohexane-1-instead of Intermediate 262. MS (ESI) m/z 357.2 [M+H-tBu+H]+.

    Intermediate 350: 5-(((1r,4r)-4-(tert-Butoxycarbonyl)-4-(methoxymethyl)cyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [2513] ##STR00438##

    [2514] The titled compound was prepared analogous to Intermediate 329 step A and B, using tert-butyl (1s,4s)-4-hydroxy-1-(methoxymethyl)cyclohexane-1-carboxylate instead of Intermediate 262. MS (ESI) m/z 357.2 [M+H-tBu+H]+.

    Intermediate 351: 4-Fluoro-2-(2-methoxyethoxy)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2515] ##STR00439##

    Step A: Intermediate 352: Methyl 2-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-4-fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [2516] ##STR00440##

    [2517] The titled compound was prepared analogous to Intermediate 295, using Intermediate 290 instead of Compound 4.

    Step B: Intermediate 353: Methyl 4-fluoro-2-(2-hydroxyethoxy)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [2518] ##STR00441##

    [2519] TBAF (1.0 M in THF, 0.43 mL, 0.43 mmol) was added to a solution of Intermediate 352 (217 mg, 0.290 mmol) in THF (6 mL), then the mixture was stirred at rt for 1 hr. Sat aq NH.sub.4Cl and CHCl.sub.3 were added to a mixture and the mixture was extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-40% EtOAc in hexane as mobile phase to give the title compound (94 mg, 64%). MS (ESI) m/z 511.2 [M+H].sup.+.

    Step C: Intermediate 354: Methyl 4-fluoro-2-(2-methoxyethoxy)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [2520] ##STR00442##

    [2521] Intermediate 353 (94 mg, 0.184 mmol) was added to a suspension of NaH (60% in oil suspension, 15 mg, 0.368 mmol) in THF (3 mL), then the reaction mixture was stirred at rt for 10 min. The reaction mixture was cooled to 0° C. and iodomethane (120 mg, 1.10 mmol) in DMF (3 mL) was added to the reaction mixture and the reaction mixture was stirred at rt for 3 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with CHCl.sub.3. The combined organic layer was concentrated in vacuo to give titled compound (96 mg, 100%). MS (ESI) m/z 525.2 [M+H].sup.+.

    Step D: 4-Fluoro-2-(2-methoxyethoxy)-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

    [2522] The titled compound was prepared analogous to Intermediate 314 Step B, using Intermediate 354 instead of Intermediate 315. MS (ESI) m/z 511.4 [M+H].sup.+.

    Intermediate 355: 2-Methoxy-5-(4-(methoxycarbonyl)phenoxy)benzoic acid

    [2523] ##STR00443##

    Step A: Intermediate 356: Methyl 4-(3-formyl-4-methoxyphenoxy)benzoate

    [2524] ##STR00444##

    [2525] CuI (89 mg, 0.465 mmol) and cesium carbonate (3.03 g, 9.30 mmol) were added to a mixture of 5-bromo-2-methoxybenzaldehyde (1 g, 4.65 mmol), methyl 4-hydroxybenzoate (1.06 g, 6.98 mmol) and N,N-dimethylglycine (195 mg, 1.40 mmol) in DME (5 mL), then the mixture was stirred at reflux for 18 hr. After being cooled to rt, aq potassium carbonate was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-15% EtOAc in hexane as mobile phase to give the title compound (191 mg, 14%). MS (APCI) m/z 287.0 [M+H].sup.+.

    Step B: 2-Methoxy-5-(4-(methoxycarbonyl)phenoxy)benzoic acid

    [2526] Sodium chlorite (85 mg, 0.94 mmol) was added to a mixture of Intermediate 356 (191 mg, 0.67 mmol) and sodium dihydrogen phosphate (22 mg, 0.18 mmol) in DMSO (5 mL) and H.sub.2O (5 mL), then the mixture was stirred at rt for 24 hr. 2 M aq HCl was added to the reaction mixture and the mixture was extracted with EtOAc, then the organ ic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (190 mg, 99%). MS (APCI) m/z 303.0 [M+H].sup.+.

    Intermediate 357: 2-Methoxy-5-(3-(methoxycarbonyl)phenoxy)benzoic acid

    [2527] ##STR00445##

    [2528] The titled compound was prepared analogous to Intermediate 355, using methyl 3-hydroxybenzoate instead of methyl 4-hydroxybenzoate. MS (APCI) m/z 303.0 [M+H].sup.+.

    Intermediate 358: 2-Methoxy-5-(2-(methoxycarbonyl)phenoxy)benzoic acid

    [2529] ##STR00446##

    [2530] The titled compound was prepared analogous to Intermediate 355, using methyl 2-hydroxybenzoate instead of methyl 4-hydroxybenzoate.

    Intermediate 359: 5-(4-(tert-Butoxycarbonyl)phenoxy)-4-cyano-2-methoxybenzoic acid

    [2531] ##STR00447##

    Step A: Intermediate 360: Methyl 5-(4-(tert-butoxycarbonyl)phenoxy)-4-cyano-2-methoxybenzoate

    [2532] ##STR00448##

    [2533] Cu(OAc).sub.2 (88 mg, 0.483 mmol), MS4A (250 mg) and 4-(tert-butoxycarbonyl)phenylboronic acid (214 mg, 0.965 mmol) were added to a solution of methyl 4-cyano-5-hydroxy-2-methoxybenzoate (100 mg, 0.483 mmol) and pyridine (0.078 mL, 0.965 mmol) in CH.sub.2Cl.sub.2 (3 mL), and the reaction mixture was stirred at rt for 20 hr. The mixture was diluted with CHCl.sub.3 and filtered, and the filtrate was concentrated in vacuo. The crude product was purified by NH.sub.2-coated silica flash chromatography using a gradient of 25-40% EtOAc in hexane as mobile phase to give titled compound (90 mg, 49%); MS (ESI) m/z 384.1 [M+H].sup.+.

    Step B: 5-(4-(tert-Butoxycarbonyl)phenoxy)-4-cyano-2-methoxybenzoic acid

    [2534] The titled compound was prepared analogous to Intermediate 314 step B, using Intermediate 360 instead of Intermediate 315. MS (ESI) m/z 368.2 [M−H]−

    Intermediate 361: 5-(4-(tert-Butoxycarbonyl)phenoxy)-4-fluoro-2-methoxybenzoic acid

    [2535] ##STR00449##

    [2536] The titled compound was prepared analogous to Intermediate 359, using 4-fluoro-5-hydroxy-2-methoxybenzoate instead of 4-cyano-5-hydroxy-2-methoxybenzoate. MS (ESI) m/z 361.2 [M−H]−

    Intermediate 362: 5-((5-(tert-Butoxycarbonyl)-1H-pyrazol-1-yl)methyl)-4-fluoro-2-methoxybenzoic acid

    [2537] ##STR00450##

    Step A: Intermediate 363: tert-Butyl 1-(2-fluoro-4-methoxy-5-(methoxycarbonyl)benzyl)-1H-pyrazole-5-carboxylate and Intermediate 364: tert-butyl 1-(2-fluoro-4-methoxy-5-(methoxycarbonyl)benzyl)-1H-pyrazole-3-carboxylate

    [2538] ##STR00451##

    [2539] Methanesulfonyl chloride (67 mg, 0.584 mmol) was added to a solution of methyl 4-fluoro-5-(hydroxymethyl)-2-methoxybenzoate and DIPEA (94 mg, 0.728 mmol) in CHCl.sub.3 (3 mL), and the reaction mixture was stirred at rt for 20 hr. Sat aq NaHCO.sub.3 was added, then the mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo.

    [2540] The residue and tert-butyl 1H-pyrazole-3-carboxylate (123 mg, 0.731 mmol) were dissolved in DMF (3 mL) and potassium carbonate (135 mg, 0.977 mmol) was added and the mixture was stirred at rt for 4 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give the first eluting compound Isomer 1: Intermediate 363 (74 mg, 42%); MS (ESI) m/z 365.2 [M+H].sup.+, and the second eluting compound Isomer 2: Intermediate 364 (84 mg, 47%); MS (ESI) m/z 365.2 [M+H].sup.+.

    Step B: 5-((5-(tert-Butoxycarbonyl)-1H-pyrazol-1-yl)methyl)-4-fluoro-2-methoxybenzoic acid

    [2541] 1 M aq LiOH (0.61 mL, 0.61 mmol) was added to a solution of Intermediate 363 (74 mg, 0.202 mmol) in DME (10 mL), and the reaction mixture was stirred at rt for 4 hr. 1 M aq HCl was added to the reaction mixture, then the reaction mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo to give titled compound (70 mg, 99%).

    Intermediate 365: 5-((3-(tert-Butoxycarbonyl)-1H-pyrazol-1-yl)methyl)-4-fluoro-2-methoxybenzoic acid

    [2542] ##STR00452##

    [2543] The titled compound was prepared analogous to Intermediate 362 step B, using Intermediate 364 instead of Intermediate 363.

    Intermediate 366: 5-(3-(tert-Butoxy)-3-oxopropyl)-2-methoxybenzoic acid

    [2544] ##STR00453##

    Step A: Intermediate 367: Methyl 5-(3-(tert-butoxy)-3-oxopropyl)-2-methoxybenzoate

    [2545] ##STR00454##

    [2546] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 20 mg) was added to a solution of methyl (E)-5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-methoxybenzoate (200 mg, 0.684 mmol) in MeOH (3 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 20 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite® to give titled compound (155 mg, 77%).

    Step B: 5-(3-(tert-Butoxy)-3-oxopropyl)-2-methoxybenzoic acid

    [2547] The titled compound was prepared analogous to Intermediate 314 step B, using Intermediate 367 instead of Intermediate 315. MS (ESI) m/z 279.2 [M−H]−

    Intermediate 368: Methyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl)acetate

    [2548] ##STR00455##

    [2549] PdCl.sub.2(dppf).sub.2.CH.sub.2Cl.sub.2 (50 mg, 0.061 mmol) and potassium acetate (242 mg, 2.47 mmol) were added to a solution of methyl 2-((3S)-6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (420 mg, 1.23 mmol) and bis(pinacolato)diboron (376 mg, 1.48 mmol) in cyclopentyl methyl ether (3 mL), then the mixture was stirred at reflux temperature for 1 hr. The mixture was cooled to ambient temperature and H.sub.2O was added, then the mixture was extracted with CHCl.sub.3 and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-25% EtOAc in hexane as mobile phase to give the title compound (340 mg, 87%). MS (ESI) m/z 319.2 [M+H].sup.+.

    Intermediate 369: Methyl (R)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl)acetate

    [2550] ##STR00456##

    [2551] The titled compound was prepared analogous to Intermediate 368, using methyl 2-[(3R)-6-(trifluoromethylsulfonyloxy)-2,3-dihydrobenzofuran-3-yl]acetate instead of methyl 2-[(3S)-6-(trifluoromethylsulfonyloxy)-2,3-dihydrobenzofuran-3-yl]acetate. MS (ESI) m/z 319.2 [M+H].sup.+.

    Intermediate 370: Ethyl 3-(6-bromopyridazin-3-yl)propanoate

    [2552] ##STR00457##

    [2553] (3-Ethoxy-3-oxopropyl)zinc(II) bromide (0.5 M in THF, 3.7 mL, 1.85 mmol) was added to a solution of 3,6-dibromopyridazine (400 mg, 1.68 mmol) and tetrakis(triphenylphosphine)palladium (194 mg, 0.168 mmol) in THF (4.2 mL), then the mixture was stirred at rt for 1 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the title compound (121 mg, 28%). MS (ESI) m/z 259.2/261.1 [M+H].sup.+.

    Intermediate 371: Benzyl 3-(5-bromopyridin-2-yl)propanoate

    [2554] ##STR00458##

    [2555] Benzyl bromide (164 mg, 0.956 mmol) was added to a mixture of 3-(5-bromo-2-pyridyl)propanoic acid (200 mg, 0.869 mmol) and potassium carbonate (180 mg, 1.304 mmol) in DMF (1.5 mL), then the mixture was stirred at rt for 1 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc/hexane (2/1), then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-25% EtOAc in hexane as mobile phase to give the title compound (159 mg, 57%). MS (ESI) m/z 320.1/322.1 [M+H].sup.+.

    Intermediate 372: tert-Butyl (5-(4-bromo-2-fluorophenethyl)-2,2-dimethyl-1,3-dioxan-5-yl)carbamate

    [2556] ##STR00459##

    Step A: Intermediate 373: tert-Butyl (Z)-(5-(4-bromo-2-fluorostyryl)-2,2-dimethyl-1,3-dioxan-5-yl)carbamate

    [2557] ##STR00460##

    [2558] Potassium tert-butoxide (10.5 g, 93.2 mmol) was added to a mixture of (4-bromo-2-fluorobenzyl)triphenylphosphonium bromide (49.4 g, 93.2 mmol) in THF (500 mL). The reaction mixture was stirred at rt for 1 hr. tert-butyl (5-formyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamate (12.1 g, 46.6 mmol) in THF (100 mL) was added to the reaction mixture and the mixture was stirred at rt for 4 hr. The mixture was poured into H.sub.2O (1 L) and extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was dissolved in Et2O and filtered off to remove triphenylphosphine oxide, then the filtrate was concentrated in vacuo and the residue was purified by flash chromatography using a gradient of 0-20% EtOAc in hexane as mobile phase to give the title compound (20.1 g, 100%).

    Step B: tert-Butyl (5-(4-bromo-2-fluorophenethyl)-2,2-dimethyl-1,3-dioxan-5-yl)carbamate

    [2559] RhCl(PPh3)2 (200 mg, 0.22 mmol) was added to a mixture of Intermediate 373 (1.0 g, 2.32 mmol) in toluene (15 mL). The reaction mixture was stirred at rt under 1 atm of hydrogen atmosphere for 15 h and 60° C. for 10 hr. After the reaction mixture was concentrated in vacuo, acetone (20 mL), dimethoxypropane (856 uL, 6.96 mmol) and p-toluenesulfonic acid hydrate (10 mg) were added to the residue and the mixture was stirred at rt for 15 hr. After the reaction mixture was concentrated in vacuo, the crude product was purified by flash chromatography using a gradient of 0-25% EtOAc in hexane as mobile phase to give the title compound (0.99 g, 99%).

    EXAMPLES

    Example 1: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Form A)

    [2560] ##STR00461##

    [2561] To a solution of Intermediate 17 in EtOH (206 g, 19% w/w, 57.9 mmol) was added EtOH (385 mL) followed by 10 wt % Pd/C (3.96 g, 5% w/w). The vessel was purged with N.sub.2 six times followed by H.sub.2 a further six times. The vessel was pressurized to 0.4 MPa with H.sub.2 and the reaction solution stirred for 20 h at between 20 and 30° C. The H.sub.2 atmosphere was completely replaced with N.sub.2 before the reaction mixture was filtered and the solids washed with EtOH (3×80 mL). A second identical batch was conducted and the collected EtOH solutions combined to give a single solution. The solvent was exchanged to EtOAc under reduced pressure maintaining the temperature below 45° C. The EtOAc solution (280 mL) was heated to between 70 and 75° C. for 0.5 h then cooled to between 40 and 45° C. and n-heptane (475 mL) added drop-wise over 0.5 h. The mixture was stirred for 0.5 h then cooled to between 20 and 25° C. over 2 h then held for a further 2 h. The heterogenous slurry was filtered then the solids washed twice with 1:2 EtOAc/n-heptane (160 mL) prior to drying at below 45° C. for 20 h to give crude title compound as a white solid (55.7 g, 87%).

    [2562] Part 1: The crude title compound (2.50 g, 4.59 mmol) was dissolved in EtOH (15.0 mL). The temperature of the solution was maintained at 25.0±2.0° C. during the drop-wise addition of water (7.50 mL) during which a precipitate formed. The heterogenous slurry was stirred for a further 1.0 h then collected via filtration. The solids were washed with a (2:3) mixture of EtOH/Water (2×5.00 mL), collected and dried under N.sub.2 to give the title compound as a white solid (1.80 g, 72%). This material was characterized as Form A and used as seed following the method described in Part 2.

    [2563] Part 2: The crude title compound (50.0 g, 91.8 mmol) was dissolved in EtOH (350 mL) then passed through a filter. EtOH (100 mL) was added to vessel then passed through the filter to give a combined EtOH solution. The temperature of the solution was maintained at 25.0±2.0° C. during the slow addition of H.sub.2O (150 mL) over 0.5 h. The solution was stirred for a further 0.5 h then seed material from Part 1 (0.005 g, 0.1% w/w) was added. The solution was held for 6 h then cooled to 20.0±0.5° C. over 2 h, then held for a further 6 h. H.sub.2O (150 mL) was added slowly over 6 h then the mixture held for a further 2 h prior to filtration. EtOH (45 mL) and H.sub.2O (30 mL) was added to vessel then used to wash the filter cake. The solids were collected and dried under N.sub.2 at below 45° C. for 12 h to give the title compound Form A as a white solid (42.2 g, 85%); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 0.97 (3H, s), 1.12-1.42 (5H, m), overlapping 1.25 (3H, S), 1.43-1.82 (10H, m), 1.92-2.1 (3H, m), 2.25 (3H, dd), 2.51 (2H, dd), 2.96 (1H, dd), 3.18 (1H, dd), 3.92 (3H, s), 4.12-4.28 (1H, m), 4.41 (1H, t), 5.81 (1H, t), 6.70 (1H, d), 7.86 (1H, d), 8.60 (1H, d). HRMS (ESI) m/z [M+H].sup.+ calcd for C30H42FN2O6: 545.3022 found: 545.3019.

    Form B of (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2564] Amorphous (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (150 mg, 275 mmol) was placed in a beaker in a brown 250 mL glass jar. Cyclohexane (20 mL) was placed at the bottom at the glass jar and sealed with a lid. After 4 weeks, the solid in the jar was isolated as Form F (cyclohexane solvate) (173 mg, 275 mmol) as a white solid.

    [2565] Form F (120 mg, 191 mmol) was heated at 80° C. on a heating block overnight (ca. 16h) resulting in Form B of the title compound (104 mg, 191 mmol) as a white solid.

    Form D of (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2566] Amorphous (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid was slurried in MeCN (7 mL) for 1 hour. The slurry was allowed to evaporate at ambient temperature for 3 days to yield Form D of the title compound (540 mg, 991 mmol) as a white solid.

    Form E of (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2567] (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid was dissolved in IPA (0.84 mL). Water (0.56 mL) was added and the mixture stirred for 20 min at 75° C. until dissolved. The clear solution was allowed to evaporate to dryness (2 days) at ambient temperature to yield Form E of the title compound (IPA solvate) (11 mg, 18 mmol) as a white solid.

    Example 2: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((cyclobutylmethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2568] ##STR00462##

    Step A Intermediate 18: Naphthalen-1-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-((cyclobutylmethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2569] To a solution of DIPEA (1.07 g, 8.31 mmol) in DCM (50.5 mL) at between 0 and 5° C. was added Intermediate 16 (5.00 g, 8.31 mmol) followed by cyclobutylmethanamine hydrochloride (1.26 g, 10.4 mmol). DIPEA (4.21 g, 32.6 mmol) was added drop-wise maintaining the temperature between 0 and 5° C., followed by the addition of T3P (8.46 g, 13.3 mmol, 50% w/w in EtOAc) over 0.5 h. The solution was warmed to between 15 and 25° C. and stirred for 2 h followed by the drop-wise addition of water (25.0 mL) maintaining the temperature below 30° C. The biphasic solution was separated and the organic phase washed with water (2×25.0 mL) then the solvent exchanged to EtOH (75.0 mL) under reduced pressure to give the title compound as a solution in EtOH that was used directly in the next step.

    Step B: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((cyclobutylmethyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2570] To the EtOH solution of Intermediate 18 was added 10 wt % Pd/C (290 mg, 5% w/w). The vessel was purged with N.sub.2 six times followed by H.sub.2 a further six times. The vessel was pressurized to 0.4 MPa with H.sub.2 and the reaction solution stirred for 20 h at between 20 and 30° C. The H.sub.2 atmosphere was completely replaced with N.sub.2 before the reaction mixture was filtered and the solids washed with EtOH (2×12.2 ml). The solvent was exchanged to EtAOc under reduced pressure maintaining the temperature below 45° C. The EtAOc solution (41.0 mL) was heated to between 70 and 75° C. for 0.5 h then cooled to between 40 and 45° C. and n-heptane (34.8 mL) added drop-wise over 0.5 h. The mixture was stirred for 0.5 h then cooled to between 20 and 25° C. over 2 h then held for a further 2 h. The heterogenous slurry was filtered then the solids washed twice with 1:2 EtOAc/n-heptane (11.6 mL) prior to drying at below 45° C. for 20 h to give the title compound as a white solid (3.28 g, 74%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 1.04-1.30 (6H, m), overlapping 1.10 (3H, s), 1.35-1.58 (5H, m), 1.59-1.69 (2H, m), 1.71-1.82 (2H, m), 1.83-1.92 (2H, m), 1.95-2.02 (1H, m), 2.01-2.10 (3H, d), 2.18-2.31 (2H, m), 2.50-2.55 (1H, d), 2.92-3.00 (1H, m), 3.06-3.14 (1H, m), 3.89 (3H, s), 4.07-4.17 (2H, m), 7.11 (1H, d), 7.67 (1H, d), 7.94 (1H, t), 8.83 (1H, d). MS (ESI): m/z [M+H].sup.+ 531.3.

    Example 3: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1R,2S,3R,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2571] ##STR00463##

    [2572] TFA (4.00 mL, 51.9 mmol) was added dropwise to Intermediate 138 (1.56 g, 2.60 mmol) in DCM (150 mL) cooled to 0° C. in 1 min under nitrogen. The resulting solution was stirred at 20° C. for 7 h. The solvents were evaporated under reduced pressure to afford the title compound (1.40 g, 97%) as a white solid after lyophilization; HRMS (ESI) m/z [M+H]+ calcd for C30H42FN2O6: 545.3022 found: 545.3036.

    Example 4: (1S,4s)-4-(2-Fluoro-4-(fluoromethoxy)-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2573] ##STR00464##

    [2574] Pd-C (50 mg, 0.05 mmol, 10%) was added to Intermediate 30 (227 mg, 0.32 mmol) in MeOH (20 mL) at 20° C. The reaction suspension was stirred at 20° C. for 14 h under an atmosphere of hydrogen (1.3 atm). The reaction mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, Method PrepAcidic-B, (gradient: 70-80%). Compound containing fractions were collected, evaporated to dryness and purified by preparative HPLC, Method PrepBasic-B, (gradient: 5-95%), to give the title compound (36 mg, 20%); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H41F2N2O6: 563.2928 found: 563.2962.

    Example 5: (1S,4s)-4-(2-Fluoro-4-methyl-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2575] ##STR00465##

    [2576] Pd-C (96 mg, 0.90 mmol) was added to a solution of Intermediate 33 (150 mg, 0.22 mmol) in EtOAc (10 mL) and the suspension was stirred at rt for 12 h. The reaction mixture was filtered and the solvents were removed under reduced pressure. The crude product was dissolved in DCM (20 mL), and the organic layer was washed with H.sub.2O (3×10 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated. The crude product was purified by reversed phase flash chromatography on a C18 column using a gradient of 0-70% MeCN in H.sub.2O as mobile phase, to give the title compound (50 mg, 42%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C30H42FN2O5: 529.3072 found: 529.3076.

    Example 6: (2R*,4r,6R)-6-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylic acid ISOMER 2

    [2577] ##STR00466##

    [2578] Intermediate 38 was dissolved in FA (5 mL) at rt. The reaction mixture was stirred at 100° C. for 4 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC to afford the title compound Example 6 (30 mg, 50%); HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.40N.sub.3O.sub.6: 550.2912 found: 550.2916. The compound was analysed by chiral SFC on a Lux Cellulose 4 column (3 um, 100×4.6 mm ID) using 30% of MeOH/DEA (99.9:0.1) in CO.sub.2 as mobile phase; t.sub.r=2.022 min which corresponds to the second eluting compound compared to a mixture of Example 6 and Example 7.

    Example 7: (2R*,4r,6R)-6-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)spiro[3.3]heptane-2-carboxylic acid Isomer 1

    [2579] ##STR00467##

    [2580] The title compound Example 7 was prepared from Intermediate 37 as described for Example 6 affording (30 mg, 44%); HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.40N.sub.3O.sub.6: 550.2912 found: 550.2900. The compound was analysed by chiral SFC on a Lux Cellulose 4 column (3 μm 100×4.6 mm ID) using 30% of MeOH/DEA (99.9:0.1) in CO.sub.2 as mobile phase. t.sub.R=1.697 min which corresponds to the first eluting compound compared to a mixture of Example 6 and Example 7.

    Example 8: (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-(isopropylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2581] ##STR00468##

    Step A Intermediate 374: Ethyl (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(isopropylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2582] ##STR00469##

    [2583] EDC (0.177 g, 0.92 mmol) was added slowly to a solution of Intermediate 106 (0.2 g, 0.42 mmol), propan-2-amine (0.074 g, 1.26 mmol), HOBt (0.141 g, 0.92 mmol), and TEA (0.292 mL, 2.09 mmol) in DMF (20 mL) at 20° C. and the reaction mixture was stirred at 60° C. for 14 h. The reaction mixture was diluted with EtOAc (200 mL), and the organic layer was washed sequentially with sat brine (150 mL), sat NaHCO.sub.3 (150 mL), and H.sub.2O (150 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to give the title compound (0.20 g, 92%) as a yellow oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 519.2.

    Step B (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-(isopropylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2584] LiOH (0.15 g, 6.26 mmol) was added to a solution of Intermediate 374 (0.2 g, 0.39 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL), and the reaction mixture was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL) and acidified with HCl (2 M). The aq layer was extracted with EtOAc (3×50 mL), and the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude product was purified by Method PrepAcidic A, (gradient: 43-50%), to give the title compound (0.104 g, 55%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C26H36FN2O6: 491.2552 found: 491.2560.

    Example 9: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(Cyclohexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2585] ##STR00470##

    Step A Intermediate 375: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(cyclohexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2586] ##STR00471##

    [2587] HATU (0.239 g, 0.63 mmol) was added to a solution of Intermediate 106 (0.20 g, 0.42 mmol), cyclohexanamine (0.058 g, 0.59 mmol) and DIPEA (0.219 mL, 1.26 mmol) in DMF (10 mL) at 20° C. and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was poured into sat NaHCO.sub.3 (150 mL), and the aq layer was extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to afford the title compound (0.20 g, 85%) as a brown oil which solidified on standing. The product was used in the next step without further purification; MS (ESI) m/z [M+H].sup.+ 559.3.

    Step B (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(Cyclohexylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2588] LiOH (0.10 g, 4.18 mmol) was added to a solution of Intermediate 375 (0.20 g, 0.36 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL) and the reaction mixture was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL), and acidified with HCl (2 M). The aq layer was extracted with EtOAc (3×50 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by Method PrepAcidic A, (gradient: 63-65%), to give the title compound (0.125 g, 65%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C29H40FN2O6: 531.2864 found: 531.2872.

    Example 10: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-(Difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2589] ##STR00472##

    Step A Intermediate 376: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-(difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2590] ##STR00473##

    [2591] DIPEA (0.198 mL, 1.13 mmol) was added dropwise to a solution of Intermediate 106 (0.18 g, 0.38 mmol), 3-(difluoromethyl)aniline (0.081 g, 0.57 mmol) and HATU (0.430 g, 1.13 mmol) in DMF (10 mL) at 20° C., and under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (200 mL), and the organic layer was washed sequentially with sat brine (200 mL), sat NaHCO.sub.3 (200 mL), and H.sub.2O (200 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:PE, 1:1), to give the title compound (0.187 g, 82%) as a pale yellow solid; MS (ESI) m/z [M+H].sup.+ 603.

    Step B (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-(Difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2592] LiOH (22 mg, 0.93 mmol) was added portion wise to Intermediate 376 (187 mg, 0.31 mmol) in EtOH (10 mL) and H.sub.2O (10 mL) and the reaction mixture was stirred at 20° C. for 5 h. The reaction mixture was diluted with EtOAc (150 mL). The organic layer was washed sequentially with H.sub.2O (125 mL), sat NaHCO.sub.3 (125 mL), and sat brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, Method PrepAcidic G, using decreasingly polar mixture of the mobile phase, to give the title compound (81 mg, 45%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C30H34F3N2O6: 575.2364 found: 575.2360.

    Example 11: (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-((3-(fluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2593] ##STR00474##

    Step A Intermediate 377: Ethyl (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-(fluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2594] ##STR00475##

    [2595] 3-(Fluoromethyl)aniline (57 mg, 0.45 mmol), HATU (215 mg, 0.57 mmol), DIPEA (0.132 mL, 0.75 mmol) and DMAP (4.6 mg, 0.04 mmol) were added to a solution of Intermediate 106 (180 mg, 0.38 mmol) in DMF (5 mL). The reaction mixture was stirred at 60° C. for 2 h, and then diluted with EtOAc (75 mL). The organic layer was washed with sat brine (3×25 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (PE: EtOAc, 1:1), to give the title compound (197 mg, 89%) as a yellow oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 585.

    Step B (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-((3-(fluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2596] LiOH (24 mg, 1.0 mmol) was added to a solution of Intermediate 377 (196 mg, 0.34 mmol) in EtOH (6 mL) and H.sub.2O (3 mL). The reaction mixture was stirred at 20° C. for 5 h, and then diluted with EtOAc (75 mL). The organic layer was washed with sat brine (3×25 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-C, using decreasingly polar mixtures of the mobile phase, to give the title compound (77 mg, 41%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C30H35F2N2O6: 557.2458 found: 557.2464.

    Example 12: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2597] ##STR00476##

    Step A Intermediate 378: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2598] ##STR00477##

    [2599] 2-Chloro-1-methylpyridinium iodide (214 mg, 0.84 mmol) and DMAP (26 mg, 0.21 mmol) were added to a solution of Intermediate 106 (200 mg, 0.42 mmol), 2-(trifluoromethyl)pyridin-4-amine (102 mg, 0.63 mmol) and DIPEA (0.37 mL, 2.09 mmol) in BuOAc (10 mL) at 20° C. The reaction mixture was stirred at 120° C. for 18 h. The reaction mixture was poured into sat NaHCO.sub.3 (150 mL) and the aq layer was extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 2:5), to give the title compound (120 mg, 46%) as a yellow oil; MS (ESI) m/z [M+H].sup.+ 622.3.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2600] LiOH (0.50 g, 20.88 mmol) was added to a solution of Intermediate 378 (0.12 g, 0.19 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL), and acidified with HCl (2 M). The aq layer was extracted with EtOAc (3×50 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-G, (gradient: 54-56%), to give the title compound (0.023 g, 18%) as a white solid; MS (ESI) m/z [M+H].sup.+ 594.2.

    Example 13: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2601] ##STR00478##

    Step A Intermediate 379: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2602] ##STR00479##

    [2603] 2-Chloro-1-methylpyridinium iodide (214 mg, 0.84 mmol) and DMAP (25 mg, 0.21 mmol) were added to a solution of Intermediate 106 (200 mg, 0.42 mmol), 5-(trifluoromethyl)pyridin-2-amine (102 mg, 0.63 mmol) and DIPEA (0.37 mL, 2.09 mmol) in BuOAc (10 mL) at 20° C. and the reaction mixture was stirred at 120° C. for 18 h. The reaction mixture was poured into sat NaHCO.sub.3 (150 mL), and the organic layer was extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 2:5), to give the title compound (220 mg, 85%) as a yellow oil.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2604] LiOH (25.04 mg, 1.05 mmol) was added to a solution of Intermediate 379 (130 mg, 0.21 mmol) in EtOH (2 mL) and H.sub.2O (1 mL) at 20° C. and the reaction mixture was stirred at 20° C. for 5 h. The reaction mixture was acidified with HCl (2 M) and diluted with EtOAc (75 mL). The organic layer was washed with sat brine (3×20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method AcidicPrep-C, using decreasingly polar mixtures as mobile phase, to give the title compound (68 mg, 51%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C29H32F4N3O6: 594.2222 found: 594.2230.

    Example 14: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2605] ##STR00480##

    Step A Intermediate 380: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2606] ##STR00481##

    [2607] 2-Chloro-1-methylpyridinium iodide (128 mg, 0.50 mmol) and DMAP (15 mg, 0.13 mmol) were added to a solution of Intermediate 106 (120 mg, 0.25 mmol), 4-(trifluoromethyl)pyridin-2-amine (81 mg, 0.50 mmol) and DIPEA (0.22 mL, 1.26 mmol) in BuOAc (10 mL) at 0-5° C. The reaction mixture was stirred at 120° C. for 15 h. The reaction mixture was poured into sat NaHCO.sub.3 (150 mL), and the aq layer was extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), to give the title compound (40 mg, 26%) as a pale yellow oil; MS (ESI) m/z [M+H].sup.+622.3. The process above was repeated to give another 65 mg of the title compound; MS (ESI) m/z [M+H].sup.+ 622.3.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2608] LiOH (0.50 g, 20.9 mmol) was added to a solution of Intermediate 380 (0.105 g, 0.17 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL) and the reaction mixture was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL) and acidified with HCl (2 M). The aq layer was extracted with EtOAc (3×50 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-G, (gradient: 56-66%), to give the title compound (0.012 g, 11%) as a white solid; MS (ESI) m/z [M+H].sup.+ 594.3.

    Example 15: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2609] ##STR00482##

    Step A Intermediate 381: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2610] ##STR00483##

    [2611] 4-((Trifluoromethyl)sulfonyl)aniline (68 mg, 0.30 mmol), T3P (240 mg, 0.75 mmol, 50% in EtOAc), DIPEA (018 mL, 1.01 mmol) and DMAP (3 mg, 0.03 mmol) were added to a solution of Intermediate 106 (120 mg, 0.25 mmol) in BuOAc (5 mL) and the reaction mixture was stirred at 120° C. overnight. The reaction mixture was diluted with EtOAc (75 mL), and washed with sat brine (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1), to give the title compound (106 mg, 62%) as a pale yellow oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 685.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-((trifluoromethyl)-sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2612] LiOH (11 mg, 0.46 mmol) was added to a solution of Intermediate 381 (106 mg, 0.15 mmol) in EtOH (3 mL) and H.sub.2O (1.5 mL). The reaction mixture was stirred at 20° C. for 8 h and then acidified with HCl (1 M). The reaction mixture was diluted with EtOAc (75 mL), and the organic layer was washed with sat brine (3×20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-C, using decreasingly polar mixtures as eluents, to give the title compound (22 mg, 21%) as a white solid; MS (ESI) m/z [M+H].sup.+ 657.

    Example 16: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((perfluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2613] ##STR00484##

    Step A Intermediate 382: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((perfluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2614] ##STR00485##

    [2615] DIPEA (0.44 mL, 2.51 mmol) was added to a solution of Intermediate 106 (120 mg, 0.25 mmol), 2,3,4,5,6-pentafluoroaniline (69 mg, 0.38 mmol) and T3P (0.75 mL, 1.26 mmol, 50% in EtOAc) in BuOAc (5 mL) and the reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was poured into sat NaHCO.sub.3 (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the title compound (120 mg, 74%) as a white solid; MS (ESI) m/z [M+Na].sup.+665.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((perfluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2616] LiOH (22 mg, 0.93 mmol) was added to a solution of Intermediate 382 (120 mg, 0.19 mmol) in THF (4 mL) and H.sub.2O (2 mL) and the reaction mixture was stirred at 20° C. for 1h. The reaction mixture was acidified with HCl (1 M), and diluted with EtOAc (25 mL). The organic layer was washed sequentially with sat brine (3×20 mL), and H.sub.2O (25 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-G, (gradient: 54-64%), to give the title compound (70 mg, 58%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C29H29F6N2O6: 615.1924 found: 615.1952.

    Example 17: (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-((3-fluoro-5-(pentafluoro-6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2617] ##STR00486##

    Step A Intermediate 383: Ethyl (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-fluoro-5-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2618] ##STR00487##

    [2619] T3P (0.75 mL, 1.26 mmol, 50% in EtOAc) was added to a solution of Intermediate 106 (0.12 g, 0.25 mmol), 3-fluoro-5-(pentafluoro-λ6-sulfaneyl)aniline (0.119 g, 0.50 mmol) and DIPEA (0.439 mL, 2.51 mmol) in BuOAc (15 mL) at 20° C., and the reaction mixture was stirred at 120° C. for 15 h. The reaction mixture was poured into sat NaHCO.sub.3 (150 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the title compound (0.150 g, 86%) as a brown gum; MS (ESI) m/z [M+H].sup.+ 697.2.

    Step B (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-((3-fluoro-5-(pentafluoro-6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2620] LiOH (0.50 g, 20.9 mmol) was added to a solution of Intermediate 383 (0.15 g, 0.22 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL) and the reaction mixture was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL), acidified with HCl (2 M), and the aq layer was extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-C, (gradient: 55-75%), to give the title compound (0.040 g, 26%) as a pale yellow solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C29H32F7N2O6S: 669.1864 found: 669.1890.

    [2621] The examples included in Table 1 below were synthesized and purified analogous to the procedure of Example 17 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00001 TABLE 1 Ex HRMS (ESI) Purification No Structure m/z [M + H].sup.+ Method 18 [00488]embedded image calcd for C30H32F5N2O7: 627.2124 found: 627.2142 Step B Method PrepAcidic-G (gradient 62-64%) 19 [00489]embedded image calcd for C31H35FN3O6: 564.2504 found: 564.2510 Step B Method PrepAcidic-G (gradient 60-64%) 20 [00490]embedded image calcd for C30H33F4N2O7: 609.2218 found: 609.2254 Step B Method PrepAcidic-G (gradient 60-70%) 21 [00491]embedded image calcd for C30H32F5N2O7: 627.2124 found: 627.2162 Step B Method PrepAcidic-G (gradient 60-70%)

    Example 22: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,5-Bis(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2622] ##STR00492##

    Step A Intermediate 384: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2623] ##STR00493##

    [2624] DIPEA (0.44 mL, 2.51 mmol) was added to a solution of Intermediate 106 (120 mg, 0.25 mmol), 3,5-bis(trifluoromethyl)aniline (86 mg, 0.38 mmol) and T3P (800 mg, 1.26 mmol, 50% in EtOAc) in BuOAc (5 mL) and the reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was poured into sat NaHCO.sub.3 (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the title compound (111 mg, 64%) as a white solid; MS (ESI) m/z [M+H].sup.+ 689. The compound was used in the next step without further purification.

    Step B (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,5-Bis(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2625] LiOH (11 mg, 0.48 mmol) was added to a solution of Intermediate 384 (111 mg, 0.16 mmol) in EtOH (3 mL) and H.sub.2O (1.5 mL) and the reaction mixture was stirred at 20° C. for 6 h. The reaction mixture was acidified with HCl (1 M) and diluted with EtOAc (50 mL). The organic layer was washed with sat brine (3×20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-G, (gradient: 63-73%), to give the title compound (62 mg, 58%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C31H32F7N2O6: 661.2142 found: 661.2180.

    [2626] The examples included in Table 2 below were synthesized and purified analogous to the procedure of Example 22 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated

    TABLE-US-00002 TABLE 2 Ex HRMS (ESI) Purification No Structure m/z [M + H].sup.+ Method 23 [00494]embedded image calcd for C30H32BrF4N2O6: 671.1374 found: 671.1406 Step B Method PrepAcidic-C 24 [00495]embedded image calcd for C31H35F4N2O6: 607.2426 found: 607.2466 Step B Method PrepAcidic-C 25 [00496]embedded image calcd for C29H33ClFN2O6: 559.2006 found: 559.2012 Step B Method PrepAcidic-C 26 [00497]embedded image calcd for C30H32ClF4N2O6: 627.1880 found: 627.1912 Step B Method PrepAcidic-C

    Example 27: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-Bromo-4-cyanophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2627] ##STR00498##

    Step A Intermediate 385: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-bromo-4-cyanophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2628] ##STR00499##

    [2629] T3P (0.45 mL, 0.75 mmol, 50% in EtOAc) was added dropwise to a solution of 4-amino-2-bromobenzonitrile (49 mg, 0.25 mmol), Intermediate 106 (120 mg, 0.25 mmol) and TEA (0.175 mL, 1.26 mmol) in BuOAc (10 mL) at 20° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 120° C. for 14 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with sat brine (150 mL), sat NaHCO.sub.3 (150 mL), and H.sub.2O (150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:5), to give the title compound (130 mg, 79%) as a pale yellow solid; MS (ESI) m/z [M+H].sup.+ 657.

    Step B (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-Bromo-4-cyanophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2630] LiOH (11 mg, 0.46 mmol) was added to a solution of Intermediate 385 (100 mg, 0.15 mmol) in EtOH (3 mL) and H.sub.2O (1.5 mL) and the reaction mixture was stirred at 20° C. for 5 h. The reaction mixture was acidified with HCl (1 M), diluted with EtOAc (100 mL), and washed with sat brine (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-C, using a gradient of decreasingly polar mixtures as mobile phase to give the title compound (24 mg, 24%) as a white solid; MS (ESI) m/z [M+H].sup.+ 630.

    [2631] The examples included in Table 3 below were synthesized analogous to the procedure of Example 27 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00003 TABLE 3 Ex HRMS (ESI) m/z Purification No Structure [M + H].sup.+ Method 28 [00500]embedded image calcd for C31H32F4N3O6: 618.2222 found: 618.2210 Step A Preparative TLC (EtOAc:PE, 1:5) Step B Method PrepAcidic-C 29 [00501]embedded image calcd for C30H32F5N2O6: 611.2174 found: 611.2188 Step A Preparative TLC (EtOAc:PE, 1:5) Step B Method PrepAcidic-C

    Example 30: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((5-Chloropyridazin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2632] ##STR00502##

    Step A Intermediate 386: tert-Butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((5-chloropyridazin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2633] ##STR00503##

    [2634] T3P (0.315 mL, 0.59 mmol, 50% in EtOAc) was added dropwise to a solution of Intermediate 67 (100 mg, 0.20 mmol), 5-chloropyridazin-3-amine (31 mg, 0.24 mmol) and DIPEA (0.19 mL, 0.79 mmol) in BuOAc (3 mL) at 20° C. and the reaction mixture was stirred at 120° C. for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc), to give the title compound (80 mg, 65%) as a brown red oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 617.4.

    Step B (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((5-Chloropyridazin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2635] TFA (0.1 mL) was added to Intermediate 386 (80 mg, 0.13 mmol) in DCM (2 mL) and the reaction mixture was stirred at 20° C. for 5 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, Method PrepAcidic-C, using decreasingly polar mixtures of mobile phase, to give the title compound (20 mg, 25%) as a white solid; MS (ESI) m/z [M+H].sup.+ 561.

    [2636] The examples included in Table 4 below were synthesized and purified analogous to the procedure of Example 30 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated

    TABLE-US-00004 TABLE 4 Ex HRMS (ESI) Purification No Structure m/z [M + H].sup.+ Method 31 [00504]embedded image MS (ESI) m/z [M + H].sup.+ 595 Step A Preparative TLC (EtOAc:PE, 1:5) Step B Method PrepAcidic-J (isocratic 49%) 32 [00505]embedded image calcd for C28H31F4N4O6: 595.2174 found: 595.2166 Step A Preparative TLC (EtOAc:PE, 1:1) Step B Method PrepAcidic-C

    Example 33: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,3-Difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2637] ##STR00506##

    Step A Intermediate 387: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,3-difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2638] ##STR00507##

    [2639] The synthesis of the title compound was performed using Intermediate 106 (0.2 g, 0.42 mmol) and 3,3-difluorocyclobutan-1-amine (0.063 g, 0.59 mmol) in an analogous manner as described for Example 9 Step A, to give the title compound (0.20 g, 84%) as a brown oil which solidified upon standing; MS (ESI) m/z [M+H].sup.+ 567.3. The product was used in the next step directly without further purification.

    Step B (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3,3-Difluorocyclobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2640] The hydrolysis of Intermediate 387 was performed in an analogous manner as described for Example 9 Step B. The crude product was purified by preparative HPLC Method PrepAcidic-A, (gradient: 44-55%), to give the title compound (0.160 g, 84%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C27H34F3N2O6: 539.2364 found: 539.2310.

    Example 34: (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-(isobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2641] ##STR00508##

    Step A Intermediate 388: tert-Butyl (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(isobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2642] ##STR00509##

    [2643] 2-Methylpropan-1-amine (19.7 mg, 0.27 mmol) was added to a solution of Intermediate 75 (70 mg, 0.13 mmol), EDC (77 mg, 0.40 mmol), HOBt (62 mg, 0.40 mmol) and DIPEA (0.12 mL, 0.67 mmol) in DMF (1 mL) and the reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with H.sub.2O (3×20 mL) and sat brine (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (PE:EtOAc, 5:1), to give the title compound (75 mg, 97%) as a yellow solid; MS (ESI) m/z [M+H].sup.+ 575.

    Step B (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-(isobutylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2644] TFA (2 mL) was added to a solution of Intermediate 388 (70 mg, 0.12 mmol) in DCM (2 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 30 min. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Method PrepAcidic O, (gradient: 50-65%), to give the title compound (50 mg, 79%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C28H40FN2O6: 519.2864 found: 519.2886;

    Example 35: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2645] ##STR00510##

    Step A Intermediate 389: tert-Butyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2646] ##STR00511##

    [2647] HATU (146 mg, 0.38 mmol) was added to a solution of Intermediate 75 (100 mg, 0.19 mmol), 2,2-dimethylpropan-1-amine (25 mg, 0.29 mmol) and DIPEA (75 mg, 0.58 mmol) in DMF (10 mL) at 25° C., and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was poured into sat brine (50 mL), and extracted with EtOAc (2×50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by flash chromatography using a gradient 0-20% EtOAc in PE as mobile phase, to give the title compound (70 mg, 62%) as a white solid; MS (ESI) m/z [M+Na].sup.+611.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2648] TFA (0.57 mL) was added to a solution of Intermediate 389 (110 mg, 0.19 mmol) in DCM (10 mL) at 25° C., and the reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was evaporated at reduced pressure and the crude product was purified by preparative HPLC, Method PrepAcidic-K, (gradient: 50-60%), to give the title compound (65 mg, 61%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C29H42FN2O6: 533.3022 found: 533.3030.

    Example 36: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-3,3-Dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2649] ##STR00512##

    Step A Intermediate 390: tert-Butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-3,3-dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2650] ##STR00513##

    [2651] HATU (146 mg, 0.38 mmol) was added to a solution of Intermediate 75 (100 mg, 0.19 mmol), (R)-3,3-dimethylbutan-2-amine (29 mg, 0.29 mmol) and DIPEA (75 mg, 0.58 mmol) in DMF (10 mL) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched with ice (75 mL), extracted with DCM (3×50 mL), and the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by flash chromatography using a gradient of 0-20% EtOAc in PE as mobile phase, to give the title compound (60 mg, 52%) as a yellow oil; MS (ESI) m/z [M+H].sup.+ 603.

    Step B (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-3,3-Dimethylbutan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2652] TFA (0.15 mL) was added to a solution of Intermediate 390 (60 mg, 0.10 mmol), TFA (0.15 mL) in DCM (10 mL) and the reaction mixture was stirred at 25° C. for 16 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, Method PrepAcidic-K, (gradient: 50-60%), to give the title product (50 mg, 91%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C30H44FN2O6: 547.3178 found: 547.3188.

    Example 37: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-Dimethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2653] ##STR00514##

    Step A Intermediate 391: tert-Butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-dimethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2654] ##STR00515##

    [2655] DIPEA (0.081 mL, 0.46 mmol) was added dropwise to a solution of Intermediate 75 (48 mg, 0.09 mmol), 2,2-dimethylbutan-1-amine hydrochloride (25.4 mg, 0.18 mmol) and HATU (105 mg, 0.28 mmol) in DMF (8 mL) at 20° C. under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 3 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with sat NaHCO.sub.3 (100 mL), and sat brine (2×100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc: PE, 1:3), to give the title compound (48 mg, 86%) as a pale yellow oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 603.

    Step B (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-Dimethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2656] TFA (2 mL) was added dropwise to a solution of Intermediate 391 (48 mg, 0.08 mmol) in DCM (2 mL) at 20° C. and the reaction mixture was stirred at 20° C. for 5 h. The solvent was evaporated to dryness and dried by lyophilization to give the title compound (28 mg, 62%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C30H44FN2O6: 547.3178 found: 547.3176.

    Example 38: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2657] ##STR00516##

    Step A Intermediate 392: tert-Butyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2658] ##STR00517##

    [2659] 3,3,3-Trifluoro-2,2-dimethylpropan-1-amine (29 mg, 0.21 mmol), HATU (329 mg, 0.87 mmol) and DIPEA (0.27 mL, 1.56 mmol) were added to a solution of Intermediate 75 (90 mg, 0.17 mmol) in DMF (5 mL), and the reaction mixture was stirred at 20° C. for 3 h. The reaction mixture was diluted with EtOAc (75 mL), and washed with sat brine (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (PE:EtOAc, 2:1), to give the title compound (110 mg, 99%) as a brown oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 617.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2660] TFA (3 mL) was added to a solution of Intermediate 392 (100 mg, 0.20 mmol) in DCM (3 mL), and the reaction mixture was stirred at 20° C. for 3h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, Method PrepAcidic-C, using decreasingly polar mixtures of the mobile phase to give the title compound (45 mg, 47%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C29H39F4N2O6: 587.2738 found: 587.2750.

    [2661] The examples included in Table 5 below were synthesized analogous to the procedure of Example 38 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated

    TABLE-US-00005 TABLE 5 HRMS or MS Ex (ESI) (m/z) Purification No Structure [M + H].sup.+ Method 39 [00518]embedded image calcd for C30H42FN2O6: 545.3022 found: 545.3032 Step A Preparative TLC (EtOAc:PE, 1:3) Step B Method PrepAcidic-K (gradient 28-38%) 40 [00519]embedded image calcd for C31H46FN2O6: 561.3334 found: 561.3340 Step A Preparative TLC (EtOAc:PE, 1:3) Step B Method PrepAcidic-K (gradient 50-80%) 41 [00520]embedded image MS (ESI) m/z [M + H].sup.+ 531 Step A Preparative TLC (EtOAc:PE, 1:1) Step B Method PrepAcidic-K (gradient 28-38%) 42 [00521]embedded image calcd for C29H42FN2O6: 533.3022 found: 533.3060 Step A crude used Step B Method PrepAcidic-K (gradient 50-60%) 43 [00522]embedded image calcd for C30H44FN2O6: 547.3178 found: 547.3204 Step A Preparative TLC (EtOAc:PE, 1:3) Step B Method PrepAcidic-K (gradient 50-70%) 44 [00523]embedded image calcd for C32H46FN2O6: 573.3334 found: 573.3348 Step A Preparative TLC (EtOAc:PE, 1:3) Step B Method PrepAcidic-K (gradient 60-70%) 45 [00524]embedded image calcd for C30H44FN2O6: 547.3178 found: 547.3188 Step A Preparative TLC (EtOAc:PE, 1:3) Step B Method PrepAcidic-K (gradient 50-70%) 46 [00525]embedded image calcd for C29H42FN2O6: 533.3022 found: 533.3018 Step A Preparative TLC (EtOAc:PE, 1:3) Step B Method PrepAcidic-K (gradient 50-60%) 47 [00526]embedded image calcd for C29H39FN3O6: 544.2818 found: 544.2840 Step A Preparative TLC (EtOAc:PE, 1:1) Step B Method PrepAcidic-K (gradient 42-52%) 48 [00527]embedded image MS (ESI) m/z [M + H].sup.+ 549 Step A Preparative TLC (EtOAc:PE, 1:1) Step B Method PrepAcidic-K (gradient 46-56%)

    Example 49: (1R,4s)-4-(2-Fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2662] ##STR00528##

    Step A Intermediate 393: Ethyl (1R,4s)-4-(2-fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2663] ##STR00529##

    [2664] HATU (125 mg, 0.33 mmol), DIPEA (0.077 mL, 0.44 mmol), and Intermediate 111 (45 mg, 0.13 mmol) was added to a solution of Intermediate 46 (35 mg, 0.11 mmol) in DMF (5 mL) and the reaction mixture was stirred at 20° C. for 2h. The reaction mixture was diluted with EtOAc (50 mL), and washed with sat brine (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1), to give the title compound (60 mg, 85%) as a white solid; MS (ESI) m/z [M+Na].sup.+663.

    Step B (1R,4s)-4-(2-Fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2665] LiOH (2 mg, 0.09 mmol) was added to a solution of Intermediate 393 (55 mg, 0.09 mmol) in EtOH (4 mL) and H.sub.2O (2 mL) and the reaction mixture was stirred at 20° C. for 5h. The reaction mixture was acidified with HCl (1 M, aq), diluted with EtOAc (25 mL), and washed with sat brine (3×5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative HPLC, Method PrepAcidic-C, using decreasingly polar mixtures of mobile phase, to give the title compound (24 mg, 42%) as a white solid; MS (ESI) m/z [M+H].sup.+ 613.

    Example 50: (1S,4s)-4-(2-Fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2666] ##STR00530##

    [2667] The title compound was synthesized and purified in two steps from Intermediate 47 and Intermediate 111 in analogy with the synthesis described for Example 49 to give the title compound (26 mg, 52%) as a pale green solid; MS (ESI) m/z [M+H].sup.+ 613.

    Example 51: (1S,4s)-4-(2-Fluoro-5-(((1R,2S)-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2668] ##STR00531##

    Step A Intermediate 394: tert-Butyl (1S,4s)-4-(2-fluoro-5-(((1R,2S)-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2669] ##STR00532##

    [2670] Intermediate 73 (102 mg, 0.27 mmol), HATU (461 mg, 1.21 mmol) and DIPEA (0.169 mL, 0.97 mmol) were added to a solution of Intermediate 49 (67 mg, 0.24 mmol) in DMF (5 mL), and the reaction mixture was stirred at 20° C. for 3 h. The reaction mixture was diluted with EtOAc (75 mL), and washed with sat brine (6×15 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (PE:EtOAc, 2:1), to give the title compound (110 mg, 71%) as a brown solid; MS (ESI) m/z [M+Na].sup.+663.

    Step B (1S,4s)-4-(2-Fluoro-5-(((1R,2S)-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2671] TFA (3 mL) was added to a solution of Intermediate 394 (100 mg, 0.16 mmol) in DCM (3 mL) and the reaction mixture was stirred at 20° C. for 2 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Method PrepAcidic-C, using decreasingly polar mixtures of the mobile phase to give the title compound (45 mg, 47%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C28H30F5N2O6: 585.2018 found: 585.2034.

    Example 52: (1R,4s)-4-(2-fluoro-5-(((3S,4R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2672] ##STR00533##

    Step A Intermediate 395: tert-Butyl (1S,4s)-4-(2-fluoro-5-(((3R,4R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2673] ##STR00534##

    [2674] HATU (312 mg, 0.82 mmol), DIPEA (0.12 mL, 0.68 mmol) and Intermediate 73 (63 mg, 0.16 mmol) were added to a solution of Intermediate 56 (40 mg, 0.14 mmol) in DMF (2 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (50 mL), and washed with sat brine (5×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (PE:EtOAc, 1:5), to give the title compound (74 mg, 82%) as a colourless oil which solidified on standing; MS (ESI) m/z [M+H].sup.+ 657.

    Step B (1S,4s)-4-(2-Fluoro-5-(((3R,4R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2675] TFA (4 mL) was added to a solution of Intermediate 395 (70 mg, 0.11 mmol) in DCM (4 mL), and the reaction mixture was stirred at rt for 6 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, Method PrepAcidic-C, using decreasingly polar mixtures of the mobile phase, to give the title compound (24 mg, 38%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C28H30F5N2O7: 601.1968 found: 601.1972

    Example 53: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide

    [2676] ##STR00535##

    [2677] A solution of NH.sub.3 (0.033 mL, 1.50 mmol, 0.5 M in THF) in THF (1 mL) was added dropwise to a solution of Example 35 (100 mg, 0.19 mmol), EDC (180 mg, 0.94 mmol), HOBt (144 mg, 0.94 mmol), and DIPEA (0.328 mL, 1.88 mmol) in DCM (1 mL) cooled to 0° C. and under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat brine (100 mL), sat NaHCO.sub.3 (2×100 mL), and H.sub.2O (100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), and then by preparative HPLC, Method Prep-Acidic O, (gradient: 44-54%), to give the title compound. (65 mg, 56%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C29H43FN3O5: 532.3182 found: 532.3212.

    Example 54: (1s,4s)-4-(5-((3-Chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2678] ##STR00536##

    [2679] Pd-C (1.5 mg, 0.01 mmol) was added to a solution of Intermediate 59 (100 mg, 0.14 mmol) in THF (5 mL) at 20° C. and the reaction mixture was stirred under a hydrogen atmosphere for 6 h. The reaction mixture was filtered through silica, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, Method PrepAcidic-M, (gradient: 18-32%), to give the title compound (29 mg, 37%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C29H35C1FN2O6: 561.2162 found: 561.2194.

    Example 55: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1R,2S)-2-(((S)-3-methylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2680] ##STR00537##

    Step A Intermediate 396: tert-Butyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(((S)-3-methylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2681] ##STR00538##

    [2682] Intermediate 63 (100 mg, 0.20 mmol) was added to a solution of (S)-3-methylbutan-2-amine (35 mg, 0.41 mmol), HATU (154 mg, 0.41 mmol) and DIPEA (0.071 mL, 0.41 mmol) in DMF (5 mL) and the reaction mixture was stirred at rt for 4 h. The reaction mixture was quenched with ice (75 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporate to give the title compound (100 mg, 88%) as yellow oil; MS (ESI) m/z [M+H].sup.+ 563.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1R,2S)-2-(((S)-3-methylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2683] Intermediate 396 (100 mg, 0.18 mmol) was added to a solution of TFA (1 mL) in DCM (2 mL), and the reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Method PrepAcidic-K, (gradient: 45-55%), to give the title compound (30 mg, 31%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C27H40FN2O6: 507.2864 found: 507.2854.

    Example 56: (1S,4s)-4-(2-Fluoro-5-(((1R,2S)-2-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2684] ##STR00539##

    Step A Intermediate 397: tert-Butyl (1S,4s)-4-(2-fluoro-5-(((1R,2S)-2-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2685] ##STR00540##

    [2686] DIPEA (0.212 mL, 1.22 mmol) was added to a solution of Intermediate 63 (120 mg, 0.24 mmol), (1-(fluoromethyl)cyclopropyl)methanamine (50 mg, 0.49 mmol) and HATU (277 mg, 0.73 mmol) in DMF (4 mL) under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with H.sub.2O (2×50 mL), sat NaHCO.sub.3 (50 mL), and sat brine (2×50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:1) to give the title compound (135 mg, 96%) as a yellow gum; MS (ESI) m/z [M+H].sup.+ 579.

    Step B (1S,4s)-4-(2-Fluoro-5-(((1R,2S)-2-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2687] TFA (1 mL) was added to a solution of Intermediate 397 (130 mg, 0.22 mmol) in DCM (4 mL) at 20° C., and the reaction mixture was stirred at 20° C. for 1 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Method PrepAcidic-K, (gradient: 40-50%), to give the title compound (65 mg, 51%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C27H37F2N2O6: 523.2614 found: 523.2606.

    Example 57: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1R,2S)-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2688] ##STR00541##

    Step A Intermediate 398: tert-Butyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1R,2S)-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2689] ##STR00542##

    [2690] DIPEA (0.106 mL, 0.61 mmol) was added dropwise to a solution of 2,2-dimethylpropan-1-amine (26 mg, 0.30 mmol), Intermediate 63 (100 mg, 0.20 mmol) and HATU (385 mg, 1.01 mmol) in DMF (8 mL) at 20° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at rt for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat brine (125 mL), sat NaHCO.sub.3 (125 mL), and H.sub.2O (125 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), to give the title compound (98 mg, 86%) as a pale yellow solid.

    Step B (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1R,2S)-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2691] TFA (2 mL) was added dropwise to a solution of Intermediate 398 (98 mg, 0.17 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at 20° C. for 5 h. The solvent was removed under reduced pressure to give the title compound (93 mg, 91%) as a colourless solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C27H40FN2O6: 507.2864 found: 507.2876.

    Example 58: (1S,4s)-4-(5-(((1R,2S)-2-((2,2-Dimethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2692] ##STR00543##

    Step A Intermediate 399: tert-Butyl (1S,4s)-4-(5-(((1R,2S)-2-((2,2-dimethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2693] ##STR00544##

    [2694] DIPEA (0.106 mL, 0.61 mmol) was added dropwise to a solution of Intermediate 63 (100 mg, 0.20 mmol), 2,2-dimethylbutan-1-amine (20 mg, 0.20 mmol) and HATU (385 mg, 1.01 mmol) in DMF (5 mL) at 20° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with sat brine (125 mL), sat NaHCO.sub.3 (125 mL), and H.sub.2O (125 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), to give the title compound (115 mg, 98%) as a pale yellow solid; MS (ESI) m/z [M+H].sup.+ 577.

    Step B (1S,4s)-4-(5-(((1R,2S)-2-((2,2-Dimethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2695] TFA (2 mL) was added dropwise to a solution of Intermediate 399 (100 mg, 0.17 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at 20° C. for 5 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, Method PrepAcidic-K, (gradient: 50-60%), to give the title compound (55 mg, 59%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C28H42FN2O6: 521.3022 found: 521.3046.

    Example 59: (1S,4s)-4-(5-(((1R,2S)-2-((2-Ethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2696] ##STR00545##

    Step A Intermediate 400: tert-Butyl (1S,4s)-4-(5-(((1R,2S)-2-((2-ethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2697] ##STR00546##

    [2698] DIPEA (0.142 mL, 0.81 mmol) was added to a solution of Intermediate 63 (100 mg, 0.20 mmol), 2-ethylbutan-1-amine (31 mg, 0.30 mmol) and HATU (154 mg, 0.41 mmol) in DMF (3 mL) at 15° C. and under a nitrogen atmosphere, and the reaction mixture was stirred at 15° C. for 3 h. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with H.sub.2O (2×50 mL), sat NaHCO.sub.3 (50 mL), and sat brine (2×50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:2), to give the title compound (100 mg, 86%) as a white solid; MS (ESI) m/z [M+H].sup.+ 577.

    Step B (1S,4s)-4-(5-(((1R,2S)-2-((2-Ethylbutyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2699] TFA (2 mL) was added to a solution of Intermediate 400 (90 mg, 0.16 mmol) in DCM (2 mL) at 15° C., and the reaction mixture was stirred at 15° C. for 4 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Method PrepAcidic-K, (gradient: 48-58%), to give the title compound (60 mg, 70%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C28H42FN2O6: 521.3022 found: 521.3030.

    [2700] The examples included in Table 6 below were synthesized and purified analogous to the procedure of Example 59 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00006 TABLE 6 Ex HRMS (ESI) m/z Purification No Structure [M + H].sup.+ Method 60 [00547]embedded image calcd for C27H40FN2O6: 507.2864 found: 507.2860 Step A: Preparative TLC (EtOAc:PE, 1:2) Step B: Method PrepAcidic-K (gradient 50-60%) 61 [00548]embedded image calcd for C28H42FN2O6: 521.3022 found: 521.3024 Step A: Preparative TLC (EtOAc:PE, 1:2) Step B: Method PrepAcidic-K (gradient 40-55%) 62 [00549]embedded image calcd for C29H44FN2O6: 535.3178 found: 535.3194 Step A: Preparative TLC (EtOAc:PE, 1:2) Step B: Method PrepAcidic-K (gradient 50-60%) 63 [00550]embedded image calcd for C28H40FN2O6: 519.2864 found: 519.2872 Step A: Preparative TLC (EtOAc:PE, 1:2) Step B: Method PrepAcidic-K (gradient 27-37%) 64 [00551]embedded image calcd for C30H44FN2O6: 547.3178 found: 547.3202 Step A: Preparative TLC (EtOAc:PE, 1:2) Step B: Method PrepAcidic-K (gradient 54-64%)

    Example 65: (1S,4s)-4-(5-(((1R,2S)-2-(((R)-3,3-Dimethylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2701] ##STR00552##

    Step A Intermediate 401: tert-Butyl (1S,4s)-4-(5-(((1R,2S)-2-(((R)-3,3-dimethylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2702] ##STR00553##

    [2703] DIPEA (0.177 mL, 1.01 mmol) was added to a solution of Intermediate 63 (100 mg, 0.20 mmol), (R)-3,3-dimethylbutan-2-amine (31 mg, 0.30 mmol) and HATU (231 mg, 0.61 mmol) in DMF (3 mL) under a nitrogen atmosphere, and the reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with H.sub.2O (2×50 mL), sat NaHCO.sub.3 (50 mL), and sat brine (2×50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:1), to give the title compound (110 mg, 94%) as a yellow gum; MS (ESI) m/z [M+H].sup.+ 577.

    Step B (1S,4s)-4-(5-(((1R,2S)-2-(((R)-3,3-Dimethylbutan-2-yl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2704] TFA (3 mL) was added to Intermediate 401 (105 mg, 0.18 mmol) in DCM (3 mL) at 20° C., an the reaction mixture was stirred at 20° C. for 30 min. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Method PrepAcidic-K, (gradient: 50-60%), to give the title compound (75 mg, 75%) as a white solid; HRMS (ESI) m/z [M+H].sup.+ calcd for C28H42FN2O6: 521.3022 found: 521.3034.

    [2705] The examples included in Table 7 below were synthesized and purified analogous to the procedure of Example 65 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00007 TABLE 7 Ex Purification No Structure (m/z) [M + H].sup.+ Method 66 [00554]embedded image calcd for C26H38FN2O6: 493.2708 found: 493.2714 Step A: Preparative TLC (EtOAc:PE, 1:1) Step B: Method PrepAcidic-K (gradient 46-56%) 67 [00555]embedded image calcd for C28H40FN2O6: 519.2864 found: 519.2872 Step A: Preparative TLC (EtOAc:PE, 1:1) Step B: Method PrepAcidic-K (gradient 45-55%) 68 [00556]embedded image calcd for C27H38FN2O6: 505.2708 found: 505.2716 Step A: Preparative TLC (EtOAc:PE, 1:1) Step B: Method PrepAcidic-K (gradient 42-52%) 69 [00557]embedded image calcd for C27H37FN3O6: 518.2660 found: 518.2644 Step A: Preparative TLC (EtOAc:PE, 1:1) Step B: Method PrepAcidic-K (gradient 37-47%) 70 [00558]embedded image calcd for C27H37F4N2O6: 561.2582 found: 561.2568 Step A: Preparative TLC (EtOAc:PE, 1:1) Step B: Method PrepAcidic-K (gradient 47-57%)

    Example 71. (1S,4s)-4-(2-Cyano-5-(((1S,2R,3S,4R)-3-((cyclopropylmethyl)carbamoyl)bicyclo[2.2.1] heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2706] ##STR00559##

    [2707] A solution of Intermediate 68 (500 μL, 0.024 g, 0.05 mmol, 0.1 M in DMF), a solution of cyclopropylmethanamine (500 μL, 0.05 mmol, 0.1 M in DMF) and a solution of DIPEA (500 L, 0.15 mmol, 0.3 M in DMF) were added to a vial at rt. A solution of HATU (500 μL, 0.15 mmol, 0.3 M in DMF) was added and the reaction mixture was stirred at 40° C. overnight. The crude mixture was washed with DMSO (3×500 μL), filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by Method SFC-A to afford the title compound (10.3 mg, 39%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.38N.sub.3O.sub.6: 524.2756 found: 524.2752.

    [2708] The examples included in Table 8 below were synthesized analogous to the procedure of Example 71 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00008 TABLE 8 Ex HRMS (ESI) Purification No. Structure m/z [M + H].sup.+ Method 72 [00560]embedded image calcd for C.sub.29H.sub.35N.sub.4O.sub.6: 535.2552 found: 535.2554 SFC-A 73 [00561]embedded image calcd for C.sub.30H.sub.40N.sub.3O.sub.6: 538.2912 found: 538.2912 SFC-A 74 [00562]embedded image calcd for C.sub.31H.sub.42N.sub.3O.sub.7: 568.3016 found: 568.3014 SFC-B 75 [00563]embedded image calcd for C.sub.31H.sub.42N.sub.3O.sub.7: 568.3016 found: 568.3020 SFC-C 76 [00564]embedded image calcd for C.sub.29H.sub.40N.sub.3O.sub.7: 542.2860 found: 542.2860 SFC-C 77 [00565]embedded image calcd for C.sub.29H.sub.39FN.sub.3O.sub.6: 544.2818 found: 544.2820 SFC-C 78 [00566]embedded image calcd for C.sub.32H.sub.44N.sub.3O.sub.6: 566.3224 found: 566.3232 SFC-A 79 [00567]embedded image calcd for C.sub.31H.sub.42N.sub.3O.sub.7: 568.3016 found: 568.3012 SFC-A 80 [00568]embedded image calcd for C.sub.31H.sub.42N.sub.3O.sub.7: 568.3016 found: 568.3010 SFC-A 81 [00569]embedded image calcd for C.sub.35H.sub.46N.sub.3O.sub.6: 604.3380 found: 604.3376 PrepBasic-C Gradient: 5-95% 82 [00570]embedded image calcd for C.sub.33H.sub.46N.sub.3O.sub.6: 580.3380 found: 580.3378 PrepBasic-C Gradient: 5-95% 83 [00571]embedded image calcd for C.sub.33H.sub.46N.sub.3O.sub.6: 580.3380 found: 580.3372 SFC-D 84 [00572]embedded image calcd for C.sub.33H.sub.46N.sub.3O.sub.6: 580.3380 found: 580.3382 SFC-D 85 [00573]embedded image calcd for C.sub.30H.sub.41N.sub.4O.sub.7: 569.2970 found: 569.2974 SFC-D 86 [00574]embedded image calcd for C.sub.32H.sub.44N.sub.3O.sub.6: 566.3224 found: 566.3222 PrepBasic-C Gradient: 5-95% 87 [00575]embedded image calcd for C.sub.32H.sub.44N.sub.3O.sub.6: 566.3224 found: 566.3240 PrepBasic-C Gradient: 5-95% 88 [00576]embedded image calcd for C.sub.31H.sub.44N.sub.3O.sub.6: 554.3224 found: 554.3222 PrepBasic-C Gradient: 5-95% 89 [00577]embedded image calcd for C.sub.28H.sub.37FN.sub.3O.sub.7: 546.2610 found: 546.2614 SFC-D 90 [00578]embedded image calcd for C.sub.30H.sub.40N.sub.3O.sub.6: 538.2912 found: 538.2912 SFC-D 91 [00579]embedded image calcd for C.sub.29H.sub.40N.sub.3O.sub.6: 526.2912 found: 526.2910 PrepBasic-C Gradient: 5-95% 92 [00580]embedded image calcd for C.sub.31H.sub.41FN.sub.3O.sub.6: 570.2979, found: 570.2987 SFC-E 93 [00581]embedded image calcd for C.sub.31H.sub.39N.sub.4O.sub.6: 563.2864 found: 563.2858 PrepBasic-C Gradient: 5-95% 94 [00582]embedded image calcd for C.sub.30H.sub.39FN.sub.3O.sub.6: 556.2818 found: 556.2810 PrepAcidic-E Gradient: 5-95% 95 [00583]embedded image calcd for C.sub.30H.sub.39FN.sub.3O.sub.6: 556.2818 found: 556.2816 PrepBasic-C Gradient: 5-95% 96 [00584]embedded image calcd for C.sub.28H.sub.36F.sub.2N.sub.3O.sub.6: 548.2566 found: 548.2570 SFC-F 97 [00585]embedded image calcd for C.sub.29H.sub.39FN.sub.3O.sub.6: 544.2818 found: 544.2818 SFC-F 98 [00586]embedded image calcd for C.sub.30H.sub.40N.sub.3O.sub.6: 538.2912 found: 538.2918 SFC-D 99 [00587]embedded image calcd for C.sub.29H.sub.40N.sub.3O.sub.6: 526.2912 found: 526.2908 SFC-F 100 [00588]embedded image calcd for C.sub.29H.sub.38N.sub.3O.sub.6: 524.2756 found: 524.2760 SFC-D 101 [00589]embedded image calcd for C.sub.32H.sub.42F.sub.2N.sub.3O.sub.7: 618.2986 found: 618.2980 SFC-F 102 [00590]embedded image calcd for C.sub.28H.sub.33F.sub.5N.sub.3O.sub.6: 602.2284 found: 602.2280 SFC-A 103 [00591]embedded image calcd for C.sub.33H.sub.46N.sub.3O.sub.7: 596.3330 found: 596.3324 SFC-F 104 [00592]embedded image calcd for C.sub.33H.sub.45N.sub.3O.sub.7: 596.3330 found: 596.3334 SFC-F 105 [00593]embedded image calcd for C.sub.34H.sub.48N.sub.3O.sub.6: 594.3538 found: 594.3538 SFC-F 106 [00594]embedded image calcd for C.sub.34H.sub.48N.sub.3O.sub.6: 594.3538 found: 594.3538 SFC-A 107 [00595]embedded image calcd for C.sub.33H.sub.43N.sub.4O.sub.6: 591.3176 found: 591.3178 SFC-A 108 [00596]embedded image calcd for C.sub.34H.sub.42N.sub.3O.sub.6: 588.3068 found: 588.3082 SFC-F 109 [00597]embedded image calcd for C.sub.32H.sub.44N.sub.3O.sub.7: 582.3174 found: 582.3170 SFC-F 110 [00598]embedded image calcd for C.sub.31H.sub.41FN.sub.3O.sub.7: 586.2922 found: 586.2920 SFC-A 111 [00599]embedded image calcd for C.sub.30H.sub.40N.sub.3O.sub.7: 554.2860 found: 554.2864 SFC-E 112 [00600]embedded image calcd for C.sub.31H.sub.40N.sub.3O.sub.6: 550.2912 found: 550.2912 SFC-F 113 [00601]embedded image calcd for C.sub.35H.sub.46N.sub.3O.sub.7: 620.3330 found: 620.3328 SFC-A 114 [00602]embedded image calcd for C.sub.31H.sub.36F.sub.2N.sub.5O.sub.6: 612.2628 found: 612.2616 SFC-A 115 [00603]embedded image calcd for C.sub.33H.sub.40N.sub.3O.sub.6: 574.2912 found: 574.2914 Method PrepBasic-I

    Example 116. (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(propylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2709] ##STR00604##

    [2710] Intermediate 68 (2.6 g, 5.5 mmol) and N-hydroxysuccinimide (636 mg, 5.5 mmol) were added to DCM (20 mL) at rt. The mixture was stirred for 30 min and cooled to 5° C. DCC (1.1 g, 5.5 mmol) was added slowly and the reaction was stirred at 5° C. for 1 h. The solvent was removed in vacuo and the residue was purified by preparative TLC with MeOH/DCM (20:1) to give 1.8 g of (1S,4s)-4-(2-cyano-5-(((1S,2R,3S,4R)-3-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (74% purity, 42%) as a white solid.

    [2711] The resulting solid (57 mg, 0.10 mmol), propan-1-amine (6.5 mg, 0.11 mmol), TEA (20.2 mg, 0.20 mmol) and DCM (2 mL) were added to a 40 mL vial. The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was directly purified by Method PrepBasic-I to give the title compound (4.2 mg, 10%) as a solid. HRMS m/z [M+H].sup.+ calcd for C.sub.28H.sub.38N.sub.3O.sub.6: 512.2756 found: 512.2754.

    [2712] The examples included in Table 9 below were synthesized according to the procedure of Example 116 using the appropriate amine (as the free base or as the corresponding HCl salt) instead of propan-1-amine. The amine is commercially available if not otherwise stated.

    TABLE-US-00009 TABLE 9 Ex HRMS (ESI) Purification No. Structure m/z [M + H].sup.+ Method 117 [00605]embedded image calcd for C.sub.31H.sub.44N.sub.3O.sub.6: 554.3224 found: 554.3206 Method PrepBasic-I 118 [00606]embedded image calcd for C.sub.34H.sub.42N.sub.3O.sub.6: 588.3068 found: 588.3056 Method PrepBasic-Q 119 [00607]embedded image calcd for C.sub.31H.sub.44N.sub.3O.sub.6: 554.3224 found: 554.3234 Method PrepBasic-Q 120 [00608]embedded image calcd for C.sub.33H.sub.46N.sub.3O.sub.6: 580.3380 found: 580.3386 Method PrepBasic-R 121 [00609]embedded image calcd for C.sub.31H.sub.42N.sub.3O.sub.6: 552.3068 found: 552.3060 Method PrepBasic-P 122 [00610]embedded image calcd for C.sub.31H.sub.44N.sub.3O.sub.7: 570.3174 found: 570.3178 Method PrepBasic-W 123 [00611]embedded image calcd for C.sub.32H.sub.36F.sub.2N.sub.3O.sub.6: 596.2566 found: 596.2572 Method FlashBasic-A 124 [00612]embedded image calcd for C.sub.31H.sub.42N.sub.3O.sub.6: 552.3068 found: 552.3078 Method PrepBasic-Y Prepared from amine Intermediate 99 125 [00613]embedded image calcd for C.sub.34H.sub.42N.sub.3O.sub.6: 588.3068 found: 588.3060 Method PrepBasic-X 126 [00614]embedded image calcd for C.sub.30H.sub.42N.sub.3O.sub.6: 540.3068 found: 540.3068 Method PrepBasic-X 127 [00615]embedded image calcd for C.sub.30H.sub.42N.sub.3O.sub.6: 540.3068 found: 540.3054 Method FlashBasic-A 128 [00616]embedded image calcd for C.sub.33H.sub.46N.sub.3O.sub.6: 580.3380 found: 580.3382 Method PrepBasic-S 129 [00617]embedded image calcd for C.sub.30H.sub.42N.sub.3O.sub.7: 556.3016 found: 556.3014 Method PrepBasic-O 130 [00618]embedded image calcd for C.sub.31H.sub.44N.sub.3O.sub.6: 554.3224 found: 554.3238 Method PrepBasic-O 131 [00619]embedded image calcd for C.sub.33H.sub.39FN.sub.3O.sub.6: 592.2818 found: 592.2826 Method PrepBasic-U 132 [00620]embedded image calcd for C.sub.31H.sub.42N.sub.3O.sub.6: 552.3068 found: 552.3070 Method FlashBasic-A 133 [00621]embedded image calcd for C.sub.30H.sub.40N.sub.3O.sub.6: 538.2912 found: 538.2908 Method PrepBasic-O 134 [00622]embedded image calcd for C.sub.33H.sub.43F.sub.3N.sub.3O.sub.6: 634.3098 found: 634.3096 Method PrepBasic-J 135 [00623]embedded image calcd for C.sub.28H.sub.37FN.sub.3O.sub.6: 530.2660 found: 530.2660 Method PrepBasic-I 136 [00624]embedded image calcd for C.sub.34H.sub.42N.sub.3O.sub.6: 588.3068 found: 588.3066 Method PrepBasic-I 137 [00625]embedded image calcd for C.sub.31H.sub.42N.sub.3O.sub.7: 568.3016 found: 568.3022 Method PrepBasic-I 138 [00626]embedded image calcd for C.sub.30H.sub.42N.sub.3O.sub.7: 556.3016 found: 556.3020 Method PrepBasic-I 139 [00627]embedded image calcd for C.sub.30H.sub.40N.sub.3O.sub.6: 538.2912 found: 538.2910 Method PrepBasic-I 140 [00628]embedded image calcd for C.sub.33H.sub.40N.sub.3O.sub.6: 574.2912 found: 574.2908 Method PrepBasic-X

    Example 141. (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(Bicyclo[1.1.1]pentan-1-ylcarbamoyl)-bicyclo[2.2.1] heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2713] ##STR00629##

    [2714] Intermediate 68 (40 mg, 0.09 mmol) was dissolved in DCM (4.2 mL). DIPEA (28 μL, 0.16 mmol) was added followed by HATU (97 mg, 0.26 mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (10 mg, 0.09 mmol). After stirring at rt for 2 h, the reaction was quenched with Na.sub.2CO.sub.3 (sat) and the biphasic mixture stirred for 2 h. The organic layer was separated and washed with DCM twice. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude material was purified by Method PrepBasic-A using a gradient of 35-75% to afford the title compound (10.5 mg, 23%). HRMS (ESI): m/z [M+H].sup.+ calcd for C.sub.30H.sub.38N.sub.3O.sub.6: 536.2761, found: 536.2786.

    Example 142. (1s,4s)-4-(2-Fluoro-4-methoxy-5-((2-(neopentylcarbamoyl)phenyl)-carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2715] ##STR00630##

    [2716] TFA (0.34 mL, 4.2 mmol) was added to a solution of Intermediate 74 (50.4 mg, 0.09 mmol) in DCM (1.8 mL) and the mixture was stirred for 2 h. The solvent was removed under reduced pressure. The crude material was purified by Method PrepAcidic-F using a gradient of 35-75% to afford the title compound (29.6 mg, 65%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.28H.sub.36FN.sub.2O.sub.6: 515.2552 found: 515.2558.

    Example 143. (1s,4s)-4-(2-Fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)-carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2717] ##STR00631##

    Step A. Intermediate 402: Tert-Butyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2718] ##STR00632##

    [2719] DIPEA (68 μL, 0.39 mmol) was added to a solution of Intermediate 73 (50 mg, 0.13 mmol) in DCM (0.9 mL). HATU (149 mg, 0.39 mmol) was added followed by 2-amino-N-[(1-methylcyclobutyl)methyl]benzamide (34.2 mg, 0.16 mmol) and the reaction mixture stirred at rt for 5 h. Na.sub.2CO.sub.3 (sat) was added and the biphasic mixture stirred for 10 min before the two layers were separated. The aq phase was washed with DCM. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure to afford the title compound. The product was used in the next step without further purification. MS (ESI): m/z [M+H].sup.+ 583.3.

    Step B. (1s,4s)-4-(2-Fluoro-4-methoxy-5-((2-(((1-methylcyclobutyl)methyl)carbamoyl)-phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2720] Intermediate 402 was dissolved in DCM (1.8 mL) and TFA (0.48 mL, 6.3 mmol) was added. The mixture was stirred for 2 h after which the solvent was removed under reduced pressure. The crude material was purified by Method PrepAcidic-F using a gradient of 35-75% to afford the title compound (57.4 mg, 84%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.36FN.sub.2O.sub.6: 527.2552 found: 527.2564.

    Example 144. (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-3-Ethylpentan-2-yl)carbamoyl)bicyclo-[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid. Isomer 1

    [2721] ##STR00633##

    [2722] TFA (0.4 mL, 5.2 mmol) was added to a solution of Intermediate 78 (67 mg, 0.11 mmol) in DCM (1.8 mL) and the mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure to afford the title compound (69.4 mg, 86%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.46FN.sub.2O.sub.6: 561.3334 found: 561.3334.

    Example 145. (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-3-Ethylpentan-2-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid. Isomer 2

    [2723] ##STR00634##

    [2724] TFA (0.3 mL, 4.3 mmol) was added to a solution of Intermediate 79 (55 mg, 0.09 mmol) in DCM (1.8 mL) and the mixture stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude compound was purified by Method PrepAcidic-F using a gradient of 35-75% to afford the title compound (45.7 mg, 91%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.46FN.sub.2O.sub.6: 561.3334 found: 561.3332.

    Example 146. (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    Example 147. (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)bicyclo-[2.2.1]heptane-2-carboxamide

    [2725] ##STR00635##

    Step A. Intermediate 403: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

    [2726] ##STR00636##

    [2727] TFA (0.4 mL, 5.2 mmol) was added to a solution of Intermediate 75 (56 mg, 0.11 mmol) in DCM (0.7 mL) and the mixture stirred at rt for 2 h. The solvent was removed under reduced pressure to afford the title compound as a 1:1 TFA adduct (66 mg). The product was used in the next step without further purification. MS (ESI): m/z [M+H].sup.+ 464.4.

    Step B. (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2728] Intermediate 403 (25 mg, 0.05 mmol) was dissolved in DCM. DIPEA (28 μL, 0.16 mmol) was added followed by HATU (61.5 mg, 0.16 mmol) and (4-fluorotetrahydropyran-4-yl)methanamine hydrochloride (9.15 mg, 0.05 mmol). The reaction mixture was stirred at rt for 2 h. Na.sub.2CO.sub.3 (sat) was added and the biphasic mixture stirred for 10 min before the two layers were separated. The aq phase was washed with DCM. The combined organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude material was purified by Method PrepBasic-D using a gradient of 15-55% to afford a first fraction containing Example 146 and a second fraction containing Example 147. The first fraction was further purified by Method PrepAcidic-E using a gradient of 5-95% to afford Example 146 (5.5 mg, 17%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.41F.sub.2N.sub.2O.sub.7: 579.2876 found: 579.2872.

    [2729] The second fraction was further purified by Method PrepAcidic-E using a gradient of 5-95% to afford Example 147 (4 mg, 13%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.42F.sub.2N.sub.3O.sub.6: 578.3036 found: 578.3044.

    Example 148: (1S,3s)-3-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

    [2730] ##STR00637##

    [2731] Intermediate 80 (17.5 mg, 0.03 mmol) was dissolved in MeOH (0.7 mL) and hydrogenated in a H-Cube® reactor at 1 mL/min, rt, Full H2, Pd/C (CatCart 30 mm). The solvent was removed under reduced pressure. The crude material was purified by Method PrepAcidic-H using a gradient of 15-55% to afford the title compound (2.1 mg, 12%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.38N.sub.3O.sub.6: 524.2756 found: 524.2744.

    Example 149: (1S,3s)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

    [2732] ##STR00638##

    [2733] Intermediate 83 (17.7 mg, 0.03 mmol) was dissolved in MeOH (0.7 mL) and hydrogenated in a H-Cube® reactor at 1 mL/min, rt, Full H2, Pd/C (CatCart 30 mm). The solvent was removed under reduced pressure. The crude material was purified by Method PrepAcidic-H using a gradient of 25-65% to afford the title compound (14.8 mg, 83%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.28H.sub.38FN.sub.2O.sub.6: 517.2708 found: 517.2738.

    Example 150: (1s,4s)-4-(2-Fluoro-4-methoxy-5-((4-(((1-methylcyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2734] ##STR00639##

    [2735] Pd(OH).sub.2/C (20 wt %, 12.1 mg, 0.02 mmol) was added to a solution of Intermediate 86 (115 mg, 0.17 mmol) in THF: MeOH (2:1, 5.7 mL). The reaction suspension was stirred at rt under an atmosphere of hydrogen (2 atm). The reaction mixture was filtered through a pad of Celite® and the solvent removed under reduced pressure. The crude material was purified by Method PrepAcidic-E using a gradient of 5-95% to afford the title compound (50.7 mg, 56%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.28H.sub.35FN.sub.3O.sub.6: 528.2504 found: 528.2512. .sup.1H NMR (600 MHz, DMSO-d6) δ 1.12 (d, 6H), 1.29 (td, 2H), 1.4-1.5 (m, 2H), 1.61 (ddd, 2H), 1.81 (ddddd, 2H), 1.89-1.99 (m, 4H), 2.08 (d, 2H), 3.33 (s, 2H), 4.01 (s, 3H), 4.24 (tt, 1H), 7.24 (d, 1H), 7.57 (d, 1H), 7.80 (d, 1H), 8.45 (d, 1H), 8.91 (t, 1H), 9.70 (s, 1H), 11.55 (s, 1H).

    [2736] The examples included in Table 10 below were synthesized analogous to the procedure of Example 150 starting from the appropriate intermediate.

    TABLE-US-00010 TABLE 10 HRMS (ESI) Purification Starting Ex No. Structure m/z [M + H].sup.+ Method Intermediate Catalyst 151 [00640]embedded image calcd for C.sub.31H.sub.46FN.sub.2O.sub.6: 561.3334 found: 561.3344 SFC-F Int. 89 Pd(OH).sub.2/ C 152 [00641]embedded image calcd for C.sub.27H.sub.35FN.sub.3O.sub.6S: 548.2224 found: 548.2242 PrepAcidic-I Gradient: 5-95% Int. 92 Pd/C 153 [00642]embedded image calcd for C.sub.29H.sub.35ClFN.sub.2O.sub.6: 561.2162 found: 561.2178 SFC-F Int. 97 Pd/C 154 [00643]embedded image calcd for C.sub.27H.sub.34FN.sub.2O.sub.6S: 533.2116 found: 533.2146 PrepBasic-E Gradient 5-95% Int. 98 Pd/C

    Example 155: (1s,4s)-4-(5-((5-Chloro-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2737] ##STR00644##

    [2738] Hydrogenation of Intermediate 95 was performed analogous to the procedure described for the synthesis of Example 150 using THF:MeOH (9:1) as solvent. The crude material was purified by Method PrepAcidic-E using a gradient of 5-95% to afford the title compound (52.8 mg, 55%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.35ClFN.sub.2O.sub.6: 561.2162 found: 561.2154. .sup.1H NMR (600 MHz, DMSO-d6) δ 1.12 (d, 6H), 1.29 (td, 2H), 1.4-1.49 (m, 2H), 1.61 (ddd, 2H), 1.74-1.89 (m, 2H), 1.89-2 (m, 4H), 2.08 (d, 2H), 3.30 (s, 2H), 3.99 (s, 3H), 4.23 (tt, 1H), 7.22 (d, 1H), 7.29 (dd, 1H), 7.67 (d, 1H), 7.76 (d, 1H), 8.70 (d, 1H), 8.74 (t, 1H), 11.93 (s, 1H).

    Example 156: (1s,4s)-4-(2-Fluoro-4-methoxy-5-((2-methyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2739] ##STR00645##

    [2740] Intermediate 96 (91.9 mg, 0.13 mmol) was dissolved in THF:MeOH (1:1) and hydrogenated in a H-Cube® reactor at 1 mL/min, 50° C., Full H2, Pd/C (CatCart 30 mm). The solvent was removed under reduced pressure. The crude material was purified by Method SFC-B to afford the title compound (53.8 mg, 73%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.38FN.sub.2O.sub.6: 541.2708 found: 541.2722.

    Example 157. (1s,4s)-4-(5-((5-Chloro-2-((cycloheptylmethyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2741] ##STR00646##

    Step A. Intermediate 404: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((5-chloro-2-((cycloheptyl-methyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2742] ##STR00647##

    [2743] Intermediate 103 (44 mg, 0.09 mmol) was dissolved in DMF (2 mL). DIPEA (31 μL, 0.18 mmol), TCFH (39 mg, 0.14 mmol) and cycloheptylmethanamine (18 mg, 0.14 mmol) were added and the mixture stirred at rt for 16 h. The crude compound was purified by Method PrepAcidic-Pand used in the next step.

    Step B. (1s,4s)-4-(5-((5-Chloro-2-((cycloheptylmethyl)carbamoyl)phenyl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2744] Hydrogenation of Intermediate 404 was performed analogous to the procedure described for the synthesis of Example 150. The crude material was purified by Method FlashAcid-A using a gradient of 5-100% to afford the title compound (3.8 mg, 5%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.32H.sub.39ClN.sub.3O.sub.6: 596.2522 found: 596.2518.

    [2745] The examples included in Table 11 below were synthesized analogous to the procedure of Example 157 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated. All Examples except Example 159 within this table were purified by Method PrepAcidic-P in Step A and by Method FlashAcid-A in Step B. Example 159 was purified by Method PrepBasic-K in Step A and by Method FlashAcid-A in Step B.

    TABLE-US-00011 TABLE 11 Ex HRMS (ESI) m/z Starting No. Structure [M + H].sup.+ amine 158 [00648]embedded image calcd for C.sub.34H.sub.35ClN.sub.3O.sub.6: 616.2208 found: 616.2196 159 [00649]embedded image calcd for C.sub.30H.sub.35ClN.sub.3O.sub.6: 568.2208 found: 568.2208 Int. 99 160 [00650]embedded image calcd for C.sub.29H.sub.32ClFN.sub.3O.sub.6: 572.1958 found: 572.1962 161 [00651]embedded image calcd for C.sub.29H.sub.31ClN.sub.3O.sub.6: 552.1896 found: 552.1910 162 [00652]embedded image calcd for C.sub.29H.sub.34ClFN.sub.3O.sub.6: 574.2114 found: 574.2134 163 [00653]embedded image calcd for C.sub.29H.sub.35ClN.sub.3O.sub.6: 556.2208 found: 556.2212 164 [00654]embedded image calcd for C.sub.28H.sub.32ClFN.sub.3O.sub.6: 560.1958 found: 560.1970 165 [00655]embedded image calcd for C.sub.30H.sub.35ClN.sub.3O.sub.6: 568.2208 found: 568.2228

    Example 166. (1s,4s)-4-(2-Cyano-5-((2-((3-fluorobenzyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2746] ##STR00656##

    Step A. Intermediate 405: Naphthalen-1-ylmethyl (1s,4s)-4-(2-cyano-5-((2-((3-fluorobenzyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2747] ##STR00657##

    [2748] Intermediate 104 (39 mg, 0.064 mmol) was dissolved in DMF (2 mL). DIPEA (21 μL, 0.12 mmol), TCFH (25 mg, 0.09 mmol) and (3-fluorophenyl)methanamine (11 mg, 0.09 mmol) were added and the reaction mixture was stirred at 80° C. for 16 h. The crude compound was purified by Method PrepAcidic-P.

    Step B. (1s,4s)-4-(2-Cyano-5-((2-((3-fluorobenzyl)carbamoyl)-5-methylphenyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2749] Hydrogenation of Intermediate 405 was performed analogous to the procedure described for the synthesis of Example 150. The crude material was purified by Method PrepBasic-M to afford the title compound (2.3 mg, 6%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.32H.sub.33FN.sub.3O.sub.6: 574.2348 found: 574.2340.

    [2750] The examples included in Table 12 below were synthesized analogous to the procedure of Example 166 using the appropriate commercially available amines (as the free base or as the corresponding HCl salt). All Examples within this table were purified by Method PrepAcidic-P in Step A and in Step B as indicated in Table 12.

    TABLE-US-00012 TABLE 12 Ex Purification HRMS (ESI) m/z No. Structure Method [M + H].sup.+ 167 [00658]embedded image Method PrepBasic-L calcd for C.sub.31H.sub.40N.sub.3O.sub.6: 550.2912 found: 550.2906 168 [00659]embedded image Method PrepBasic-M calcd for C.sub.30H.sub.38N.sub.3O.sub.6: 536.2756 found: 536.2752 169 [00660]embedded image Method PrepBasic-V calcd for C.sub.32H.sub.40N.sub.3O.sub.6: 562.2912 found: 562.2906 170 [00661]embedded image Method PrepBasic-V calcd for C.sub.30H.sub.38N.sub.3O.sub.6: 536.2756 found: 536.2756 171 [00662]embedded image Method PrepBasic-V calcd for C.sub.30H.sub.36N.sub.3O.sub.6: 534.2598 found: 534.2590 172 [00663]embedded image Method PrepBasic-V calcd for C.sub.30H.sub.35FN.sub.3O.sub.6: 552.2504 found: 552.2508 173 [00664]embedded image Method PrepBasic-V calcd for C.sub.30H.sub.34N.sub.3O.sub.6: 532.2442 found: 532.2446 174 [00665]embedded image Method PrepBasic-V calcd for C.sub.30H.sub.36N.sub.3O.sub.6: 534.2598 found: 534.2594

    Example 175. (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4,4,4-trifluorobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2751] ##STR00666##

    Step A. Intermediate 406: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4,4,4-trifluorobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2752] ##STR00667##

    [2753] HATU (0.239 g, 0.63 mmol) was added to a mixture of Intermediate 106 (0.2 g, 0.42 mmol), 4,4,4-trifluorobutan-1-amine (0.075 g, 0.59 mmol) and DIPEA (0.219 mL, 1.26 mmol) in DMF (10 mL) at 20° C. The resulting solution was stirred at 60° C. for 3 h. The reaction mixture was poured into sat NaHCO.sub.3 (150 mL), extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (0.2 g, 81%) as a yellow oil which solidified on standing. The crude product was used in the next step directly without further purification. MS (ESI): m/z [M+H].sup.+ 587.4.

    Step B. (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4,4,4-trifluorobutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2754] LiOH (0.10 g, 4.18 mmol) was added to Intermediate 406 (0.20 g, 0.34 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL) and acidified with HCl (2 M, aq). The aq layer was extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a colorless oil which solidified on standing. The crude product was purified by preparative HPLC using Method PrepAcidic-A to afford the title compound (0.165 g, 87%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.27H.sub.35F.sub.4N.sub.2O.sub.6: 559.2426 found: 559.2374.

    [2755] The examples included in Table 13 below were synthesized in a similar way to the procedure of Example 175 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00013 TABLE 13 Ex HRMS (ESI) m/z Purification No. Structure [M + H].sup.+ Method 176 [00668]embedded image Calcd for C.sub.28H.sub.38FN.sub.2O.sub.6: 517.2708 found: 512.2700 Method Prep Acidic-A 177 [00669]embedded image Calcd for C.sub.27H.sub.36FN.sub.2O.sub.6: 503.2552 found: 503.2536 Method Prep Acidic-A (Gradient: 44%-54%) 178 [00670]embedded image Calcd for C.sub.28H.sub.36FN.sub.2O.sub.6: 515.2552 found: 515.2540 Method Prep Acidic-C (Gradient: 53%-53%)

    Example 179. (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2756] ##STR00671##

    Step A. Intermediate 407: Ethyl (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2757] ##STR00672##

    [2758] HATU (260 mg, 0.68 mmol) was added portion wise to Intermediate 111 (194 mg, 0.57 mmol), Intermediate 119 (180 mg, 0.57 mmol) and DIPEA (221 mg, 1.71 mmol) in DMF (10 mL) at Rt. The resulting solution was stirred at 60° C. for 2 h. The reaction mixture was poured into sat NaHCO.sub.3 (200 mL), extracted with EtOAc (3×75 mL), the organic layer was washed with brine (2×100 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (260 mg, 72%) as a brown gum. The product was used in the next step directly without further purification. MS (ESI): m/z [M+H].sup.+ 661.2.

    Step B. (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2759] The hydrolysis of Intermediate 407 was carried out in an analogous way to Example 175 Step B. Purification by Method PrepAcidic-C (Gradient: 32%-32%) afforded the title compound (0.142 g, 74.8%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.32F.sub.5N.sub.2O.sub.6: 611.2174 found: 611.2182.

    Example 180. (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2760] ##STR00673##

    Step A. Intermediate 408: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2761] ##STR00674##

    [2762] EDC (0.177 g, 0.92 mmol) was added slowly to a mixture of Intermediate 106 (0.2 g, 0.42 mmol), 2,2-dimethylpropan-1-amine (0.110 g, 1.26 mmol) and HOBt (0.141 g, 0.92 mmol), Et.sub.3N (0.292 mL, 2.09 mmol) in DMF (20 mL) at 20° C. The resulting solution was stirred at 60° C. for 15 h. The reaction mixture was diluted with EtOAc (200 mL) and washed sequentially with brine (150 mL, sat), sat NaHCO.sub.3 (150 mL), and H.sub.2O (150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (0.2 g, 87%) as a yellow oil which solidified on standing. MS (ESI): m/z [M+H].sup.+ 547.5.

    Step B. (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2763] The hydrolysis of Intermediate 408 and following purification was carried out in an analogous way to Example 175 Step B. to afford the title compound (0.142 g, 74.8%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.28H.sub.40FN.sub.2O.sub.6: 519.2864 found: 519.2888.

    Example 181 (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((4-(Difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2764] ##STR00675##

    Step A. Intermediate 409: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((4-(difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2765] ##STR00676##

    [2766] 4-(Difluoromethyl)aniline (71.4 mg, 0.50 mmol), HATU (239 mg, 0.63 mmol), DIPEA (108 mg, 0.84 mmol) and DMAP (5.12 mg, 0.04 mmol) were added to Intermediate 106 (200 mg, 0.42 mmol) and the mixture was stirred at 20° C. overnight. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with brine (3×20 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in DCM as mobile phase to give the title compound (220 mg, 87%) as an orange solid. MS (ESI): m/z [M+H].sup.+ 603.

    Step B. (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((4-(Difluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2767] LiOH (26.2 mg, 1.10 mmol) was added to Intermediate 409 (220 mg, 0.37 mmol) in a solution of EtOH (6 mL)/H.sub.2O (3 mL). The reaction mixture was stirred at 20° C. for 5 h. The reaction mixture was acidified with 1 M HCl. Purification by Method PrepAcidic-C afforded the title compound (47.0 mg, 22%) as a light orange solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.34F.sub.3N.sub.2O.sub.6: 575.2364 found: 575.2388.

    [2768] The examples included in Table 14 below were synthesized in a similar way to the procedure of Example 181 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00014 TABLE 14 Ex HRMS (ESI) m/z Purification No. Structure [M + H].sup.+ Method 182 [00677]embedded image Calcd for C.sub.29H.sub.33F.sub.6N.sub.2O.sub.6S: 651.1958 found: 651.1942 Method Prep Acidic-C 183 [00678]embedded image Calcd for C.sub.29H.sub.33F.sub.6N.sub.2O.sub.6S: 651.1958 found: 651.1994 Method Prep Acidic-C

    Example 184. (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,6-Difluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2769] ##STR00679##

    Step A. Intermediate 410: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,6-difluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2770] ##STR00680##

    [2771] T3P (0.800 g, 1.26 mmol) was added to Intermediate 106 (0.20 g, 0.42 mmol), 2,6-difluoroaniline (0.065 g, 0.50 mmol) and DIPEA (0.366 mL, 2.09 mmol) in butyl acetate (20 mL) at 20° C. The resulting solution was stirred at 120° C. for 15 h. The reaction mixture was poured into sat NaHCO.sub.3 (150 mL), extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (0.200 g, 81%) as a brown gum. This was used in the next step without further purification. MS (ESI): m/z [M+H].sup.+ 589.2.

    Step B. (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,6-Difluorophenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2772] The hydrolysis of Intermediate 410 was carried out in an analogous way to Example 175 Step B. Purification by Method PrepAcidic-A (Gradient: 49%-59%) afforded the title compound (152 mg, 80%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.32F.sub.3N.sub.2O.sub.6: 561.2208 found: 561.2182.

    [2773] The examples included in Table 15 below were synthesized in a similar way to the procedure of Example 184 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00015 TABLE 15 Ex HRMS (ESI) m/z No. Structure [M + H].sup.+ Purification Method 185 [00681]embedded image Calcd for C.sub.29H.sub.33FIN.sub.2O.sub.6: 651.1362 found: 651.1364 Method PrepAcidic-C (Gradient: 58%-58%) 186 [00682]embedded image Calcd for C.sub.30H.sub.32ClF.sub.4N.sub.2O.sub.6: 627.1880 found: 627.1896 Method PrepAcidic-A (Gradient: 60%-70%) 187 [00683]embedded image Calcd for C.sub.29H.sub.31F.sub.4N.sub.2O.sub.6: 579.2112 found: 579.2130 Method PrepAcidic-G (Gradient: 60%-70%) 188 [00684]embedded image Calcd for C.sub.31H.sub.35F.sub.4N.sub.2O.sub.6: 607.2426 found: 607.2426 Method PrepAcidic-A (Gradient: 50%-80%) 189 [00685]embedded image Calcd for C.sub.33H.sub.42FN.sub.2O.sub.6: 581.3022 found: 581.3032 Method PrepAcidic-C (Gradient: 50%-75%) 190 [00686]embedded image Calcd for C.sub.32H.sub.38FN.sub.2O.sub.6: 565.2708 found: 565.2754 Method PrepAcidic-A (Gradient: 40%-80%)

    Example 191 (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-Cyano-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2774] ##STR00687##

    Step A. Intermediate 411: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-cyano-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2775] ##STR00688##

    [2776] T3P (0.800 g, 1.26 mmol) was added to Intermediate 106 (0.12 g, 0.25 mmol), 3-amino-5-(trifluoromethyl)benzonitrile (0.084 g, 0.45 mmol) and DIPEA (0.439 mL, 2.51 mmol) in butyl acetate (15 mL) at 20° C. The resulting solution was stirred at 120° C. for 15 h. The reaction mixture was poured into sat NaHCO.sub.3 (150 mL), extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (0.150 g, 92%) as a brown gum which was used as such in the next step. MS (ESI): m/z [M+H].sup.+ 646.3.

    Step B. Intermediate 412: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-Carbamoyl-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2777] ##STR00689##

    [2778] LiOH (0.50 g, 20.88 mmol) was added to Intermediate 411 (0.15 g, 0.23 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL), the reaction mixture was acidified with 2 M HCl. The aq layer was extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford colorless oil which solidified on standing. The crude product was purified by Method PrepAcidic-G (Gradient: 54%-64%) to afford the title compound (0.050 g, 34%) as a pale yellow solid along with Example 191 (10.0 mg, 7%) as a pale yellow solid. MS (ESI): m/z [M+H].sup.+ 618.2.

    Step C. (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-Cyano-5-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2779] PdCl.sub.2 (13.95 mg, 0.08 mmol) was added to Intermediate 412 (50 mg, 0.08 mmol) in MeCN (4 mL) and H.sub.2O (4.00 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into brine (150 mL, sat), extracted with EtOAc (3×75 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford yellow oil. The crude product and the product isolated in the step above (10.0 mg) were combined and purified by Method PrepAcidic-G (Gradient: 60%-70%) to afford the title compound (38.0 mg, 73.2%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.32F.sub.4N.sub.3O.sub.6: 618.2222 found: 618.2236.

    Example 192 (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylicacid

    [2780] ##STR00690##

    Step A. Intermediate 413: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2781] ##STR00691##

    [2782] DMAP (3.07 mg, 0.03 mmol) was added Intermediate 106 (120 mg, 0.25 mmol), 4-methyl-3-(trifluoromethyl)aniline (52.8 mg, 0.30 mmol), T3P (480 mg, 0.75 mmol) and DIEPA (0.176 mL, 1.01 mmol) in butyl acetate (5 mL). The resulting mixture was stirred at 120° C. for 16 h.

    [2783] The reaction mixture was poured into sat NaHCO.sub.3 (100 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (109 mg, 68%) as a white solid. This was used without further purification in the next step. MS (ESI): m/z [M+H].sup.+ 635.

    Step B. (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2784] The hydrolysis of Intermediate 413 was carried out in an analogous way to Example 181 Step B. Purification by Method PrepAcidic-C afforded the title compound (61 mg, 57%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.35F.sub.4N.sub.2O.sub.6: 607.2426 found: 607.2454.

    [2785] The examples included in Table 16 below were synthesized in a similar way to the procedure of Example 192 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00016 TABLE 16 Ex Purification No. Structure HRMS (m/z) [M + H].sup.+ Method 193 [00692]embedded image Calcd for C.sub.30H.sub.33F.sub.4N.sub.2O.sub.6: 593.2270 found: 593.2294 Method PrepAcidic-C 194 [00693]embedded image Calcd for C.sub.31H.sub.35F.sub.4N.sub.2O.sub.7: 623.2374 found: 623.2364 Method PrepAcidic-C 195 [00694]embedded image Calcd for C.sub.30H.sub.34F.sub.3N.sub.2O.sub.7: 591.2312 found: 591.2332 Method PrepAcidic-C

    Example 196 (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-((3-isopropylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2786] ##STR00695##

    Step A. Intermediate 414: Ethyl (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-((3-isopropylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2787] ##STR00696##

    [2788] The compound was synthesized analogous to the procedure of Example 184 Step A. from Intermediate 106 and 3-isopropylaniline to afford the title compound (120 mg, 80%) as a white solid which was used without further purification in the next step. MS (ESI): m/z [M+H].sup.+ 595.

    Step B. (1S,4s)-4-(2-Fluoro-5-(((1S,2R,3S,4R)-3-((3-isopropylphenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2789] The hydrolysis of Intermediate 414 was carried out in an analogous way to Example 181 Step B. Purification by Method PrepAcidic-C afforded the title compound (56 mg, 48%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.32H.sub.40FN.sub.2O.sub.6: 567.2864 found: 567.2888.

    Example 197 (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2790] ##STR00697##

    Step A. Intermediate 415: Ethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2791] ##STR00698##

    [2792] HATU (96 mg, 0.25 mmol) was added to a solution of Intermediate 106 (100 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was stirred at ambient temperature for 5 minutes before 2-ethylbutan-1-amine (25.4 mg, 0.25 mmol) and DIPEA (73.0 μL, 0.42 mmol) was added and the reaction was stirred for 4 h. H.sub.2O and EtOAc were added and the two phases were separated. The aq phase was extracted with EtOAc and the organic extracts were combined and washed with H.sub.2O (two times), dried over MgSO.sub.4 and evaporated. The crude product was purified by flash chromatography using heptane/EtOAc 1/2 as eluent to afford the title compound (86 mg, 73%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.69-0.8 (m, 6H), 1.18 (dq, 6H), 1.25-1.36 (m, 6H), 1.63 (d, 3H), 1.73 (dd, 2H), 1.93-2.09 (m, 5H), 2.23 (d, 1H), 2.35-2.47 (m, 2H), 2.51 (s, 1H), 2.94-3.13 (m, 2H), 3.93 (s, 3H), 4.15 (q, 2H), 4.41 (t, 2H), 5.52 (t, 1H), 6.71 (d, 1H), 7.87 (d, 1H), 8.58 (d, 1H). MS (ESI): m/z [M+H].sup.+ 561.5.

    Step B. (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-ethylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2793] MeOH (0.4 mL) and NaOH(aq) (0.4 mL, 1.9 M) was added to a solution of Intermediate 415 (86 mg, 0.15 mmol) in THF (1.6 mL) and the mixture was stirred at ambient temperature for 18 hrs. H.sub.2O was added followed by 1 M HCl to pH approximately 4. EtOAc was added and the two phases were separated. The aq phase was extracted with EtOAc and the combined organic extracts were washed with H.sub.2O, dried over MgSO.sub.4 and evaporated. The crude product was purified by flash chromatography using 5% MeOH in EtOAc as eluent to afford the title compound (76 mg, 93%). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.42FN.sub.2O.sub.6: 533.3022 found: 533.2992.

    [2794] The examples included in Table 17 below were synthesized in a similar way to the procedure of Example 197 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00017 TABLE 17 Ex HRMS Purification No. Structure (m/z) [M + H].sup.+ Method 198 [00699]embedded image Calcd for C.sub.28H.sub.38FN.sub.2O.sub.6: 517.2708 found: 517.2708 Flash chromatography using 5% MeOH in EtOAc 199 [00700]embedded image Calcd for C.sub.29H.sub.42FN.sub.2O.sub.6: 533.3022 found: 533.3068 Flash chromatography using 5% MeOH in EtOAc 200 [00701]embedded image Calcd for C.sub.29H.sub.42FN.sub.2O.sub.6: 533.3022 found: 533.3054 Flash chromatography using 5% MeOH in EtOAc

    Example 201 (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2795] ##STR00702##

    Step A. Intermediate 416: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2796] ##STR00703##

    [2797] HATU (322 mg, 0.85 mmol), DIPEA (0.296 mL, 1.69 mmol) and Intermediate 111 (231 mg, 0.68 mmol) were added to Intermediate 124 (130 mg, 0.56 mmol) in DMF (5 mL). The reaction mixture was stirred at Rt for 1.5 h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (10 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product which was purified by preparative TLC (PE/EtOAc 1/1), to afford the title compound (240 mg, 77%) as a yellow oil. MS (ESI): m/z [M+H].sup.+ 553.

    Step B. (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2798] The hydrolysis of Intermediate 416 was carried out in an analogous way to Example 181 Step B. Purification by Method PrepAcidic-D afforded the title compound (106 mg, 46%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.34FN.sub.2O.sub.6: 525.2396 found: 525.2368.

    Example 202 (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R*)-2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid (Isomer 1) & Example 203 (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R*)-2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid (Isomer 2)

    [2799] ##STR00704##

    Step A. Intermediate 417: Ethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((RS)-2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [2800] ##STR00705##

    [2801] The compound was synthesized analogous to the procedure of Example 197 Step A. from Intermediate 106 and 2-methylbutan-1-amine. The crude product was purified by flash chromatography using heptane/EtOAc 1/2 as eluent to afford the title compound (85 mg, 74%). MS (ESI): m/z [M+H].sup.+ 547.5.

    Step B. Intermediate 418: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((RS)-2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [2802] ##STR00706##

    [2803] The hydrolysis of Intermediate 417 was carried out in an analogous way to Example 197 Step B. The crude product was purified by flash chromatography using 5% MeOH in EtOAc as eluent to afford the title compound (75 mg, 93%). MS (ESI): m/z [M+H].sup.+ 519.3.

    Step C. Example 202 (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R*)-2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid (Isomer 1) & Example 203 (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((R*)-2-methylbutyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid (Isomer 2)

    [2804] The isomers of Intermediate 418 (75 mg, 0.14 mmol) were separated by preparative chiral HPLC on a Chiralpak IA column (5 um, 250×20 mm ID) using 0.1% of FA in a heptane:IPA (85:15) system as mobile phase to give the first eluting compound Isomer 1: Example 202 (28 mg, 37%); HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.28H.sub.40FN.sub.2O.sub.6: 519.2864 found: 519.2882 and the second eluting compound Isomer 2: Example 203 (26 mg, 35%); HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.28H.sub.40FN.sub.2O.sub.6: 519.2864 found: 519.2868.

    Example 204 (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1-methylcyclohexane-1-carboxylic acid & Example 205 (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1-methylcyclohexane-1-carboxylic acid

    [2805] ##STR00707##

    Step A. Intermediate 419: Naphthalen-1-ylmethyl 4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzylidene)-1-methylcyclohexane-1-carboxylate

    [2806] ##STR00708##

    [2807] DIPEA (0.129 mL, 0.74 mmol), HATU (188 mg, 0.49 mmol) and finally (1-methylcyclobutyl)methanamine hydrochloride (36.8 mg, 0.27 mmol) was added to Intermediate 126 (148 mg, 0.25 mmol) in DCM (1.10 mL) added. The reaction was stirred for 2 h. DCM and NaHCO.sub.3 (aq) was added and the phases was separated. The organic phase was evaporated and the crude product was purified by flash chromatography using a gradient of 10-50% EtOAc in heptane as mobile phase to give the title compound (136 mg, 81%) as a film/solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.95 (s, 3H), 1.20 (d, 4H), 1.26-1.45 (m, 4H), 1.62-1.8 (m, 6H), 2.00 (s, 2H), 2.03-2.17 (m, 3H), 2.19-2.29 (m, 4H), 2.40 (dd, 1H), 2.43-2.54 (m, 2H), 2.95 (ddd, 1H), 3.18 (dd, 1H), 3.94 (s, 3H), 4.41 (t, 1H), 5.60 (q, 3H), 6.05 (s, 1H), 6.61 (d, 1H), 7.39-7.6 (m, 4H), 7.81-7.92 (m, 2H), 7.99 (dd, 2H), 8.48 (dd, 1H). MS (ESI): m/z [M+H].sup.+ 681.7.

    Step B. Intermediate 420: 4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1-methylcyclohexane-1-carboxylic acid

    [2808] ##STR00709##

    [2809] Intermediate 419 (136 mg, 0.20 mmol) was dissolved in ethanol (19.975 mL) and hydrogenated in a H-Cube® reactor at 1 ml/min, rt, Full H2, Pd/C (CatCart 30 mm). The solvent was evaporated and the crude product was purified by Method PrepBasic-D (Gradient 10%-50%) to give the title compound (80 mg, 74%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.97 (d, 3H), 1.04-1.26 (m, 7H), 1.33 (d, 2H), 1.43-1.83 (m, 13H), 2.02-2.09 (m, 1H), 2.13-2.27 (m, 2H), 2.43-2.57 (m, 4H), 2.87-3 (m, 1H), 3.17 (dd, 1H), 3.94 (d, 3H), 4.44 (t, 1H), 5.80 (dt, 1H), 6.62 (dd, 1H), 7.9-8 (m, 1H), 8.49 (t, 1H). MS (ESI): m/z [M+H].sup.+ 543.6.

    Step C. Example 204 (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1-methylcyclohexane-1-carboxylic acid & Example 205 (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1-methylcyclohexane-1-carboxylic acid

    [2810] The isomers of Intermediate 420 (80 mg, 0.15 mmol) were separated by preparative SFC on a YMC SA (IA) column (5 um, 250×20 mm ID) using 31% EtOH/FA 100/0.5 in CO.sub.2(g) (123 bar) as mobile phase to give the first eluting compound Example 204 (30 mg, 40%); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.97 (s, 3H), 1.05-1.25 (m, 8H), 1.32 (d, 2H), 1.47-1.63 (m, 7H), 1.66-1.83 (m, 4H), 2.05 (d, 1H), 2.21 (dd, 3H), 2.49 (dd, 4H), 2.92 (dd, 1H), 3.17 (dd, 1H), 3.94 (s, 3H), 4.43 (t, 1H), 5.88 (s, 1H), 6.61 (d, 1H), 7.95 (d, 1H), 8.47 (d, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.44FN.sub.2O.sub.5: 543.3228 found: 543.3218, and the second eluting compound Example 205 (30 mg, 40%); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.95 (s, 3H), 1.14-1.3 (m, 7H), 1.33 (s, 2H), 1.47-1.59 (m, 6H), 1.59-1.8 (m, 8H), 2.05 (d, 1H), 2.23 (d, 1H), 2.46-2.54 (m, 4H), 2.91-2.96 (m, 1H), 3.17 (dd, 1H), 3.94 (s, 3H), 4.43 (t, 1H), 5.66 (s, 1H), 6.61 (d, 1H), 7.95 (d, 1H), 8.48 (d, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H4.sub.4FN.sub.2O.sub.5: 543.3228 found: 543.3214.

    Example 206 (1R,4s)-4-(2-Fluoro-5-(((1R,2S,3R,4S)-3-((4-fluoro-3-(pentafluoro-?6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2811] ##STR00710##

    Step A. Intermediate 421: tert-butyl (1R,4s)-4-(2-fluoro-5-(((1R,2S,3R,4S)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2812] ##STR00711##

    [2813] DIEPA (0.822 mL, 4.71 mmol) was added dropwise to Intermediate 130 (815 mg, 1.57 mmol), 4-fluoro-3-(pentafluoro-λ6-sulfanyl)aniline (446 mg, 1.88 mmol) (Trasher, J. P. et al, J. Fluorine Chemistry (2001), 112(2), pp 287-295) and T3P (2994 mg, 4.71 mmol) in butyl acetate (30 mL) at 0° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The reaction mixture was diluted with EtOAc (1 L), and washed sequentially with NaHCO.sub.3 (1×250 mL, sat), brine (3×300 mL, sat), and H.sub.2O (2×300 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by reverse phase flash C-18 chromatography using a gradient of 0-75% MeCN in H.sub.2O as mobile phase followed by preparative chiral SFC on a Phenomenex Lux Cellulose-4 column AXIA Packed (5 um, 250×21 mm ID) using 17% MeOH in CO.sub.2(g) as mobile phase to give the title compound (850 mg, 73%) as a pale yellow gum.

    Step B. (1R,4s)-4-(2-Fluoro-5-(((1R,2S,3R,4S)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2814] TFA (0.407 mL, 5.28 mmol) was added dropwise to Intermediate 421 (650 mg, 0.88 mmol) in DCM (50 mL) cooled to 0° C. over a period of 1 minute under nitrogen. The resulting solution was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure to afford the title compound (570 mg, 88%) as a white solid by lyophilization. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.34F.sub.7N.sub.2O.sub.6S: 683.2020 found: 683.2018.

    Step C. (1R,4s)-4-(2-Fluoro-5-(((1R,2S,3R,4S)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2815] Part of the material from Example 206 Step B. above (450 mg, 0.66 mmol) was submitted to further purification by preparative SFC on a YMC SA (IA) column (5 um, 250×30 mm ID) using 25% IPA/FA 100/0.5 in CO.sub.2(g) (120 bar) as mobile phase to give the title compound (351 mg, 78%). .sup.1H NMR (500 MHz, DMSO-d6) δ 1.10 (s, 3H), 1.16-1.31 (m, 5H), 1.31-1.45 (m, 2H), 1.45-1.66 (m, 2H), 1.80 (t, 2H), 2.00 (dd, 3H), 2.13 (d, 1H), 2.43 (d, 1H), 2.75 (d, 1H), 3.80 (s, 3H), 4.03 (tt, 1H), 4.31 (t, 1H), 7.09 (d, 1H), 7.45 (dd, 1H), 7.50 (d, 1H), 7.62 (ddd, 1H), 8.33 (dd, 1H), 8.62 (d, 1H), 10.42 (s, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.34F.sub.7N.sub.2O.sub.6S: 683.2020 found: 683.2042.

    Example 207 (1S,4s)-4-(4-(Difluoromethoxy)-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2816] ##STR00712##

    Step A. Intermediate 422: Naphthalen-1-ylmethyl (1S,4s)-4-(4-(difluoromethoxy)-2-fluoro-5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2817] ##STR00713##

    [2818] DIPEA (0.305 mL, 1.75 mmol) was added dropwise to Intermediate 147 (195 mg, 0.39 mmol), Intermediate 21 (116 mg, 0.43 mmol) and EDC (186 mg, 0.97 mmol) HOBt (149 mg, 0.97 mmol) in DMF (10 mL) at 20° C. over a period of 1 min under nitrogen. The resulting solution was stirred at 25° C. for 14 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with NaHCO.sub.3 (1×75 mL, sat), NH.sub.4Cl (1×75 mL, sat), and brine (1×100 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. which was purified by preparative TLC (EtOAc/PE 1/4), to afford the title compound (258 mg, 92%) as a pale yellow solid. MS (ESI): m/z [M+H].sup.+ 719.

    Step B. (1S,4s)-4-(4-(Difluoromethoxy)-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2819] Intermediate 422 (258 mg, 0.36 mmol) and Pd-C (40 mg, 0.38 mmol) in MeOH (15 mL) was stirred under an atmosphere of hydrogen at 1.25 atm and 28° C. for 14 h. The solvent was removed under reduced pressure and the crude product was purified by Method PrepAcidic-L (Gradient: 70%-95%) to afford the title compound (82 mg, 39.3%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 0.95 (s, 3H), 1.05-1.35 (m, 8H), 1.36-1.58 (m, 6H), 1.61-1.81 (m, 4H), 1.87-1.99 (m, 2H), 2-2.14 (m, 4H), 2.22 (s, 1H), 2.65 (d, 1H), 2.93 (dd, 1H), 3.06 (dd, 1H), 4.09 (t, 1H), 4.25-4.35 (m, 1H), 7.11 (t, 1H, OCHF2), 7.25 (d, 1H), 7.37 (d, 1H), 7.95 (t, 1H), 8.25 (d, 1H), 12.33 (s, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.40F.sub.3N.sub.2O.sub.6: 581.2832 found: 581.2882.

    Example 208 (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2820] ##STR00714##

    Step A. Intermediate 423: tert-Butyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2821] ##STR00715##

    [2822] Intermediate 73 (2.216 g, 5.80 mmol), HATU (6.61 g, 17.39 mmol), DIEA (4.05 mL, 23.18 mmol) and Intermediate 153 (2.1 g, 5.80 mmol) in DMF (50 mL) were stirred at 20° C. for 3h. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (3×5 mL, sat), NaHCO.sub.3 (3× 5 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by flash chromatography using a gradient of 0-50% EtOAc in PE as mobile phase to give the title compound (3.61 g, 86%) as a pale yellow solid. MS (ESI): m/z [M+H].sup.+ 685.

    Step B. (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2823] ##STR00716##

    [2824] TFA (10 mL, 129.80 mmol) was added dropwise to Intermediate 423 (2.4 g, 3.30 mmol) in DCM (15 mL) at 0° C. over a period of 1 min under air. The resulting solution was stirred at rt for 14 h. The solvent was removed under reduced pressure and the crude product was purified by preparative SFC on a Lux Cellulose (Chiral-A (LUX-3)) column (5 μm, 250×34.6 mm ID) using 10% IPA/DEA 100/0.1 in CO.sub.2(g) as mobile phase to afford the title compound (1.600 g, 72.2%) as a white solid. The product was combined with two other batches (2.8 g, 4.17 mmol) and purified by preparative SFC on a Chiralpak IA column (5 μm, 50×250 mm ID) using 60% MeOH/IPA 100/0.1 in CO.sub.2(g) as mobile phase to afford the title compound (2.0 g, 71%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.35F.sub.4N.sub.2O.sub.8S: 671.2044 found: 671.2026.

    Example 209 2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2825] ##STR00717##

    Step A. Intermediate 424: Ethyl 2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-(pentafluoro-λ.SUP.6.-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylate

    [2826] ##STR00718##

    [2827] 3-(pentafluoro-λ.sup.6-sulfanyl)aniline (201 mg, 0.92 mmol), HATU (952 mg, 2.50 mmol), DIPEA (0.291 mL, 1.67 mmol) and DMAP (10.19 mg, 0.08 mmol) were added to Intermediate 157 (380 mg, 0.83 mmol) in DMF (3 mL). The reaction mixture was stirred at 20° C. overnight. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with brine (3×25 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product which was purified by preparative TLC (PE/EtOAc 1/1), to afford the title compound (also containing some methyl ester present in the starting material) (180 mg, 32.9%) as a yellow oil which solidified on standing. MS (ESI): m/z [M+H].sup.+ 657 (ethyl ester). MS (ESI): m/z [M+H].sup.+ 643 (methyl ester).

    Step B. 2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-(pentafluoro-λ.SUP.6.-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2828] LiOH (19.69 mg, 0.82 mmol) was added to Intermediate 424 (180 mg, 0.27 mmol) in EtOH (4 mL)/H.sub.2O (2 mL).The reaction mixture was stirred at 20° C. for 5h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with brine (3×50 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by Method PrepAcidic-C to afford the title compound (58.0 mg, 32%) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 1.37 (dd, 3H), 1.58-1.77 (m, 2H), 2.12 (d, 1H), 2.28 (d, 1H), 2.58 (s, 1H), 2.86 (d, 1H), 3.97 (s, 3H), 4.49 (d, 1H), 7.01 (d, 1H), 7.42 (dt, 2H), 7.56 (t, 3H), 8.06 (dd, 3H), 8.27 (s, 1H).HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.27F.sub.6N.sub.2O.sub.5S: 629.1540 found: 629.1552.

    Example 210 2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((4-(pentafluoro-λ.SUP.6.-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2829] ##STR00719##

    Step A. Intermediate 425: Ethyl 2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((4-(pentafluoro-λ.SUP.6.-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylate

    [2830] ##STR00720##

    [2831] 4-(pentafluoro-λ.sup.6-sulfanyl)aniline (106 mg, 0.48 mmol), HATU (250 mg, 0.66 mmol), DIEA (0.153 mL, 0.88 mmol) and DMAP (5.36 mg, 0.04 mmol) were added to Intermediate 157 (200 mg, 0.44 mmol).The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with brine (3×50 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by preparative TLC (PE/EtOAc 1/1), to afford the title compound (also containing some methyl ester present in the starting material) (103 mg, 36%) as a white solid. MS (ESI): m/z [M+H].sup.+ 657 (ethyl ester) MS (ESI): m/z [M+H].sup.+ 643 (methyl ester).

    Step B. 2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((4-(pentafluoro-λ.SUP.6.-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2832] LiOH (11.27 mg, 0.47 mmol) was added to Intermediate 425 (103 mg, 0.16 mmol) in EtOH (4 mL)/H.sub.2O (2.0 mL).The reaction mixture was stirred at 20° C. for 5h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with brine (3×50 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by Method PrepAcidic-C to afford the title compound (80 mg, 79%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.27F6N.sub.2O.sub.5S: 629.1540 found: 629.1594.

    Example 211 (1s,4s)-4-(5-((2,4-Dimethyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2833] ##STR00721##

    Step A. Intermediate 426: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((2,4-dimethyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2834] ##STR00722##

    [2835] Intermediate 13 (121 mg, 0.26 mmol) and HATU (197 mg, 0.52 mmol) was diluted in DCM (1161 μL) and DIPEA (136 μL, 0.78 mmol) was added. The mixture was added to Intermediate 161 (81 mg, 0.29 mmol) and the reaction was stirred overnight. The crude product was purified by flash chromatography using a gradient of 10-60% EtOAc in heptane as mobile phase to give the title compound (121 mg, 38%) as a solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.02 (s, 3H). 1.18 (s, 3H), 1.21-1.32 (m, 3H), 1.54 (s, 2H), 1.62 (s, 1H), 1.69-1.82 (m, 4H), 1.92-2.02 (m, 2H), 2.24 (s, 3H), 2.29 (d, 2H), 2.35 (s, 3H), 3.31 (d, 2H), 3.99 (s, 3H), 4.15 (td, 1H), 5.61 (s, 2H), 6.37 (t, 1H), 6.80 (d, 1H), 7.16 (s, 2H), 7.41-7.63 (m, 4H), 7.88 (dd, 3H), 8.01 (d, 1H), 9.72 (s, 1H). MS (ESI): m/z [M+H].sup.+ 695.7.

    Step B. (1s,4s)-4-(5-((2,4-Dimethyl-6-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2836] Intermediate 426 (69 mg, 0.10 mmol) was dissolved in THF/MeOH 1/9 10 mL and hydrogenated in a H-Cube® reactor at 1 mL/min, rt, Full H2, Pd/C (CatCart 30 mm). The compound was purified by Method SFC-B to give the title compound (40 mg, 73%). .sup.1H NMR (600 MHz, DMSO-d6) δ 0.98 (s, 3H), 1.11 (s, 3H), 1.23-1.32 (m, 2H), 1.39-1.49 (m, 4H), 1.6-1.76 (m, 2H), 1.8-1.87 (m, 2H), 1.87-1.94 (m, 2H), 2.07 (d, 2H), 2.17 (s, 3H), 2.32 (s, 3H), 3.17 (d, 2H), 3.94 (s, 3H), 4.18 (dt, 1H), 7.13 (s, 1H), 7.20 (d, 2H), 7.66 (d, 1H), 8.24 (t, 1H), 10.05 (s, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.40FN.sub.2O.sub.6: 555.2864 found: 555.2874.

    Example 212 (1s,4s)-4-(5-((4,5-Dimethyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2837] ##STR00723##

    Step A. Intermediate 427: Naphthalen-1-ylmethyl (1s,4s)-4-(5-((4,5-dimethyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [2838] ##STR00724##

    [2839] Intermediate 13 (125 mg, 0.27 mmol) and HATU (204 mg, 0.54 mmol) was diluted in DCM (1199 μL) and DIPEA (140 μL, 0.80 mmol) and the mixture was added to Intermediate 163 (83 mg, 0.29 mmol) and the reaction was stirred for 2 h. Added DCM and NaHCO.sub.3 (aq) and separated the phases. The residue was purified by flash chromatography using a gradient of 5-50% EtOAc in heptane as mobile phase to give the title compound (92 mg, 49.4%) as solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.18 (s, 6H), 1.22-1.32 (m, 3H), 1.61 (d, 2H), 1.74 (d, 2H), 1.91 (d, 3H), 1.99 (d, 2H), 2.30 (d, 8H), 3.43 (d, 2H), 4.05 (s, 3H), 4.18 (s, 1H), 5.61 (s, 2H), 6.01 (s, 1H), 6.77 (d, 1H), 7.18 (s, 1H), 7.41-7.62 (m, 4H), 7.82-7.96 (m, 3H), 8.01 (d, 1H), 8.46 (s, 1H), 11.60 (s, 1H). MS (ESI): m/z [M+H].sup.+ 695.7.

    Step B. (1s,4s)-4-(5-((4,5-Dimethyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2840] Intermediate 427 (92 mg, 0.13 mmol) was dissolved in MeOH/THF and hydrogenated in a H-Cube® reactor at 1 mL/min, rt, Full H2, Pd/C (CatCart 30 mm). Evaporated the solvent to give the crude product as a solid which was purified by Method SFC-B. .sup.1H NMR (600 MHz, DMSO) δ 1.12 (d, 6H), 1.29 (td, 2H), 1.41-1.51 (m, 2H), 1.60 (ddd, 2H), 1.81 (dddd, 2H), 1.89-2 (m, 4H), 2.08 (d, 2H), 2.26 (d, 6H), 3.29 (s, 2H), 3.97 (s, 3H), 4.21 (tt, 1H), 4.21 (tt, 1H), 7.19 (d, 1H), 7.43 (s, 1H), 7.74 (d, 1H), 8.39 (s, 1H), 8.53 (t, 1H), 11.77 (s, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.31H.sub.40FN.sub.2O.sub.6: 555.2864 found: 555.2868.

    Example 213 (1s,4s)-4-(2-Fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2841] ##STR00725##

    Step A. Intermediate 428: Ethyl (1s,4s)-4-(2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2842] ##STR00726##

    [2843] Pd.sub.2(dba).sub.3 (40.5 mg, 0.04 mmol) and Xantphos (51.2 mg, 0.09 mmol) were added to Intermediate 165 (150 mg, 0.44 mmol), Intermediate 166 (212 mg, 0.49 mmol) and Cs.sub.2CO.sub.3 (432 mg, 1.33 mmol) in 1,4-dioxane (15 mL) at 20° C. The resulting suspension was stirred at 110° C. for 15 h under nitrogen. The reaction mixture was poured into brine (150 mL, sat), extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford yellow oil. The residue was purified by preparative TLC (EtOAc/PE 2/5), to afford the title compound (120 mg, 43.5%) as a pale yellow oil. MS (ESI): m/z [M+H].sup.+ 647.2.

    Step B. (1s,4s)-4-(2-Fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclohex-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2844] LiOH (0.50 g, 20.88 mmol) was added to Intermediate 428 (0.12 g, 0.19 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL), the reaction mixture was acidified with 2 M HCl. The aq layer was extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford colorless oil which solidified on standing. The crude product was purified by Method PrepAcidic-A (Gradient 50%-67%) to give the title compound (0.019 g, 16.58%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6): δ 1.57-1.69 (m, 8H), 1.7-1.84 (m, 4H), 2.29-2.41 (m, 1H), 2.44-2.49 (m, 2H), 2.8-2.95 (m, 2H), 3.89 (s, 3H), 4.39 (s, 1H), 7.19 (d, 1H), 7.49 (t, 1H), 7.59 (d, 1H), 7.93-7.99 (m, 1H), 8.21 (dd, 1H), 9.70 (s, 1H), 11.97 (s, 1H), 12.16 (s, 1H). MS (ESI): m/z [M+Na].sup.+619.4.

    Example 214 (1s,4s)-4-(2-Fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2845] ##STR00727##

    Step A. Intermediate 429: Ethyl (1s,4s)-4-(2-fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [2846] ##STR00728##

    [2847] Pd.sub.2(dba).sub.3 (40.5 mg, 0.04 mmol) and Xantphos (51.2 mg, 0.09 mmol) were added to Intermediate 165 (150 mg, 0.44 mmol), Intermediate 168 (205 mg, 0.49 mmol) and Cs.sub.2CO.sub.3 (432 mg, 1.33 mmol) in 1,4-dioxane (15 mL) at 20° C. The resulting suspension was stirred at 110° C. for 15 h under nitrogen. The reaction mixture was combined with a second batch prepared in the same way (0.59 mmol scale) were poured into brine (150 mL, sat), extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford a brown oil. The residue was purified by preparative TLC (EtOAc/PE 1/3), to afford the title compound (160 mg, 25.4%, total yield based on the two batches combined) as a pale yellow oil which solidified on standing. MS (ESI): m/z [M+Na].sup.+633.2.

    Step B. (1s,4s)-4-(2-Fluoro-5-((2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)cyclopent-1-en-1-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [2848] LiOH (0.50 g, 20.88 mmol) was added to Intermediate 429 (0.16 g, 0.26 mmol) in THF (4 mL), MeOH (1 mL) and H.sub.2O (1 mL) at 20° C. The resulting solution was stirred at 20° C. for 15 h. The reaction mixture was poured into H.sub.2O (150 mL), the reaction mixture was acidified with 2 M HCl. The aq layer was extracted with EtOAc (3×50 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford colorless oil which solidified on standing. The crude product was purified by Method PrepAcidic-A (Gradient 72%-83%) to give the title compound (0.068 g, 44.5%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.28H.sub.28F.sub.5N.sub.2O.sub.6: 583.1862 found: 583.1844.

    Example 215 (1s,4s)-4-(2-Fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)naphthalen-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2849] ##STR00729##

    Step A. Intermediate 430: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)naphthalen-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2850] ##STR00730##

    [2851] Intermediate 170 (130 mg, 0.51 mmol) was added to Intermediate 13 (358 mg, 0.77 mmol), T3P (1626 mg, 5.11 mmol), DIPEA (198 mg, 1.53 mmol) in EtOAc (10 mL) at 20° C. The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with NH.sub.4Cl (1×200 mL, sat), H.sub.2O (1×200 mL), and brine (1×200 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by preparative TLC (MeOH/DCM 1/10), to afford the title compound (90 mg, 24.6%) as a yellow solid.

    Step B. (1s,4s)-4-(2-Fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)-naphthalen-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2852] Pd-C (1.336 mg, 0.01 mmol) was added to Intermediate 430 (90 mg, 0.13 mmol) in EtOAc (1 mL)/MeOH (2 mL)/THF (1 mL) at 20° C. and the reaction mixture was placed under an atmosphere of hydrogen and stirred at 30° C. for 2 h. The reaction mixture was filtered through silica. The solvent was removed by distillation under vacuum. The crude product was purified by preparative Method PrepAcidic-N (Gradient: 15%-25%) to afford the title compound (35.0 mg, 48%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.33H.sub.38FN.sub.2O.sub.6: 577.2708 found: 577.2714.

    Example 216 (1s,4s)-4-(2-Fluoro-4-methoxy-5-((4-methyl-2-(((1-methylcyclobutyl)methyl)-carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2853] ##STR00731##

    Step A. Intermediate 431: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((4-methyl-2-(((1-methylcyclobutyl)methyl)carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2854] ##STR00732##

    [2855] Intermediate 172 (130 mg, 0.48 mmol) was added to Intermediate 13 (271 mg, 0.58 mmol), T3P (1539 mg, 4.84 mmol) and DIPEA (188 mg, 1.45 mmol) in n-Butyl acetate (10 mL) at 20° C. The resulting solution was stirred at 120° C. for 3 h. The reaction mixture was concentrated and diluted with EtOAc (150 mL) and washed sequentially with NH.sub.4Cl (1×200 mL, sat), H.sub.2O (1×200 mL) and brine (1×200 mL, sat). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford the crude product which was purified by preparative TLC (PE/EtOAc 3/1), afford the title compound (100 mg, 30.4%) as a yellow solid. MS (ESI): m/z [M+Na].sup.+703.3.

    Step B. (1s,4s)-4-(2-Fluoro-4-methoxy-5-((4-methyl-2-(((1-methylcyclobutyl)methyl)-carbamoyl)phenyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2856] Pd-C (1.563 mg, 0.01 mmol) was added to Intermediate 431 (100 mg, 0.15 mmol) in MeOH (1 mL)/THF (0.5 mL) EtOAc (0.5 mL)/at 20° C. and the reaction mixture was placed under an atmosphere of hydrogen and stirred at 30° C. for 2 h. The reaction mixture was filtered through silica. The solvent was removed by distillation under vacuum to give the crude product which was purified by Method PrepBasic-H (Gradient 47-65%) to afford the title compound (40.0 mg, 50.4%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.30H.sub.38FN.sub.2O.sub.6: 541.2708 found: 541.2736.

    Example 217 (1s,4s)-4-(2-Fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2857] ##STR00733##

    Step A. Intermediate 432: Naphthalen-1-ylmethyl (1s,4s)-4-(2-fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [2858] ##STR00734##

    [2859] Intermediate 174 (100 mg, 0.34 mmol) was added to Intermediate 13 (189 mg, 0.41 mmol), T3P (1076 mg, 3.38 mmol) and DIPEA (131 mg, 1.01 mmol) in n-butyl acetate (8 mL) at 20° C. The resulting solution was stirred at 120° C. for 12 h. The reaction mixture was concentrated and diluted with EtOAc (150 mL), and washed sequentially with NH.sub.4Cl (1×150 mL, sat), H.sub.2O (1×150 mL), and brine (1×150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product which was purified by preparative TLC (EtOAc:PE,1:3), to afford the title compound (100 mg, 41.8%) as a yellow solid. MS (ESI): m/z [M+H].sup.+ 708.

    Step B. (1s,4s)-4-(2-Fluoro-4-methoxy-5-((3-(((1-methylcyclobutyl)methyl)carbamoyl)-pyrazolo[1,5-a]pyrimidin-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [2860] Palladium (1.504 mg, 0.010 mmol) was added to Intermediate 432 (100 mg, 0.14 mmol) in THF (1 mL)/MeOH (2 mL)/EtOAc (1 mL) at 20° C. was placed under an atmosphere of hydrogen and stirred at 30° C. for 2 h. The reaction mixture was filtered through silica. The solvent was removed by distillation under vacuum to give the crude product which was purified by Method PrepAcidic-E (Gradient: 22%-32%) to afford the title compound (40.0 mg, 49.9%) as a white solid. HRMS (ESI) m/z [M+H].sup.+ calcd for C.sub.29H.sub.35FN.sub.5O.sub.6: 568.2566 found: 568.2574.

    Example 218: rac-3-(4-Methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)propanoic acid

    [2861] ##STR00735##

    Step A: Intermediate 433: rac-tert-Butyl 3-(4-methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)propanoate

    [2862] ##STR00736##

    [2863] HATU (29 mg, 0.075 mmol) and DIPEA (0.033 mL, 0.19 mmol) were added to a solution of Intermediate 213 (25 mg, 0.069 mmol) and Intermediate 366 (19 mg, 0.069 mmol) in DMF (0.3 mL), then the mixture was stirred at rt for 18 h. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-45% EtOAc in hexane as mobile phase to give the title compound (17 mg, 43%). MS (ESI) m/z 623.3 [M+H].sup.+.

    Step B: rac-3-(4-methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)propanoic acid

    [2864] A mixture of TFA (0.1 mL) and Intermediate 433 (12 mg, 0.019 mmol) was stirred at rt for 1 hr. The reaction mixture was concentrated in vacuo to give the title compound (10 mg, 92%). MS (ESI) m/z 567.3 [M+H].sup.+.

    Example 219: (1R,2S,3R,4S)-3-(5-((1H-Pyrazol-4-yl)methyl)-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2865] ##STR00737##

    Step A: Intermediate 434: Methyl 5-((1-benzyl-1H-pyrazol-4-yl)(hydroxy)methyl)-4-fluoro-2-methoxybenzoate

    [2866] ##STR00738##

    [2867] Isopropylmagnesium chloride-lithium chloride complex (1.0 M in THF, 1.2 mL, 1.2 mmol) was added to a solution of methyl 4-fluoro-5-iodo-2-methoxybenzoate (300 mg, 0.968 mmol) in THF (5 mL) at −78° C., then the mixture was stirred at −78° C. for 15 min. 1-Benzylpyrazole-4-carbaldehyde (200 mg, 1.074 mmol) in THF (5 mL) was added dropwise, then the mixture was stirred at rt for 12 hr. Aq potassium carbonate was added to the reaction mixture, then the mixture was extracted with CHCl.sub.3 and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 30-60% EtOAc in hexane as mobile phase to give the title compound (110 mg, 31%). MS (API) m/z 371.1 [M+H].sup.+.

    Step B: Intermediate 435: (1S,2S,3R,4R)-3-(5-((RS)-(1-Benzyl-1H-pyrazol-4-yl)(hydroxy)methyl)-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

    [2868] ##STR00739##

    [2869] 2 M aq NaOH (0.4 mL, 0.80 mmol) was added to a solution of Intermediate 434 (110 mg, 0.297 mmol) in MeOH (2 mL) and the mixture was stirred at rt for 5 hr. 2 M aq HCl was added to the reaction mixture and the mixture was concentrated in vacuo to give 5-((1-benzyl-1H-pyrazol-4-yl)(hydroxy)methyl)-4-fluoro-2-methoxybenzoic acid, to which EDC (120 mg, 0.626 mmol), HOAt (42 mg, 0.309 mmol) and TEA (0.2 mL, 1.0 mmol) were added, followed by Intermediate 256 (100 mg, 0.899 mmol) in DMF (2 mL), then the mixture was stirred at rt for 12 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-3% MeOH in CHCl.sub.3 as mobile phase to give the title compound (88 mg, 41%). MS (ESI) m/z 699.2 [M+H].sup.+.

    Step C: (1R,2S,3R,4S)-3-(5-((1H-Pyrazol-4-yl)methyl)-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2870] Acetic anhydride (2.0 mL) was added to a solution of Intermediate 435 (88 mg, 0.126 mmol) in pyridine (2 mL) and the mixture was stirred at rt for 1 hr. The mixture was concentrated in vacuo and aq citric acid was added, then the mixture was extracted with EtOAc and the combined organic layer was concentrated in vacuo to give (RS)-(1-benzyl-1H-pyrazol-4-yl)(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)methyl acetate. The solid was dissolved in EtOAc (10 mL) and acetic acid (10 mL), then Palladium (10% Pd/C, moisture by 50% H.sub.2O, 50 mg) added. The reaction mixture was stirred under 7 atm of hydrogen atmosphere at 50 C for 12 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®. The filtrate was concentrated in vacuo and aq potassium carbonate was added, then the mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in CHCl.sub.3 as mobile phase to give titled compound (56 mg, 74%). HRMS (ESI) m/z [M+H].sup.+ calcd for C27H27F4N4O5S: 595.1632 found: 595.1628.

    Example 220: 2-(4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazol-1-yl)acetic acid

    [2871] ##STR00740##

    Step A: Intermediate 436: tert-Butyl 2-(4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)benzyl)-1H-pyrazol-1-yl)acetate

    [2872] ##STR00741##

    [2873] tert-Butyl bromoacetate (0.011 mL, 0.074 mmol) was added to a mixture of Example 219 (40 mg, 0.0673 mmol) and cesium carbonate (33 mg, 0.101 mmol) in DMF (1 mL) and the mixture was stirred at 70° C. for 2 hr. The mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give titled compound (19 mg, 39%). MS (ESI) m/z 709.6 [M+H].sup.+.

    Step B: 2-(4-(2-Fuoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazol-1-yl)acetic acid

    [2874] A mixture of Intermediate 436 (19 mg, 0.0261 mmol) in TFA (1 mL) was stirred at rt for 1 hr. The mixture was concentrated in vacuo to give titled compound (20 mg, 99%). HRMS (ESI) m/z [M+H].sup.+ calcd for C29H29F4N4O7S: 653.1688 found: 653.1708.

    Example 221: 1-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-5-carboxylic acid

    [2875] ##STR00742##

    Step A: Intermediate 437: tert-Butyl 1-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-5-carboxylate

    [2876] ##STR00743##

    [2877] EDC (39 mg, 0.201 mmol), HOAt (28 mg, 0.201 mmol) and TEA (0.028 mL, 0.201 mmol) were added to a solution of Intermediate 362 (71 mg, 0.201 mmol) and Intermediate 226 (67 mg, 0.168 mmol) in DMF (3 mL), then the mixture was stirred at rt for 4 hr. 1 M aq HCl was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (43 mg, 37%). MS (ESI) m/z 695.3 [M+H].sup.+.

    Step B: 1-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-5-carboxylic acid

    [2878] The titled compound was prepared analogous to Example 218 Step B, using Intermediate 437 instead of Intermediate 433. MS (ESI) m/z 639.3 [M+H].sup.+.

    Example 222: 1-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-3-carboxylic acid

    [2879] ##STR00744##

    Step A: Intermediate 438: tert-Butyl 1-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-3-carboxylate

    [2880] ##STR00745##

    [2881] The titled compound was prepared analogous to Example 221 Step A, using Intermediate 365 instead of Intermediate 362. MS (ESI) m/z 695.4 [M+H].sup.+.

    Step B: 1-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)benzyl)-1H-pyrazole-3-carboxylic acid

    [2882] The titled compound was prepared analogous to Example 218 Step B, using Intermediate 438 instead of Intermediate 433. MS (ESI) m/z 639.3 [M+H].sup.+.

    Example 223: rac-2-(4-Methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)benzyl)benzoic acid

    [2883] ##STR00746##

    Step A: Intermediate 439: Methyl 5-((2-(1,3-dioxolan-2-yl)phenyl)(acetoxy)methyl)-2-methoxybenzoate

    [2884] ##STR00747##

    [2885] Magnesium (49 mg, 2.008 mmol) was added to a solution of 2-(2-bromophenyl)-1,3-dioxolane (425 mg, 1.854 mmol) in THF (3 mL), then the mixture was stirred at reflux for 30 min. After the mixture was cooled to −78 C, methyl 5-formyl-2-methoxybenzoate (300 mg, 1.545 mmol) in THF (7 mL) was added to the mixture and the mixture was stirred at rt for 12 hr. H.sub.2O was added to the mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo.

    [2886] The residue was dissolved in pyridine (4 mL), and Ac.sub.2O (2 mL) was added. The reaction mixture was stirred at rt for 2 hr, then the mixture was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 40% EtOAc in hexane as mobile phase to give the title compound (542 mg, 91%).

    Step B: Intermediate 440: 5-(2-formylbenzyl)-2-methoxybenzoic acid

    [2887] ##STR00748##

    [2888] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 30 mg) was added to a solution of Intermediate 439 (542 mg, 1.403 mmol) in EtOAc (10 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 12 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. After the filtrate was concentrated in vacuo.

    [2889] The residue was dissolved in MeOH (10 mL), and 2 M aq NaOH (1.4 mL, 2.8 mmol) was added and the mixture was stirred at rt for 12 hr. The mixture was acidified with aq citric acid (acetal was removed in this process) and extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (290 mg, 77%). MS (ESI) m/z 270.9 [M+H].sup.+.

    Step C: Intermediate 441: rac-(1R,2R,3S,4S)-3-(5-(2-Formylbenzyl)-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

    [2890] ##STR00749##

    [2891] The titled compound was prepared analogous to Example 218 Step A, using Intermediate 440 instead of Intermediate 366. MS (ESI) m/z 613.3 [M+H].sup.+.

    Step D: rac-2-(4-Methoxy-3-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)benzyl)benzoic acid

    [2892] Sodium chlorite (10 mg, 0.111 mmol) was added to a mixture of Intermediate 441 (39 mg, 0.064 mmol) and sodium dihydrogen phosphate (20 mg, 0.167 mmol) in DMSO (0.4 mL) and H.sub.2O (0.4 mL), then the mixture was stirred at rt for 30 min. Aq citric acid was added to the reaction mixture and the precipitate was collected by filtration to give the title compound (38 mg, 95%). MS (APCI) m/z 629.0 [M+H].sup.+.

    Example 224: rac-2′-Fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2893] ##STR00750##

    Step A: Intermediate 442: rac-(1R,2R,3S,4S)-3-(5-Bromo-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

    [2894] ##STR00751##

    [2895] EDC (205 mg, 1.07 mmol), HOAt (145 mg, 1.07 mmol) and TEA (0.30 mL, 2.14 mmol) were added to a solution of Intermediate 213 (350 mg, 0.97 mmol) and 5-bromo-4-fluoro-2-methoxybenzoic acid (254 mg, 1.02 mmol) in CHCl.sub.3 (15 mL), then the mixture was stirred at rt for 5 hr. H.sub.2O was added to the reaction mixture, then organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 20-50% EtOAc in hexane as mobile phase to give the title compound (436 mg, 76%). MS (ESI) m/z 589.0/591.0 [M−H]−

    Step B: Intermediate 443: rac-tert-Butyl 2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylate

    [2896] ##STR00752##

    [2897] Tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) was added to the mixture of Intermediate 442 (35 mg, 0.059 mmol) and (4-tert-butoxycarbonylphenyl)boronic acid (26 mg, 0.118 mmol) in sat aq NaHCO.sub.3 (0.6 mL) and DME (0.6 mL), and the mixture was stirred at reflux for 1 hr. The mixture was cooled to ambient temperature and extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 20-80% EtOAc in hexane as mobile phase to give the title compound (29 mg, 71%). MS (ESI) m/z 689.3 [M+H].sup.+.

    Step C: rac-2′-Fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2898] The mixture of Intermediate 443 (180 mg, 0.017 mmol) and TFA (1 mL, 13 mmol) were stirred at rt for 4 hr. After the reaction mixture was concentrated in vacuo, the crude product was purified by flash chromatography using 0-10% MeOH in CHCl.sub.3 as mobile phase to give the title compound (82 mg, 50%). MS (ESI) m/z 633.3 [M+H].sup.+.

    Example 225: rac-2′-Fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid

    [2899] ##STR00753##

    [2900] The titled compound was prepared analogous to Example 224 Step B and C, (3-tert-butoxycarbonylphenyl)boronic acid instead of (4-tert-butoxycarbonylphenyl)boronic acid. MS (ESI) m/z 633.3 [M+H].sup.+.

    Example 226: rac-2′-Fluoro-3,4′-dimethoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2901] ##STR00754##

    [2902] Tetrakis(triphenylphosphine)palladium (10 mg, 0.008 mmol) was added to the mixture of Intermediate 442 (50 mg, 0.084 mmol) and methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Compound 5) (50 mg, 0.171 mmol) in sat aq NaHCO.sub.3 (1 mL) and DME (1 mL), and the mixture was stirred at reflux for 24 hr. The mixture was cooled to ambient temperature and acidified by 2 M aq HCl, then extracted with EtOAc and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 7% MeOH in CHCl.sub.3 as mobile phase to give the title compound (37 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 1.31 (s, 2H), 1.53 (br d, J=9.07 Hz, 1H), 2.22 (br d, J=9.07 Hz, 1H), 2.76 (s, 1H), 3.03 (br s, 1H), 3.83 (s, 3H), 3.89 (s, 3H), 4.32 (t, J=8.16 Hz, 1H), 6.99 (d, J=7.86 Hz, 1H), 7.10 (s, 1H), 7.17 (d, J=12.70 Hz, 1H), 7.67 (d, J=7.56 Hz, 1H), 7.70-7.78 (m, 2H), 7.85-7.95 (m, 2H), 8.61 (s, 1H), 8.67 (d, J=8.77 Hz, 1H), 10.75 (s, 1H). HRMS (ESI) m/z [M+H].sup.+. calcd for C31H27F4N2O8S: 663.1418 found: 663.1446.

    [2903] The examples included in Table 18 below were synthesized analogously to the procedure of Example 226 using the specified boronic acid or boronate ester instead of Compound 5. The boronic acid or boronate ester is commercially available if not otherwise stated.

    TABLE-US-00018 TABLE 18 Ex MS No. Boronic acid/Boronate ester Product (ESI) 227 [00755]embedded image [00756]embedded image m/z 651.3 [M + H].sup.+ 228 [00757]embedded image [00758]embedded image m/z 634.2 [M + H].sup.+ 229 [00759]embedded image [00760]embedded image m/z. 622.0 [M + H].sup.+ 230 [00761]embedded image [00762]embedded image m/z 662.9 [M + H].sup.+ 231 [00763]embedded image [00764]embedded image HRMS m/z [M + H].sup.+ 651.1220 232 [00765]embedded image [00766]embedded image m/z 651.3 [M + H].sup.+ 233 [00767]embedded image [00768]embedded image m/z 651.3 [M + H].sup.+ 234 [00769]embedded image [00770]embedded image HRMS m/z [M + H].sup.+ 647.1494 235 [00771]embedded image [00772]embedded image m/z 647.3 [M + H].sup.+

    Example 236: 2′,3-Difluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2904] ##STR00773##

    Step A-1: Intermediate 444: benzyl 5-bromo-4-fluoro-2-methoxybenzoate

    [2905] ##STR00774##

    [2906] Oxalyl chloride (1.02 mL, 12.05 mmol) was added to a mixture of 5-bromo-4-fluoro-2-methoxybenzoic acid (2.0 g, 8.03 mmol) and DMF (0.05 mL, 0.6 mmol), then the mixture was stirred at rt for 2 hr. The mixture was concentrated in vacuo and dissolved in toluene (20 mL). Benzyl alcohol (1.73 g, 16.06 mmol), 4-(dimethylamino)pyridine (50 mg, 0.41 mmol) and TEA (2.0 mL, 14.4 mmol) were added to the reaction mixture and the mixture was stirred at rt for 1 hr. The reaction mixture was washed with sat aq NaHCO.sub.3 and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10% EtOAc in hexane as mobile phase to give the title compound (2.45 g, 90%). MS (APCI) m/z 338.9/340.9 [M+H].sup.+.

    Step A-2: Intermediate 445: benzyl 4-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

    [2907] ##STR00775##

    [2908] PdCl.sub.2(dppf).sub.2.CH.sub.2Cl.sub.2 (38 mg, 0.05 mmol) and potassium acetate (309 mg, 3.1 mmol) were added to a solution of Intermediate 444 (350 mg, 1.03 mmol) and bis(pinacolato)diboron (314 mg, 1.24 mmol) in cyclopentyl methyl ether (2.5 mL), then the mixture was stirred at reflux temperature for 1 hr. The mixture was cooled to ambient temperature and H.sub.2O was added, then the mixture was extracted with CHCl.sub.3 and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 40% EtOAc in hexane as mobile phase to give the title compound (362 mg, 91%).

    Step B: Intermediate 446: 4-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid

    [2909] ##STR00776##

    [2910] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 88 mg) was added to a solution of Intermediate 445 (876 mg, 2.27 mmol) in EtOH (12 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 1 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. The filtrate was concentrated in vacuo to give titled compound (650 mg, 97%). MS (ESI) m/z 297.1 [M+H].sup.+.

    Step C: Intermediate 447: (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2911] ##STR00777##

    [2912] HATU (493 mg, 1.16 mmol) and DIPEA (0.41 mL, 2.36 mmol) were added to a solution of Intermediate 226 (350 mg, 0.97 mmol) and Intermediate 446 (346 mg, 1.17 mmol) in DMF (2 mL), then the mixture was stirred at rt for 1 hr. H.sub.2O was added to the reaction mixture, then the precipitate was collected by filtration and dried under pump vacuum to give titled compound (740 mg, 98%). MS (ESI) m/z 641.3 [M+H].sup.+.

    Step D: Intermediate 448: methyl 2′,3-difluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylate

    [2913] ##STR00778##

    [2914] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4 mg, 0.005 mmol) was added to the mixture of Intermediate 447 (70 mg, 0.11 mmol) and methyl 4-bromo-2-fluorobenzoate (Compound 6) (38 mg, 0.16 mmol) in 2 M aq Na.sub.2CO.sub.3 (0.5 mL) and DME (2 mL), and the mixture was stirred at reflux for 2 hr. The mixture was cooled to ambient temperature and diluted with EtOAc, then the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the title compound (38 mg, 53%). MS (ESI) m/z 667.3 [M+H].sup.+.

    Step E: 2′,3-difluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2915] 1 M aq LiOH (0.58 mL, 0.58 mmol) was added to a solution of Intermediate 448 (38 mg, 0.058 mmol) in DME (2 mL) and the mixture was stirred at rt for 18 hr. 1 M aq HCl and CHCl.sub.3 were added to the reaction mixture and the layer was separated. Combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-15% MeOH in CHCl.sub.3 as mobile phase to give the title compound (19 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.35 (m, 3H), 1.45-1.66 (m, 2H), 2.00-2.07 (m, 1H), 2.15-2.19 (m, 1H), 2.45-2.50 (m, 1H), 2.81-2.86 (m, 1H), 3.88 (s, 3H), 4.38 (t, J=8.8 Hz, 1H), 7.17 (d, J=13.0 Hz, 1H), 7.22-7.31 (m, 1H), 7.68-7.73 (m, 2H), 7.81 (d, J=9.4 Hz, 1H), 7.82-7.92 (m, 2H), 8.54-8.62 (m, 2H), 10.63 (s, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C30H26F5N2O7S: 653.1376 found: 653.1402.

    [2916] The examples included in Table 19 below were synthesized analogously to the procedure of Example 236 steps D and E using the specified starting material instead of Compound 6. Step E was not conducted for Example 244 or Example 248.

    TABLE-US-00019 TABLE 19 Ex MS No. Step D SM Product (ESI) 237 [00779]embedded image [00780]embedded image HRMS m/z [M + H].sup.+ 665.1700 238 [00781]embedded image [00782]embedded image HRMS m/z [M + H].sup.+ 665.1676 239 [00783]embedded image [00784]embedded image m/z 678.2 [M + H].sup.+ 240 [00785]embedded image [00786]embedded image HRMS m/z [M + H].sup.+ 666.1644 241 [00787]embedded image [00788]embedded image HRMS m/z [M + H].sup.+ 666.1536 242 [00789]embedded image [00790]embedded image HRMS m/z [M + H].sup.+ 664.1752 243 [00791]embedded image [00792]embedded image HRMS m/z [M + H].sup.+ 670.1294 244 [00793]embedded image [00794]embedded image HRMS m/z [M + H].sup.+ 663.1820 245 Intermediate 370 [00795]embedded image HRMS m/z [M + H].sup.+ 665.1714 246 [00796]embedded image [00797]embedded image HRMS m/z [M + H].sup.+ 649.1652 247 [00798]embedded image [00799]embedded image HRMS m/z [M + H].sup.+ 651.1426 248 [00800]embedded image [00801]embedded image HRMS m/z [M + H].sup.+ 670.1346 249 [00802]embedded image [00803]embedded image HRMS m/z [M + H].sup.+ 680.1642 250 [00804]embedded image [00805]embedded image HRMS m/z [M + H].sup.+ 635.1462

    Example 251: 4-((2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)butanoic acid

    [2917] ##STR00806##

    Step A: Intermediate 449: (1R,2S,3R,4S)-3-(5-bromo-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2918] ##STR00807##

    [2919] HATU (686 mg, 1.81 mmol) and DIPEA (0.78 mL, 4.51 mmol) were added to a mixture of Intermediate 226 (600 mg, 1.50 mmol) and 5-bromo-4-fluoro-2-methoxybenzoic acid (412 mg, 1.65 mmol) in DMF (4 mL), then the mixture was stirred at rt for 1 hr. H.sub.2O was added to the reaction mixture, then the precipitate was filtered and dried under air to give crude product. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (722 mg, 81%). MS (ESI) m/z 593.1/595.1 [M+H].sup.+.

    Step B: Intermediate 450: methyl 4-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)butanoate

    [2920] ##STR00808##

    [2921] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg, 0.007 mmol) was added to the mixture of Intermediate 449 (80 mg, 0.135 mmol) and methyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate (Compound 7) (65 mg, 0.20 mmol) in 2 M aq Na.sub.2CO.sub.3 (0.5 mL) and DME (2 mL), and the mixture was stirred at reflux for 2 hr. The mixture was cooled to ambient temperature and diluted with EtOAc, then the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 20-60% EtOAc in hexane as mobile phase to give the title compound (68 mg, 71%). MS (ESI) m/z 707.5 [M+H].sup.+.

    Step C: 4-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)butanoic acid

    [2922] The titled compound was prepared analogous to Example 236 step E, using Intermediate 450 instead of Intermediate 448. MS (ESI) m/z 693.6 [M+H].sup.+.

    Example 252: 2′-Fluoro-4′-methoxy-3,5-dimethyl-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2923] ##STR00809##

    Step A: Intermediate 451: methyl 2′-fluoro-4′-methoxy-3,5-dimethyl-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylate

    [2924] ##STR00810##

    [2925] The titled compound was prepared analogous to Example 251 step B, using (4-methoxycarbonyl-3,5-dimethyl-phenyl)boronic acid instead of Compound 7. MS (ESI) m/z 677.3 [M+H].sup.+.

    Step B: 2′-fluoro-4′-methoxy-3,5-dimethyl-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [2926] Lithium iodide (50 mg, 0.37 mmol) was added to a solution of Intermediate 451 (50 mg, 0.074 mmol) in pyridine (3 mL), then the mixture was stirred at 80° C. for 17.5 hr. The mixture was concentrated in vacuo and 1 M aq HCl was added to the reaction mixture, then the mixture was extracted with CHCl.sub.3 and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in EtOAc as mobile phase to give the title compound (10 mg, 20%). MS (ESI) m/z 663.2 [M+H].sup.+.

    [2927] The examples included in Table 20 below were synthesized analogously to the procedure of Example 251 steps B and C using the specified starting material instead of Compound 7.

    TABLE-US-00020 TABLE 20 Ex MS No. Step B SM Product (ESI) 253 [00811]embedded image [00812]embedded image HRMS m/z [M + H].sup.+ 691.1788 254 [00813]embedded image [00814]embedded image HRMS m/z [M + H].sup.+ 691.1702 255 [00815]embedded image [00816]embedded image HRMS m/z [M + H].sup.+ 653.1704

    Example 256: 2-((2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)-2-methylpropanoic acid

    [2928] ##STR00817##

    Step A: Intermediate 452: tert-butyl 2-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)-2-methylpropanoate

    [2929] ##STR00818##

    [2930] The titled compound was prepared analogous to Example 251 step B, using tert-butyl 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propanoate instead of Compound 7. MS (ESI) m/z 749.7 [M+H].sup.+.

    Step B: 2-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)-2-methylpropanoic acid

    [2931] TFA (0.35 mL) was added to a solution of Intermediate 452 (104 mg, 0.14 mmol) in CHCl.sub.3 (0.35 mL). The mixture was stirred at rt for 3 hr, then the mixture was concentrated in vacuo to give titled compound (90 mg, 94%). HRMS (ESI) m/z [M+H].sup.+ calcd for C33H33F4N2O8S: 693.1888 found: 693.1920.

    Example 257: 2-((2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid

    [2932] ##STR00819##

    Step A: Intermediate 453: tert-butyl 2-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetate

    [2933] ##STR00820##

    [2934] The titled compound was prepared analogous to Example 251 Step B, using tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate instead of Compound 7. MS (ESI) m/z 721.3 [M+H].sup.+.

    Step B: 2-((2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid

    [2935] The titled compound was prepared analogous to Example 256 Step B, using Intermediate 453 instead of Intermediate 452. HRMS (ESI) m/z [M+H].sup.+ calcd for C31H29F4N2O8S: 665.1576 found: 665.1562.

    Example 258: 3-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)propanoic acid

    [2936] ##STR00821##

    Step A: Intermediate 454: benzyl 3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)propanoate

    [2937] ##STR00822##

    [2938] The titled compound was prepared analogous to Example 236 step D, using benzyl 3-(5-bromo-2-pyridyl)propanoate instead of Compound 6. MS (ESI) m/z 754.3 [M+H].sup.+.

    Step B: 3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)propanoic acid

    [2939] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 10 mg) was added to a solution of Intermediate 454 (46 mg, 0.062 mmol) in MeOH (3 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 1 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®@. The filtrate was concentrated in vacuo to give the title compound (41 mg, 100%). HRMS (ESI) m/z [M+H].sup.+ calcd for C31H30F4N3O7S: 664.1736 found: 664.1756.

    Example 259: 3-(2′-Fluoro-3,4′-dimethoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [2940] ##STR00823##

    Step A: Intermediate 455: tert-butyl 3-(2′-fluoro-3,4′-dimethoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoate

    [2941] ##STR00824##

    [2942] The titled compound was prepared analogous to Example 236 Step D, using tert-butyl 3-(4-bromo-2-methoxyphenyl)propanoate instead of Compound 6. MS (ESI) m/z 749.4 [M+H].sup.+.

    Step B: 3-(2′-fluoro-3,4′-dimethoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [2943] The titled compound was prepared analogous to Example 256 Step B, using Intermediate 455 instead of Intermediate 452. MS (ESI) m/z 693.3 [M+H].sup.+.

    Example 260: (E)-3-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)acrylic acid

    [2944] ##STR00825##

    Step A: Intermediate 456: tert-butyl (E)-3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)acrylate

    [2945] ##STR00826##

    [2946] The titled compound was prepared analogous to Example 236 Step D, using tert-butyl (E)-3-(5-bromo-2-pyridyl)prop-2-enoate instead of Compound 6. MS (ESI) m/z 718.4 [M+H].sup.+.

    Step B: (E)-3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)acrylic acid

    [2947] ##STR00827##

    [2948] The titled compound was prepared analogous to Example 256 Step B, using Intermediate 456 instead of Intermediate 452. HRMS (ESI) m/z [M+H].sup.+ calcd for C31H28F4N3O7S: 662.1578 found: 662.1608.

    Example 261: (1R*,2R*)-2-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Isomer 2) and Example 262: (1R*,2R*)-2-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Isomer 1)

    [2949] ##STR00828##

    Step A: Intermediate 457: rac-tert-Butyl (1R,2R)-2-(5-bromopyridin-2-yl)cyclopropane-1-carboxylate

    [2950] ##STR00829##

    [2951] Sodium hydride (60% in oil suspension, 68 mg, 1.69 mmol) was added to DMSO (3.5 mL), then the mixture was stirred at rt for 15 min. Trimethylsulfoxonium iodide (372 mg, 1.69 mmol) was added to a reaction mixture and the mixture was stirred at rt for 5 min. tert-Butyl (E)-3-(5-bromopyridin-2-yl)acrylate (400 mg, 1.41 mmol) was added to a reaction mixture and the mixture was stirred at rt for 1 hr. Ice H.sub.2O was added to a reaction mixture and the mixture was extracted with CHCl.sub.3. The combined organic layer was concentrated in vacuo and the crude product was purified by flash chromatography using 0-10% EtOAc in hexane as mobile phase to give titled compound (224 mg, 53%). MS (ESI) m/z 298.1/300.1 [M+H].sup.+.

    Step B: Intermediate 458: tert-Butyl (1R*,2R*)-2-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)cyclopropane-1-carboxylate (Isomer 1) and Intermediate 459: tert-Butyl (1R*,2R*)-2-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)cyclopropane-1-carboxylate (Isomer 2)

    [2952] ##STR00830##

    [2953] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.8 mg, 0.011 mmol) and cesium carbonate (71 mg, 0.22 mmol) were added to a solution of Intermediate 457 (66 mg, 0.22 mmol) and Intermediate 447 (70 mg, 0.11 mmol) in DME (0.5 mL) and H.sub.2O (0.1 mL), then the mixture was stirred at reflux temperature for 1 hr. The mixture was cooled to ambient temperature and H.sub.2O was added, then the mixture was extracted with CHCl.sub.3 and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the first eluting compound Intermediate 458 (30 mg, 38%); MS (ESI) m/z 732.3 [M+H].sup.+, and the second eluting compound Intermediate 459 (9 mg, 11%); MS (ESI) m/z 732.4 [M+H].sup.+.

    Step C: (1R*,2R*)-2-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyridin-2-yl)cyclopropane-1-carboxylic acid

    [2954] The titled compounds were prepared analogous to Example 256 Step B, using Intermediate 458 instead of Intermediate 452 to give Example 261, and Intermediate 459 instead of Intermediate 452 to give Example 262. HRMS (ESI) m/z [M+H].sup.+ calcd for C32H30F4N3O7S: 676.1736 found: 676.1752.

    Example 263: (1R*,2R*)-2-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylic acid (Isomer 1) and Example 264: (1R*,2R*)-2-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylic acid (Isomer 2)

    [2955] ##STR00831##

    Step A: Intermediate 460: rac-tert-Butyl (1R,2R)-2-(5-chloropyrazin-2-yl)cyclopropane-1-carboxylate

    [2956] ##STR00832##

    [2957] The titled compound was prepared analogous to Example 261 Step A, using tert-butyl (E)-3-(5-chloropyrazin-2-yl)acrylate instead of tert-butyl (E)-3-(5-bromopyridin-2-yl)acrylate. MS (ESI) m/z 255.1/257.1 [M+H].sup.+.

    Step B: Intermediate 461: rac-Benzyl 5-(5-((1R,2R)-2-(tert-butoxycarbonyl)cyclopropyl)pyrazin-2-yl)-4-fluoro-2-methoxybenzoate

    [2958] ##STR00833##

    [2959] (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (9 mg, 0.011 mmol) was added to the mixture of cesium carbonate (69 mg, 0.212 mmol), Intermediate 460 (27 mg, 0.106 mmol) and Intermediate 445 (45 mg, 0.116 mmol) in H.sub.2O (0.1 mL) and DME (0.5 mL), then the mixture was stirred at reflux for 4 hr. The mixture was cooled to ambient temperature and extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-25% EtOAc in hexane as mobile phase to give the title compound (51 mg, 43%). MS (ESI) m/z 479.2 [M+H].sup.+.

    Step C: Intermediate 462: rac-5-(5-((1R,2R)-2-(tert-Butoxycarbonyl)cyclopropyl)pyrazin-2-yl)-4-fluoro-2-methoxybenzoic acid

    [2960] ##STR00834##

    [2961] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 10 mg) was added to a solution of Intermediate 461 (19 mg, 0.039 mmol) in EtOH (12 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 1 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®@. The filtrate was concentrated in vacuo to give titled compound (15 mg, 100%). MS (ESI) m/z 389.1 [M+H].sup.+.

    Step D: Intermediate 463: tert-butyl (1R*,2R*)-2-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylate

    [2962] ##STR00835##

    [2963] The titled compound was prepared analogous to Example 236 step C, using Intermediate 462 instead of Intermediate 446. MS (ESI) m/z 733.3 [M+H].sup.+.

    [2964] Step E: Intermediate 464: tert-Butyl (1RS,2RS)-2-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylate (Isomer 1) and Intermediate 465: tert-butyl (1RS,2RS)-2-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylate (Isomer 2)

    ##STR00836##

    [2965] Intermediate 463 obtained in Example 263 step D (29 mg) was separated by chiral HPLC (column: CHIRALPAK IC (250 mm*30 mm); mobile phase: [MeOH/MeCN/DEA=70/30/0.1]) to give the first eluting compound Intermediate 464 (10 mg, 48%); MS (ESI) m/z 733.3 [M+H].sup.+, and the second eluting compound Intermediate 465 (10 mg, 48%); MS (ESI) m/z 733.3 [M+H].sup.+.

    Step F: (1R*,2R*)-2-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)cyclopropane-1-carboxylic acid

    [2966] The titled compounds were prepared analogous to Example 256 Step B, using Intermediate 464 instead of Intermediate 452 to give Example 263, and Intermediate 465 instead of Intermediate 452 to give Example 264. MS (ESI) m/z 677.6 [M+H].sup.+.

    Example 265: (1R,2S,3R,4S)-3-(4′-(2-Amino-1,3-dihydroxypropan-2-yl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2967] ##STR00837##

    Step A: Intermediate 466: (1R,2S,3R,4S)-3-(4′-(1,3-dihydroxy-2-nitropropan-2-yl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2968] ##STR00838##

    [2969] The titled compound was prepared analogous to Example 236 step D, using 2-(4-bromophenyl)-2-nitropropane-1,3-diol instead of Compound 6. MS (ESI) m/z 710.2 [M+H].sup.+.

    Step B: (1R,2S,3R,4S)-3-(4′-(2-amino-1,3-dihydroxypropan-2-yl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2970] NaBH.sub.4 (30 mg, 0.791 mmol) was added to a mixture of Intermediate 466 (56 mg, 0.079 mmol) and NiCl2 (12 mg, 0.095 mmol) in MeOH (1.6 mL). The reaction mixture was stirred at rt for 1 hr. CHCl.sub.3 and 2 M aq HCl were added to the reaction mixture and the mixture was basified with sat aq NaHCO.sub.3. The mixture was extracted with CHCl.sub.3 and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% MeOH in CHCl.sub.3 as mobile phase to give the title compound (8 mg, 15%). MS (ESI) m/z 680.4 [M+H].sup.+.

    Example 266: (1R,2S,3R,4S)-3-(4′-(3-Amino-4-hydroxy-3-(hydroxymethyl)butyl)-3′,6-difluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2971] ##STR00839##

    Step A: Intermediate 467: tert-Butyl (5-(2-(2′,3-difluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)ethyl)-2,2-dimethyl-1,3-dioxan-5-yl)carbamate

    [2972] ##STR00840##

    [2973] The titled compound was prepared analogous to Example 236 step D, using Intermediate 372 instead of Compound 6.

    Step B: (1R,2S,3R,4S)-3-(4′-(3-Amino-4-hydroxy-3-(hydroxymethyl)butyl)-3′,6-difluoro-4-methoxy-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [2974] A mixture of Intermediate 467 (77 mg, 0.090 mmol) in TFA (0.2 mL) was stirred at rt for 12 hr. Aq potassium carbonate was added to the reaction mixture and the mixture was extracted with CHCl.sub.3. The combined organic layer was concentrated in vacuo. The crude product was purified by NH flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (40 mg, 62%). HRMS (ESI) m/z [M+H].sup.+ calcd for C34H37F5N3O7S: 726.2266 found: 726.2288.

    Example 267: (RS)-2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylic acid

    [2975] ##STR00841##

    Step A: Intermediate 468: Ethyl (RS)-2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylate

    [2976] ##STR00842##

    [2977] The titled compound was prepared analogous to Example 251 step B, using ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate instead of Compound 7. MS (ESI) m/z 667.3 [M+H].sup.+.

    Step B: (RS)-2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylic acid

    [2978] The titled compound was prepared analogous to Example 236 step E, using Intermediate 468 instead of Intermediate 448. MS (ESI) m/z 639.3 [M+H].sup.+.

    Example 268: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid and Example 269: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid and (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid and

    [2979] ##STR00843##

    Step A: Intermediate 469: Ethyl 4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylate

    [2980] ##STR00844##

    [2981] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 88 mg) was added to a solution of Intermediate 468 (120 mg, 0.18 mmol) in EtOH (3 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 5 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography using 20-60% EtOAc in hexane as mobile phase to give titled compound (100 mg, 83%). MS (ESI) m/z 669.3 [M+H].sup.+.

    Step B: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid and (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid

    [2982] 1 M aq LiOH (1.49 mL, 1.49 mmol) was added to a solution of Intermediate 469 (100 mg, 0.15 mmol) in DME (2 mL) and the mixture was stirred at rt for 12 hr. 1 M aq HCl and EtOAc were added to the reaction mixture and the layer was separated. Combined organic layer was concentrated in vacuo. The crude product was purified by reversed phase HPLC on a C18 column using a gradient of 50-60% MeCN in TFA (0.05% in H.sub.2O) as mobile phase to give the first eluting compound Isomer 1: Example 268 (8 mg, 8%); MS (ESI) m/z 641.3 [M+H].sup.+, and the second eluting compound Isomer 2: Example 269 (28 mg, 29%); MS (ESI) m/z 641.3 [M+H].sup.+.

    Example 270: 6-Fluoro-4-methoxy-N3-((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)-[1,1′-biphenyl]-3,4′-dicarboxamide

    [2983] ##STR00845##

    Step A: Intermediate 470: (1S,2S,3R,4R)-3-(5-Bromo-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

    [2984] ##STR00846##

    [2985] The titled compound was prepared analogous to Example 224 step A, using Intermediate 256 instead of Intermediate 213. MS (APCI) m/z 590.9/593.0 [M+H].sup.+.

    Step B: 6-Fluoro-4-methoxy-N3-((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)-[1,1′-biphenyl]-3,4′-dicarboxamide

    [2986] PdCl.sub.2(dppf).sub.2.CH.sub.2Cl.sub.2 (18 mg, 0.022 mmol) was added to the mixture of Intermediate 470 (130 mg, 0.22 mmol) and 4-carbamoylbenzeneboronic acid (73 mg, 0.44 mmol) in sat aq NaHCO.sub.3 (0.4 mL) and DME (3 mL), and the mixture was stirred at reflux for 3 hr. The mixture was cooled to ambient temperature and extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (50 mg, 36%). HRMS (ESI) m/z [M+H].sup.+ calcd for C30H26F4N3O6S: 632.1472 found: 632.1432.

    Example 271: 2-(4-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)acetic acid

    [2987] ##STR00847##

    Step A: Intermediate 471: tert-Butyl 2-(4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)acetate

    [2988] ##STR00848##

    [2989] The titled compound was prepared analogous to Example 270 step B, using tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate instead of 4-carbamoylbenzeneboronic acid.

    Step B: 2-(4-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)acetic acid

    [2990] A mixture of TFA (1 mL) and Intermediate 471 (84 mg, 0.12 mmol) was stirred at rt for 1 hr. After the reaction mixture was concentrated in vacuo, the crude product was purified by reversed phase HPLC on a C18 column using a gradient of 25-55% MeCN in TFA (0.05% in H.sub.2O) as mobile phase to give the title compound (85 mg, 93%). HRMS (ESI) m/z [M+H].sup.+ calcd for C28H25F4N4O7S: 637.1374 found: 637.1362.

    Example 272: rac-4-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid

    [2991] ##STR00849##

    Step A: Intermediate 472: rac-(1R,2R,3S,4S)-3-(4-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

    [2992] ##STR00850##

    [2993] The titled compound was prepared analogous to Example 236 step C, using Intermediate 213 instead of Intermediate 226. MS (ESI) m/z 639.3 [M+H].sup.+.

    Step B: Intermediate 473: rac-tert-Butyl 4-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinate

    [2994] ##STR00851##

    [2995] Tris(dibenzylideneacetone)dipalladium(0) (5.0 mg, 0.005 mmol) and ((2,4,6-tri-isopropyl)phenyl)dicyclohexylphosphine (6.5 mg, 0.014 mmol) were added to the mixture of Intermediate 472 (35 mg, 0.055 mmol), tert-butyl 4-chloropyridine-2-carboxylate (18 mg, 0.082 mmol) and CsF (25 mg, 0.165 mmol) in cyclopentyl methyl ether (0.5 mL), and the mixture was stirred at reflux for 3 hr. The mixture was cooled to ambient temperature, then H.sub.2O and CHCl.sub.3 was added to the reaction mixture. The mixture was extracted with CHCl.sub.3 and combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (25 mg, 66%). MS (ESI) m/z 690.3 [M+H].sup.+.

    Step C: rac-4-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid

    [2996] A mixture of TFA (0.2 mL) and Intermediate 473 (24 mg, 0.034 mmol) was stirred at rt for 2 hr. After the reaction mixture was concentrated in vacuo, the crude product was purified by flash chromatography using a gradient of 0-20% MeOH in CHCl.sub.3 as mobile phase to give the title compound (10 mg, 45%). MS (ESI) m/z 634.3 [M+H].sup.+.

    Example 273: rac-2′-Fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-2-carboxylic acid

    [2997] ##STR00852##

    [2998] The titled compound was prepared analogous to Example 272 Step B and C, using tert-butyl 2-bromobenzoate instead of tert-butyl 4-chloropyridine-2-carboxylate. MS (ESI) m/z 633.3 [M+H].sup.+.

    Example 274: rac-5-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)picolinic acid

    [2999] ##STR00853##

    [3000] The titled compound was prepared analogous to Example 272 Step B and C, using tert-butyl 5-bromopyridine-2-carboxylate instead of tert-butyl 4-chloropyridine-2-carboxylate. MS (ESI) m/z 634.1 [M+H].sup.+.

    Example 275: rac-2-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)oxazole-4-carboxylic acid

    [3001] ##STR00854##

    [3002] Tetrakis(triphenylphosphine)palladium (7.2 mg, 0.006 mmol) was added to the mixture of Intermediate 472 (40 mg, 0.063 mmol), ethyl 2-chlorooxazole-4-carboxylate (Compound 8) (14 mg, 0.082 mmol) in sat aq NaHCO.sub.3 (0.3 mL) and DME (0.3 mL), and the mixture was stirred at reflux for 4 hr. The mixture was cooled to ambient temperature, then 1 M aq HCl was added to the reaction mixture until pH<2. The mixture was extracted with CHCl.sub.3 and combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-20% MeOH in CHCl.sub.3 as mobile phase to give the title compound (8 mg, 20%). MS (ESI) m/z 624.3 [M+H].sup.+.

    [3003] The examples included in Table 21 below were synthesized analogously to Example 275, using the specified starting material instead of Compound 8.

    TABLE-US-00021 TABLE 21 Ex MS No. SM Product (ESI) 276 [00855]embedded image [00856]embedded image m/z 635.3 [M + H].sup.+ 277 [00857]embedded image [00858]embedded image m/z 634.3 [M + H].sup.+ 278 [00859]embedded image [00860]embedded image m/z 634.2 [M + H].sup.+ 279 [00861]embedded image [00862]embedded image m/z 634.3 [M + H].sup.+ 280 [00863]embedded image [00864]embedded image m/z 635.3 [M + H].sup.+ 281 [00865]embedded image [00866]embedded image HRMS m/z [M + H].sup.+ 647.1512 282 [00867]embedded image [00868]embedded image HRMS m/z [M + H].sup.+ 661.1606 283 [00869]embedded image [00870]embedded image HRMS m/z [M + H].sup.+ 661.1640

    Example 284: rac-5-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-3-carboxylic acid

    [3004] ##STR00871##

    Step A: Intermediate 474: rac-Methyl 5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-3-carboxylate

    [3005] ##STR00872##

    [3006] Tetrakis(triphenylphosphine)palladium (5.4 mg, 0.005 mmol) was added to the mixture of Intermediate 472 (30 mg, 0.047 mmol), methyl 5-bromothiophene-3-carboxylate (Compound 9) (12 mg, 0.056 mmol) in sat aq NaHCO.sub.3 (0.5 mL) and DME (0.5 mL), and the mixture was stirred at reflux for 2 hr. After the mixture was cooled to ambient temperature the mixture was extracted with CHCl.sub.3 and combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-4% MeOH in CHCl.sub.3 as mobile phase to give the title compound (31 mg, 75%). MS (ESI) m/z 653.2 [M+H].sup.+.

    Step B: rac-5-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenyl)thiophene-3-carboxylic acid

    [3007] The titled compound was prepared analogous to Example 236 step E, using Intermediate 474 instead of Intermediate 448. MS (ESI) m/z 639.2 [M+H].sup.+.

    [3008] The examples included in Table 22 below were synthesized analogously to Example 284, using the specified starting material instead of Compound 9.

    TABLE-US-00022 TABLE 22 Ex MS No. SM Product (ESI) 285 [00873]embedded image [00874]embedded image m/z 639.2 [M + H].sup.+ 286 [00875]embedded image [00876]embedded image m/z 640.2 [M + H].sup.+ 287 [00877]embedded image [00878]embedded image m/z 640.2 [M + H].sup.+ 288 [00879]embedded image [00880]embedded image HRMS m/z [M + H].sup.+ 673.1642

    Example 289: (S)-2-(Dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1RS,2SR,3RS,4SR)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [3009] ##STR00881##

    Step A: Intermediate 475: (S)-2-((tert-Butoxycarbonyl)amino)-3-(2′-fluoro-4′-methoxy-5′-(((1RS,2RS,3SR,4SR)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [3010] ##STR00882##

    [3011] Tetrakis(triphenylphosphine)palladium (9 mg, 0.008 mmol) was added to the mixture of Intermediate 472 (50 mg, 0.078 mmol), (2S)-3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoic acid (54 mg, 0.157 mmol) in sat aq NaHCO.sub.3 (1 mL) and DME (1 mL), and the mixture was stirred at reflux for 3 hr. The mixture was cooled to ambient temperature, then aq citric acid was added to the reaction mixture. The mixture was extracted with EtOAc and combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in CHCl.sub.3 as mobile phase to give the title compound (50 mg, 82%).

    Step B: (S)-2-(Dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1RS,2SR,3RS,4SR)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [3012] A mixture of Intermediate 475 (50 mg, 0.064 mmol) in 4 M HCl in EtOAc (1 mL) was stirred at rt for 12 hr. MeCN (1 mL) and H.sub.2O (1 mL) were added to the reaction mixture, then HCHO (37% in H.sub.2O, 21 mg, 0.258 mmol) and NaBH(OAc).sub.3 (41 mg, 0.193 mmol) were added and the mixture was stirred at rt for 3 hr. The mixture was concentrated in vacuo and the crude product was purified by reversed phase HPLC on a C18 column using a gradient of 20-45% MeCN in TFA (0.05% in H.sub.2O) as mobile phase to give the title compound (50 mg, 82%). HRMS (ESI) m/z [M+H].sup.+ calcd for C34H36F4N3O7S: 706.2204 found: 706.2212.

    Example 290: (R)-2-(Dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1RS,2SR,3RS,4SR)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [3013] ##STR00883##

    [3014] The titled compound was prepared analogous to Example 289, using (2R)-3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoic acid instead of (2S)-3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoic acid. HRMS (ESI) m/z [M+H].sup.+ calcd for C34H36F4N3O7S: 706.2204 found: 706.2202.

    Example 291: (R)-2-Amino-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [3015] ##STR00884##

    Step A: Intermediate 476: (R)-2-((tert-Butoxycarbonyl)amino)-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [3016] ##STR00885##

    [3017] Tetrakis(triphenylphosphine)palladium (20 mg, 0.097 mmol) was added to the mixture of Intermediate 447 (100 mg, 0.179 mmol), (2R)-3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoic acid (123 mg, 0.358 mmol) in sat aq NaHCO.sub.3 (1 mL) and DME (1 mL), and the mixture was stirred at reflux for 3 hr. The mixture was cooled to ambient temperature, then aq citric acid was added to the reaction mixture. The mixture was extracted with CHCl.sub.3 and combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (86 mg, 62%).

    Step B: (R)-2-Amino-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [3018] A mixture of Intermediate 476 (86 mg, 0.11 mmol) in 4 M HCl in EtOAc (1 mL) was stirred at rt for 1 hr. The mixture was concentrated and the crude product was purified by reversed phase HPLC on a C18 column using a gradient of 20-50% MeCN in TFA (0.05% in H.sub.2O) as mobile phase to give the title compound (41 mg, 47%). HRMS (ESI) m/z [M+H].sup.+ calcd for C32H32F4N3O7S: 678.1892 found: 678.1902.

    Example 292: (R)-2-(Dimethylamino)-3-(2′-fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)propanoic acid

    [3019] ##STR00886##

    [3020] NaBH(OAc).sub.3 (36 mg, 0.171 mmol) was added to a mixture of HCHO (37% in H.sub.2O, 0.013 mL, 0.171 mmol) and Example 291 (45 mg, 0.057 mmol) in MeCN (1 mL), and the mixture was stirred at rt for 12 hr. The mixture was concentrated and the crude product was purified by reversed phase HPLC on a C18 column using a gradient of 25-55% MeCN in TFA (0.05% in H.sub.2O) as mobile phase to give the title compound (45 mg, 97%). HRMS (ESI) m/z [M+H].sup.+ calcd for C34H36F4N3O7S: 706.2204 found: 706.2186.

    [3021] The examples included in Table 23 below were synthesized analogously to Example 291 followed by Example 292, using the specified starting material instead of (2R)-3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoic acid for Example 291 Step A.

    TABLE-US-00023 TABLE 23 Ex SM MS No. (Step A) Product (ESI) 293 [00887]embedded image [00888]embedded image HRMS m/z [M + H].sup.+ 706.2256 294 [00889]embedded image [00890]embedded image m/z 692.1 [M + H].sup.+ 295 [00891]embedded image [00892]embedded image m/z 692.1 [M + H].sup.+

    Example 296: rac-2′-Fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid

    [3022] ##STR00893##

    Step A: Intermediate 477: 3-Benzyl 4′-(tert-butyl) 6-fluoro-4-methoxy-[1,1′-biphenyl]-3,4′-dicarboxylate

    [3023] ##STR00894##

    [3024] Tetrakis(triphenylphosphine)palladium (100 mg, 0.087 mmol) was added to the mixture of Intermediate 444 (300 mg, 0.884 mmol) and (4-tert-butoxycarbonylphenyl)boronic acid (300 mg, 1.35 mmol) in sat aq NaHCO.sub.3 (3 mL) and DME (3 mL), and the mixture was stirred at reflux for 2 hr. The mixture was cooled to ambient temperature and extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 15% EtOAc in hexane as mobile phase to give the title compound (386 mg, 99%). MS (APCI) m/z 381.0 [M+H].sup.+.

    Step B: Intermediate 478: 4′-(tert-Butoxycarbonyl)-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxylic acid

    [3025] ##STR00895##

    [3026] 1 M aq NaOH (2.0 mL, 2.0 mmol) was added to the solution of Intermediate 477 (386 mg, 0.88 mmol) in MeOH (10 mL), and the mixture was stirred at rt for 12 hr. The mixture was concentrated in vacuo, then 1 M aq HCl was added to the mixture and residual precipitate was collected by filtration to give the title compound (160 mg, 52%). MS (APCI) m/z 364.1 [M+H].sup.+.

    Step C: Intermediate 479: rac-tert-Butyl 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylate

    [3027] ##STR00896##

    [3028] WSC.Math.HCl (55 mg, 0.289 mmol), HOAt (20 mg, 0.145 mmol) and TEA (0.06 mL, 0.434 mmol) were added to a solution of Intermediate 214 (60 mg, 0.145 mmol) and Intermediate 478 (50 mg, 0.145 mmol) in CHCl.sub.3 (1 mL), then the mixture was stirred at rt for 12 hr. The mixture was concentrated in vacuo and the crude product was used without further purification.

    Step D: rac-2′-Fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid

    [3029] The mixture of Intermediate 479 (180 mg, 0.017 mmol) and TFA (2 mL, 26 mmol) were stirred at rt for 12 hr. After the reaction mixture was concentrated in vacuo, the crude product was purified by flash chromatography using 7% MeOH in CHCl.sub.3 as mobile phase to give the title compound (94 mg, 18%). HRMS (ESI) m/z [M+H].sup.+ calcd for C30H24F5N2O7S: 651.1218 found: 651.1202.

    [3030] The examples included in Table 24 below were synthesized analogously to Example 296, using the specified starting material for Step A instead of (4-tert-butoxycarbonylphenyl)boronic acid, and the specified starting material for Step C instead of Intermediate 214.

    TABLE-US-00024 TABLE 24 Ex SM SM MS No. (Step A) (Step C) Product (ESI) 297 [00897]embedded image Int. 214 [00898]embedded image HRMS m/z [M + H].sup.+ 651.1230 298 [00899]embedded image Int. 215 [00900]embedded image m/z 645.3 [M + H].sup.+ 299 [00901]embedded image Int. 216 [00902]embedded image m/z 609.0 [M + H].sup.+ 300 [00903]embedded image Int. 216 [00904]embedded image m/z 609.0 [M + H].sup.+ 301 [00905]embedded image Int. 183 [00906]embedded image 302 [00907]embedded image Int. 183 [00908]embedded image m/z 609.0 [M + H].sup.+ 303 [00909]embedded image Int. 231 [00910]embedded image m/z 635.2 [M + H].sup.+ 304 [00911]embedded image Int. 224 [00912]embedded image m/z 497.5 [M + H].sup.+

    Example 305: rac-2′-Fluoro-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [3031] ##STR00913##

    Step A: Intermediate 480: rac-(1R,2R,3S,4S)-3-(3-bromo-4-fluorobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

    [3032] ##STR00914##

    [3033] T3P (1.7 M in EtOAc, 0.57 mL, 0.97 mmol) and DIPEA (0.25 mL, 1.46 mmol) were added to a solution of Intermediate 213 (175 mg, 0.49 mmol) and 3-bromo-4-fluorobenzoic acid (117 mg, 0.53 mmol) in EtOAc (3 mL), then the mixture was stirred at rt for 17 hr. Sat aq NaHCO.sub.3 was added to the reaction mixture, then organic layer was separated and concentrated in vacuo. After H.sub.2O and a few drop of THF were added to a crude mixture, residual precipitate was collected by filtration and washed with H.sub.2O and MeOH to give the title compound (239 mg, 88%). MS (APCI) m/z 560.9/562.9 [M+H].sup.+.

    Step B: Intermediate 481: rac-methyl 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylate

    [3034] ##STR00915##

    [3035] Tetrakis(triphenylphosphine)palladium (9.3 mg, 0.008 mmol) was added to the mixture of Intermediate 480 (90 mg, 0.16 mmol) and (4-methoxycarbonylphenyl)boronic acid (43 mg, 0.241 mmol) in sat aq NaHCO.sub.3 (0.5 mL) and DME (2 mL), and the mixture was stirred at reflux for 7 hr. The mixture was cooled to ambient temperature and extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 10-35% EtOAc in hexane as mobile phase to give the title compound (58 mg, 58%). MS (APCI) m/z 617.0 [M+H].sup.+.

    Step C: rac-2′-Fluoro-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [3036] 1 M aq LiOH (0.81 mL, 0.81 mmol) was added to a solution of Intermediate 481 (50 mg, 0.81 mmol) in DME (3 mL), and the reaction mixture was stirred at rt for 6 hr. 2 M aq HCl was added to the reaction mixture to adjust pH<2 and the reaction mixture was extracted with CHCl.sub.3 twice and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-6% MeOH in EtOAc as mobile phase to give the title compound (30 mg, 61%). MS (APCI) m/z 603.0 [M+H].sup.+.

    Example 306: rac-2′,4′-Difluoro-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [3037] ##STR00916##

    [3038] The titled compound was prepared analogous to Example 305, using 3-bromo-2,4-difluorobenzoic acid instead of 3-bromo-4-fluorobenzoic acid. MS (APCI) m/z 621.0 [M+H].sup.+.

    Example 307: rac-2′-Fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid

    [3039] ##STR00917##

    Step A: Intermediate 482: 3-Benzyl 4′-methyl 6-fluoro-4-methoxy-[1,1′-biphenyl]-3,4′-dicarboxylate

    [3040] ##STR00918##

    [3041] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (203 mg, 0.28 mmol) and K.sub.3PO.sub.4 (2.39 mg, 11.3 mmol) were added to a solution of Intermediate 444 (350 mg, 1.03 mmol) and (4-methoxycarbonylphenyl)boronic acid (2.03 g, 11.26 mmol) in toluene (28.7 mL) and H.sub.2O (5.7 mL), then the mixture was stirred at reflux temperature for 1.5 hr. The mixture was cooled to ambient temperature and H.sub.2O was added, then the mixture was extracted with EtOAc and the organic layer was concentrated in vacuo. The crude product was purified by NH flash chromatography using a gradient of 10-30% EtOAc in hexane as mobile phase to give the title compound (2.11 g, 95%). MS (ESI) m/z 287.1 [M+H].sup.+.

    Step B: Intermediate 483: 6-Fluoro-4-methoxy-4′-(methoxycarbonyl)-[1,1′-biphenyl]-3-carboxylic acid

    [3042] ##STR00919##

    [3043] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 235 mg) was added to a solution of Intermediate 482 (2.35 g, 5.95 mmol) in MeOH (23 mL) and THF (23 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 15 min. The hydrogen in the reaction vessel was replaced with argon, then the reaction mixture was diluted with hot EtOAc and filtered with Celite®®. The filtrate was concentrated in vacuo and triturated with IPA to give titled compound (1.80 g, 99%). MS (ESI) m/z 305.1 [M+H].sup.+.

    Step C: Intermediate 484: rac-Methyl 2′-fluoro-4′-methoxy-5′-((1R,2R,5S,6S)-4-oxo-3-azatricyclo[4.2.1.02,5]non-7-ene-3-carbonyl)-[1,1′-biphenyl]-4-carboxylate

    [3044] ##STR00920##

    [3045] Oxalyl chloride (500 mg, 0.334 mmol) was added to a mixture of Intermediate 483 (600 mg, 1.97 mmol) in CH.sub.2Cl.sub.2 (12 mL) and DMF (0.02 mL), then the mixture was stirred at rt for 1 hr. The mixture was concentrated and the residue was dissolved in CH.sub.2Cl.sub.2. The reaction mixture was cooled to 0° C. and DMAP (48 mg, 0.394 mmol), TEA (0.83 mL, 5.92 mmol) and rac-(1R,2R,5S,6S)-3-azatricyclo[4.2.1.02,5]non-7-en-4-one were added, then the mixture was stirred at rt for 17 hr. Sat aq NaHCO.sub.3 was added to the reaction mixture and extracted with CHCl.sub.3. The organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 30% EtOAc in hexane as mobile phase to give the title compound (603 mg, 73%). MS (ESI) m/z 422.3 [M+H].sup.+.

    Step D: Intermediate 485: rac-Methyl 2′-fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylate

    [3046] ##STR00921##

    [3047] A mixture of 4-fluoro-3-(trifluoromethyl)aniline (61 mg, 0.332 mmol) and Intermediate 484 (70 mg, 0.166 mmol) in acetic acid (1 mL) was stirred at rt for 3 hr. After the reaction mixture was concentrated, sat aq NaHCO.sub.3 was added and the mixture was extracted with EtOAc. Combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 25-50% EtOAc in hexane as mobile phase to give the title compound (84 mg, 83%). MS (ESI) m/z 601.3 [M+H].sup.+.

    Step E: rac-2′-Fluoro-5′-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid

    [3048] 4 M aq NaOH (0.196 mL, 0.79 mmol) was added to a solution of Intermediate 485 (80 mg, 0.131 mmol) in MeOH (0.8 mL) and THF (0.8 mL), then the reaction mixture was stirred at rt for 17 hr. After the reaction mixture was concentrated in vacuo, 2 M aq HCl was added to the reaction mixture to adjust pH<2, then the residual precipitate was collected by filtration. The crude solid was purified by flash chromatography using 0-10% MeOH in CHCl.sub.3 as mobile phase to give the title compound (63 mg, 82%). MS (ESI) m/z 587.3 [M+H].sup.+.

    [3049] The examples included in Table 25 below were synthesized analogously to Example 307 steps D and E, using the specified starting material for Step D instead of 4-fluoro-3-(trifluoromethyl)aniline.

    TABLE-US-00025 TABLE 25 Ex MS No. SM Product (ESI) 308 [00922]embedded image [00923]embedded image HRMS m/z [M + H].sup.+ 587.1630 309 [00924]embedded image [00925]embedded image m/z 544.3 [M + H].sup.+ 310 [00926]embedded image [00927]embedded image m/z 544.5 [M + H].sup.+ 311 [00928]embedded image [00929]embedded image m/z 640.3 [M + H].sup.+ 312 [00930]embedded image [00931]embedded image m/z 640.3 [M + H].sup.+

    Example 313: 2′-Fluoro-4′-methoxy-5′-(((1R*,2S*,3R*,4S*)-3-(((S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid (Isomer 1) and

    Example 314: 2′-Fluoro-4′-methoxy-5′-(((1R*,2S*,3R*,4S*)-3-(((S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid (Isomer 2)

    [3050] ##STR00932##

    [3051] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 5 mg) was added to a solution of Example 311 (56 mg, 0.088 mmol) in EtOAc (1 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 1 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®@. The filtrate was concentrated in vacuo to give titled compound (50 mg, 89%). MS (APCI) m/z 642.0 [M+H].sup.+.

    [3052] The product (50 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [CO2/MeOH/AcOH=60/40/0.2]) to give the first eluting compound Isomer 1: Example 313 (18 mg, 36%); MS (APCI) m/z 642.0 [M+H].sup.+, and the second eluting compound Isomer 2: Example 314 (15 mg, 30%); MS (APCI) m/z 642.0 [M+H].sup.+.

    Example 315: rac-2′-Fluoro-5′-(((1R,2S,3R,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid

    [3053] ##STR00933##

    [3054] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 5 mg) was added to a solution of Example 307 (57 mg, 0.097 mmol) in EtOAc (1 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 1 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. The filtrate was concentrated in vacuo to give titled compound (57 mg, 100%). MS (APCI) m/z 587.0 [M+H].sup.+.

    Example 316: rac-2′-Fluoro-4-hydroxy-4′-methoxy-5′-(((1R,2S,3R,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid

    [3055] ##STR00934##

    Step A: Intermediate 486: rac-4-(benzyloxy)-2′-fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid

    [3056] ##STR00935##

    [3057] The titled compound was prepared analogous to Example 226, using methyl 2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate instead of Compound 5. MS (ESI) m/z 739.4 [M+H].sup.+.

    Step B: rac-2′-Fluoro-4-hydroxy-4′-methoxy-5′-(((1R,2S,3R,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid

    [3058] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 30 mg) was added to a solution of Intermediate 486 (50 mg, 0.068 mmol) in acetic acid (0.5 mL) and EtOAc (5 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 3 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®@. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-10% MeOH in CHCl.sub.3 as mobile phase to give the title compound (36 mg, 65%). MS (APCI) m/z 651.0 [M+H].sup.+.

    Example 317: 2′-Fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid

    [3059] ##STR00936##

    Step A: Intermediate 487: 4-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)benzamide

    [3060] ##STR00937##

    [3061] The titled compound was prepared analogous to Example 236 Step C, using Intermediate 217 instead of Intermediate 226. MS (ESI) m/z 615.5 [M+H].sup.+.

    Step B: 2′-Fluoro-4′-methoxy-5′-(((1R,2S)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid

    [3062] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (12 mg, 0.016 mmol) and K.sub.3PO.sub.4 (151 mg, 0.71 mmol) were added to the mixture of Intermediate 487 (201 mg, 0.33 mmol) and 3-bromobenzoic acid (68 mg, 0.34 mmol) in H.sub.2O (0.5 mL) and toluene (6 mL), and the mixture was stirred at reflux for 2 hr. The mixture was cooled to ambient temperature and diluted with EtOAc, then 10% aq citric acid was added and the mixture was extracted with EtOAc. The combined organic layer was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-13% MeOH in CHCl.sub.3 as mobile phase to give the title compound (73 mg, 36%). MS (ESI) m/z 609.4 [M+H].sup.+.

    [3063] The examples included in Table 26 below were synthesized analogously to Example 317, using the specified starting material instead of 3-bromobenzoic acid.

    TABLE-US-00026 TABLE 26 Ex MS No. SM Product (ESI) 318 [00938]embedded image [00939]embedded image HRMS m/z [M + H].sup.+ 623.1460 319 [00940]embedded image [00941]embedded image HRMS m/z [M + H].sup.+ 637.1616 320 [00942]embedded image [00943]embedded image HRMS m/z [M + H].sup.+ 623.1480 321 [00944]embedded image [00945]embedded image HRMS m/z [M + H].sup.+ 637.1630

    Example 322: 3-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-1,3,4-thiadiazol-2-yl)propanoic acid

    [3064] ##STR00946##

    Step A: Intermediate 488: tert-Butyl (E)-3-(5-bromo-1,3,4-thiadiazol-2-yl)acrylate

    [3065] ##STR00947##

    [3066] NaH (60% in oil suspension, 199 mg, 4.974 mmol) was added to the solution of tert-butyl 2-diethoxyphosphorylacetate (1.25 g, 4.974 mmol) in THF (10 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. 5-bromo-1,3,4-thiadiazole-2-carbaldehyde (800 mg, 4.145 mmol) was added to the reaction mixture at 0° C., then the mixture was stirred at 0° C. for 1 hr. H.sub.2O was added to the reaction mixture and extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-20% EtOAc in hexane as mobile phase to give the title compound (233 mg, 19%). MS (ESI) m/z 291.0/293.0 [M+H].sup.+.

    Step B: Intermediate 489: Benzyl (E)-5-(5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-1,3,4-thiadiazol-2-yl)-4-fluoro-2-methoxybenzoate

    [3067] ##STR00948##

    [3068] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (24 mg, 0.034 mmol) and cesium carbonate (224 mg, 0.687 mmol) were added to the mixture of Intermediate 445 (146 mg, 0.378 mmol) and Intermediate 488 (100 mg, 0.343 mmol) in H.sub.2O (0.5 mL) and DME (1 mL), and the mixture was stirred at reflux for 1 hr. The mixture was cooled to ambient temperature, the mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-35% EtOAc in hexane as mobile phase to give the title compound (69 mg, 43%).

    Step C: Intermediate 490: 5-(5-(3-(tert-Butoxy)-3-oxopropyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-2-methoxybenzoic acid

    [3069] ##STR00949##

    [3070] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 16 mg) was added to a solution of Intermediate 489 (60 mg, 0.128 mmol) in MeOH (3 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 4 days. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. The filtrate was concentrated in vacuo to give titled compound (25 mg, 51%). MS (ESI) m/z 383.1 [M+H].sup.+.

    Step D: Intermediate 491: tert-Butyl 3-(5-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-1,3,4-thiadiazol-2-yl)propanoate

    [3071] ##STR00950##

    [3072] HATU (27 mg, 0.0719 mmol) was added to a solution of Intermediate 490 (25 mg, 0.0654 mmol), Intermediate 226 (29 mg, 0.0719 mmol) and DIPEA (25 mg, 0.196 mmol) in DMF (1 mL) and the reaction mixture was stirred at rt for 10 min. H.sub.2O was added to the reaction mixture and the reaction mixture was stirred vigorously. The precipitate was collected by filtration and the crude material was dried under air to give titled compound (47 mg, 100%). MS (ESI) m/z 727.6 [M+H].sup.+.

    Step E: 3-(5-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-1,3,4-thiadiazol-2-yl)propanoic acid

    [3073] The titled compound was prepared analogous to Example 256 Step B, using Intermediate 491 instead of Intermediate 452. MS (ESI) m/z 671.5 [M+H].sup.+.

    Example 323: 3-(2-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-5-yl)propanoic acid

    [3074] ##STR00951##

    Step A: Intermediate 492: tert-butyl (E)-3-(2-chloropyrimidin-5-yl)acrylate

    [3075] ##STR00952##

    [3076] The titled compound was prepared analogous to Example 322 Step A, using 2-chloropyrimidine-5-carbaldehyde instead of 5-bromo-1,3,4-thiadiazole-2-carbaldehyde. MS (ESI) m/z 241.1/243.1 [M+H].sup.+.

    Step B: Intermediate 493: Benzyl (E)-5-(5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)pyrimidin-2-yl)-4-fluoro-2-methoxybenzoate

    [3077] ##STR00953##

    [3078] (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (28 mg, 0.033 mmol) and cesium carbonate (217 mg, 0.665 mmol) were added to the mixture of Intermediate 445 (141 mg, 0.366 mmol) and Intermediate 492 (80 mg, 0.332 mmol) in H.sub.2O (0.3 mL) and DME (1.6 mL), and the mixture was stirred at reflux for 1 hr. The mixture was cooled to ambient temperature, the mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-35% EtOAc in hexane as mobile phase to give the title compound (105 mg, 68%). MS (ESI) m/z 465.2 [M+H].sup.+.

    Step C: Intermediate 494: 5-(5-(3-(tert-Butoxy)-3-oxopropyl)pyrimidin-2-yl)-4-fluoro-2-methoxybenzoic acid

    [3079] ##STR00954##

    [3080] The titled compound was prepared analogous to Example 322 Step C, using Intermediate 493 instead of Intermediate 489. MS (ESI) m/z 377.2 [M+H].sup.+

    Step D: Intermediate 495: tert-Butyl 3-(2-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-5-yl)propanoate

    [3081] ##STR00955##

    [3082] The titled compound was prepared analogous to Example 322 Step D, using Intermediate 494 instead of Intermediate 490. MS (ESI) m/z 721.3 [M+H].sup.+.

    Step E: 3-(2-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrimidin-5-yl)propanoic acid

    [3083] The titled compound was prepared analogous to Example 256 Step B, using Intermediate 495 instead of Intermediate 452. HRMS (ESI) m/z [M+H].sup.+ calcd for C30H29F4N4O7S: 665.1688 found: 665.1694.

    Example 324: rac-3-(5-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)propanoic acid

    [3084] ##STR00956##

    Step A: Intermediate 496: tert-Butyl (E)-3-(5-bromopyrazin-2-yl)acrylate

    [3085] ##STR00957##

    [3086] The titled compound was prepared analogous to Example 322 Step A, using 2-bromopyrazine-5-carbaldehyde instead of 5-bromo-1,3,4-thiadiazole-2-carbaldehyde. MS (ESI) m/z 285.0/287.0 [M+H].sup.+.

    Step B: Intermediate 497: 5-(5-(3-(tert-Butoxy)-3-oxopropyl)pyrazin-2-yl)-4-fluoro-2-methoxybenzoic acid

    [3087] ##STR00958##

    [3088] The titled compound was prepared analogous to Example 322 Step B and C, using Intermediate 496 instead of Intermediate 488. MS (ESI) m/z 377.3 [M+H].sup.+.

    Step C: Intermediate 498: rac-tert-Butyl 3-(5-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)propanoate

    [3089] ##STR00959##

    [3090] HATU (10 mg, 0.0263 mmol) was added to a solution of Intermediate 497 (9 mg, 0.0239 mmol), Intermediate 231 (11 mg, 0.0263 mmol) and DIPEA (9 mg, 0.0713 mmol) in DMF (0.5 mL) and the reaction mixture was stirred at rt for 14 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 20-80% EtOAc in hexane as mobile phase to give titled compound (12 mg, 70%). MS (ESI) m/z 721.2 [M+H].

    Step D: rac-3-(5-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)pyrazin-2-yl)propanoic acid

    [3091] The titled compound was prepared analogous to Example 256 Step B, using Intermediate 498 instead of Intermediate 452. MS (ESI) m/z 665.3 [M+H].sup.+.

    Example 325: (1R,2S,3R,4S)-3-(6-Fluoro-4-methoxy-4′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3092] ##STR00960##

    Step A: Intermediate 499: Methyl 4′-cyano-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-carboxylate

    [3093] ##STR00961##

    [3094] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (54 mg, 0.0767 mmol) was added to the mixture of methyl 5-bromo-4-fluoro-2-methoxybenzoate (403 mg, 1.53 mmol) and 4-cyanophenylboronic acid (270 mg, 1.838 mmol) in 2 M aq Na.sub.2CO.sub.3 (2.0 mL, 4.0 mmol) and toluene (6 mL), and the mixture was stirred at reflux for 5 hr. The mixture was cooled to ambient temperature and extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-30% EtOAc in hexane as mobile phase to give the title compound (438 mg, 89%). MS (ESI) m/z 286.1 [M+H].sup.+.

    Step B: Intermediate 500: Methyl 6-fluoro-4-methoxy-4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-carboxylate

    [3095] ##STR00962##

    [3096] Tri-(n-butyl)tin azide (466 mg, 1.40 mmol) was added to the solution of Intermediate 499 (200 mg, 0.701 mmol) in toluene (2 mL), and the mixture was stirred at reflux for 15 hr. After the mixture was concentrated in vacuo, the crude product was purified by flash chromatography using a gradient of 0-20% MeOH in CHCl.sub.3 as mobile phase to give the title compound (149 mg, 65%). MS (ESI) m/z 329.2 [M+H].sup.+.

    Step C: Intermediate 501: 6-Fluoro-4-methoxy-4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-carboxylic acid

    [3097] ##STR00963##

    [3098] The titled compound was prepared analogous to Example 296 Step B, using Intermediate 500 instead of Intermediate 477. MS (ESI) m/z 315.2 [M+H].sup.+.

    Step D: (1R,2S,3R,4S)-3-(6-Fluoro-4-methoxy-4′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3099] The titled compound was prepared analogous to Example 322 Step D, using Intermediate 501 instead of Intermediate 490. HRMS (ESI) m/z [M+H].sup.+ calcd for C30H27F4N6O5S: 659.1694 found: 659.1700.

    Example 326: rel-(1R,2R,3S,4S)-3-(6-Fluoro-4-methoxy-4′-(2-sulfamoylethyl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (Isomer 1) and

    Example 327: rel-(1R,2R,3S,4S)-3-(6-fluoro-4-methoxy-4′-(2-sulfamoylethyl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (Isomer 2)

    [3100] ##STR00964##

    Step A: Intermediate 502: 6-Fluoro-4-methoxy-4′-(2-sulfamoylethyl)-[1,1′-biphenyl]-3-carboxylic acid

    [3101] ##STR00965##

    [3102] The titled compound was prepared analogous to Example 322 Step B and C, using 2-(4-bromophenyl)ethane-1-sulfonamide instead of Intermediate 488. MS (ESI) m/z 354.1 [M+H].sup.+.

    Step B: Intermediate 503: rac-(1R,2R,3S,4S)-3-(6-Fluoro-4-methoxy-4′-(2-sulfamoylethyl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3103] ##STR00966##

    [3104] EDC (50 mg, 0.258 mmol), HOAt (35 mg, 0.258 mmol) and TEA (0.036 mL, 0.258 mmol) were added to a solution of Intermediate 231 (103 mg, 0.258 mmol) and Intermediate 502 (76 mg, 0.215 mmol) in DMF (3 mL), then the mixture was stirred at rt for 4 hr. Sat aq NaHCO.sub.3 was added and the mixture was extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 50-90% EtOAc in hexane as mobile phase to give the title compound (144 mg, 96%). MS (ESI) m/z 698.6 [M+H].sup.+.

    Step C: rel-(1R,2R,3S,4S)-3-(6-Fluoro-4-methoxy-4′-(2-sulfamoylethyl)-[1,1′-biphenyl]-3-carboxamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3105] Intermediate 503 (121 mg) was separated by chiral HPLC (column: CHIRALPAK IE (250 mm×30 mm); mobile phase: [Hex/EtOH=40/60]) to give the first eluting compound Isomer 1: Example 326 (60 mg, 50%); MS (APCI) m/z 698.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 327 (60 mg, 49%); HRMS (ESI) m/z [M+H].sup.+ calcd for C31H32F4N3O7S2: 698.1612 found: 698.1626.

    Example 328: 2′-Fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [3106] ##STR00967##

    Step A: Intermediate 504: Methyl 2′-fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylate

    [3107] ##STR00968##

    [3108] The titled compound was prepared analogous to Example 322 Step D, using Intermediate 483 instead of Intermediate 490 and using 2-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of Intermediate 226. MS (ESI) m/z 629.4 [M−H].sup.−.

    Step B: 2′-Fluoro-4′-methoxy-5′-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid

    [3109] The titled compound was prepared analogous to Example 307 Step E, using Intermediate 504 instead of Intermediate 485. 1H NMR (400 MHz, DMSO-d6) δ 4.09 (s, 3H), 7.27-7.37 (m, 2H), 7.58-7.68 (m, 3H), 7.84-7.92 (m, 3H), 8.00-8.07 (m, 2H), 8.21 (d, J=9.4 Hz, 1H), 8.26 (dt, J=6.9, 2.2 Hz, 1H), 8.58 (d, J=7.7 Hz, 1H), 8.84 (s, 1H), 11.13 (s, 1H), 11.58 (s, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C29H21F4N2O7S: 617.1000 found: 617.1002.

    Example 329: 2-((2′-Cyano-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid

    [3110] ##STR00969##

    Step A: Intermediate 505: (1R,2S,3R,4S)-3-(5-Bromo-4-cyano-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3111] ##STR00970##

    [3112] The titled compound was prepared analogous to Example 236 Step C, using 5-bromo-4-cyano-2-methoxybenzoic acid instead of Intermediate 446. MS (ESI) m/z 600.1/602.1 [M+H].sup.+.

    Step B: 2-((2′-Cyano-4′-methoxy-5′-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid

    [3113] The titled compound was prepared analogous to Example 226, using ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate instead of Compound 5 and using Intermediate 505 instead of Intermediate 442. HRMS (ESI) m/z [M+H].sup.+ calcd for C32H29F3N3O8S: 672.1622 found: 672.1658.

    Example 330: 2-((2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid

    [3114] ##STR00971##

    Step A: Intermediate 506: (1R,2S,3R,4S)-3-(5-Bromo-4-fluoro-2-methoxybenzamido)-N-neopentylbicyclo[2.2.1]heptane-2-carboxamide

    [3115] ##STR00972##

    [3116] The titled compound was prepared analogous to Example 236 Step C, using 5-bromo-4-fluoro-2-methoxybenzoic acid instead of Intermediate 446 and using Intermediate 224 instead Intermediate 226. MS (ESI) m/z 455.4/457.4 [M+H].sup.+.

    Step B: 2-((2′-Fluoro-4′-methoxy-5′-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)oxy)acetic acid

    [3117] The titled compound was prepared analogous to Example 226, using ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate instead of Compound 5 and using Intermediate 506 instead of Intermediate 442. MS (ESI) m/z 527.5 [M+H].sup.+

    Example 331: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1SR,2SR,3RS,4RS)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3118] ##STR00973##

    Step A: Intermediate 507: rac-Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [3119] ##STR00974##

    [3120] HATU (1.82 g, 4.79 mmol) was added to a solution of Intermediate 13 (172 mg, 0.369 mmol), Intermediate 176 (123 mg, 0.516 mmol) and DIPEA (95 mg, 0.737 mmol) in DMF (1.8 mL) and the reaction mixture was stirred at rt for 1 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-70% EtOAc in hexane as mobile phase to give the title compound (235 mg, 93%). MS (ESI) m/z 687.3 [M+H].sup.+.

    Step B: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1SR,2SR,3RS,4RS)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3121] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 120 mg) was added to a solution of Intermediate 507 (233 mg, 0.34 mmol) in MeOH (3 mL) and THF (3 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 2 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-10% MeOH in CHCl.sub.3 as mobile phase to give the title compound (187 mg, 1000%). MS (ESI) m/z 547.3 [M+H].sup.+.

    [3122] The examples included in Table 27 below were synthesized analogous to the procedure of Example 331 using indicated acids and amines.

    TABLE-US-00027 TABLE 27 Ex. MS No. Acid Amine Product (ESI) 332 Int. 342 Int. 176 [00975]embedded image m/z 563.2 [M + H].sup.+ 333 Int. 70  Int. 176 [00976]embedded image m/z 554.3 [M + H].sup.+ 334 Int. 70  Int. 182 [00977]embedded image m/z 653.4 [M + H].sup.+ 335 Int. 13  Int. 195 [00978]embedded image m/z 675.6 [M + H].sup.+ 336 Int. 13  Int. 191 [00979]embedded image m/z 675.2 [M + H].sup.+ 337 Int. 13  Int. 247 [00980]embedded image m/z 537.4 [M + H].sup.+ 338 Int. 342 Int. 247 [00981]embedded image m/z 553.4 [M + H].sup.+ 339 Int. 342 Int. 248 [00982]embedded image m/z 565.4 [M + H].sup.+ 340 Int. 13  Int. 236 [00983]embedded image m/z 661.6 [M + H].sup.+ 341 Int. 13  Int. 240 [00984]embedded image m/z 661.6 [M + H].sup.+ 342 Int. 13  Int. 244 [00985]embedded image m/z 647.5 [M + H].sup.+ 343 Int. 13  Int. 207 [00986]embedded image m/z 661.4 [M + H].sup.+ 344 Int. 13  Int. 245 [00987]embedded image m/z 659.5 [M + H].sup.+ 345 Int. 13  Int. 243 [00988]embedded image m/z 509.2 [M + H].sup.+ 346 Int. 13  Int. 184 [00989]embedded image m/z 493.5 [M + H].sup.+ 347 Int. 13  Int. 185 [00990]embedded image m/z 643.2 [M + H].sup.+ 348 Int. 70  Int. 186 [00991]embedded image m/z 512.3 [M + H].sup.+ 349 Int. 13  Int. 237 [00992]embedded image m/z 673.5 [M + H].sup.+ 350 Int. 13  Int. 242 [00993]embedded image m/z 521.3 [M + H].sup.+ 351 Int. 13  Int. 217 [00994]embedded image m/z 645.3 [M + H].sup.+ 352 Int. 13  Int. 218 [00995]embedded image HRMS m/z [M + H].sup.+ 657.1868 m/z 353 Int. 13  Int. 219 [00996]embedded image HRMS m/z [M + H].sup.+ 683.2038 354 Int. 13  Int. 239 [00997]embedded image m/z 673.3 [M + H].sup.+ 355 Int. 13  Int. 196 [00998]embedded image HRMS m/z [M + H].sup.+ 663.1818 356 Int. 13  Int. 241 [00999]embedded image m/z 647.5 [M + H].sup.+ 357 Int. 13  Int. 238 [01000]embedded image m/z 661.6 [M + H].sup.+ 358 Int. 13  Int. 180 [01001]embedded image m/z 547.5 [M + H].sup.+ 359 Int. 13  Int. 211 [01002]embedded image m/z 675.4 [M + H].sup.+ 360 Int. 70  Int. 190 [01003]embedded image HRMS m/z [M + H].sup.+ 526.2904 361 Int. 70  Int. 189 [01004]embedded image m/z 540.2 [M + H].sup.+ 362 Int. 342 Int. 243 [01005]embedded image m/z 525.2 [M + H].sup.+ 363 Int. 342 Int. 242 [01006]embedded image m/z 537.5 [M + H].sup.+ 364 Int. 342 Int. 22  [01007]embedded image HRMS m/z [M + H].sup.+ 561.2940 365 Int. 342 Int. 220 [01008]embedded image HRMS m/z [M + H].sup.+ 615.2712 366 Int. 342 Int. 231 [01009]embedded image m/z 687.4 [M + H].sup.+ 367 Int. 13  Int. 231 [01010]embedded image m/z 671.6 [M + H].sup.+ 368 Int. 302 Int. 187 [01011]embedded image m/z 554.4 [M + H].sup.+ 369 Int. 13  Int. 221 [01012]embedded image m/z 545.3 [M + H].sup.+ 370 Int. 13  Int. 222 [01013]embedded image m/z 533.3 [M + H].sup.+ 371 Int. 13  Int. 235 [01014]embedded image m/z 683.6 [M + H].sup.+ 372 Int. 299 Int. 22  [01015]embedded image m/z 595.3 [M + H].sup.+ 373 Int. 295 Int. 22  [01016]embedded image HRMS m/z [M + H].sup.+ 577.3086 374 Int. 296 Int. 22  [01017]embedded image HRMS m/z [M + H].sup.+ 545.3040 375 Int. 316 Int. 22  [01018]embedded image HRMS m/z [M + H].sup.+ 541.3296 376 Int. 318 Int. 22  [01019]embedded image HRMS m/z [M + H].sup.+ 555.3410 377 Int. 305 Int. 22  [01020]embedded image m/z 540.4 [M + H].sup.+ 378 Int. 306 Int. 22  [01021]embedded image m/z 551.4 [M + H].sup.+ 379 Int. 307 Int. 22  [01022]embedded image m/z 551.4 [M + H].sup.+ 380 Int. 308 Int. 22  [01023]embedded image m/z 559.8 [M + H].sup.+ 381 Int. 314 Int. 22  [01024]embedded image HRMS m/z [M + H].sup.+ 527.3142 382 Int. 316 Int. 223 [01025]embedded image m/z 543.4 [M + H].sup.+ 383 Int. 318 Int. 223 [01026]embedded image m/z 557.4 [M + H].sup.+ 384 Int. 309 Int. 223 [01027]embedded image m/z 561.4 [M + H].sup.+ 385 Int. 309 Int. 22  [01028]embedded image HRMS m/z [M + H].sup.+ 559.3184 386 Int. 343 Int. 224 [01029]embedded image m/z 547.4 [M + H].sup.+ 387 Int. 70  Int. 254 [01030]embedded image m/z 552.8 [M + H].sup.+ 388 Int. 70  Int. 221 [01031]embedded image HRMS m/z [M + H].sup.+ 552.3078 389 Int. 70  Int. 222 [01032]embedded image HRMS m/z [M + H].sup.+ 540.3106 390 Int. 296 Int. 223 [01033]embedded image m/z 547.3 [M + H].sup.+ 391 Int. 351 Int. 22  [01034]embedded image m/z 589.3 [M + H].sup.+

    Example 392: (1S,4s)-4-(2-Chloro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3123] ##STR01035##

    Step A: Intermediate 508: Naphthalen-1-ylmethyl (1S,4s)-4-(2-chloro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [3124] ##STR01036##

    [3125] The titled compound was prepared analogous to Example 331 step A, Intermediate 312 instead of Intermediate 13, and using Intermediate 22 instead of Intermediate 176. MS (ESI) m/z 701.4 [M+H].sup.+

    Step B: (1S,4s)-4-(2-Chloro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3126] Zinc chloride (10 mg, 0.074 mmol) and palladium (10% Pd/C, moisture by 50% H.sub.2O, 22 mg) were added to a solution of Intermediate 508 (125 mg, 0.18 mmol) in EtOAc (2 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 56 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. CHCl.sub.3 and H.sub.2O were added to the filtrate and the organic layer was separated. The organic layer was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (17 mg, 17%) and unreacted starting material (75 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 0.93 (s, 3H), 1.11 (s, 3H), 1.12-1.33 (m, 5H), 1.36-1.79 (m, 10H), 1.82-1.93 (m, 2H), 1.95-2.10 (m, 4H), 2.21-2.25 (m, 1H), 2.60-2.66 (m, 1H), 2.96 (dd, J=13.2, 5.5 Hz, 1H), 3.09 (dd, J=13.2, 6.3 Hz, 1H), 3.88 (s, 3H), 4.06-4.14 (m, 1H), 4.16-4.26 (m, 1H), 7.22 (s, 1H), 7.63 (s, 1H), 7.92-7.98 (m, 1H), 8.94 (br d, J=8.0 Hz, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C30H42C1N2O6: 561.2726 found: 561.2764.

    Example 393: (1S,4s)-4-(2,4-Difluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3127] ##STR01037##

    Step A: Intermediate 509: Benzyl 2,4-difluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

    [3128] ##STR01038##

    [3129] The titled compound was prepared analogous to Intermediate 314 step A, using Intermediate 292 instead of methyl 4-bromo-5-hydroxy-2-methoxybenzoate.

    Step B: Intermediate 510: 5-(((1s,4s)-4-Carboxy-4-methylcyclohexyl)oxy)-2,4-difluorobenzoic acid

    [3130] ##STR01039##

    [3131] The titled compound was prepared analogous to Example 331 step B, using Intermediate 509 instead of Intermediate 507. MS (ESI) m/z 315.1 [M+H].sup.+.

    Step C: (1S,4s)-4-(2,4-Difluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3132] EDC (41 mg, 0.214 mmol) and HOAt (29 mg, 0.213 mmol) were added to a mixture of Intermediate 510 (59 mg, 0.188 mmol) in DMF (2.5 mL), then the mixture was stirred at rt for 10 min. Intermediate 22 (55 mg, 0.202 mmol) and TEA (0.03 mL, 0.216 mmol) were added to the mixture and the mixture was stirred at 0° C. for 1.5 hr. 1 M aq HCl was added to the reaction mixture to adjust pH-2 and the mixture was extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-8% MeOH in CHCl.sub.3 as mobile phase to give the title compound (67 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 0.96 (s, 3H), 1.11 (s, 3H), 1.12-1.34 (m, 5H), 1.36-1.81 (m, 10H), 1.82-1.94 (m, 2H), 1.97-2.14 (m, 4H), 2.20-2.25 (m, 1H), 2.63-2.69 (m, 1H), 2.98 (dd, J=13.2, 6.1 Hz, 1H), 3.05 (dd, J=13.2, 6.1 Hz, 1H), 4.05-4.12 (m, 1H), 4.22-4.31 (m, 1H), 7.33-7.48 (m, 2H), 7.95-8.03 (m, 1H), 8.31-8.39 (m, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C29H39F2N2O5: 533.2822 found: 533.2824.

    Example 394: (1R,4s)-4-(5-(((1SR,2RS,3SR,5SR)-2,3-Dihydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3133] ##STR01040##

    Step A: Intermediate 511: Naphthalen-1-ylmethyl (1R,4s)-4-(5-(((1SR,2RS,3SR,5SR)-2,3-dihydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [3134] ##STR01041##

    [3135] The titled compound was prepared analogous to Example 331 step A, using Intermediate 252 instead of Intermediate 176. MS (ESI) m/z 817.3 [M+H].sup.+.

    Step B: (1R,4s)-4-(5-(((1SR,2RS,3SR,5SR)-2,3-Dihydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3136] The titled compound was prepared analogous to Example 331 step B, using Intermediate 511 instead of Intermediate 507. MS (ESI) m/z 677.2 [M+H].sup.+.

    Example 395: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3aRS,4SR,5SR,6aSR)-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3137] ##STR01042##

    Step A: Intermediate 512: Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3aRS,4SR,5SR,6aSR)-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [3138] ##STR01043##

    [3139] Dimethoxymethane (70 mg, 0.911 mmol) was added to a solution of Intermediate 511 (74 mg, 0.0911 mmol) and p-toluenesulfonic acid hydrate (2 mg, 0.011 mmol) in toluene (3 mL) and the reaction mixture was stirred at reflux for 3 hr. Sat aq NaHCO.sub.3 was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 20-60% EtOAc in hexane as mobile phase to give the title compound (68 mg, 89%). MS (ESI) m/z 829.7 [M+H].sup.+.

    Step B: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3aRS,4SR,5SR,6aSR)-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3140] The titled compound was prepared analogous to Example 331 step B, using Intermediate 512 instead of Intermediate 507. MS (ESI) m/z 689.6 [M+H]+

    Example 396: (1R,4s)-4-(2-Fluoro-5-(((1SR,2RS,5SR)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3141] ##STR01044##

    Step A: Intermediate 513: Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-5-(((1SR,2RS,5SR)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [3142] ##STR01045##

    [3143] The titled compound was prepared analogous to Example 331 step A, using Intermediate 200 instead of Intermediate 176. MS (ESI) m/z 801.3 [M+H].sup.+.

    Step B: (1R,4s)-4-(2-Fluoro-5-(((1SR,2RS,5SR)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3144] The titled compound was prepared analogous to Example 331 step B, using Intermediate 513 instead of Intermediate 507. HRMS (ESI) m/z [M+H].sup.+ calcd for C29H33F4N2O9S: 661.1838 found: 661.1860.

    Example 397: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1SR,2RS,5SR)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3145] ##STR01046##

    Step A: Intermediate 514: Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1SR,2RS,5SR)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [3146] ##STR01047##

    [3147] Iodomethane (141 mg, 0.99 mmol) and Ag2O (12 mg, 0.049 mmol) were added to a solution of Intermediate 513 (20 mg, 0.025 mmol) in THF (0.5 mL), and the reaction mixture was stirred at 40° C. for 4 hr. The reaction mixture was cooled down to rt and the mixture was filtered, then the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-70% EtOAc in hexane as mobile phase to give the title compound (20 mg, 98%). MS (ESI) m/z 815.5 [M+H].sup.+.

    Step B: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1SR,2RS,5SR)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3148] The titled compound was prepared analogous to Example 331 step B, using Intermediate 514 instead of Intermediate 507. MS (ESI) m/z 675.4 [M+H].sup.+.

    Example 398: (1S,4s)-4-(4-Chloro-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3149] ##STR01048##

    Step A: Intermediate 515: Naphthalen-1-ylmethyl (1S,4s)-4-(4-chloro-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [3150] ##STR01049##

    [3151] The titled compound was prepared analogous to Example 331 step A, using Intermediate 300 instead of Intermediate 13, and using Intermediate 22 instead of Intermediate 176. MS (ESI) m/z 689.4/691.4 [M+H].sup.+.

    Step B: (1S,4s)-4-(4-Chloro-2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3152] TFA (3 mL) was added to a mixture of Intermediate 515 (210 mg, 0.09 mmol) and anisole (0.07 mL). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was concentrated and the crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (120 mg, 72%). 1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.06 (s, 3H) 1.22-1.26 (m, 4H) 1.29 (br d, J=1.38 Hz, 3H) 1.49-1.70 (m, 5H) 1.75-1.81 (m, 2H) 1.85-1.91 (m, 1H) 1.98-2.03 (m, 1H) 2.08-2.14 (m, 1H) 2.25 (br s, 2H) 2.34 (br d, J=4.13 Hz, 1H) 2.42-2.49 (m, 2H) 2.95-3.03 (m, 1H) 3.26-3.37 (m, 1H) 4.16-4.25 (m, 1H) 4.29-4.37 (m, 1H) 5.64-5.70 (m, 1H) 7.07-7.13 (m, 1H) 7.20-7.25 (m, 1H). MS (ESI) m/z 549.3/551.3 [M+H].sup.+.

    [3153] The examples included in Table 28 below were synthesized analogous to the procedure of Example 398 using indicated acids and amines.

    TABLE-US-00028 TABLE 28 Ex. MS No. Acid Amine Product (ESI) 399 Int. 320 Int. 22 [01050]embedded image m/z 567.4 [M + H].sup.+ 400 Int. 303 Int. 22 [01051]embedded image m/z 515.4 [M + H].sup.+ 401 Int. 302 Int. 22 [01052]embedded image HRMS m/z [M + H].sup.+ 540.2868 402 Int. 304 Int. 22 [01053]embedded image m/z 571.5 [M + H].sup.+ 403 Int. 297 Int. 22 [01054]embedded image HRMS m/z [M + H].sup.+ 561.2740 404 Int. 313 Int. 22 [01055]embedded image HRMS m/z [M + H].sup.+ 552.3100 405 Int. 298 Int. 22 [01056]embedded image m/z 541.4 [M + H].sup.+ 406 Int. 310 Int. 22 [01057]embedded image m/z 539.3 [M + H].sup.+ 407 Int. 311 Int. 22 [01058]embedded image m/z 548.4 [M + H].sup.+ 408 Int. 301 Int. 22 [01059]embedded image HRMS m/z [M + H].sup.+ 549.2528 409 Int. 312 Int. 225 [01060]embedded image HRMS m/z [M + H].sup.+ 603.2438 410 Int. 312 Int. 221 [01061]embedded image HRMS m/z [M + H].sup.+ 561.2720 411 Int. 312 Int. 223 [01062]embedded image HRMS m/z [M + H].sup.+ 563.2330 412 Int. 312 Int. 224 [01063]embedded image HRMS m/z [M + H].sup.+ 549.2754 413 Int. 302 Int. 221 [01064]embedded image HRMS m/z [M + H].sup.+ 540.2880 414 Int. 70 Int. 255 [01065]embedded image m/z 540.4 [M + H].sup.+ 415 Int. 335 Int. 22 [01066]embedded image m/z 549.5 [M + H].sup.+ 416 Int. 335 Int. 226 [01067]embedded image HRMS m/z [M + H].sup.+ 675.1820 417 Int. 13 Int. 21 [01068]embedded image HRMS m/z [M + H].sup.+ 543.2862

    Example 418: (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3154] ##STR01069##

    Step A: Intermediate 516: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo [2.2.1]heptane-2-carboxamide

    [3155] ##STR01070##

    [3156] EDC (53 mg, 0.28 mmol) and HOBt (30 mg, 0.22 mmol) were added to a mixture of 1 (100 mg, 0.184 mmol) in CHCl.sub.3 (1 mL), then the mixture was stirred at rt for 5 min. 28% aq NH.sub.3 (0.5 mL) was added to a mixture and the mixture was stirred at rt for 12 hr. Sat aq NaHCO.sub.3 was added and the mixture was extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (96 mg, 96%). MS (ESI) m/z 544.4 [M+H].sup.+.

    Step B: Intermediate 517: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Cyano-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3157] ##STR01071##

    [3158] DIPEA (0.19 mL, 1.40 mmol) and trifluoroacetic anhydride (0.16 mL, 1.21 mmol) were added to a solution of Intermediate 516 (94 mg, 0.172 mmol) in THF (3 mL), then the mixture was stirred at rt for 12 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the title compound (57 mg, 63%). MS (ESI) m/z 526.4 [M+H].sup.+.

    Step C: Intermediate 518: (1R,2S,3R,4S)-3-(4-Fluoro-5-(((1s,4S)-4-(N′-hydroxycarbamimidoyl)-4-methylcyclohexyl)oxy)-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3159] ##STR01072##

    [3160] 50% hydroxylamine solution (0.20 mL, 3.40 mmol) was added to a solution of Intermediate 517 (49 mg, 0.09 mmol) in EtOH (0.5 mL), then the mixture was stirred at 70° C. for 12 hr. Sat aq NH.sub.4Cl was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo to give titled compound (50 mg, 97%). MS (ESI) m/z 559.4 [M+H].sup.+.

    Step D: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3161] 1,1′-Carbonyldiimidazole (18 mg, 0.11 mmol) was added to a solution of Intermediate 518 (50 mg, 0.09 mmol) in DME (0.5 mL), then the mixture was stirred at 100° C. for 2 hr. After the mixture was cooled to ambient temperature, 1 M aq HCl was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude material was purified by reversed phase HPLC on a C18 column using a gradient of 30-60% MeCN in (NH.sub.4).sub.2CO.sub.3 (10 mM in H.sub.2O) as mobile phase to give the title compound (25 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 0.93 (s, 3H), 1.10-1.25 (m, 3H), 1.21 (s, 3H), 1.38-1.79 (m, 12H), 1.83-1.91 (m, 2H), 1.97-2.02 (m, 1H), 2.04-2.13 (m, 3H), 2.21-2.25 (m, 1H), 2.61-2.65 (m, 1H), 2.96 (dd, J=13.2, 5.5 Hz, 1H), 3.09 (dd, J=13.2, 6.3 Hz, 1H), 3.87 (s, 3H), 4.06-4.15 (m, 1H), 4.16-4.25 (m, 1H), 7.09 (d, J=12.7 Hz, 1H), 7.67 (d, J=9.9 Hz, 1H), 7.87-7.93 (m, 1H), 8.88 (br d, J=8.0 Hz, 1H). MS (ESI) m/z 585.4 [M+H].sup.+.

    Example 419: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3162] ##STR01073##

    Step A: Intermediate 519: tert-Butyl 2-((1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carbonyl)hydrazine-1-carboxylate

    [3163] ##STR01074##

    [3164] HATU (209 mg, 0.55 mmol) was added to a solution of Example 1 (200 mg, 0.37 mmol) and tert-butyl carbazate (58 mg, 0.44 mmol) in DMF (3 mL), then the mixture was stirred at rt for 12 hr. Sat aq NaHCO.sub.3 was added and the precipitate was collected by filtration and washed with H.sub.2O, then the material was dried to give titled compound (244 mg, 100%). MS (ESI) m/z 659.9 [M+H].sup.+.

    Step B: Intermediate 520: (1R,2S,3R,4S)-3-(4-Fluoro-5-(((1s,4S)-4-(hydrazinecarbonyl)-4-methylcyclohexyl)oxy)-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3165] ##STR01075##

    [3166] TFA (0.52 mL) was added to a solution of Intermediate 519 (241 mg, 0.37 mmol) in CHCl.sub.3 (1 mL), then the mixture was stirred at rt for 6 hr. The reaction mixture was treated with PolaPak, then concentrated in vacuo to give titled compound (162 mg, 79%). MS (ESI) m/z 559.4 [M+H].sup.+.

    Step C: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3167] 1,1′-Carbonyldiimidazole (71 mg, 0.44 mmol) was added to a solution of Intermediate 520 (162 mg, 0.29 mmol) in DME (1.2 mL), then the mixture was stirred at 100° C. for 12 hr. After the mixture was cooled to ambient temperature, 1 M aq HCl was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude material was purified by reversed phase HPLC on a C18 column using a gradient of 40-70% MeCN in (NH.sub.4).sub.2CO.sub.3 (10 mM in H.sub.2O) as mobile phase to afford the title compound (125 mg, 58%). MS (ESI) m/z 585.4 [M+H].sup.+.

    Example 420: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(1H-tetrazol-5-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3168] ##STR01076##

    Step A: Intermediate 521: (1s,4s)-4-(2-Fluoro-4-methoxy-5-(methoxycarbonyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3169] ##STR01077##

    [3170] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 169 mg) was added to a solution of Intermediate 12 (845 mg, 1.76 mmol) in EtOH (10 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 6 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered through Celite®®, then the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (460 mg, 77%). MS (ESI) m/z 341.2 [M+H].sup.+.

    Step B: Intermediate 522: Methyl 5-(((1s,4s)-4-carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

    [3171] ##STR01078##

    [3172] EDC (387 mg, 2.02 mmol) and HOBt (218 mg, 1.62 mmol) were added to a solution of Intermediate 521 (458 mg, 1.35 mmol) in CHCl.sub.3 (10 mL), then the mixture was stirred at rt for 20 min. Aq NH.sub.3 (3 mL) was added to a mixture and the mixture was stirred at rt for 12 hr. Sat aq NaHCO.sub.3 was added and the mixture was extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (462 mg, 100%). MS (ESI) m/z 340.2 [M+H].sup.+.

    Step C: Intermediate 523: Methyl 5-(((1s,4s)-4-cyano-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzoate

    [3173] ##STR01079##

    [3174] DIPEA (1.14 mL, 8.17 mmol) and trifluoroacetic anhydride (0.57 mL, 4.08 mmol) were added to a solution of Intermediate 522 (462 mg, 1.36 mmol) in THF (10 mL), then the mixture was stirred at rt for 2 hr. Sat aq NaHCO.sub.3 was added to the reaction mixture and the mixture was extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in hexane as mobile phase to give the title compound (192 mg, 41%). MS (ESI) m/z 322.4 [M+H].sup.+.

    Step D: Intermediate 524: Methyl 4-fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-(1H-tetrazol-5-yl)cyclohexyl)oxy)benzoate

    [3175] ##STR01080##

    [3176] Sodium azide (202 mg, 3.11 mmol) and NH.sub.4Cl (234 mg, 4.38 mmol) were added to a solution of Intermediate 523 (100 mg, 0.29 mmol) in DMF (1.5 mL), then the mixture was stirred at 120° C. for 6 hr. After the mixture was cooled to ambient temperature, sat aq NaHCO.sub.3 was added to the reaction mixture and the mixture was extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude material was purified by reversed phase HPLC on a C18 column using a gradient of 10-60% MeCN in (NH.sub.4).sub.2CO.sub.3 (10 mM in H.sub.2O) as mobile phase to afford the title compound (31 mg, 29%). MS (ESI) m/z 365.2 [M+H].sup.+.

    Step E: Intermediate 525: 4-Fluoro-2-methoxy-5-(((1s,4s)-4-methyl-4-(1H-tetrazol-5-yl)cyclohexyl)oxy)benzoic acid

    [3177] ##STR01081##

    [3178] 2 M aq NaOH (0.12 mL, 0.23 mmol) was added to a solution of Intermediate 524 (28 mg, 0.077 mmol) in THF (0.2 mL), then the mixture was stirred at rt for 4 hr. 2 M aq HCl was added to the reaction mixture and the mixture was concentrated in vacuo. The crude material was purified by reversed phase HPLC on a C18 column using a gradient of 20-30% MeCN in (NH.sub.4).sub.2CO.sub.3 (10 mM in H.sub.2O) as mobile phase to afford titled compound (15 mg, 57%). MS (ESI) m/z 351.2 [M+H].sup.+.

    Step F: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-(1H-tetrazol-5-yl)cyclohexyl)oxy)benzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3179] The titled compound was prepared analogous to Example 331 step A, using Intermediate 525 instead of Intermediate 13, and using Intermediate 22 instead of Intermediate 176. HRMS m/z [M+H].sup.+ 569.3238.

    Example 421: (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-Carbamoyl-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3180] ##STR01082##

    [3181] The titled compound was prepared analogous to Example 418 step A, using Example 369 instead of Example 1. MS (ESI) m/z 544.2 [M+H].sup.+.

    Example 422: (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1RS,2RS,3SR,4SR)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid

    [3182] ##STR01083##

    Step A: Intermediate 526: benzyl 4-fluoro-5-(((1r,4r)-4-hydroxy-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-2-methoxybenzoate

    [3183] ##STR01084##

    [3184] Di-2-methoxyethyl azodicarboxylate (142 mg, 0.604 mmol) was added to a solution of Intermediate 271 (121 mg, 0.403 mmol), benzyl 4-fluoro-5-hydroxy-2-methoxybenzoate (134 mg, 0.483 mmol) and triphenylphosphine in THF (2 mL) at 0° C., then the mixture was stirred at rt for 5 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc hexane as mobile phase to afford the title compound (118 mg, 52%). MS (ESI) m/z 559.3 [M+H].sup.+.

    Step B: Intermediate 527: 5-(((1r,4r)-4-Carboxy-4-hydroxycyclohexyl)oxy)-4-fluoro-2-methoxybenzoic acid

    [3185] ##STR01085##

    [3186] The titled compound was prepared analogous to Example 236 step B, using Intermediate 526 instead of Intermediate 445. MS (ESI) m/z 329.1 [M+H].sup.+

    Step C: (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1RS,2RS,3SR,4SR)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid

    [3187] The titled compound was prepared analogous to Example 331 step A, using Intermediate 527 instead of Intermediate 13, and using Intermediate 231 instead of Intermediate 176. MS (ESI) m/z 673.3 [M+H].sup.+.

    Example 423: (1R,4r)-1-(Cyanomethyl)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3188] ##STR01086##

    Step A: Intermediate 528: ethyl (1R,4r)-1-(cyanomethyl)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [3189] ##STR01087##

    [3190] EDC (82 mg, 0.427 mmol) and HOAt (58 mg, 0.427 mmol) were added to a mixture of Intermediate 322 (135 mg, 0.356 mmol), Intermediate 22 (117 mg, 0.429 mmol) and TEA (43 mg, 0.427 mmol) in DMF (5 mL) and the reaction mixture was stirred at rt for 17 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10-50% EtOAc in hexane as mobile phase to give the title compound (172 mg, 81%). MS (ESI) m/z 598.3 [M+H].sup.+.

    Step B: (1R,4r)-1-(Cyanomethyl)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3191] 1 M aq LiOH (1.44 mL, 1.44 mmol) was added to a solution of Intermediate 528 (172 mg, 0.287 mmol) in DME (5 mL) and the mixture was stirred at rt for 24 hr. 1 M aq HCl and CHCl.sub.3 were added to the reaction mixture and the layer was separated. Combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-3% MeOH in CHCl.sub.3 as mobile phase to give the title compound (163 mg, 100%). MS (ESI) m/z 570.6 [M+H].sup.+.

    Example 424: (1S,4s)-1-(Cyanomethyl)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3192] ##STR01088##

    Step A: Intermediate 529: Ethyl (1S,4s)-1-(cyanomethyl)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [3193] ##STR01089##

    [3194] The titled compound was prepared analogous to Example 331 step A, using Intermediate 325 instead of Intermediate 13, and using Intermediate 22 instead of Intermediate 176. MS (ESI) m/z 598.3 [M+H].sup.+.

    Step B: (1S,4s)-1-(Cyanomethyl)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3195] The titled compound was prepared analogous to Example 423 step B, using Intermediate 529 instead of Intermediate 528. HRMS (ESI) m/z [M+H].sup.+ calcd for C31H41FN3O6: 570.2974 found: 570.2998.

    Example 425: (1RS,3SR,5SR,6RS)-3-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid

    [3196] ##STR01090##

    Step A: Intermediate 530: Ethyl (1RS,3SR,5SR,6RS)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylate

    [3197] ##STR01091##

    [3198] The titled compound was prepared analogous to Example 331 step A, using Intermediate 331 instead of Intermediate 13, and using Intermediate 22 instead of Intermediate 176. MS (ESI) m/z 557.6 [M+H].sup.+.

    Step B: (1RS,3SR,5SR,6RS)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid

    [3199] The titled compound was prepared analogous to Example 423 Step B, using Intermediate 530 instead of Intermediate 528. MS (ESI) m/z 529.5 [M+H].sup.+.

    Example 426: (1RS,3SR,5SR,6RS)-3-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid

    [3200] ##STR01092##

    Step A: Intermediate 531: Ethyl (1RS,3SR,5SR,6RS)-3-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylate

    [3201] ##STR01093##

    [3202] The titled compound was prepared analogous to Example 331 step A, using Intermediate 334 instead of Intermediate 13, and using Intermediate 22 instead of Intermediate 176. MS (ESI) m/z 557.3 [M+H].sup.+.

    Step B: (1RS,3SR,5SR,6RS)-3-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)bicyclo[3.1.0]hexane-6-carboxylic acid

    [3203] The titled compound was prepared analogous to Example 423 Step B, using Intermediate 531 instead of Intermediate 528. MS (ESI) m/z 529.2 [M+H].sup.+.

    [3204] The examples included in Table 29 below were synthesized analogous to the procedure of Example 423 using indicated acids and amines.

    TABLE-US-00029 TABLE 29 Example Reagent 1 Reagent 2 Product MS 427 Int. 355 Int. 213 [01094]embedded image MS (APCI) m/z 631.0 [M + H].sup.+ 428 Int. 357 Int. 213 [01095]embedded image MS (APCI) m/z 631.0 [M + H].sup.+ 429 Int. 358 Int. 213 [01096]embedded image MS (APCI) m/z 631.0 [M + H].sup.+ 430 Int. 346 Int. 226 [01097]embedded image HRMS (ESI) m/z [M + H].sup.+ 645.1724 431 Int. 344 Int. 22  [01098]embedded image MS (ESI) m/z 540.4 [M + H].sup.+ 432 Int. 348 Int. 233 [01099]embedded image HRMS (ESI) m/z [M + H].sup.+ 669.1868 433 Int. 348 Int. 219 [01100]embedded image MS (ESI) m/z 669.2 [M + H].sup.+

    Example 434: 6-Fluoro-4-methoxy-N3-((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-[1,1′-biphenyl]-3,4′-dicarboxamide

    [3205] ##STR01101##

    [3206] The titled compound was prepared analogous to Example 418 step A, using Example 250 instead of Example 1. MS (ESI) m/z 634.0 [M+H].sup.+.

    Example 435: 6-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)hexanoic acid

    [3207] ##STR01102##

    Step A: Intermediate 532: (1R,2S,3R,4S)-3-(4-Fluoro-5-hydroxy-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3208] ##STR01103##

    [3209] HATU (1.03 g, 2.71 mmol) and DIPEA (0.85 mL, 4.93 mmol) were added to a solution of Intermediate 226 (1.08 g, 2.71 mmol) and 4-fluoro-5-hydroxy-2-methoxybenzoic acid (459 mg, 2.47 mmol) in DMF (4 mL), then the mixture was stirred at rt for 20 min. H.sub.2O was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10-70% EtOAc in hexane as mobile phase to give the title compound (1.40 g, 100%). MS (ESI) m/z 531.2 [M+H].sup.+.

    Step B: Intermediate 533: Ethyl 6-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)hexanoate

    [3210] ##STR01104##

    [3211] Ethyl 6-bromohexanoate (25 mg, 0.12 mmol) was added to a mixture of Intermediate 532 (40 mg, 0.075 mmol) and potassium carbonate (31 mg, 0.23 mmol) in DMF (0.2 mL), then the mixture was stirred at 80° C. for 6 hr. H.sub.2O was added to a mixture and the mixture was extracted with CHCl.sub.3, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 40% EtOAc in hexane as mobile phase to give the title compound (50 mg, 100%).

    Step C: 6-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)hexanoic acid

    [3212] 1 M aq NaOH (1 mL, 1.00 mmol) was added to a solution of Intermediate 533 (50 mg, 0.075 mmol) in MeOH (1 mL), then the reaction mixture was stirred at rt for 20 hr. 10% Aq citric acid was added to a reaction mixture to neutralize and the mixture was extracted with CHCl.sub.3 three times, then the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-4% MeOH in CHCl.sub.3 as mobile phase to give the title compound (30 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ, 1.22-1.71 (m, 11H), 1.95-2.02 (m, 1H), 2.12-2.15 (m, 1H), 2.20 (t, J=7.7 Hz, 2H), 2.42-2.47 (m, 1H), 2.81 (d, J=8.2 Hz, 1H), 3.81 (s, 3H), 3.82-3.95 (m, 2H), 4.34 (t, J=7.9 Hz, 1H), 7.09 (d, J=13.00 Hz, 1H), 7.47 (d, J=10.0 Hz, 1H), 7.70-7.77 (m, 2H), 7.80-7.91 (m, 1H), 8.57 (br s, 1H), 8.64 (d, J=8.8 Hz, 1H), 10.63 (s, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C29H33F4N2O8S: 645.1888 found: 645.1938.

    [3213] The examples included in Table 30 below were synthesized analogous to the procedure of Example 435 using the specified alkylating reagent. For Examples marked with a #, Step C was performed using Pd-C/H.sub.2 in MeOH instead of 1 M NaOH in MeOH.

    TABLE-US-00030 TABLE 30 Ex. No. Alkylating reagent Product MS 436 EtO.sub.2C(CH.sub.2).sub.6Br [01105]embedded image HRMS (ESI) m/z [M + H].sup.+ 659.2056 437 EtO.sub.2C(CH.sub.2).sub.8Br [01106]embedded image MS (APCI) m/z 687.1 [M + H].sup.+ 438 [01107]embedded image [01108]embedded image MS (APCI) m/z 665.0 [M + H].sup.+ 439 [01109]embedded image [01110]embedded image MS (APCI) m/z 671.0 [M + H].sup.+ 440 [01111]embedded image [01112]embedded image MS (APCI) m/z 671.0 [M + H].sup.+ 441 [01113]embedded image [01114]embedded image MS (ESI) m/z 697.3 [M + H].sup.+ 442 # Int. 268 [01115]embedded image MS (ESI) m/z 659.2 [M + H].sup.+ 443 [01116]embedded image [01117]embedded image HRMS (ESI) (ESI) m/z [M + H].sup.+ 629.1610 444 [01118]embedded image [01119]embedded image HRMS (ESI) (ESI) m/z [M + H].sup.+ 629.1552 445 [01120]embedded image [01121]embedded image MS (APCI) m/z 671.1 [M + H].sup.+ 446 # Intermediate 272, Isomer 1 [01122]embedded image MS (ESI) m/z 657.3 [M + H].sup.+ First eluting diastereomers. Cis or Trans cyclohexane. 447 # Intermediate 272, Isomer 2 [01123]embedded image MS (ESI) m/z 657.3 [M + H].sup.+ Second eluting diastereomers. Cis or Trans cyclohexane.

    Example 448: rac-2-((2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid

    [3214] ##STR01124##

    Step A: Intermediate 534: rac-(1R,2R,3S,4S)-3-(4-fluoro-5-hydroxy-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

    [3215] ##STR01125##

    [3216] The titled compound was prepared analogous to Example 435 Step A, using Intermediate 213 instead of Intermediate 226. MS (ESI) m/z 529.2 [M+H].sup.+.

    Step B: Intermediate 535: rac-Methyl 2-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoate

    [3217] ##STR01126##

    [3218] Methyl 2-(chloromethyl)benzoate (7.7 mg, 0.042 mmol) and potassium iodide (13 mg, 0.076 mmol) were added to a mixture of Intermediate 534 (20 mg, 0.038 mmol) and potassium carbonate (5.8 mg, 0.042 mmol) in DMF (0.5 mL), then the mixture was stirred at rt for 24 hr. H.sub.2O was added to a mixture and the mixture was stirred vigorously for 3 hr. The residual precipitate was collected by filtration and dried under pump vacuum to give the title compound (22 mg, 86%). MS (ESI) m/z 677.3 [M+H].sup.+.

    Step C: rac-2-((2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)methyl)benzoic acid

    [3219] LiOH (6.7 mg, 0.81 mmol) in H.sub.2O (0.14 mL) was added to a solution of Intermediate 535 (19 mg, 0.028 mmol) in THF (0.3 mL), and the reaction mixture was stirred at rt for 24 hr. 2 M aq HCl was added to the reaction mixture to adjust pH<2 and the reaction mixture was extracted with CHCl.sub.3 twice and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-5% MeOH in EtOAc as mobile phase to give the title compound (12 mg, 65%). MS (ESI) m/z 663.3 [M+H]+

    [3220] The examples included in Table 31 below were synthesized analogously to Example 448 Step B and C, using the specified starting material instead of methyl 2-(chloromethyl)benzoate.

    TABLE-US-00031 TABLE 31 Ex MS No. SM Product (ESI) 449 [01127]embedded image [01128]embedded image m/z 663.3 [M + H].sup.+ 450 [01129]embedded image [01130]embedded image m/z 663.3 [M + H].sup.+ 451 [01131]embedded image [01132]embedded image HRMS m/z [M + H].sup.+ 629.1592 452 [01133]embedded image [01134]embedded image m/z 705.4 [M + H].sup.+ 453 [01135]embedded image [01136]embedded image m/z 677.3 [M + H].sup.+ 454 [01137]embedded image [01138]embedded image m/z 705.4 [M + H].sup.+ 455 [01139]embedded image [01140]embedded image m/z 643.3 [M + H].sup.+ 456 [01141]embedded image [01142]embedded image m/z 615.3 [M + H].sup.+ 457 [01143]embedded image [01144]embedded image m/z 655.3 [M + H].sup.+

    Example 458: 1-Amino-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3221] ##STR01145##

    Step A: Intermediate 536: Methyl 1-((tert-butoxycarbonyl)amino)-4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate

    [3222] ##STR01146##

    [3223] Methanesulfonyl chloride (600 mg, 5.00 mmol) was added to a solution of methyl 1-((tert-butoxycarbonyl)amino)-4-hydroxycyclohexane-1-carboxylate (100 mg, 0.366 mmol) and TEA (1.46 mL, 10.5 mmol) in CHCl.sub.3 (2 mL), then the mixture was stirred at 0° C. for 1 hr. H.sub.2O was added to the reaction mixture and the layer was separated. Combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (129 mg, 79%). MS (APCI) m/z 352.1 [M+H].sup.+.

    Step B: Intermediate 537: Methyl 1-((tert-butoxycarbonyl)amino)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [3224] ##STR01147##

    [3225] The titled compound was prepared analogous to Example 435 Step B, using Intermediate 536 instead of ethyl 6-bromohexanoate. MS (ESI) m/z 784.5 [M−H]−

    Step C: Intermediate 538: 1-((tert-Butoxycarbonyl)amino)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3226] ##STR01148##

    [3227] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 537 instead of Intermediate 533. MS (ESI) m/z 772.5 [M+H].sup.+.

    Step D: 1-Amino-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3228] A mixture of Intermediate 538 (13 mg, 0.017 mmol) in 4 M HCl in EtOAc (0.5 mL) was stirred at rt for 1 hr. The mixture was concentrated and dried in vacuo to give the title compound as a mixture of trans and cis (12 mg, 100%). MS (APCI) m/z 672.0 [M+H].sup.+.

    Example 459: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-(methylsulfonamido)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3229] ##STR01149##

    Step A: Intermediate 539: tert-Butyl ((1S,4s)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexyl)carbamate

    [3230] ##STR01150##

    [3231] The titled compound was prepared analogous to Example 435 Step B, using (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate instead of ethyl 6-bromohexanoate. MS (APCI) m/z 728.1 [M+H].sup.+.

    Step B: Intermediate 540: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Aminocyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3232] ##STR01151##

    [3233] The titled compound was prepared analogous to Example 458 Step D, using Intermediate 539 instead of Intermediate 538. MS (ESI) m/z 628.3 [M+H].sup.+.

    Step C: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-(methylsulfonamido)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3234] Methanesulfonyl chloride (25 mg, 0.22 mmol) was added to a solution of Intermediate 540 (92 mg, 0.146 mmol) and TEA (0.041 mL, 0.29 mmol) in CHCl.sub.3 (2 mL), then the mixture was stirred at rt for 18 hr. The mixture was concentrated to remove CHCl.sub.3, then H.sub.2O was added to the residue and the mixture was stirred. Precipitate was collected by filtration and dried under air to give the title compound (73 mg, 71%). MS (ESI) m/z 706.3 [M+H].sup.+.

    Example 460: (1R,2S,3R,4S)-3-(4-fluoro-2-methoxy-5-(((1r,4R)-4-(methylsulfonamido)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3235] ##STR01152##

    Step A: Intermediate 541: tert-Butyl ((1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexyl)carbamate

    [3236] ##STR01153##

    [3237] The titled compound was prepared analogous to Example 435 Step B, using (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate instead of ethyl 6-bromohexanoate. MS (APCI) m/z 728.1 [M+H].sup.+.

    Step B: Intermediate 542: (1R,2S,3R,4S)-3-(5-(((1r,4R)-4-Aminocyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3238] ##STR01154##

    [3239] The titled compound was prepared analogous to Example 458 Step D, using Intermediate 541 instead of Intermediate 538. MS (ESI) m/z 628.4 [M+H].sup.+.

    Step C: (1R,2S,3R,4S)-3-(4-Fluoro-2-methoxy-5-(((1r,4R)-4-(methylsulfonamido)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3240] The titled compound was prepared analogous to Example 459 Step C, using Intermediate 542 instead of Intermediate 540. HRMS (ESI) m/z [M+H].sup.+ calcd for C30H36F4N3O8S2: 706.1874 found: 706.1870.

    Example 461: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((3aS,4S,5R,6S,7R,7aR)-6-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)hexahydro-4,7-methanobenzo[d][1,3]dioxol-5-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3241] ##STR01155##

    Step A: Intermediate 543: Methyl (1S,4s)-4-(5-(((1S,2R,3S,4R,5R,6S)-5,6-dihydroxy-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [3242] ##STR01156##

    [3243] The titled compound was prepared analogous to Example 435 Step A, using Intermediate 249 instead of Intermediate 226, and using Intermediate 348 instead of 4-fluoro-5-hydroxy-2-methoxybenzoic acid. HRMS (ESI) m/z [M+H].sup.+ calcd for C31H33F4N2O10S: 701.1786 found: 701.1804.

    Step B: Intermediate 544: Methyl (1S,4s)-4-(2-fluoro-4-methoxy-5-(((3aS,4S,5R,6S,7R,7aR)-6-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)hexahydro-4,7-methanobenzo[d][1,3]dioxol-5-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [3244] ##STR01157##

    [3245] p-Toluenesulfonic acid hydrate (2.7 mg, 0.014 mmol) was added to the mixture of Intermediate 543 (99 mg, 0.141 mmol) and dimethoxymethane (0.123 mL, 1.41 mmol) in toluene (3 mL), and the mixture was stirred at reflux for 3 hr. The mixture was cooled to ambient temperature and sat aq NaHCO.sub.3 was added, then the mixture was extracted with EtOAc and combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 30-90% EtOAc in hexane as mobile phase to give the title compound (89 mg, 89%). MS (ESI) m/z 715.6 [M+H].sup.+.

    Step C: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((3aS,4S,5R,6S,7R,7aR)-6-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)hexahydro-4,7-methanobenzo[d][1,3]dioxol-5-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3246] ##STR01158##

    [3247] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 544 instead of Intermediate 533. MS (ESI) m/z 701.2 [M+H].sup.+.

    Example 462: (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-(((1r,4R)-4-sulfamoylcyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3248] ##STR01159##

    Step A: Intermediate 545: (1S,2S,3R,4R)-3-(4-Fluoro-2-methoxy-5-(((1r,4R)-4-(N-(4-methoxybenzyl)sulfamoyl)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (Isomer 1) and Intermediate 546: (1S,2S,3R,4R)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-(N-(4-methoxybenzyl)sulfamoyl)cyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (Isomer 2)

    [3249] ##STR01160##

    [3250] EDC (41 mg, 0.213 mmol), HOAt (29 mg, 0.213 mmol) and TEA (0.030 mL, 0.213 mmol) were added to a solution of Intermediate 232 (71 mg, 0.18 mmol) and Intermediate 338 (83 mg, 0.18 mmol) in DMF (3 mL), then the mixture was stirred at rt for 3 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 30-90% EtOAc in hexane as mobile phase to give the first eluting compound Isomer 1: Intermediate 545 (29 mg, 20%); MS (ESI) m/z 812.7 [M+H].sup.+, and the second eluting compound Isomer 2: Intermediate 546 (113 mg, 79%); MS (ESI) m/z 812.3 [M+H].sup.+.

    Step B: (1S,2S,3R,4R)-3-(4-Fluoro-2-methoxy-5-(((1r,4R)-4-sulfamoylcyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3251] TFA (1 mL) was added to a solution of Intermediate 545 (29 mg, 0.036 mmol) in CHCl.sub.3 (1 mL), then the mixture was stirred at rt for 16 hrs. The reaction mixture was concentrated and azeotroped with toluene. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (21 mg, 84%). MS (ESI) m/z 692.2 [M+H].sup.+.

    Example 463: (1S,2S,3R,4R)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-sulfamoylcyclohexyl)oxy)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3252] ##STR01161##

    [3253] The titled compound was prepared analogous to Example 462 Step B, using Intermediate 546 instead of Intermediate 545. MS (ESI) m/z 692.2 [M+H].sup.+.

    Example 464: (1S,4s)-4-(2-Bromo-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3254] ##STR01162##

    Step A: Intermediate 547: (1R,2S,3R,4S)-3-(4-bromo-5-hydroxy-2-methoxybenzamido)-N-3-((trifluoromethyl)sulfonyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3255] ##STR01163##

    [3256] The titled compound was prepared analogous to Example 435 Step A, using 4-bromo-5-hydroxy-2-methoxybenzoic acid instead of 4-fluoro-5-hydroxy-2-methoxybenzoic acid. MS (ESI) m/z 591.1/593.1 [M+H].sup.+.

    Step B: Intermediate 548: Methyl (1S,4s)-4-(2-bromo-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [3257] ##STR01164##

    [3258] The titled compound was prepared analogous to Example 435 Step B, using methyl (1r,4r)-4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate instead of ethyl 6-bromohexanoate and Intermediate 547 instead of Intermediate 532. MS (ESI) m/z 731.3/733.3 [M+H].sup.+.

    Step C: (1S,4s)-4-(2-Bromo-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3259] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 548 instead of Intermediate 533. HRMS (ESI) m/z [M+H].sup.+ calcd for C30H33BrF3N2O8S: 717.1088 found: 717.1124.

    Example 465: (1S,4s)-4-(4-Methoxy-2-methyl-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3260] ##STR01165##

    Step A: Intermediate 549: Methyl (1S,4s)-4-(4-methoxy-2-methyl-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [3261] ##STR01166##

    [3262] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.9 mg, 0.004 mmol) was added to the mixture of Intermediate 548 (60 mg, 0.082 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (15 mg, 0.12 mmol) in 2 M aq Na.sub.2CO.sub.3 (0.5 mL) and DME (2 mL), and the mixture was stirred at reflux for 5 hr. The mixture was cooled to ambient temperature, then the mixture was extracted with CHCl.sub.3 and combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 30-70% EtOAc in hexane as mobile phase to give the title compound (48 mg, 87%). MS (ESI) m/z 667.3 [M+H].sup.+.

    Step B: (1S,4s)-4-(4-Methoxy-2-methyl-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3263] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 549 instead of Intermediate 533. HRMS (ESI) m/z [M+H].sup.+ calcd for C31H36F3N2O8S: 653.2138 found: 653.2158.

    Example 466: (1S,4s)-4-(4-Methoxy-3-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3264] ##STR01167##

    Step A: Intermediate 550: Methyl (1S,4s)-4-(4-methoxy-3-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [3265] ##STR01168##

    [3266] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 20 mg) was added to a solution of Intermediate 548 (60 mg, 0.082 mmol) in EtOAc (3 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 10 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. The filtrate was concentrated in vacuo to give titled compound (53 mg, 99%). MS (ESI) m/z 639.2 [M+H].sup.+.

    Step B: (1S,4s)-4-(4-Methoxy-3-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3267] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 550 instead of Intermediate 533. HRMS (ESI) m/z [M+H].sup.+ calcd for C30H34F3N2O8S: 639.1982 found: 639.1954.

    Example 467: (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3268] ##STR01169##

    Step A: Intermediate 551: Methyl (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylate

    [3269] ##STR01170##

    [3270] Tetrakis(triphenylphosphine)palladium (6 mg, 0.0052 mmol) was added to the mixture of Intermediate 548 (76 mg, 0.104 mmol) and dicyanozinc (18 mg, 0.157 mmol) in DMF (2 mL), and the mixture was stirred at 120° C. for 16 hr. The mixture was cooled to ambient temperature and sat aq NaHCO.sub.3 was added, then the mixture was extracted with EtOAc and combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 30-60% EtOAc in hexane as mobile phase to give the title compound (25 mg, 36%). MS (ESI) m/z 678.3 [M+H].sup.+.

    Step B: (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3271] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 551 instead of Intermediate 533. MS (ESI) m/z 664.3 [M+H].sup.+.

    Example 468: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((2SR,3RS)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3272] ##STR01171##

    Step A: Intermediate 552: Naphthalen-1-ylmethyl (1R,4s)-4-(2-cyano-4-methoxy-5-(((1S,2SR,3RS,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [3273] ##STR01172##

    [3274] The titled compound was prepared analogous to Example 331 Step A, using Intermediate 70 instead of Intermediate 13, and using Intermediate 187 instead of Intermediate 176. MS (ESI) m/z 704.5 [M+H].sup.+.

    Step B: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((2SR,3RS)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3275] The titled compound was prepared analogous to Example 331 Step B, using Intermediate 552 instead of Intermediate 507. MS (ESI) m/z 566.4 [M+H].sup.+.

    Example 469: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1RS,2SR,3RS,4SR)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3276] ##STR01173##

    [3277] TFA (2.06 mL, 26.9 mmol) was added to a mixture of Intermediate 552 (290 mg, 0.412 mmol) and anisole (89 mg, 0.82 mmol), then the reaction mixture was stirred at rt for 1 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (189 mg, 81%). MS (ESI) m/z 564.4 [M+H].sup.+.

    Example 470: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((2SR,3RS)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3278] ##STR01174##

    Step A: Intermediate 553: Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1RS,2SR,3RS,4SR)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

    [3279] ##STR01175##

    [3280] The titled compound was prepared analogous to Example 331 Step A, using Intermediate 187 instead of Intermediate 176. MS (ESI) m/z 697.5 [M+H].sup.+.

    Step B: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((2SR,3RS)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3281] The titled compound was prepared analogous to Example 331 Step B, using Intermediate 553 instead of Intermediate 507. MS (ESI) m/z 559.4 [M+H].sup.+.

    Example 471: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1RS,2SR,3RS,4SR)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3282] ##STR01176##

    [3283] The titled compound was prepared analogous to Example 469, using Intermediate 553 instead of Intermediate 552. MS (ESI) m/z 557.4 [M+H].sup.+.

    Example 472: (1R,3r)-3-((2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid and Example 473: (1S,3s)-3-((2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid

    [3284] ##STR01177##

    Step A: Intermediate 554: tert-Butyl 3-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylate

    [3285] ##STR01178##

    [3286] The titled compound was prepared analogous to Example 331 Step A, using Intermediate 339 instead of Intermediate 13, and using Intermediate 232 instead of Intermediate 176. MS (ESI) m/z 699.2 [M+H].sup.+.

    Step B: Intermediate 555: 3-((2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid

    [3287] ##STR01179##

    [3288] TFA (1 mL) was added to a solution of Intermediate 554 (193 mg, 0.277 mmol) in CHCl.sub.3 (1 mL), then the reaction mixture was stirred at rt for 5 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of 0-10% MeOH in CHCl.sub.3 as mobile phase to give the title compound (153 mg, 80%). MS (ESI) m/z 643.5 [M+H].sup.+.

    Step C: (1R,3r)-3-((2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid and (1S,3s)-3-((2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid

    [3289] Intermediate 555 (141 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm×30 mm); mobile phase: [CO2/MeOH=60/40]) to give the first eluting compound Isomer 1: Example 472 (76.2 mg, 54%); MS (ESI) m/z 643.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 473 (65.2 mg, 46%); MS (ESI) m/z 643.2 [M+H].sup.+.

    Example 474: 2-((1R,3r)-3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetic acid and

    Example 475: 2-((1S,3s)-3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetic acid

    [3290] ##STR01180##

    Step A: Intermediate 556: Methyl 2-(3-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetate

    [3291] ##STR01181##

    [3292] The titled compound was prepared analogous to Example 331 Step A, using Intermediate 340 instead of Intermediate 13, and using Intermediate 232 instead of Intermediate 176. MS (ESI) m/z 657.2 [M+H].sup.+.

    Step B: Intermediate 557: 2-(3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetic acid

    [3293] ##STR01182##

    [3294] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 556 instead of Intermediate 533. MS (ESI) m/z 643.5 [M+H].sup.+.

    Step C: 2-((1R,3r)-3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetic acid and

    2-((1S,3s)-3-(2-fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclobutyl)acetic acid

    [3295] Intermediate 557 (139 mg) was separated by chiral HPLC (column: CHIRALPAK IC (250 mm*30 mm); mobile phase: [C02/MeOH=90/10]) to give the first eluting compound Isomer 1: Example 474 (72.0 mg, 52%); MS (ESI) m/z 643.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 475 (48.9 mg, 35%); MS (ESI) m/z 643.1 [M+H].sup.+.

    Example 476: 2-((1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetic acid and

    Example 477: 2-((1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetic acid

    [3296] ##STR01183##

    Step A: Intermediate 558: Ethyl 2-(4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetate

    [3297] ##STR01184##

    [3298] The titled compound was prepared analogous to Example 331 Step A, using Intermediate 341 instead of Intermediate 13, and using Intermediate 22 instead of Intermediate 176. MS (ESI) m/z 587.3 [M+H].sup.+.

    Step B: Intermediate 559: 2-(4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetic acid

    [3299] ##STR01185##

    [3300] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 558 instead of ethyl Intermediate 533. MS (ESI) m/z 559.6 [M+H].sup.+.

    Step C: 2-((1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetic acid and 2-((1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexyl)acetic acid

    [3301] Intermediate 559 (160 mg) was separated by chiral HPLC (column: CHIRALPAK IE (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/AcOH=75/25/0.1]) to give the first eluting compound Isomer 1: Example 476 (72 mg, 415); MS (ESI) m/z 559.3 [M+H]5, and the second eluting compound Isomer 2: Example 477 (66 mg, 38%); MS (ESI) m/z 559.3 [M+H].sup.+.

    [3302] The examples included in Table 32 below were synthesized analogously to Example 331 Step A followed by Example 472 Step B, using the specified starting materials instead of Intermediate 13 and Intermediate 176.

    TABLE-US-00032 TABLE 32 Ex SM SM MS No. 1 2 Product (ESI) 478 Intermediate 336 Intermediate 22  [01186]embedded image m/z 655.3 [M + H].sup.+ 479 Intermediate 349 Intermediate 232 [01187]embedded image m/z 701.6 [M + H].sup.+ 480 Intermediate 350 Intermediate 232 [01188]embedded image m/z 701.2 [M + H].sup.+ 481 Intermediate 349 Intermediate 224 [01189]embedded image m/z 563.6 [M + H].sup.+ 482 Intermediate 349 Intermediate 226 [01190]embedded image HRMS m/z [M + H].sup.+ 701.2184 483 Intermediate 359 Intermediate 22  [01191]embedded image m/z 532.2 [M + H].sup.+ 484 Intermediate 361 Intermediate 213 [01192]embedded image HRMS m/z [M + H].sup.+ 649.1258

    Example 485: (1R,4r)-4-(2-Fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxycarbonyl)cyclohexane-1-carboxylic acid

    [3303] ##STR01193##

    Step A: Intermediate 560: 1-(tert-Butyl) 1-methyl (1s,4s)-4-(2-fluoro-4-isopropoxy-5-(methoxycarbonyl)phenoxy)cyclohexane-1,1-dicarboxylate

    [3304] ##STR01194##

    [3305] Di-2-methoxyethyl azodicarboxylate (154 mg, 0.66 mmol) in THF (2 mL) was added dropwise to a solution of Intermediate 283 (94 mg, 0.41 mmol), Intermediate 273 (160 mg, 0.62 mmol) and triphenylphosphine (173 mg, 0.66 mmol) in THF (2 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with EtOAc and the mixture was washed with H.sub.2O twice, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-25% EtOAc in hexane as mobile phase to give title compound (122 mg, 63%).

    Step B: Intermediate 561: 5-(((1s,4s)-4-(tert-Butoxycarbonyl)-4-carboxycyclohexyl)oxy)-4-fluoro-2-isopropoxybenzoic acid

    [3306] ##STR01195##

    [3307] LiOH (15 mg, 0.62 mmol) in H.sub.2O (0.7 mL) was added to a solution of Intermediate 560 (432 mg, 0.843 mmol) in THF (2 mL), and the reaction mixture was stirred at rt for 22 hr. 10% aq citric acid was added to the reaction mixture until pH<2, the reaction mixture was extracted with CHCl.sub.3 twice and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in CHCl.sub.3 as mobile phase to give title compound (90 mg, 79%). MS (ESI) m/z 385.2 [M+H-tBu]+

    Step C: Intermediate 562: (1S,4s)-1-(tert-Butoxycarbonyl)-4-(2-fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3308] ##STR01196##

    [3309] HATU (82 mg, 0.216 mmol) was added to a solution of Intermediate 561 (89 mg, 0.216 mmol), Intermediate 22 (70 mg, 0.237 mmol) and DIPEA (84 mg, 0.648 mmol) in DMF (1 mL) and the reaction mixture was stirred at rt for 1 hr. H.sub.2O and 10% aq citric acid were added to the reaction mixture and the mixture was extracted with EtOAc, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-9% MeOH in CHCl.sub.3 as mobile phase to give the title compound (46 mg, 34%). MS (ESI) m/z 659.4 [M+H].sup.+.

    Step D: Intermediate 563: 1-(tert-Butyl) 1-methyl (1S,4s)-4-(2-fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1,1-dicarboxylate

    [3310] ##STR01197##

    [3311] Diazomethyl(trimethyl)silane (1.0 M in hexane, 0.08 mL, 0.155 mmol) was added to toluene (0.4 mL) and MeOH (0.4 mL) and the mixture was stirred at rt for 2 min. Intermediate 562 (43 mg, 0.065 mmol) was added to the mixture, and the mixture was stirred at rt for 30 min. The mixture was concentrated in vacuo and the crude product was purified by flash chromatography using 0-50% EtOAc in hexane as mobile phase to give the title compound (32 mg, 73%). MS (ESI) m/z 673.4 [M+H].sup.+.

    Step E: (1R,4r)-4-(2-Fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(methoxycarbonyl)cyclohexane-1-carboxylic acid

    [3312] The titled compound was prepared analogous to Example 472 Step B, using Intermediate 563 instead of Intermediate 554. MS (ESI) m/z 617.3 [M+H].sup.+.

    Example 486: (1S,4s)-4-(2-Fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid

    [3313] ##STR01198##

    Step A: Intermediate 564: tert-Butyl (1S,4s)-4-(2-fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylate

    [3314] ##STR01199##

    [3315] Sodium borohydride (35 mg, 0.92 mmol) and MeOH (0.5 mL) were added to a mixture of Intermediate 563 in THF (1 mL) and the mixture was stirred at rt for 2 hr. Sat aq NH.sub.4Cl was added to the reaction mixture, and the mixture was extracted with CHCl.sub.3 and the combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 0-75% EtOAc in hexane as mobile phase to give the title compound (14 mg, 47%). MS (ESI) m/z 645.4 [M+H].sup.+.

    Step B: (1S,4s)-4-(2-Fluoro-4-isopropoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid

    [3316] The titled compound was prepared analogous to Example 472 Step B, using Intermediate 564 instead of Intermediate 554. 1H NMR (400 MHz, DMSO-d6) δ 0.85 (s, 3H), 1.10-1.71 (m, 20H), 1.80-1.93 (m, 2H), 1.97-2.12 (m, 4H), 2.24-2.28 (m, 1H), 2.59-2.64 (m, 1H), 2.79 (dd, J=13.2, 5.2 Hz, 1H), 3.07 (dd, J=13.2, 6.9 Hz, 1H), 3.16 (s, 2H), 3.18 (s, 2H), 3.36 (s, 2H), 4.02-4.11 (m, 2H), 4.24-4.32 (m, 1H), 4.67-4.76 (sep, J=6.0 Hz, 1H), 7.10 (d, J=13.2 Hz, 1H), 7.60 (d, J=9.9 Hz, 1H), 7.74 (m, 1H), 8.46 (d, J=9.3 Hz, 1H); HRMS (ESI) m/z [M+H].sup.+ calcd for C32H46FN2O7: 589.3284 found: 589.3278.

    Example 487: (1R,4s)-4-(5-(((3RS,4SR)-1-Acetyl-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3317] ##STR01200##

    Step A: Intermediate 565: 1-(tert-Butyl) 3-methyl (3RS,4SR)-4-(4-fluoro-2-methoxy-5-(((1s,4R)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)piperidine-1,3-dicarboxylate

    [3318] ##STR01201##

    [3319] The titled compound was prepared analogous to Example 331 Step A, using rac-1-(tert-butyl) 3-methyl (3R,4S)-4-aminopiperidine-1,3-dicarboxylate instead of Intermediate 176. MS (ESI) m/z 707.4 [M+H].sup.+.

    Step B: Intermediate 566: rac-(3R,4S)-1-(tert-butoxycarbonyl)-4-(4-fluoro-2-methoxy-5-(((1s,4R)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)piperidine-3-carboxylic acid

    [3320] ##STR01202##

    [3321] The titled compound was prepared analogous to Example 435 Step C, using Intermediate 565 instead of Intermediate 533.

    Step C: Intermediate 567: tert-Butyl (3RS,4SR)-4-(4-fluoro-2-methoxy-5-(((1s,4R)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidine-1-carboxylate

    [3322] ##STR01203##

    [3323] Propylphosphonic acid anhydride (1.7 M in EtOAc, 0.34 mL, 0.59 mmol) and DIPEA (0.15 mL, 0.87 mmol) were added to a solution of 3-((trifluoromethyl)sulfonyl)aniline (39 mg, 0.17 mmol) and Intermediate 566 (100 mg, 0.145 mmol) in EtOAc (3 mL), then the mixture was stirred at rt for 2 days. Sat aq NaHCO.sub.3 was added to the reaction mixture, then organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 10-85% EtOAc in hexane as mobile phase to give the title compound (67 mg, 52%). MS (ESI) m/z 900.8 [M+H].sup.+.

    Step D: Intermediate 568: Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3RS,4SR)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate hydrochloride

    [3324] ##STR01204##

    [3325] A mixture of Intermediate 567 (67 mg, 0.075 mmol) in 4 M HCl in MeOH (1 mL) was stirred at rt for 4 hr. The mixture was concentrated and dried in vacuo to give the title compound (63 mg, 100%).

    Step E: Intermediate 569: Naphthalen-1-ylmethyl (1R,4s)-4-(5-(((3RS,4SR)-1-acetyl-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [3326] ##STR01205##

    [3327] Acetic anhydride (15 mg, 0.149 mmol) was added to a solution of Intermediate 568 (62 mg, 0.075 mmol) in pyridine (2 mL), then the mixture was stirred at rt for 20 hrs. The reaction mixture was concentrated and azeotroped with toluene. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (65 mg, 100%). MS (ESI) m/z 842.4 [M+H].sup.+.

    Step F: (1R,4s)-4-(5-(((3RS,4SR)-1-Acetyl-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3328] The titled compound was prepared analogous to Example 331 Step B, using Intermediate 569 instead of Intermediate 507. MS (ESI) m/z 702.2 [M+H].sup.+.

    Example 488: (1S,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [3329] ##STR01206##

    Step A: Intermediate 570: Methyl (1S,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [3330] ##STR01207##

    [3331] HATU (73 mg, 0.19 mmol) was added to a solution of Intermediate 234 (71 mg, 0.17 mmol), Intermediate 348 (62 mg, 0.19 mmol) and DIPEA (0.09 mL, 0.52 mmol) in DMF (0.4 mL) and the reaction mixture was stirred at rt for 5 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-60% EtOAc in hexane as mobile phase to give the title compound (109 mg, 92%). MS (ESI) m/z 681.2 [M+H].sup.+.

    Step B: (1S,4s)-4-(2-Fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(pentafluoro-6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [3332] LiOH (19 mg, 0.793 mmol) in H.sub.2O (0.4 mL) was added to a solution of Intermediate 570 (108 mg, 0.159 mmol) in THF (0.8 mL), then the mixture was stirred at rt for 12 hr. 1 M aq HCl and CHCl.sub.3 were added to the reaction mixture and the layer was separated. Combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (93 mg, 88%). HRMS (ESI) m/z [M+H].sup.+ calcd for C29H30F7N2O6S: 667.1708 found: 667.1714.

    [3333] The examples included in Table 33 below were synthesized analogous to the procedure of Example 488 using Intermediate 111 and indicated amines.

    TABLE-US-00033 TABLE 33 Example Amine Product MS 489 Int. 227 [01208]embedded image MS (APCI) 673.0 [M + H].sup.+ 490 Int. 217 [01209]embedded image HRMS (ESI) m/z [M + H].sup.+ 631.1720 491 Int. 226 [01210]embedded image HRMS (ESI) m/z [M + H].sup.+ 657.1928 492 Int. 228 [01211]embedded image HRMS m/z [M + H].sup.+ 585.1992 493 Int. 253 [01212]embedded image HRMS (ESI) m/z [M + H].sup.+ 621.1848 494 Int. 249 [01213]embedded image MS (ESI) 689.2 [M + H].sup.+ 495 Int. 213 [01214]embedded image MS (ESI) 655.3 [M + H].sup.+ 496 Int. 246 [01215]embedded image MS (ESI) 661.6 [M + H].sup.+

    Example 497: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((4-methoxy-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3334] ##STR01216##

    Step A: Intermediate 571: Ethyl (1S,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [3335] ##STR01217##

    [3336] The titled compound was prepared analogous to Example 488 Step A, using Intermediate 227 instead of Intermediate 234. MS (ESI) m/z 701.3 [M+H].sup.+.

    Step B: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((4-methoxy-3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid

    [3337] 2 M aq NaOH (0.65 mL, 1.3 mmol) was added to a solution of Intermediate 571 (185 mg, 0.159 mmol) in MeOH (1 mL), then the mixture was stirred at rt for 3 days. 1 M aq HCl and CHCl.sub.3 were added to the reaction mixture and the layer was separated. Combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 5% MeOH in CHCl.sub.3 as mobile phase to give the title compound (26 mg, 14%). HRMS (ESI) m/z [M+H].sup.+ calcd for C31H33F4N2O9S: 685.1838 found: 685.1810.

    Example 498: (1S,4s)-4-(2-Fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [3338] ##STR01218##

    Step A: Intermediate 572: Methyl (1S,4s)-4-(2-fluoro-5-(((1R,2R,3S,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [3339] ##STR01219##

    [3340] The titled compound was prepared analogous to Example 488 Step A, using Intermediate 229 instead of Intermediate 234. MS (ESI) m/z 623.3 [M+H].sup.+.

    Step B: (1S,3s)-3-((2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)methyl)cyclobutane-1-carboxylic acid

    [3341] 2 M aq NaOH (5.6 mL, 2.8 mmol) was added to a solution of Intermediate 572 (396 mg, 0.636 mmol) in MeOH (1.3 mL), then the mixture was stirred at rt for 4 days. Aq citric acid and CHCl.sub.3 were added to the reaction mixture and the layer was separated. Combined organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using 5% MeOH in CHCl.sub.3 as mobile phase to give the first eluting trans isomer: (1S,4s)-4-(2-fluoro-5-(((1R,2R,3R,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid (18 mg, 7%); MS (APCI) m/z 609.1 [M+H].sup.+, and the second eluting cis isomer: Example 498 (285 mg, 88%); MS (APCI) m/z 609.1 [M+H].sup.+.

    Example 499: (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-Carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

    [3342] ##STR01220##

    [3343] The titled compound was prepared analogous to Example 418 step A, using Example 498 instead of Example 1. HRMS (ESI) m/z [M+H].sup.+ calcd for C30H31F5N3O5: 608.2178 found: 608.2170.

    Example 500: (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-Carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3344] ##STR01221##

    [3345] The titled compound was prepared analogous to Example 418 step A, using Example 179 instead of Example 1. HRMS (ESI) m/z [M+H].sup.+ calcd for C30H33F5N3O5: 610.2334 found: 610.2348.

    Example 501: (1R,4s)-4-(2-Fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [3346] ##STR01222##

    Step A: Intermediate 573: Methyl (1R,4s)-4-(2-fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylate

    [3347] ##STR01223##

    [3348] The titled compound was prepared analogous to Example 488 Step A, using Intermediate 230 instead of Intermediate 234. MS (ESI) m/z 623.4 [M+H].sup.+.

    Step B: (1R,4s)-4-(2-Fluoro-5-(((1S,2S,3R,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-4-methoxyphenoxy)cyclohexane-1-carboxylic acid

    [3349] The titled compound was prepared analogous to Example 488 Step B, using Intermediate 573 instead of Intermediate 570. MS (ESI) m/z 609.1 [M+H].sup.+.

    Example 502: (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3350] ##STR01224##

    Step A: Intermediate 574: Methyl (1R,2S,3R,4S)-3-(4-cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [3351] ##STR01225##

    [3352] HATU (289 mg, 0.76 mmol) was added to a solution of methyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride (155 mg, 0.76 mmol), Intermediate 70 (300 mg, 0.63 mmol) and DIPEA (0.33 mL, 1.90 mmol) in DMF (3 mL) and the reaction mixture was stirred at rt for 1 hr. H.sub.2O was added to the reaction mixture and the precipitate was collected by filtration, and dried in vacuo to give the title compound (415 mg, 100%). MS (ESI) m/z 623.4 [M+H].sup.+.

    Step B: Intermediate 575: (1R,2S,3R,4S)-3-(4-Cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [3353] ##STR01226##

    [3354] The titled compound was prepared analogous to Example 488 Step B, using Intermediate 574 instead of Intermediate 570. MS (ESI) m/z 609.4 [M+H].sup.+.

    Step C: Intermediate 576: 3,3,3-Trifluoro-2,2-dimethylpropyl (1R,2S,3R,4S)-3-(4-cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [3355] ##STR01227##

    [3356] HATU (70 mg, 0.185 mmol) was added to a solution of Intermediate 575 (94 mg, 0.154 mmol), 3,3,3-trifluoro-2,2-dimethylpropylamine hydrochloride (41 mg, 0.23 mmol) and DIPEA (0.08 mL, 0.463 mmol) in DMF (0.8 mL) and the reaction mixture was stirred at rt for 1 hr. H.sub.2O was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in hexane as mobile phase to give the title compound (85 mg, 75%). MS (ESI) m/z 732.4 [M+H].sup.+.

    Step D: (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-((3,3,3-trifluoro-2,2-dimethylpropyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3357] The titled compound was prepared analogous to Example 331 Step B, using Intermediate 576 instead of Intermediate 507. 1H NMR (400 MHz, DMSO-d6) δ 1.01 (s, 3H), 1.02 (s, 3H), 1.05 (s, 3H), 1.20-1.72 (m, 10H), 1.83-1.95 (m, 2H), 2.02-2.12 (m, 2H), 2.39-2.49 (m, 2H), 2.93 (dd, J=11.0, 6.7 Hz, 1H), 3.15 (dd, J=13.75, 6.05 Hz, 1H), 3.20-3.50 (m, 1H), 3.94 (s, 3H), 4.24-4.40 (m, 2H), 7.52 (s, 1H), 7.64 (s, 1H), 8.18 (t, J=6.33 Hz, 1H), 9.83 (d, J=7.15 Hz, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C30H39F3N3O6: 594.2786 found: 594.2774.

    Example 503: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-2,2-Dimethylcyclopentyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3358] ##STR01228##

    Step A: Intermediate 577: Methyl (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylate

    [3359] ##STR01229##

    [3360] The titled compound was prepared analogous to Example 502 Step A, Intermediate 13 instead of Intermediate 70, and using methyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride instead of methyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride. MS (ESI) m/z 616.6 [M+H].sup.+.

    Step B: Intermediate 578: (1S,2S,3R,4R)-3-(4-Fluoro-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [3361] ##STR01230##

    [3362] The titled compound was prepared analogous to Example 502 Step B, using Intermediate 577 instead of Intermediate 574. MS (ESI) m/z 602.5 [M+H].sup.+.

    Step C: Intermediate 579: Naphthalen-1-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-(((R*)-2,2-dimethylcyclopentyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (Isomer 1) and Intermediate 580: Naphthalen-1-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-(((R*)-2,2-dimethylcyclopentyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (Isomer 2)

    [3363] ##STR01231##

    [3364] The titled compound was prepared analogous to Example 502 Step C, using Intermediate 578 instead of Intermediate 575 and using rac-2,2-dimethylcyclopentylamine instead of 3,3,3-trifluoro-2,2-dimethylpropylamine hydrochloride. The crude product was purified by flash chromatography using a gradient of 0-40% EtOAc in hexane as mobile phase to give the first eluting compound Isomer 1: Intermediate 579 (20 mg, 52%); MS (ESI) m/z 697.4 [M+H].sup.+, and the second eluting compound Isomer 2: Intermediate 580 (16 mg, 41%); MS (ESI) m/z 697.4 [M+H].sup.+.

    Step D: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-2,2-Dimethylcyclopentyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3365] The titled compound was prepared analogous to Example 331 Step B, using Intermediate 579 instead of Intermediate 507. MS (ESI) m/z 559.3 [M+H].sup.+.

    Example 504: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R*)-2,2-Dimethylcyclopentyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3366] ##STR01232##

    [3367] The titled compound was prepared analogous to Example 331 Step B, using Intermediate 580 instead of Intermediate 507. MS (ESI) m/z 559.3 [M+H].sup.+.

    Example 505: (1S,3s)-3-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclobutane-1-carboxylic acid

    [3368] ##STR01233##

    [3369] EDC (31 mg, 0.163 mmol), HOAt (22 mg, 0.163 mmol) and TEA (0.070 mL, 0.501 mmol) were added to a solution of Intermediate 326 (56 mg, 0.188 mmol) and Intermediate 232 (50 mg, 0.125 mmol) in DMF (4 mL), then the mixture was stirred at rt for 3 hr. 1 M aq HCl was added to the reaction mixture and the mixture was extracted with EtOAc, then organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-10% MeOH in hexane as mobile phase to give the title compound (81 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ 1.31-1.47 (m, 3H), 1.37 (s, 3H), 1.53-1.75 (m, 3H), 2.26-2.36 (m, 2H), 2.37-2.45 (m, 2H), 2.47-2.55 (m, 1H), 2.56-2.62 (m, 1H), 3.11 (dd, J=11.2, 4.2 Hz, 1H), 3.96 (s, 3H), 4.39-4.47 (m, 1H), 4.78-4.87 (m, 1H), 7.20 (d, J=13.0 Hz, 1H), 7.55 (d, J=10.0 Hz, 1H), 7.76-7.84 (m, 2H), 7.93-7.98 (m, 1H), 8.70-8.73 (m, 1H), 9.76 (d, J=7.3 Hz, 1H), 10.76 (s, 1H). MS (ESI) m/z 643.6 [M+H].sup.+.

    Example 506: (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methoxycyclohexane-1-carboxylic acid

    [3370] ##STR01234##

    [3371] The titled compound was prepared analogous to Example 505, using Intermediate 329 instead of Intermediate 326, and using Intermediate 22 instead of Intermediate 232. MS (ESI) m/z 561.5 [M+H].sup.+.

    Example 507: (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid

    [3372] ##STR01235##

    Step A: Intermediate 581: tert-Butyl (1R,4r)-4-(2-fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylate

    [3373] ##STR01236##

    [3374] The titled compound was prepared analogous to Example 331 step A, using Intermediate 337 instead of Intermediate 13, and using Intermediate 22 instead of Intermediate 176. MS (ESI) m/z 603.7 [M+H].sup.+.

    Step B: (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid

    [3375] The titled compound was prepared analogous to Example 398 step B, using 1-Intermediate 581 instead of Intermediate 515. MS (ESI) m/z 547.6 [M+H].sup.+.

    Example 508: (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methoxycyclohexane-1-carboxylic acid

    [3376] ##STR01237##

    [3377] The titled compound was prepared analogous to Example 505, using Intermediate 329 instead of Intermediate 326. MS (ESI) m/z 687.2 [M+H].sup.+.

    Example 509: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1R,2R,3S,4S)-3-((3-(pentafluoro-A6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid (Isomer 1) and

    Example 510: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2S,3R,4R)-3-((3-(pentafluoro-6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)cyclohexane-1-carboxylic acid (Isomer 2)

    [3378] ##STR01238##

    [3379] The racemic product obtained in Example 432 (201 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane:2-PrOH:AcOH=70/30/0.1]) to give the first eluting compound Isomer 1: Example 509 (86.5 mg, 34%); MS (ESI) m/z 651.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 510 (57 mg, 23%); HRMS (ESI) m/z [M+H].sup.+ calcd for C29H33F6N2O6S: 651.1958 found: 651.1940.

    Example 511: (1S,2S,3R,4R)-3-(5-(((1s,4S)-4-Carbamoylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)-N-(3-(pentafluoro-λ6-sulfaneyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

    [3380] ##STR01239##

    [3381] The titled compound was prepared analogous to Example 418 step A, using Example 510 instead of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.91 (m, 14H), 2.11-2.22 (m, 1H), 2.45-2.52 (m, 1H), 2.55-2.60 (m, 1H), 3.09 (dd, J=10.9, 4.2 Hz, 1H), 3.96 (s, 3H), 4.37-4.47 (m, 2H), 6.70 (br s, 1H), 7.13-7.25 (m, 2H), 7.52-7.61 (m, 2H), 7.65-7.72 (m, 2H), 8.44-8.48 (m, 1H), 9.77 (d, J=7.3 Hz, 1H), 10.56 (s, 1H). MS (ESI) m/z 650.6 [M+H].sup.+.

    Example 512: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3aR*,4S*,5S*,6aS*)-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid and

    Example 513: (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3aR*,4S*,5S*,6aS*)-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3382] ##STR01240##

    [3383] The racemic product obtained in Example 395 (39 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane:EtOH:AcOH=30/70/0.1]) to give the first eluting compound Isomer 1: Example 512 (18.4 mg, 47%); MS (ESI) m/z 689.6 [M+H].sup.+, and the second eluting compound Isomer 2: Example 513 (17.8 mg, 46%); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H33F4N2O10S: 689.1786 found: 689.1794.

    Example 514: (1R,4s)-4-(5-(((3R*,4S*)-1-Acetyl-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 515: (1R,4s)-4-(5-(((3R*,4S*)-1-acetyl-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)piperidin-4-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3384] ##STR01241##

    [3385] The racemic product obtained in Example 487 (32.3 mg) was separated by chiral HPLC (column: CHIRALPAK IF (250 mm*30 mm); mobile phase: [MTBE/EtOH/AcOH=85/15/0.1]) to give the first eluting compound Isomer 1: Example 514 (16.6 mg, 52%); MS (ESI) m/z 702.6 [M+H].sup.+, and the second eluting compound Isomer 2: Example 515 (15.4 mg, 48%); MS (ESI) m/z 702.2 [M+H].sup.+.

    Example 516: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cycloheptyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 517: (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S*,2R*)-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cycloheptyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3386] ##STR01242##

    [3387] The racemic product obtained in Example 354 (100 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane:2-PrOH:AcOH=65/35/0.1]) to give the first eluting compound Isomer 1: Example 516 (46.0 mg, 46%); MS (ESI) m/z 673.6 [M+H].sup.+, and the second eluting compound Isomer 2: Example 517 (44.6 mg, 45%); MS (ESI) m/z 673.2 [M+H].sup.+.

    Example 518: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4S*)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 519: (1R,4s)-4-(2-fluoro-4-methoxy-5-(((3S*,4S*)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-4-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1)

    [3388] ##STR01243##

    [3389] The racemic product obtained in Example 341 (28.5 mg) was separated by chiral HPLC (column: CHIRALPAK IF (250 mm*30 mm); mobile phase: [Hexane:EtOH:AcOH=50/50/0.1]) to give the first eluting compound Isomer 1: Example 518 (9.3 mg, 33%, 100% ee); MS (ESI) m/z 661.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 519 (13.1 mg, 46%, 100% ee); MS (ESI) m/z 661.2 [M+H].sup.+.

    Example 520: (1R,4s)-4-(2-Fluoro-5-(((1S*,2S*,3R*,4R*)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 521: (1R,4s)-4-(2-fluoro-5-(((1S*,2S*,3R*,4R*)-3-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3390] ##STR01244##

    [3391] The racemic product obtained in Example 371 (95.2 mg) was separated by chiral HPLC (column: CHIRALPAK ID (250 mm*30 mm); mobile phase: [Hexane:2-PrOH:AcOH=65/35/0.1]) to give the first eluting compound Isomer 1: Example 520 (19.7 mg, 21%, 100% ee); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H34F7N2O6S: 683.2020 found: 683.2022 m/z and the second eluting compound Isomer 2: Example 521 (16.6 mg, 17%, 99.9% ee); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H34F7N2O6S: 683.2020 found: 683.2054.

    Example 522: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*,4S*)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 523: (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S*,2R*,4S*)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3392] ##STR01245##

    [3393] The racemic product obtained in Example 335 (79.8 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/EtOH/AcOH=60/40/0.1]) to give the first eluting compound Isomer 1: Example 522 (23.9 mg, 30%, 100% ee); MS (ESI) m/z 675.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 523 (35.3 mg, 44%, 99.8% ee); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H35F4N2O9S: 675.1994 found: 675.2002.

    Example 524: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*,4R*)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 525: (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S*,2R*,4R*)-4-methoxy-2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3394] ##STR01246##

    [3395] The racemic product obtained in Example 336 (35.3 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/AcOH=70/30/0.1]) to give the first eluting compound Isomer 1: Example 524 (15 mg, 43%, 100% ee); 1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.20-1.41 (m, 4H) 1.42-1.71 (m, 2H) 1.85-2.00 (m, 2H) 2.04-2.21 (m, 2H) 2.22-2.41 (m, 3H) 2.52 (dt, J=14.31, 5.64 Hz, 1H) 3.32 (s, 3H) 3.50-3.59 (m, 1H) 3.70 (s, 3H) 4.01-4.15 (m, 2H) 4.85-5.01 (m, 1H) 6.57 (d, J=12.10 Hz, 1H) 7.41 (t, J=7.98 Hz, 1H) 7.47 (d, J=7.98 Hz, 1H) 7.62 (d, J=7.70 Hz, 1H) 7.68 (d, J=9.63 Hz, 1H) 8.22 (br d, J=7.70 Hz, 1H) 8.47 (s, 1H) 8.94 (br s, 1H); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H35F4N2O9S: 675.1994 found: 675.2026, and the second eluting compound Isomer 2: Example 525 (15 mg, 42%, 99.7% ee); 1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.20-1.41 (m, 4H) 1.42-1.71 (m, 2H) 1.85-2.00 (m, 2H) 2.04-2.21 (m, 2H) 2.22-2.41 (m, 3H) 2.52 (dt, J=14.31, 5.64 Hz, 1H) 3.32 (s, 3H) 3.50-3.59 (m, 1H) 3.70 (s, 3H) 4.01-4.15 (m, 2H) 4.85-5.01 (m, 1H) 6.57 (d, J=12.10 Hz, 1H) 7.41 (t, J=7.98 Hz, 1H) 7.47 (d, J=7.98 Hz, 1H) 7.62 (d, J=7.70 Hz, 1H) 7.68 (d, J=9.63 Hz, 1H) 8.22 (br d, J=7.70 Hz, 1H) 8.47 (s, 1H) 8.94 (br s, 1H); MS (ESI) m/z 675.2 [M+H].sup.+.

    Example 526: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,5S*)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 527: (1R,4s)-4-(2-fluoro-4-methoxy-5-(((1S*,2S*,5S*)-2-methoxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3396] ##STR01247##

    [3397] The racemic product obtained in Example 359 (30.3 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [MTBE/EtOH/AcOH=96/4/0.1]) to give the first eluting compound Isomer 1: Example 526 (12.8 mg, 42%); MS (ESI) m/z 675.3 [M+H].sup.+, and the second eluting compound Isomer 2: Example 527 (5.8 mg, 19%); MS (ESI) m/z 675.2 [M+H].sup.+.

    Example 528: (1R,4s)-4-(2-Fluoro-5-(((1S*,2S*,5S*)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 529: (1R,4s)-4-(2-Fluoro-5-(((1S*,2S*,5S*)-2-hydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3398] ##STR01248##

    [3399] The racemic product obtained in Example 343 (149 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [MTBE/EtOH/AcOH=96/4/0.1]) to give the first eluting compound Isomer 1: Example 528 (52.8 mg, 36%, 100% ee); MS (ESI) m/z 661.3 [M+H].sup.+, and the second eluting compound Isomer 2: Example 529 (53.4 mg, 36%, 100% ee); MS (ESI) m/z 661.3 [M+H].sup.+.

    Example 530: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 531: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3400] ##STR01249##

    [3401] The racemic product obtained in Example 331 (170 mg) was separated by chiral HPLC (column: CHIRALPAK IC (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/EtOH/AcOH=60/20/20/0.5]) to give the first eluting compound Isomer 1: Example 530 (74 mg, 44%); MS (ESI) m/z 547.3 [M+H].sup.+, and the second eluting compound Isomer 2: Example 531 (72 mg, 42%); MS (ESI) m/z 547.3 [M+H].sup.+.

    Example 532: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 1) and

    Example 533: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 2)

    [3402] ##STR01250##

    [3403] The racemic product obtained in Example 332 (85 mg) was separated by chiral HPLC (column: CHIRALPAK IB N (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/AcOH=50/50/0.1]) to give the first eluting compound Isomer 1: Example 532 (16 mg, 19%); MS (ESI) m/z 563.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 533 (16 mg, 19%); MS (ESI) m/z 563.2 [M+H].sup.+.

    Example 534: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 535: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3404] ##STR01251##

    [3405] The racemic product obtained in Example 333 (65 mg) was separated by chiral HPLC (column: CHIRALPAK IB N (250 mm*30 mm); mobile phase: [Hexane/EtOH/AcOH=50/50/0.1]) to give the first eluting compound Isomer 1: Example 534 (31 mg, 48%); HRMS (ESI) m/z [M+H]+calcd for C30H40N3O7: 554.2860 found: 554.2870, and the second eluting compound Isomer 2: Example 535 (31 mg, 48%); MS (ESI) m/z 554.3 [M+H].sup.+.

    Example 536: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-(3,3,3-trifluoropropyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 537: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-(3,3,3-trifluoropropyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3406] ##STR01252##

    Step A: Intermediate 582: ((1R,4s)-4-(5-(((1S*,2S*,3R*,4R*)-7-(tert-Butoxycarbonyl)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and Intermediate 583: (1R,4s)-4-(5-(((1S*,2S*,3R*,4R*)-7-(tert-Butoxycarbonyl)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3407] ##STR01253##

    [3408] The racemic product obtained in Example 334 (145 mg) was separated by chiral HPLC (column: CHIRALPAK IC (250 mm*30 mm); mobile phase: [Hexane/EtOH/AcOH=75/25/0.5]) to give the first eluting compound Isomer 1: Intermediate 582 (74 mg, 50%); MS (ESI) m/z 653.4 [M+H].sup.+, and the second eluting compound Isomer 2: Intermediate 583 (70 mg, 48%); MS (ESI) m/z 653.3 [M+H].sup.+.

    Step B: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)-7-(3,3,3-trifluoropropyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3409] A solution of Intermediate 582 (68 mg, 0.104 mmol) in 4 M HCl in cyclopentyl methyl ether (0.5 mL) was stirred at rt for 1 h and the reaction mixture was concentrated in vacuo to give the resulting amine hydrochloride (62 mg, 100%).

    [3410] NaBH.sub.4 (32 mg, 0.15 mmol) was added to a solution of the resulting amine hydrochloride (30 mg, 0.051 mmol), DIPEA (7 mg, 0.056 mmol) and 3,3,3-trifluoropropanal (57 mg, 0.51 mmol) in CHCl.sub.3 (1 mL) and the reaction mixture was stirred at rt for 20 min. Aq citric acid (10%) was added to the reaction mixture and the mixture was extracted with CHCl.sub.3, then the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-7% MeOH in CHCl.sub.3 as mobile phase to give the title compound, Example 536 (31 mg, 94%). HRMS (ESI) m/z [M+H].sup.+ calcd for C33H44F3N4O6: 649.3208 found: 649.3186. Step B was repeated with Intermediate 583 instead of Intermediate 582 to give the title compound, Example 537 MS (ESI) m/z 649.3 [M+H]+

    Example 538: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((2S*,3R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 539: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((2S*,3R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3411] ##STR01254##

    [3412] The racemic product obtained in Example 468 (260 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [MTBE/EtOH/AcOH=95/5/0.1]) to give the first eluting compound Isomer 1: Example 538 (114 mg, 41%); HRMS (ESI) m/z [M+H].sup.+ calcd for C32H44N3O6: 566.3224 found: 566.3220, and the second eluting compound Isomer 2: Example 539 (114 mg, 41%); MS (ESI) m/z 566.4 [M+H].sup.+.

    Example 540: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1R*,2S*,3R*,4S*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 541: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1R*,2S*,3R*,4S*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3413] ##STR01255##

    [3414] The racemic product obtained in Example 469 (180 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [MTBE/EtOH/AcOH=95/5/0.1]) to give the first eluting compound Isomer 1: Example 540 (65 mg, 36%); HRMS (ESI) m/z [M+H].sup.+ calcd for C32H42N3O6: 564.3068 found: 564.3074, and the second eluting compound Isomer 2: Example 541 (64 mg, 36%); MS (ESI) m/z 564.4 [M+H].sup.+.

    Example 542: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((2S*,3R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2) and

    Example 543: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((2S*,3R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1)

    [3415] ##STR01256##

    [3416] The racemic product obtained in Example 470 (207 mg) was separated by chiral HPLC (column: CHIRALPAK ID (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/AcOH=60/40/0.1]) to give the first eluting compound Isomer 1: Example 542 (85 mg, 41%); HRMS (ESI) m/z [M+H]+calcd for C31H44FN2O6: 559.3178 found: 559.3176, and the second eluting compound Isomer 2: Example 543 (78 mg, 38%); MS (ESI) m/z 559.4 [M+H].sup.+.

    Example 544: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1R*,2S*,3R*,4S*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 545: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1R*,2S*,3R*,4S*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]oct-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3417] ##STR01257##

    [3418] The racemic product obtained in Example 471 (114 mg) was separated by chiral HPLC (column: CHIRALPAK ID (250 mm*30 mm); mobile phase: [Hexane/EtOH/AcOH=60/40/0.1]) to give the first eluting compound Isomer 1: Example 544 (53 mg, 46%); MS (ESI) m/z 557.4 [M+H].sup.+, and the second eluting compound Isomer 2: Example 545 (40 mg, 35%); MS (ESI) m/z 557.4 [M+H].sup.+.

    Example 546: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*,4R*)-4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 547: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*,4R*)-4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3419] ##STR01258##

    [3420] The racemic product obtained in Example 337 (155 mg) was separated by chiral HPLC (column: CHIRALPAK IG (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/AcOH=60/40/0.5]) to give the first eluting compound Isomer 1: Example 546 (62.8 mg, 41%); MS (ESI) m/z 537.4 [M+H].sup.+, and the second eluting compound Isomer 2: Example 547 (62.6 mg, 40%); MS (ESI) m/z 537.4 [M+H].sup.+.

    Example 548: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*,4R*)-4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 1) and

    Example 549: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*,4R*)-4-methoxy-2-(neopentylcarbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 2)

    [3421] ##STR01259##

    [3422] The racemic product obtained in Example 338 (101 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [MTBE/EtOH/MeOH/AcOH=90/5/5/0.5]) to give the first eluting compound Isomer 1: Example 548 (40 mg, 40%); MS (ESI) m/z 553.4 [M+H].sup.+, and the second eluting compound Isomer 2: Example 549 (40 mg, 40%); MS (ESI) m/z 553.4 [M+H].sup.+.

    Example 550: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*,4R*)-4-methoxy-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 1) and

    Example 551: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*,4R*)-4-methoxy-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclopentyl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 2)

    [3423] ##STR01260##

    [3424] The racemic product obtained in Example 339 (74 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [MTBE/EtOH/MeOH/AcOH=90/5/5/0.5]) to give the first eluting compound Isomer 1: Example 550 (28 mg, 37%); MS (ESI) m/z [M+H].sup.+, and the second eluting compound Isomer 2: Example 551 (26 mg, 35%); MS (ESI) m/z [M+H].sup.+.

    Example 552: 2′-Fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid (Isomer 1) and

    Example 553: 2′-Fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-4-carboxylic acid (Isomer 2)

    [3425] ##STR01261##

    [3426] The racemic product obtained in Example 224 (260 mg) was separated by chiral HPLC (column: CHIRALPAK IF (250 mm*30 mm); mobile phase: [Hexane/EtOH/MeOH/AcOH=55/25/20/0.1]) to give the first eluting compound Isomer 1: Example 552 (127 mg, 49%, 100% ee); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H25F4N2O7S: 633.1312 found: 633.1328, and the second eluting compound Isomer 2: Example 553 (125 mg, 48%, 99.8% ee); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H25F4N2O7S: 633.1312 found: 633.1352.

    Example 554: 2′-Fluoro-4′-methoxy-5′-(((1R,2R,3S,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid (Isomer 1) and

    Example 555: 2′-Fluoro-4′-methoxy-5′-(((1S,2S,3R,4R)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid (Isomer 2)

    [3427] ##STR01262##

    [3428] The racemic product obtained in Example 225 (260 mg) was separated by chiral HPLC (column: CHIRALPAK IF (250 mm*30 mm); mobile phase: [Hexane/MeOH/THF/AcOH=80/10/10/0.1]) to give the first eluting compound Isomer 1: Example 554 (130 mg, 50%, 99.8% ee); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H25F4N2O7S: 633.1312 found: 633.1348, and the second eluting compound Isomer 2: Example 555 (130 mg, 50%, 99.8% ee); HRMS (ESI) m/z [M+H]+calcd for C30H25F4N2O7S: 633.1312 found: 633.1308.

    Example 556: rel-2′-Fluoro-4-hydroxy-4′-methoxy-5′-(((1R,2S,3R,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid (Isomer 1) and

    Example 557: rel-2′-Fluoro-4-hydroxy-4′-methoxy-5′-(((1R,2S,3R,4S)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-[1,1′-biphenyl]-3-carboxylic acid (Isomer 2)

    [3429] ##STR01263##

    [3430] The racemic product obtained in Example 316 (30 mg) was separated by chiral HPLC (column: CHIRALPAK IE (250 mm*30 mm); mobile phase: [Hex/EtOH/THF/TFA=80/10/10/0.1]) to give the first eluting compound Isomer 1: Example 556 (6.1 mg, 20%, 100% ee); MS (APCI) m/z 651.0 [M+H].sup.+, and the second eluting compound Isomer 2: Example 557 (8.3 mg, 28%, 99% ee); MS (APCI) m/z 651.0 [M+H].sup.+.

    Example 558: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4S*)-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 559: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4S*)-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3431] ##STR01264##

    [3432] The racemic product obtained in Example 340 (56.4 mg) was separated by chiral HPLC (column: CHIRALPAK ID (250 mm*30 mm); mobile phase: [Hex/2-PrOH/AcOH=65/35/0.5]) to give the first eluting compound Isomer 1: Example 558 (28.6 mg, 50%, 100% ee); MS (ESI) m/z 661.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 559 (28.0 mg, 50%, 99.7% ee); HRMS (ESI) m/z [M+H].sup.+ calcd for C29H33F4N2O9S: 661.1838 found: 661.1848.

    Example 560: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 561: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3433] ##STR01265##

    [3434] The racemic product obtained in Example 342 (73.4 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/EtOH/AcOH=60/40/0.1]) to give the first eluting compound Isomer 1: Example 560 (31.5 mg, 43%); MS (ESI) m/z 647.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 561 (30.6 mg, 42%); HRMS (ESI) m/z [M+H].sup.+ calcd for C28H31F4N2O9S: 647.1680 found: 647.1700.

    Example 562: (1R,4s)-4-(5-(((1S*,2R*,3S*,5S*)-2,3-Dihydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 563: (1R,4s)-4-(5-(((1S*,2R*,3S*,5S*)-2,3-Dihydroxy-5-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)cyclopentyl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3435] ##STR01266##

    [3436] The racemic product obtained in Example 394 (139 mg) was separated by chiral HPLC (column: CHIRALPAK IF (250 mm*30 mm); mobile phase: [Hexane/EtOH/AcOH=60/40/0.1]) to give the first eluting compound Isomer 1: Example 562 (60.2 mg, 43%); MS (ESI) m/z 677.4 [M+H].sup.+, and the second eluting compound Isomer 2: Example 563 (57.0 mg, 41%); MS (ESI) m/z 677.4 [M+H].sup.+.

    Example 564: (1R,4s)-4-(2-Fluoro-5-(((3S*,4R*)-4-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 565: (1R,4s)-4-(2-Fluoro-5-(((3S*,4R*)-4-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3437] ##STR01267##

    [3438] The racemic product obtained in Example 344 (138 mg) was separated by chiral HPLC (column: CHIRALPAK IF (250 mm*30 mm); mobile phase: [Hexane/EtOH/AcOH=60/40/0.1]) to give the first eluting compound Isomer 1: Example 564 (64.6 mg, 47%); MS (ESI) m/z 659.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 565 (64.3 mg, 47%); MS (ESI) m/z 659.2 [M+H].sup.+.

    Example 566: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 567: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3439] ##STR01268##

    [3440] The racemic product obtained in Example 345 (193 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/EtOH/AcOH=60/20/20/0.1]) to give the first eluting compound Isomer 1: Example 566 (83.1 mg, 43%); MS (ESI) m/z 509.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 567 (81.5 mg, 42%); MS (ESI) m/z 509.2 [M+H].sup.+.

    Example 568: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*)-2-(neopentylcarbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 569: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2R*)-2-(neopentylcarbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3441] ##STR01269##

    [3442] The racemic product obtained in Example 346 (145 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/EtOH/AcOH=65/10/25/0.1]) to give the first eluting compound Isomer 1: Example 568 (66.1 mg, 46%); MS (ESI) m/z 493.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 569 (65.4 mg, 45%); MS (ESI) m/z 493.2 [M+H].sup.+.

    Example 570: (1R,4s)-4-(2-Fluoro-5-(((1S*,2R*)-2-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 571: (1R,4s)-4-(2-Fluoro-5-(((1S*,2R*)-2-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)cyclobutyl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3443] ##STR01270##

    [3444] The racemic product obtained in Example 347 (214 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/EtOH/AcOH=65/10/25/0.1]) to give the first eluting compound Isomer 1: Example 570 (100.6 mg, 47%); MS (ESI) m/z 643.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 571 (106.2 mg, 50%); MS (ESI) m/z 643.2 [M+H].sup.+.

    Example 572: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1S*,2R*)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 573: (1R,4s)-4-(2-Cyano-4-methoxy-5-(((1S*,2R*)-2-(((1-methylcyclobutyl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3445] ##STR01271##

    [3446] The racemic product obtained in Example 348 (145 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/EtOH/AcOH=65/10/25/0.1]) to give the first eluting compound Isomer 1: Example 572 (66.1 mg, 46%); MS (ESI) m/z 512.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 573 (65.4 mg, 45%); MS (ESI) m/z 512.3 [M+H].sup.+.

    Example 574: (1R,4s)-4-(2-Fluoro-5-(((3S*,4S*)-4-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 575: (1R,4s)-4-(2-Fluoro-5-(((3S*,4S*)-4-((4-fluoro-3-(pentafluoro-λ6-sulfaneyl)phenyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3447] ##STR01272##

    [3448] The racemic product obtained in Example 349 (161 mg) was separated by chiral HPLC (column: CHIRALPAK IG (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/AcOH=70/30/0.1] to give the first eluting compound Isomer 1: Example 574 (71.5 mg, 44%); MS (ESI) m/z 673.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 575 (80.6 mg, 50%); MS (ESI) m/z 673.2 [M+H].sup.+.

    Example 576: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2) and

    Example 577: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1)

    [3449] ##STR01273##

    [3450] The racemic product obtained in Example 350 (170 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/EtOH/MeOH/AcOH=65/20/15/0.1]) to give the first eluting compound Isomer 1: Example 577 (72.6 mg, 43%, 100% ee); MS (ESI) m/z 521.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 576 (74.5 mg, 44%, 99.9% ee); MS (ESI) m/z 521.2 [M+H].sup.+.

    Example 578: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 1) and

    Example 579: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-(neopentylcarbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 2)

    [3451] ##STR01274##

    [3452] The racemic product obtained in Example 362 (102 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hexane/2-PrOH/EtOH/MeOH/AcOH=45/10/45/0.1]) to give the first eluting compound Isomer 1: Example 578 (43.6 mg, 43%, 100% ee); MS (ESI) m/z 525.2 [M+H].sup.+, and the second eluting compound Isomer 2: Example 579 (42.2 mg, 41%, 99.7% ee); MS (ESI) m/z 525.2 [M+H].sup.+.

    Example 580: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 1) and

    Example 581: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((3S*,4R*)-4-(((1-methylcyclobutyl)methyl)carbamoyl)tetrahydrofuran-3-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 2)

    [3453] ##STR01275##

    [3454] The racemic product obtained in Example 363 (40 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [CO2/MeOH=60/40]) to give the first eluting compound Isomer 1: Example 580 (14.2 mg, 36%); MS (ESI) m/z 537.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 581 (20 mg, 50%); MS (ESI) m/z 537.5 [M+H].sup.+.

    Example 582: (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1R*,2R*,3S*,4S*)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid (Isomer 1) and

    Example 583: (1R,4r)-4-(2-Fluoro-4-methoxy-5-(((1R*,2R*,3S*,4S*)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-hydroxycyclohexane-1-carboxylic acid (Isomer 2)

    [3455] ##STR01276##

    [3456] The racemic product obtained in Example 422 (16 mg) was separated by chiral HPLC (column: CHIRALPAK IE (250 mm*30 mm); mobile phase: [Hex/2-PrOH/MeOH/AcOH=65/30/5/0.5]) to give the first eluting compound Isomer 1: Example 582 (5 mg, 31%); MS (ESI) m/z 673.3 [M+H].sup.+, and the second eluting compound Isomer 2: Example 583 (5 mg, 31%); MS (ESI) m/z 673.3 [M+H].sup.+.

    Example 584: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 1) and

    Example 585: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-(hydroxymethyl)cyclohexane-1-carboxylic acid (Isomer 2)

    [3457] ##STR01277##

    [3458] The racemic product obtained in Example 366 (13 mg) was separated by chiral HPLC (column: CHIRALPAK IA (250 mm*30 mm); mobile phase: [Hex/EtOH/AcOH=60/40/0.1]) to give the first eluting compound Isomer 1: Example 584 (6.5 mg, 50%); MS (ESI) m/z 687.6 [M+H].sup.+, and the second eluting compound Isomer 2: Example 585 (4.2 mg, 32%); MS (ESI) m/z 687.6 [M+H].sup.+.

    Example 586: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1) and

    Example 587: (1R,4s)-4-(2-Fluoro-4-methoxy-5-(((1S*,2S*,3R*,4R*)-3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2)

    [3459] ##STR01278##

    [3460] The racemic product obtained in Example 367 (133 mg) was separated by chiral HPLC (column: CHIRALPAK IE (250 mm*30 mm); mobile phase: [Hexane/EtOH/AcOH=75/25/0.1]) to give the first eluting compound Isomer 1: Example 586 (44.6 mg, 39%); MS (ESI) m/z 671.5 [M+H].sup.+, and the second eluting compound Isomer 2: Example 587 (51.7 mg, 45%); HRMS (ESI) m/z [M+H].sup.+ calcd for C31H35F4N2O8S: 671.2044 found: 671.2064.

    Example 588: (1R,4s)-4-(2-Cyano-4-fluoro-5-(((2S*,3R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 2) and

    Example 589: (1R,4s)-4-(2-Cyano-4-fluoro-5-(((2S*,3R*)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (Isomer 1)

    [3461] ##STR01279##

    [3462] The racemic product obtained in Example 368 (90 mg) was separated by chiral HPLC (column: CHIRALPAK IB N (250 mm*30 mm); mobile phase: [Hex/2-PrOH/AcOH=75/25/0.1]) to give the first eluting compound Isomer 1: Example 589 (39.7 mg, 41%, 99.7% ee); MS (ESI) m/z 554.4 [M+H].sup.+, and the second eluting compound Isomer 2: Example 588 (36.8 mg, 38%, 99.7% ee); MS (ESI) m/z 554.4 [M+H].sup.+.

    Example 590: rel-2′-Fluoro-5′-(((1R,2S,3R,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid (Isomer 1) and

    Example 591: rel-2′-Fluoro-5′-(((1R,2S,3R,4S)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid (Isomer 2)

    [3463] ##STR01280##

    [3464] The racemic product obtained in Example 315 (57 mg) was separated by chiral HPLC (column: CHIRALPAK IF (250 mm*30 mm); mobile phase: [Hex/EtOH/THF/AcOH=75/15/10/0.1]) to give the first eluting compound Isomer 1: Example 590 (20 mg, 35%, 100% ee); MS (ESI) m/z 587.0 [M−H]−, and the second eluting compound Isomer 2: Example 591 (19 mg, 33%, 100% ee); HRMS (ESI) m/z [M+H].sup.+ calcd for C30H26F5N2O5: 589.1756 found: 589.1774.

    Example 592: (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3465] ##STR01281##

    Step A: Intermediate 584: (1S,2S,3R,4R)-3-(4-Cyano-2-methoxy-5-(((1s,4S)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

    [3466] ##STR01282##

    [3467] 2 M aq LiOH (10.6 mL, 21.12 mmol) was added to a solution of Intermediate 71 (2.60 g, 4.18 mmol) in DME (50 mL), then the reaction mixture was stirred at rt for 12 hr. 10% aq citric acid was added to the reaction mixture until pH<3, then the reaction mixture was extracted with EtOAc twice and the combined organic layer was concentrated in vacuo to give titled compound (2.5 g 97%). MS (ESI) m/z 609.3 [M+H].sup.+.

    Step B: Intermediate 585: Naphthalen-1-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-cyano-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [3468] ##STR01283##

    [3469] HATU (344 mg, 0.904 mmol) and DIPEA (0.43 mL, 2.46 mmol) were added to Intermediate 584 (500 mg, 0.821 mmol) and (1-methylcyclobutyl)methylamine hydrochloride (134 mg, 0.986 mmol) in DMF (4 mL), then the mixture was stirred at rt for 30 min. H.sub.2O (50 mL) was added to the reaction mixture and the residual precipitate was collected by filtration, then the residue was dried under vacuum pump to give the title compound (611 mg, 100%). MS (ESI) m/z 690.4 [M+H].sup.+.

    Step C: (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3470] ##STR01284##

    [3471] Palladium (10% Pd/C, moisture by 50% H.sub.2O, 200 mg) was added to a solution of Intermediate 585 (609 mg, 0.883 mmol) in MeOH (4.4 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 3 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. After the filtrate was concentrated in vacuo, the crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give titled compound (389 mg, 80%). .sup.1H NMR (400 MHz, DMSO-d6) δ 0.99 (s, 3H), 1.21 (s, 3H), 1.23-1.41 (m, 5H), 1.45-1.85 (m, 10H), 1.96-2.13 (m, 3H), 2.18-2.29 (m, 3H), 2.35-2.40 (m, 1H), 2.65-2.71 (m, 1H), 3.06 (dd, J=13.2, 5.8 Hz, 1H), 3.17 (dd, J=13.2, 6.3 Hz, 1H), 3.98 (s, 3H), 4.26-4.33 (m, 1H), 4.34-4.43 (m, 1H), 7.37 (s, 1H), 7.72 (s, 3H), 7.84-7.91 (m, 1H), 9.09 (d, J=8.5 Hz, 1H). HRMS (ESI) m/z [M+H].sup.+ calcd for C31H42N3O6: 552.3068 found: 552.3064.

    Form A of (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3472] The product from Step C (104 mg, 0.19 mmol) was dissolved in DMSO and purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 45-80% acetonitrile in H.sub.2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. The desired fractions were freezedried to give Form A of the title compound (79 mg, 76%) as a white solid.

    Form B of (1S,4s)-4-(2-Cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3473] To a solution of Intermediate 585 (21.5 g, 31.2 mmol) in EtOH (260 mL) was added 10% Pd(C) (4.0 g) at 25° C. The mixture was stirred under H.sub.2 (50 Psi) at 25° C. for 3 h. The reaction mixture was filtered and the filter cake was washed with EtOH (200 mL). The combined filtrate was concentrated under reduced pressure to give a residue which was triturated with PE/EtOAc (10:1, 300 mL) at 25° C. for 30 min, then filtered. The filter cake was dried in vacuum and the residue was purified by Method PrepAcidic-O, combined with a second batch prepared by the same method, and the solvent removed. The residue was purified by Method SFC-H to afford Form B of the title compound (20.0 g, 65.6%, based on the combined theoretical amount: 30.4 g) as a white solid.

    Example 593: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methoxycyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3474] ##STR01285##

    Step A: Intermediate 586: Naphthalen-1-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-(((1-methoxycyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

    [3475] ##STR01286##

    [3476] HATU (104 mg, 0.274 mmol) was added to a solution of Intermediate 578 (150 mg, 0.249 mmol), (1-methoxycyclobutyl)methanamine hydrochloride (44 mg, 0.274 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMF (1 mL) and the reaction mixture was stirred at rt for 1 h. H.sub.2O was added to the reaction mixture and the precipitate was collected by filtration, and dried in vacuo to give the title compound (138 mg, 79%). MS (ESI) m/z 699.3 [M+H].sup.+.

    Step B: (1S,4s)-4-(2-Fluoro-4-methoxy-5-(((1S,2R,3S,4R)-3-(((1-methoxycyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3477] ##STR01287##

    [3478] Palladium (10% Pd/C, moisture by 50% water, 70 mg) was added to a solution of Intermediate 586 (138 mg, 0.198 mmol) in EtOH (2 mL). The reaction mixture was stirred under 1 atm of hydrogen atmosphere at rt for 3 hr. The hydrogen in the reaction vessel was replaced with argon and the reaction mixture was filtered with Celite®®. After the filtrate was concentrated in vacuo, the crude product was purified by flash chromatography using a gradient of 0-5% MeOH in CHCl.sub.3 as mobile phase to give titled compound (81 mg, 73%). MS (ESI) m/z 561.3 [M+H].sup.+. The Examples included in Table 34 were synthesized analogous to the procedure of Example 593 using the appropriate amines (as the free base or as the corresponding HCl salt).

    TABLE-US-00034 TABLE 34 Example Amine Product MS (ESI) 594 [01288]embedded image [01289]embedded image m/z 575.3 [M + H].sup.+ 595 [01290]embedded image [01291]embedded image m/z 556.3 [M + H].sup.+ 596 [01292]embedded image [01293]embedded image m/z 559.2 [M + H].sup.+ 597 [01294]embedded image [01295]embedded image m/z 559.2 [M + H].sup.+ 598 [01296]embedded image [01297]embedded image m/z 517.4 [M + H].sup.+ 599 [01298]embedded image [01299]embedded image m/z 531.2 [M + H].sup.+ 600 [01300]embedded image [01301]embedded image m/z 529.3 [M + H].sup.+ 601 [01302]embedded image [01303]embedded image m/z 559.2 [M + H].sup.+ 602 [01304]embedded image [01305]embedded image m/z 519.5 [M + H].sup.+ 603 [01306]embedded image [01307]embedded image m/z 573.5 [M + H].sup.+ 604 [01308]embedded image [01309]embedded image HRMS m/z [M + H].sup.+ 678.2504 m/z 605 [01310]embedded image [01311]embedded image HRMS m/z [M + H].sup.+ 664.2340 m/z 606 [01312]embedded image [01313]embedded image m/z 664.1 [M + H].sup.+ 607 [01314]embedded image [01315]embedded image m/z 678.2 [M + H].sup.+ 608 [01316]embedded image [01317]embedded image HRMS m/z [M + H].sup.+ 547.2612 m/z 609 [01318]embedded image [01319]embedded image m/z 549.3 [M + H].sup.+ 610 [01320]embedded image [01321]embedded image m/z 549.3 [M + H].sup.+ 611 [01322]embedded image [01323]embedded image m/z 535.5 [M + H].sup.+ 612 [01324]embedded image [01325]embedded image m/z 549.3 [M + H].sup.+ 613 [01326]embedded image [01327]embedded image m/z 599.3 [M + H].sup.+ 614 [01328]embedded image [01329]embedded image m/z 585.5 [M + H].sup.+ 615 [01330]embedded image [01331]embedded image m/z 558.3 [M + H].sup.+ 616 [01332]embedded image [01333]embedded image m/z 558.3 [M + H].sup.+ 617 [01334]embedded image [01335]embedded image HRMS m/z [M + H].sup.+ 559.3160 m/z 618 [01336]embedded image [01337]embedded image m/z 595.2 [M + H].sup.+ 619 [01338]embedded image [01339]embedded image m/z 553.3 [M + H].sup.+ 620 [01340]embedded image [01341]embedded image m/z 567.3 [M + H].sup.+

    Example 621: (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3479] ##STR01342##

    [3480] The titled compound was prepared analogously to Example 71, using 2,2-dimethylpropan-1-amine instead of cyclopropylmethanamine. HRMS (ESI) m/z [M+H].sup.+ calcd for C30H42N3O6: 540.3068 found: 540.3076.

    Form A of (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3481] Naphthalen-1-ylmethyl (1S,4s)-4-(2-cyano-4-methoxy-5-(((1R,2R,3S,4S)-3-(neopentylcarbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate (0.95 g, 1.40 mmol) (which may be prepared analogously to Intermediate 585 using 2,2-dimethylpropan-1-amine instead of 1-methylcyclobutyl)methylamine hydrochloride) and Pd (C) (200 mg, 0.19 mmol) in MeOH (40 mL) was stirred at 20° C. under H.sub.2 (g) 1.2 atm for 5 h. The mixture was filtered through a Celite® pad and the solvents were removed under reduced pressure. The crude material was purified by C18-flash chromatography, elution gradient 0 to 55% MeCN in H.sub.2O. Pure fractions were evaporated to dryness to afford Form A of the title compound (0.580 g, 77%) as a white solid.

    Form B of (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

    [3482] (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (5.1 mg) was dissolved in 50 μL of IPA at room temperature. This solution was stirred for 2 days, and then evaporated under an open condition for 6 days to give Form B seed crystals.

    [3483] Further (1S,4s)-4-(2-cyano-4-methoxy-5-(((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid (32.5 g, 60.18 mmol) was dissolved in hot EtOH (50 mL), then the mixture was cooled to room temperature. Heptane (125 mL) and above seed crystals were added, then the mixture was stirred at rt for 1 hr. The precipitate was collected by filtration and dried under reduced pressure at 50° C. for 1 day to give the title compound (20.09 g, 62%) as Form B crystals.

    [3484] The examples included in Table 35 below were synthesized analogous to the procedure of Example 71 using the appropriate amines (as the free base or as the corresponding HCl salt). The amine is commercially available if not otherwise stated.

    TABLE-US-00035 TABLE 35 Example Amine Product MS (ESI) 622 [01343]embedded image [01344]embedded image HRMS m/z [M + H].sup.+ 554.2670 623 [01345]embedded image [01346]embedded image m/z 560.3 [M + H].sup.+ 624 [01347]embedded image [01348]embedded image HRMS m/z [M + H].sup.+ 559.3160

    [3485] Biological and Physicochemical Data

    [3486] RXFP1 Hu cAMP (Test A)

    [3487] To screen for modulators of hRXFP1, an assay identifying compounds that stimulate cAMP production via the Gs-coupled hRXFP1 receptor was used. cAMP HiRange HTRF kit (available from CisBio Bioassays, France; catalogue number 62AM6PEJ) was employed in large according to manufacturer's recommendations for detection of cAMP. The HTRF method is a competitive immunoassay between native cAMP produced by cells and cAMP labeled with the dye d2. The tracer binding is visualized with a cryptate labeled antibody for cAMP and the signal is thus inversely proportional to the amount of produced cAMP.

    [3488] Preparation of Assay Reagents:

    [3489] Assay buffer: HBSS (ThermoFisher, 14065) with 5 mM Hepes (ThermoFisher, 15630) pH 7.4 containing 0.1% BSA (Sigma, A8806)

    [3490] Cells: Jump-In™ T-REx™ CHO-Kl Cells (ThermoFisher) stably transfected with human RXFP1 was employed. Cells were induced to express human RXFP1 by treatment with 10 ng/ml doxycycline for 24 h. Cells were then cryopreserved for long term storage. At the start of each experiment, cells were thawn, washed with PBS and resuspended in assay buffer to 1.875*10{circumflex over ( )}5 cells/ml

    [3491] cAMP standard: stock standard cAMP provided in the CisBio kit was diluted in assay buffer to a top final concentration of 2.8 μM in the assay.

    [3492] HTRF detection reagents: cAMP-d2 and anti-cAMP cryptate reconstituted according to CisBio instructions were diluted 1:40 in lysis buffer provided with the HTRF-kit.

    [3493] Step by Step Procedure for Running the Assay:

    [3494] 1. 40 nL test compounds dissolved in DMSO were aquostically dispensed (Labcyte Echo) to white 384-well plates (Greiner; 784075), sealed and stored at room temperature until assayed.

    [3495] 2. 40 nL 200 nM Relaxin-2 in DMSO (1 nM final concentration) was added to 100% control wells and 40 nL DMSO added to 0% wells with Echo acoustic dispenser at the day of assay.

    [3496] 3. 4 μL assay buffer with 1 mM IBMX (0.5 mM final concentration) to block phosphodiesterases was added with Multidrop Combi (ThermoFisher).

    [3497] 4. 4 μL cell solution at 1.875*10{circumflex over ( )}5 cells/ml was added with Multidrop Combi to give 750 cells/well.

    [3498] 5. 45 min incubation at room temperature.

    [3499] 6. 4 μL cAMP-d2 in lysis buffer was added with Multidrop Combi.

    [3500] 7. 4 μL anti-cAMP cryptate in lysis buffer was added with Multidrop Combi

    [3501] 8. 2 h incubation at room temperature

    [3502] 9. Homogenous Time-Resolved Fluorescence (HTRF) signal was detected with an Envision (PerkinElmer) or Pherastar (BMG Labtech) reader (λex=340 nm, λem=665 and 615 nm).

    [3503] Using a cAMP standard curve, HTRF data was converted to amount cAMP produced in the samples which was subsequentially used for calculation of concentration responses. Concentration response data were fitted with a four parameter logistic fit, the Hill equation. The results from the assay are reported in Table 36 as EC.sub.50 (μM) and S.sub.inf (%).

    [3504] EC.sub.50 is defined as the concentration at which the stimulatory activity reaches 50% of its maximum level. Where the assay was run multiple times for the same compound, the geometric mean is reported.

    [3505] S.sub.inf is the fitted activity level, efficacy, at infinite concentration of test compound. To facilitate comparison of efficacy data, efficacy was normalized to % effect of the response stimulated by a saturating concentration of relaxin (1 nM). Where the assay was run multiple times for the same compound, the arithmetic mean is reported.

    [3506] Human Plasma Protein Binding (Test B)

    [3507] The assay was conducted according to the Human Plasma Protein Binding Assay described in pages 167-170 of Wernevik, J. et al., “A Fully Integrated Assay Panel for Early Drug Metabolism and Pharmacokinetics Profiling”, Assay and Drug Development Technologies, 2020, 18(4), 157-179. Data are reported in Table 36 as fraction unbound (f.sub.u) (% free). Where the assay was run multiple times for the same compound, the arithmetic mean is reported.

    [3508] Human Liver Microsomal Stability (Test C)

    [3509] The assay was conducted according to the Human Liver Microsome Stability Assay described in pages 170-174 of Wernevik, J. et al., “A Fully Integrated Assay Panel for Early Drug Metabolism and Pharmacokinetics Profiling”, Assay and Drug Development Technologies, 2020, 18(4), 157-179. Data are reported in Table 36 as CL.sub.int(μl/min/mg protein). Where the assay was run multiple times for the same compound, the arithmetic mean is reported.

    [3510] Human Hepatocyte Stability (Test D)

    [3511] The metabolic stability of compounds in human hepatocytes was assessed using the following protocol:

    [3512] 1. Prepare 10 mM stock solutions of compound and control compounds in appropriate solvent (DMSO). Place incubation medium (L-15 Medium) in a 37° C. water bath, and allow warming for at least 15 minutes prior to use.

    [3513] 2. Add 80 μL of acetonitrile to each well of the 96-well deep well plate (“Quenching plate”).

    [3514] 3. In a new 96-well plate, dilute the 10 mM test compounds and the control compounds to 100 μM by combining 198 μL of acetonitrile and 2 μL of 10 mM stock solution.

    [3515] 4. Remove a vial of cryopreserved (less than −150° C.) human hepatocytes (LiverPool™ 10-Donor Human hepatocytes obtained from Bioreclamation IVT (Product No. S01205)) from storage, ensuring that vials remain at cryogenic temperatures until thawing process ensues. As quickly as possible, thaw the cells by placing the vial in a 37° C. water bath and gently shaking the vials. Vials should remain in water bath until all ice crystals have dissolved and are no longer visible. After thawing is complete, spray vial with 70% ethanol, transfer the vial to a bio-safety cabinet.

    [3516] 5. Open the vial and pour the contents into the 50 mL conical tube containing thawing medium. Place the 50 mL conical tube into a centrifuge and spin at 100 g for 10 minutes (room temperature). Upon completion of spin, aspirate thawing medium and resuspend hepatocytes in enough incubation medium to yield ˜1.5×10.sup.6 cells/mL.

    [3517] 6. Using Cellometer® Vision, count cells and determine the viable cell density. Cells with poor viability (<80% viability) are not acceptable for use. Dilute cells with incubation medium to a working cell density of 1.0×10.sup.6 viable cells/mL.

    [3518] 7. Transfer 247.5 μL of hepatocytes into each well of a 96-well cell incubation plate.

    [3519] Place the plate on Eppendorf Thermomixer Comfort plate shaker to allow the hepatocytes to warm for 10 minutes.

    [3520] 8. Add 2.5 μL of 100 μM test compound or control compounds into an incubation well containing cells to initiate the reaction.

    [3521] 9. Incubate the plate at 37° C. and 900 rpm on an Eppendorf Thermomixer Comfort plate shaker. At 0.5, 5, 15, 30, 45, 60, 80, 100 and 120 min, transfer 20 μL of the incubated mixture to a separate “Quenching plate”, then mix the sample by vortex for 2 min.

    [3522] 10. Centrifuge the quenching plates for 20 minutes at 4,000 rpm. Transfer 30 μL of supernatant of each compound into a 96-well analysis plate. 4 compounds are pooled together into one cassette. Then dilute the pooled sample by adding of 180 μl of pure water. All incubations are performed in singlicate.

    [3523] All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. In vitro intrinsic clearance (in vitro Cl.sub.int, in μL/min/10.sup.6 cells) of parent compound was determined by regression analysis of the Ln percent parent disappearance vs. time curve. The in vitro intrinsic clearance (in vitro Cl.sub.int, in μL/min/10.sup.6 cells) is reported in Table 36, and was determined from the slope value using the following equation:


    in vitro Cl.sub.int=kV/N

    [3524] V=incubation volume (0.25 mL);

    [3525] N=number of hepatocytes per well (0.25×10.sup.6 cells)

    [3526] Where the assay was run multiple times for the same compound, the geometric mean is reported.

    [3527] Rat Hepatocyte Stability (Test E)

    [3528] The assay was conducted according to the Rat Hepatocyte Stability Assay described in pages 170-174 of Wernevik, J. et al., “A Fully Integrated Assay Panel for Early Drug Metabolism and Pharmacokinetics Profiling”, Assay and Drug Development Technologies, 2020, 18(4), 157-179. Data are reported in Table 36 as mean Cl.sub.int(μl/min/10.sup.6 cells). Where the assay was run multiple times for the same compound, the geometric mean is reported.

    [3529] Solubility (Test F)

    [3530] The assay was conducted according to the Solubility Assay described in pages 164-167 of Wernevik, J. et al., “A Fully Integrated Assay Panel for Early Drug Metabolism and Pharmacokinetics Profiling”, Assay and Drug Development Technologies, 2020, 18(4), 157-179. Data are reported in Table 36 as solubility (SM). Where the assay was run multiple times for the same compound, the arithmetic mean is reported.

    TABLE-US-00036 TABLE 36 Assay data Test D Test E Test B Test C Human Rat Human Human Liver Hepatocyte Hepatocyte Plasma Microsomal Stability Stability Test A Protein Stability Cl.sub.int Cl.sub.int Test F EC.sub.50 S.sub.inf Binding Cl.sub.int (μL/min/10.sup.6 (μL/min/10.sup.6 Solubility Example (μM) (%) (% free) (μl/min/mg) cells) cells) (μM) 1 0.017 109 4.3 23 4.8 11 >500 2 0.23 101 1.9 14 2 27 >1000 3 >50 3.7 17 8.5 11 860 4 0.0047 103 36 6.9 >1000 5 >1.7 85 2.4 16 15 11 800 6 0.72 89 4.2 35 21 820 7 1.3 86 4.4 23 23 820 8 >50 23 1.7 38 980 9 >7.3 100 11 9.2 67 27 10 0.50 104 2.2 32 11 130 750 11 2.3 104 3.3 36 >300 >1000 12 0.41 107 2.7 23 64 850 13 6.3 115 3.1 24 10 520 14 0.51 83 1.8 18 27 770 15 0.42 94 1.3 14 13 390 16 0.33 93 2.2 9.3 49 330 17 0.048 110 <0.21 20 11 150 18 3.2 105 1.2 27 49 400 19 0.47 97 2.3 17 93 630 20 0.048 102 0.74 28 63 980 21 0.023 110 0.55 39 28 850 22 0.29 130 0.23 23 14 51 23 0.020 109 0.24 26 19 8.7 24 1 97 1.8 29 45 590 25 0.42 102 0.59 31 130 440 26 0.19 105 31 38 250 27 0.13 88 0.40 29 >300 990 28 0.044 96 0.94 32 51 690 29 0.11 111 0.72 22 22 130 30 >40 3.6 <3 18 >1000 31 0.75 81 3.7 18 13 940 32 >40 100 13 10 26 >1000 33 >5 88 15 <3 110 >1000 34 0.23 103 4.8 5.7 <1 19 880 35 0.039 101 8.2 14 2.7 23 >730 36 0.031 107 6.9 33 5.8 7.2 22 37 0.020 103 3.8 27 4.8 22 830 38 0.028 106 5.6 13 4.2 9 38 39 0.74 96 4.8 24 8.2 59 980 40 0.81 97 3.4 190 30 52 2.5 41 >5.5 114 8 8.9 21 820 42 4.3 95 5.4 <3 19 >1000 43 0.083 106 1.3 33 5 25 770 44 0.016 107 2.1 110 17 35 300 45 1.3 94 6.9 15 12 960 46 0.071 104 7.6 12 12 380 47 0.20 111 21 <3 <1 17 >1000 48 0.38 96 13 <3 18 1000 49 >50 3.2 <3 <1 24 50 >50 1.9 <3 <1 60 51 0.058 112 0.50 8.5 55 170 52 0.15 108 0.94 13 34 890 53 0.16 122 130 150 39 54 0.49 108 1.1 16 13 2.8 55 >8.4 100 <3 16 >1000 56 12 105 21 <3 17 980 57 0.66 99 4.9 11 >1000 58 0.26 99 7 6.5 1.9 19 >1000 59 0.55 100 2.4 22 27 960 60 1.1 105 7 11 >1000 61 15 96 7.4 13 >1000 62 >4.2 93 94 55 >1000 63 >50 11 19 610 64 0.15 107 74 67 870 65 0.16 99 5.5 3.1 9.7 >1000 66 3.1 101 <3 12 >1000 67 0.27 105 <3 2.6 18 >1000 68 0.84 97 14 4.4 14 >1000 69 >2.7 93 33 6.3 6.4 970 70 0.40 99 <3 9 >1000 71 0.39 97 17 <3 28 940 72 >3.1 75 40 <3 14 950 73 0.22 114 12 11 18 850 74 >5 26 <3 10 920 75 1.1 110 25 <3 14 880 76 41 100 47 <3 12 790 77 0.23 108 21 4 3.7 12 650 78 0.030 120 6.9 44 37 820 79 >5 28 7.5 31 980 80 0.41 105 16 8 23 890 81 0.031 111 2.7 97 57 250 82 0.032 114 2.5 54 41 330 83 0.017 111 1.6 130 25 250 84 0.015 112 4 160 19 340 85 >9.4 50 <3 15 920 86 0.020 115 4.1 64 26 540 87 0.11 109 6.7 20 24 690 88 0.033 124 4.4 40 26 610 89 >5 50 <3 17 780 90 0.14 111 14 <3 <1 18 800 91 0.27 114 5.9 20 59 830 92 0.14 122 12 8.4 32 920 93 0.37 103 24 <3 16 920 94 >0.71 111 14 9 32 830 95 0.48 123 18 4.4 21 880 96 0.44 97 26 <3 24 890 97 0.24 113 20 5 <1 13 770 98 0.055 133 13 8.7 4.9 22 810 99 0.14 113 20 6.2 <1 11 920 100 >4.6 100 30 <3 9.6 920 101 >3.5 100 20 <3 28 990 102 0.16 122 12 4.4 1.9 14 820 103 >5 10 11 38 860 104 0.27 122 6.4 59 28 920 105 0.0048 125 2.5 >300 48 220 106 0.0097 112 1.7 >300 29 170 107 8.3 112 26 7.9 34 1000 108 0.34 106 109 0.25 103 17 11 26 810 110 0.74 102 44 <3 19 950 111 0.68 100 31 <3 18 860 112 0.47 95 16 6.8 17 830 113 >9.4 28 11 30 950 114 >9.4 17 17 94 810 116 0.86 106 117 0.11 100 118 0.043 99 119 0.56 99 120 0.045 95 121 0.13 98 122 1.3 71 123 0.72 107 124 0.16 101 125 0.016 116 126 0.047 98 127 0.99 71 128 0.046 88 129 0.24 107 130 0.078 95 131 0.084 99 132 0.28 113 133 0.45 100 134 0.044 104 135 1.1 76 136 0.029 102 137 >2.3 93 138 1.2 100 115 0.22 94 139 0.16 95 140 0.084 95 141 0.074 107 16 8.3 <1 17 920 142 0.32 129 1.2 <3 3.3 9.8 6.5 143 0.15 130 0.68 <3 6.9 24 1.6 144 0.093 106 3 240 17 29 29 145 1.3 95 0.81 180 14 53 870 146 >1.9 87 24 <3 <1 14 1000 147 >4.2 111 36 88 6.1 67 1000 148 >5 0.59 7.4 18 890 149 0.59 94 11 7.6 11 840 150 0.46 95 1.8 <3 4.9 39 16 151 >2.9 87 1.7 90 56 570 152 >9.4 4.3 18 17 38 153 0.13 146 <0.34 5.6 37 0.80 154 >2.1 95 <0.30 11 70 160 155 0.0084 126 0.49 5.4 11 30 37 156 1.9 97 3.2 4.3 22 770 157 0.088 118 158 0.11 118 159 0.078 125 160 0.16 125 161 0.13 170 162 0.069 107 163 0.067 151 164 0.13 142 165 0.012 111 166 0.58 137 167 0.12 147 168 >2.2 121 169 0.27 111 170 0.19 136 171 0.44 119 172 0.98 125 173 0.19 126 174 0.11 132 175 >5.9 100 14 5.8 110 >1000 176 >4.3 75 9.3 8 120 210 177 >2.2 100 15 3.5 130 >1000 178 >2.7 95 17 8.6 39 >1000 179 0.016 106 1 42 13 32 >800 180 0.95 100 14 6.8 2.2 130 >1000 181 0.60 95 2.3 13 4.1 48 680 182 0.019 107 0.45 34 35 200 183 0.42 99 0.50 23 13 50 184 >40 8.6 7.4 70 >1000 185 0.20 108 0.37 48 83 270 186 0.018 110 0.24 27 20 80 187 0.25 105 0.41 15 21 580 188 0.27 103 0.64 36 38 290 189 0.13 101 1.5 34 23 83 190 0.68 110 1.6 23 120 420 191 >3.6 86 1.1 20 15 >1000 192 0.035 109 0.67 21 43 120 193 0.062 105 0.93 29 61 >1000 194 0.47 99 0.53 31 24 530 195 0.83 131 1.6 28 130 860 196 0.22 103 1.7 40 79 290 197 1.4 106 45 12 28 1000 198 1.2 99 12 6.6 77 920 199 21 100 26 2.6 20 1000 200 0.59 100 32 3.7 15 55 201 7.2 98 1.6 23 7.6 190 940 202 2.2 102 14 5.6 57 890 203 2.9 118 19 5 34 1000 204 0.18 106 0.29 78 18 61 205 0.58 99 0.58 49 26 180 206 >0.15 99 42 49 14 35 207 0.0043 105 3.5 34 26 10 560 208 <0.0020 108 1 54 15 35 130 209 0.088 101 0.10 21 23 54 210 >3.6 50 0.049 <3 10 67 211 >9.3 100 1.4 5.2 12 29 212 0.31 134 <2.7 6.5 17 4 213 0.18 98 0.18 16 4 8 6.5 214 0.29 115 0.090 <3 2.3 5.3 400 215 0.20 143 0.20 <3 20 <0.23 216 0.21 132 0.64 <3 4.2 19 3.1 217 >9.4 0.19 43 17 <7.3 218 >40 219 0.28 113 0.19 >300 78 130 5 220 1.5 109 0.95 10 7.2 14 940 221 >40 222 >40 223 >40 224 0.19 92 0.16 6.3 19 870 225 0.24 98 0.10 6.6 22 10 226 0.30 105 0.62 12 11 16 870 227 0.42 102 228 1.1 110 229 3.3 55 230 1 116 231 0.48 112 <0.31 <3 7.7 13 17 232 1.1 108 233 1.7 105 234 0.088 110 <0.30 4.7 6.5 9.3 690 235 5 75 236 0.21 103 0.50 13 14 >1000 237 0.38 101 4.6 32 17 >1000 238 0.14 102 42 13 27 890 239 0.13 100 240 0.13 97 2.3 19 12 780 241 0.14 99 0.69 12 12 550 242 0.20 109 110 26 30 900 243 0.099 96 2.2 58 26 110 900 244 0.10 111 53 36 240 245 0.64 104 5 45 13 15 980 246 0.29 85 20 16 860 247 0.050 104 14 9.5 12 190 248 0.22 108 <3.3 74 18 32 2 249 0.32 113 3.4 43 11 15 190 250 0.19 101 <0.32 16 32 18 900 251 0.033 101 252 0.78 86 253 0.031 102 <0.32 24 8.8 >1000 254 0.034 114 0.30 31 12 >1000 255 0.55 101 2 26 13 12 1000 256 0.25 99 0.050 8.1 12 <7 257 0.059 96 0.35 16 9.5 >1000 258 0.12 106 1.7 65 30 35 >1000 259 0.058 97 260 0.28 108 0.57 69 69 360 261 0.13 107 0.89 57 84 >1000 262 0.026 95 263 0.084 106 264 0.082 101 265 0.23 78 266 0.11 103 <0.34 68 9.4 8.8 267 >0.35 93 0.39 32 14 680 268 0.86 84 269 2.9 44 270 0.12 107 <0.26 120 32 38 2 271 0.23 98 0.81 <3 3.7 7 920 272 4.9 107 273 >40 274 5.7 61 275 11 83 276 3.3 95 277 7.4 122 278 5 104 279 >40 280 >40 281 0.87 170 0.31 5.5 5 9.1 11 282 0.49 105 <0.25 6.2 12 48 283 0.22 87 <0.29 12 15 220 284 0.82 85 285 0.30 75 286 13 29 287 0.57 111 288 0.23 107 <0.32 5.1 5 21 24 289 0.47 112 1 21 7.2 11 36 290 0.20 105 291 0.37 106 <1.2 18 22 13 292 0.077 110 1.2 24 4.6 14 18 293 0.39 118 27 8.4 41 21 294 0.37 95 295 0.50 100 296 0.22 98 <0.32 15 22 17 640 297 0.12 98 <0.33 9.1 9.4 12 8 298 0.91 82 299 2.9 81 300 3.9 78 301 7.3 69 302 5.3 75 303 0.26 114 304 3.1 95 305 >40 306 3.1 73 307 0.18 90 308 1.1 109 0.16 4.9 14 33 >1000 309 4 80 310 >40 311 7.7 67 312 7.5 50 313 >40 314 7.8 74 316 0.32 107 317 1.2 75 318 0.60 89 0.55 13 37 710 319 0.75 79 0.44 18 29 380 320 0.46 119 0.67 14 11 9.6 >1000 321 0.34 101 0.45 33 59 950 322 0.80 107 323 0.42 108 9.3 58 16 21 850 324 0.19 101 325 0.12 109 <0.30 18 5 880 326 0.11 114 <0.35 65 8 4.6 8 327 >40 328 0.19 117 <0.10 <3 11 329 0.14 108 0.81 30 5.6 26 1000 330 0.53 97 331 0.26 90 332 0.29 103 333 0.15 98 334 0.0043 96 335 0.54 104 338 4.1 104 340 1.8 100 341 0.20 86 342 0.55 132 344 0.034 93 345 >40 346 2.2 96 347 0.0064 115 348 0.56 101 349 1.8 113 350 3.9 97 351 0.018 109 64 15 46 590 352 0.0030 105 0.26 13 38 340 353 0.00041 114 <0.23 61 21 23 45 354 0.011 95 355 0.037 114 2.1 32 8 19 430 356 2.2 119 357 5.4 101 358 5.1 99 359 0.17 91 360 0.10 101 15 8.4 3.6 17 >1000 361 0.78 91 364 0.014 106 11 <5.1 6.2 19 >1000 365 0.057 113 7.8 14 9.3 15 980 366 0.0022 103 367 0.0032 110 369 0.011 95 370 0.024 102 371 0.0011 125 372 0.021 96 373 0.025 105 3.9 23 5.1 16 1000 374 0.044 102 2.9 44 5.3 21 680 375 0.10 115 4.4 38 3.1 32 240 376 0.088 103 2.5 44 3.9 28 300 377 13 100 378 >2.5 379 0.48 100 380 >2.5 381 0.11 114 3.8 36 6.1 21 1000 382 0.13 90 383 0.12 89 384 0.13 108 385 0.030 106 4.1 50 8 19 780 386 0.070 114 387 0.012 99 388 0.0036 103 3.4 34 49 55 680 389 0.0095 106 6 5.8 8 11 910 390 0.18 95 391 0.11 99 392 0.0086 104 2.7 36 4.7 15 470 393 0.053 96 1.4 37 6.7 12 53 394 >40 395 0.031 101 396 0.64 91 5 47 16 16 21 397 >40 398 0.13 90 399 0.053 92 400 0.18 91 401 0.049 115 2.7 16 5.4 17 1000 402 0.62 131 403 0.067 104 1.5 81 13 25 660 404 0.086 109 2.3 50 11 19 1000 405 0.20 92 406 0.33 96 407 0.26 99 408 0.024 106 0.87 32 6.5 20 670 409 0.015 107 3.4 18 3.1 7.1 960 410 0.0062 105 0.48 20 49 21 280 411 0.024 108 1.8 7.9 2.1 17 710 412 0.037 110 5.3 13 2.6 24 930 413 0.016 107 1.5 9.3 4.5 21 820 414 0.021 100 415 1.7 103 416 0.32 103 1.2 9.9 10 >1000 417 0.0098 102 4.8 24 5.1 17 900 418 0.064 100 419 0.16 107 420 0.033 107 421 0.044 96 422 0.086 102 423 2.1 89 424 0.078 100 6.7 13 10 21 990 425 17 78 426 >40 427 0.68 86 428 5.1 80 429 >40 430 >0.23 101 3 61 22 760 431 0.13 115 432 0.016 121 433 0.0053 109 0.38 43 14 17 240 434 0.59 82 <0.36 110 13 130 435 0.35 103 1.4 63 150 >300 880 436 0.54 115 0.82 70 97 >300 220 437 0.95 104 438 0.26 112 439 0.17 104 440 1.2 111 441 >40 442 0.58 103 443 0.54 101 1.5 31 26 21 760 444 0.12 117 2.5 18 15 22 >1000 445 0.15 101 446 0.90 98 447 0.83 94 448 2.6 77 449 1.6 108 450 0.61 107 451 0.31 127 0.93 15 68 700 452 0.98 104 453 2 155 454 1.9 76 455 0.16 91 456 3.6 129 457 2.9 56 458 0.11 104 459 0.32 91 460 0.37 103 0.32 300 47 2 461 0.19 100 7.5 2.9 7.4 980 462 0.35 125 463 0.34 111 464 0.064 104 0.54 57 30 200 465 0.12 97 0.76 74 36 300 466 0.093 106 2.1 37 29 >1000 467 0.019 99 3.7 37 47 >1000 468 0.0041 93 469 0.036 99 470 0.017 102 471 0.091 95 472 0.28 91 473 0.14 104 474 0.65 118 475 0.20 100 476 0.30 81 477 1.1 84 478 0.0066 99 479 0.0078 104 480 0.098 100 481 0.28 96 482 0.011 112 1.5 56 18 78 >1000 483 0.61 92 484 0.25 101 <0.31 9.4 7.2 13 400 485 0.28 95 486 0.0076 107 6.8 35 22 28 950 487 >40 488 <0.0036 115 0.13 23 12 22 1000 489 0.012 115 490 0.30 127 1.9 30 17 16 940 491 0.042 102 2.1 42 15 23 550 492 0.16 106 1.8 36 18 19 1000 493 0.42 108 1.3 <3 2.4 4 38 494 6.9 90 495 0.12 98 496 >40 497 0.32 108 3.3 <3 4.4 19 >1000 498 >0.030 113 0.86 23 7.7 17 >980 499 0.10 128 0.51 200 28 96 13 500 0.064 110 0.44 >300 45 98 8 501 2.5 82 502 0.0085 106 4 <4.5 5.3 7.2 910 503 0.060 102 504 0.60 91 505 0.014 94 506 0.32 98 507 0.54 118 508 0.013 112 509 0.013 125 <0.070 9.4 5 7 1000 510 1.6 63 511 0.037 117 512 0.023 104 12 4.2 25 880 513 >40 514 15 107 515 >40 516 0.0080 104 517 >40 518 0.13 95 2.1 22 5 13 990 519 >17 101 520 0.00049 108 <0.070 12 5.7 7.5 460 521 0.71 99 522 >40 523 0.27 95 4 >300 49 34 920 524 0.025 110 3.6 16 6.2 23 920 525 >40 526 >40 527 0.080 101 528 >40 529 0.50 96 530 0.17 96 531 >40 532 0.14 104 533 >40 534 0.099 106 7.1 16 43 19 >1000 535 >40 536 0.0051 97 3.3 250 130 43 420 537 6 77 538 11 100 539 0.0031 102 3.2 63 64 28 700 540 0.020 104 6 20 8.5 19 1000 541 18 100 542 0.011 110 2.5 66 32 12 800 543 0.45 88 544 >40 545 0.045 91 546 >40 547 1.7 114 548 21 117 549 1.3 94 550 >40 551 0.70 107 552 0.14 98 0.060 7.2 12 16 >1000 553 >50 <0.30 9.9 9.2 18 >1000 554 0.15 103 <0.30 <3 5.4 18 700 555 >50 <0.30 21 13 18 560 556 0.13 114 557 3.1 68 558 >40 559 1.2 102 2.5 9.4 4.1 8.4 900 560 >40 561 0.13 104 3.7 17 6.3 55 930 562 >40 563 >40 564 >40 565 0.023 113 566 >40 567 10 86 568 >40 569 1.1 97 570 9.2 128 571 0.0025 100 572 >40 573 0.28 94 574 >40 575 0.29 101 576 4.2 118 577 >40 578 >40 579 13 120 580 >40 581 3.2 94 582 0.029 104 583 0.35 84 584 0.00070 106 585 0.24 93 586 0.0015 105 0.33 12 4.3 17 190 587 2.2 113 588 0.0076 95 589 2.1 83 590 >40 591 0.15 111 <0.36 19 140 28 >1000 592 0.0058 100 6.3 19 5.6 18 >890 593 0.52 118 594 0.53 96 595 0.57 116 596 1.1 105 597 0.40 106 598 0.89 99 599 0.26 91 600 0.14 104 601 2.1 116 602 0.25 100 603 0.094 99 604 0.11 105 6.7 110 13 14 10 605 0.079 106 8.6 25 4.3 12 890 606 0.42 90 607 0.16 92 608 0.075 115 3.5 20 3.4 8.2 880 609 0.40 108 610 0.23 105 611 >40 612 3.1 119 613 0.076 109 614 0.15 96 615 0.12 100 616 2 101 617 0.050 101 2.4 120 12 13 810 618 0.10 93 619 0.39 103 620 0.69 93 621 0.024 114 12 <3 <1.2 15 910 622 0.024 105 17 <5.1 1.7 11 >860 623 0.18 104 624 0.026 113 12 16 3.3 7.9 1000

    [3531] Human RXFP1 cGMP Production Assay (Test G)

    [3532] To profile compounds for RXFP1 agonist activity with respect to cGMP production, the Green GENIe cGMP Assay (Montana Molecular; catalogue number D800G) was employed. The assay is based on an mNeonGreen fusion protein fluorescent biosensor delivered to mammalian cells in a BacMam vector. Fluorescence is reduced when cGMP is bound to the biosensor.

    [3533] Preparation of Assay Reagents:

    [3534] Assay buffer: DPBS (Gibco; 14040133) containing 0.100 BSA (Sigma; A8806)

    [3535] Cells: HEK293s cells stably transfected with human RXFP1 in pIRESneo3 was employed. Cells were cultured in DMEM medium (Gibco; 31966) with 10% FBS complemented with 0.8 mg/mL to maintain RXFP1 expression.

    [3536] Step by Step Protocol for Running the Assay:

    [3537] Day 1 [3538] 1. Cells were splitted one day ahead of transduction and seeded to 63 000 cells/cm2 in DMEM medium with 10% FBS without antibiotics in a tissue culture flask.

    [3539] Day 2 [3540] 2. After PBS wash cells were detached using accutase (Gibco; 1737341), resuspended in medium and collected in a 50 mL tube. [3541] 3. Cells were counted with a CEDEX (Innovatis) and diluted with medium to 267 000 cell/mL. [3542] 4. A viral transduction mastermix was prepared by mixing reagents in the following proportions for a single well: [3543] 6μGENIe BacMAM vector [3544] 0.2 μL 500 mM sodium butvrate [3545] 13.8 μL DMEM medium with 10% FBS [3546] 20 μL total volume [3547] 5. Cells and transduction mastermix were mixed in proportions 30 μL cells and 20 μL mastermix for a single well. [3548] 6. 50 μL cell-transduction mix from above was dispensed per well into Black poly-D-lysine coated μclear 384-well plates (Greiner; 781946). [3549] 7. Plate was incubated in the dark at 37° C., 5% CO2 for 24 h.

    [3550] Day 3 [3551] 8. Medium was removed from plates using a Bluewasher (BluCatBio). [3552] 9. 20 μL assay buffer was added with a Multidrop Combi (ThermoFisher). [3553] 10. Plate was incubated in the dark at room temperature for 30 min prior to assaying. [3554] 11. Plates were assayed using a FLIPR Tetra (Molecular Devices): 10 μL compound diluted with assay buffer was added to each well by the FLIPR Tetra and measuring green fluorescence over time for up to 3 h.

    [3555] Data was processed using Screener software (Genedata AG). After subtraction of background fluorescence (before addition of compounds), area under curve values from 0 to 90 min after compound addition was used for calculation of responses. Concentration response data were fitted with a four parameter logistic fit and EC.sub.50 values (nM) are reported in Table 37.

    [3556] Human RXFP1 Phospho-ERK Assay (Test H)

    [3557] To profile compounds for RXFP1 agonist activity with respect to ERK phosphorylation, the advanced phospho-ERK (Thr202/Tyr204) cellular kit (CisBio; 64AERPEH) was employed. The assay uses two antibodies. One labeled with a donor fluorophore (Eu cryptate), a second with an acceptor (d2). The first antibody specific binds to phosphorylated ERK, the second binds another motif of ERK and independently of its phosphorylation state. ERK phosphorylation enables immune-complex formation involving the two antibodies, thereby generating a FRET signal. Its intensity is proportional to the concentration of phosphorylated ERK in the sample. Assay was performed according to manufacturers recommendations.

    [3558] Preparation of Assay Reagents:

    [3559] Cells: HEK293s cells stably transfected with human RXFP1 in pIRESneo3 was employed. Cells were cultured in DMEM medium (Gibco; 31966) with 10% FBS complemented with 0.8 mg/mL to maintain RXFP1 expression. Assay was performed on cells kept in continuous culture.

    [3560] Dilution of test compounds: Compounds were diluted to desired concentrations with serum-free DMEM without phenol red (Gibco; 31053-038). DMSO concentration was adjusted to 0.4%.

    [3561] Antibody mix: The Eu and d2 labelled anti ERK1/2 antibodies were separately diluted 20-fold with detection buffer provided in the kit. Shortly prior to the experiment, equal volumes of each diluted antibody solution were combined to an antibody mix.

    [3562] Step by Step Protocol for Running the Assay:

    [3563] Day 1 [3564] 1. Cells were detached from culture flasks using accutase (Gibco; 1737341), resuspended in DMEM medium without phenol red containing 10% FBS and collected in a 50 mL tube. [3565] 2. Cells were counted with a CEDEX (Innovatis) and diluted with the medium above to 320 000 cell/mL. [3566] 3. 100 μL cell suspension was dispensed per well into Black μclear poly-D-lysine coated μclear 96-well plates (Greiner; 655946). [3567] 4. Plates were incubated at 37° C., 5% CO2 for 24 h.

    [3568] Day 2 [3569] 5. Serum starvation: Medium was removed and replaced with 50 μL serum-free DMEM without phenol red. Plates were incubated at 37° C., 5% CO2 for 5 h. [3570] 6. 50 μL test compound solutions were added per well. [3571] 7. Plates were incubated at room temperature for 5 min. [3572] 8. Stimulation was stopped by rapidly removing medium and adding 50 μL lysis buffer (diluted to 1×final concentration prior to addition) per well. [3573] 9. Plates were transferred to −80° C. and lysates frozen.

    [3574] Day 3 [3575] 10. Plates were thawed and shaken at room temperature for 30 min. [3576] 11. Cells lysates were homogenized by pipetting. [3577] 12. 16 μL homogenate per well was transferred to white low volume 384-well plates (Greiner; 784075) [3578] 13. 4 μL antibody mix was added per well. [3579] 14. Plates were incubated at room temperature in the dark for 4 h. [3580] 15. Homogenous Time-Resolved Fluorescence (HTRF) signal was detected with a Pherastar (BMG Labtech) reader (λex=340 nm, λem=665 and 615 nm).

    [3581] HTRF ratio data was processed using Screener software (Genedata AG). Concentration response data were fitted with a four parameter logistic fit and EC.sub.50 value (nM) reported in Table 37.

    TABLE-US-00037 TABLE 37 Assay Data Test G Test H cGMP assay phospo-ERK assay Compound EC.sub.50 (nM) EC.sub.50 (nM) Example 1 50 6.3 Example 3 2200 1092 Example 208 9.3 1.2 Example 353 3.7 0.36 Example 433 19 Example 552 300 81 Example 592 29 2.5 Example 621 72 6.8 Example 622 107 5.2 relaxin2 0.085 0.038

    [3582] Those skilled in the art will appreciate that the biological assays described above may be performed using alternative equipment and minor variations to the protocol without significantly affecting the results.

    [3583] The above description of illustrative embodiments is intended only to acquaint others skilled in the art with Applicant's invention, its principles, and its practical application so that others skilled in the art may readily adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples, while indicating embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the illustrative embodiments described in this specification, and may be variously modified. In addition, it is to be appreciated that various features of the invention that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

    [3584] Any publications disclosed within the specification are hereby incorporated by reference.