S1P and/or ATX modulating agents

Abstract

Compounds of formula (I), and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX).

Claims

1. A compound represented by formula (I): ##STR00178## or a pharmaceutically acceptable salt thereof, wherein: X is O; X.sup.1, X.sup.2, and X.sup.5 are each independently CR.sup.4 or N; one of X.sup.3 or X.sup.4 is C and is attached by a single bond to Ring A, and the other X.sup.4 is CR.sup.4 or N, provided that no more than two of X.sup.1, X.sup.2, X.sup.3, X.sup.4 or X.sup.5 are N; L.sup.1 is a direct bond, —C(O)— or C.sub.1-7alkylene; Ring A is phenyl which is optionally substituted with from 1 to 3 R.sup.5; R.sup.1 is a monocyclic C.sub.3-8cycloalkyl which is substituted with from 1 to 6 independently selected R.sup.6; R.sup.2 is a C.sub.1-7alkyl substituted with C(O)OR.sup.11, or a C.sub.3-8cycloalkyl substituted with —C(O)OR.sup.11 or —CH.sub.2C(O)OR.sup.11, R.sup.3 is hydrogen; or R.sup.2 and R.sup.3 together with the nitrogen to which they are attached form a heterocycloalkyl selected from; ##STR00179##  and R.sup.4 and R.sup.5, for each occurrence, are independently selected from hydrogen, halo, hydroxyl, nitro, cyano, C.sub.1-7alkyl, C.sub.1-7haloalkyl, C.sub.1-7alkoxy, C.sub.1-4haloalkoxy, C.sub.2-7alkenyl, C.sub.2-7alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, —NR.sup.cR.sup.d, —C(O)NR.sup.cR.sup.d, —N(R.sup.c)C(O)R.sup.b, —C(O)R.sup.a, —S(O).sub.pR.sup.a, and —N(R.sup.c)S(O).sub.2R.sup.b, wherein p is 0, 1, or 2; R.sup.6, for each occurrence, is independently selected from halo, hydroxyl, mercapto, nitro, C.sub.1-7alkyl, C.sub.1-7haloalkyl, C.sub.1-7alkoxy, C.sub.1-4haloalkoxy, C.sub.1-7alkylthio, C.sub.2-7alkenyl, C.sub.2-7alkynyl, cyano, —NR.sup.aR.sup.b; or two R.sup.6 on the same carbon atom together with the carbon to which they are attached form a C.sub.3-8spirocycloalkyl; R.sup.7 and R.sup.8, for each occurrence, are each independently hydrogen or C.sub.1-4alkyl; R.sup.9, for each occurrence, is independently halo or C.sub.1-4alkyl; R.sup.11 for each occurrence is independently hydrogen or C.sub.1-7alkyl; R.sup.a and R.sup.b for each occurrence are independently selected from hydrogen, C.sub.1-7alkyl, C.sub.2-7alkenyl, C.sub.2-7alkynyl; R.sup.c and R.sup.d for each occurrence are independently selected from hydrogen, C.sub.1-7alkyl, C.sub.2-7alkenyl, C.sub.2-7alkynyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is cyclohexyl which is substituted with from 1 to 3 independently selected R.sup.6.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X.sup.1, X.sup.2, X.sup.4 and X.sup.5 are CR.sup.4; X.sup.3 and X.sup.6 are C; and X.sup.3 is attached to Ring A by a single bond.

4. The compound of claim 1, wherein R.sup.4, for each occurrence, is independently selected from hydrogen, halo and C.sub.1-4haloalkyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from: ##STR00180##

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is a C.sub.1-7alkyl which is substituted with —C(O)OR.sup.11; and R.sup.3 is hydrogen.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is a C.sub.3-8cycloalkyl which is substituted with —C(O)OR.sup.11 or —CH.sub.2C(O)OR.sup.11; and R.sup.3 is hydrogen.

8. A compound, or pharmaceutically acceptable salt thereof, selected from: 1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid; 3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid; 3-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid; 4-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)butanoic acid; (R)-1-((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid; (R)-1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid; 3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid; 4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)butanoic acid; 3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclobutanecarboxylic acid; (1S,4S)-4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexanecarboxylic acid; (1R,4R)-4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexanecarboxylic acid; 2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)azetidin-3-yl)acetic acid; 2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)acetic acid; 2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)acetic acid; 3-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid; 4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid; 1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-ol; (1R,3S)-3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid; (1S,3R)-3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid; ethyl 1-((4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-yl)methyl)piperidine-4-carboxylate; 1-((4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-yl)methyl)piperidine-4-caboxylic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-methylbiphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-2′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)cyclopentanecarboxylic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-fluorobiphenyl-3 -yl)methylamino)cyclopentanecarboxylic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-(trifluoromethyl)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid; 3-((4′-(Spiro[4.5]decan-8-yloxy)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid; 3-((4′-(4,4-Dimethylcyclohexyloxy)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid; 3-((4′-(cis-4-Ethylcyclohexyloxy)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid; 1-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzyl)piperidine-4-carboxylic acid; 3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzylamino)propanoic acid; 3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzylamino)cyclopentanecarboxylic acid; 3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-3-yl)benzylamino)propanoic acid; 3-(3-(6-(trans-4-tert-Butylcyclohexyloxy)pyridazin-3-yl)benzylamino)propanoic acid; 3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyrimidin-2-yl)benzylamino)propanoic acid; 3-(3-(2-(trans-4-tert-Butylcyclohexyloxy)pyrimidin-5-yl)benzylamino)propanoic acid; 3-(3-(6-(trans-4-tert-Butylcyclohexyloxy)p yrimidin-4- yl)benzylamino)prop anoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-6-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-4-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-2,4-difluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-5-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((4′-(trans-4-tert-Butylcyclohexyloxy)-5-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-6-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-4-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-2,4-difluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5-fluorobiphenyl-3-yl)methylamino)propanoic acid; 3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid; 3-(3-(5-(cis-4-(Trifluoromethyl)cyclohexyloxy)pyridin-2-yl)benzylamino)propanoic acid; 3-(3-(5-(cis-4-(Trifluoromethyl)cyclohexyloxy)pyrimidin-2-yl)benzylamino)propanoic acid; (S)-1-(4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenylcarbonyl) pyrrolidine-3-carboxylic acid; 1-(4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenylcarbonyl)piperidine-4-carboxylic acid; 2-(1-(4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenylcarbonyl)azetidin-3-yl)acetic acid; 3-(4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenyl-4-ylcarboxamido)propanoic acid; 1-(4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenylcarbonyl)azetidine-3-carboxylic acid; 4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid; and 3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid.

9. A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

10. A method of treating multiple sclerosis in a patient, comprising administering to said patient an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

11. A method of treating, or reducing chronic pain in a mammal comprising administering to said mammal an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

(1) The compounds of formula (I), or a pharmaceutically acceptable salt thereof, can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mol ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

(2) Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

(3) Furthermore, the compounds of formula (I) may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

(4) The compounds of formula (I) can be prepared by the synthetic protocols illustrated in Scheme 1, where X, X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, R.sup.1, R.sup.2, R.sup.3, L.sup.1 and A are as defined herein, Hal is a halogen, and LG is a leaving group, such as a halogen or trifluoromethanesulfonate.

(5) ##STR00023##

(6) In Scheme 1, compound 1-1 is reacted with at least a stoichiometric amount and in some embodiments an excess of compound 1-2. The reaction is typically conducted under conventional coupling conditions well known in the art. In one embodiment, the reaction is conducted with the use of a coupling agent such as DIAD in the presence of PPh.sub.3 in a suitable solvent, such as toluene. The reaction is continued until substantially complete which typically occurs within about 1 to 12 hours. Upon reaction completion, compound 1-3 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.

(7) A halogenated compound 1-3, in some embodiments a brominated compound, is then coupled with an appropriately substituted boronic acid derivative of formula B (OH).sub.2-A (compound 1-4), or a boronic ester thereof, in an inert solvent, for example aqueous 1,4-dioxane, in the presence of a mild base, for example potassium carbonate or sodium bicarbonate. In some embodiments the reaction is conducted in the presence of a metal catalyst with an appropriate ligand, for example dichlorobis(triphenylphosphine) palladium(II) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), at an elevated temperature (e.g., 90-170° C.), for about 10 minutes to about 5 hours. It will be appreciated that the R.sup.1 substituent can be added before or after the coupling reaction. For example compound 2-1 can be reacted with compound 2-2 (where LG is a leaving group such as a halo, hydroxyl, alkoxy, trifluoromethanesulfonyl, and the like) to provide compound 1-5. Alternatively, a halogenated compound 1-8, in some embodiments a brominated compound, is coupled with compound 1-7, or a boronic ester thereof, to provide compound 1-5. Upon reaction completion, compound 1-5 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.

(8) The —NR.sup.2R.sup.3 moiety may be coupled to compound 1-5 under reductive amination conditions with an appropriate amine HNR.sup.2R.sup.3 (compound 1-6) as shown in Scheme 1 to provide compounds of formula (I). Reductive amination conditions include a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent, such as methylene chloride, at ambient temperature, or in a microwave. Alternatively, compounds of formula (I) are provided via compound 1-7. In such methods, halogenated compound 1-9 is coupled with an appropriately substituted boronic acid compound 1-7, or a boronic ester thereof, under reaction conditions described above. Upon reaction completion, compounds of formula (I) can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. It will also be appreciated that the —NR.sup.2R.sup.3 substitutent can be further modified (e.g., hydrolysed) after the addition of the —NR.sup.2R.sup.3 substitutent.

(9) TABLE-US-00001 List of Abbreviations and Acronyms Abbreviation Meaning ° C. Degree Celsius Ac Acetate ATX Autotaxin bs/br.s. Broad singlet BSA Bovine serum albumin Bu Butyl CNTF Ciliary neurotrophic factor d Doublet DCE Dichloroethane DCM Dichloromethane dd Doublet of doublets ddH.sub.2O Double-distilled water DIAD Diisopropyl azodicarboxylate DIPEA Diisopropylethylamine DMEM Dulbecco's modified Eagle's medium DMSO Dimethylsulfoxide DNase Deoxyribonuclease dppf 1,1′-Bis(diphenylphosphino)ferrocene EA Ethylacetate EC.sub.50 Half maximal effective concentration EC.sub.80 Eighty percent maximal effective concentration EGTA Ethylene glycol tetraacetic acid Emax Mmaximum possible effect eq Equivalents Et Ethyl g Grams h Hours HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetrameth- yluronium hexafluorophosphate HBSS Hank's buffered saline solution HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPCD Hydroxypropyl-β-cyclodextrin HPLC High-performance liquid chromatography Hz Hertz IC.sub.50 The half maximal inhibitory concentration IgG-HPR Horseradish Peroxidase-Conjugated Goat Anti-Mouse Iu International unit J Coupling constant KDa KiloDalton Kg Kilogram L Liter LCMS Liquid chromatography-mass spectrometry LPA Lysophosphatidic acid LPC Lysolecithin LPLD Lysophospholipase D M Molar m multiplet m/z mass-to-charge ratio M + H Mass peak plus hydrogen MAG Myelin associated glycoprotein MBP Myelin basic protein Me Methyl mg Milligram MHz Megahertz min Minute mL Milliliter mM Millimolar mm Millimeter mmol Millimole MOG Myelin oligodendrocyte glycoprotein mol Mole Ms Methanesulfonyl MS Mass spectrometry MSD Meso Scale Discovery-R N Normal nL Nanoliter nM Nanometer NMR Nuclear magnetic resonance OPC Oligodendrocyte precursor cells PBS Phosphate buffered saline PE Petroleum ether PFA Paraformaldehyde Ph Phenyl pmol Picomole prep Preparative q Quartet quin quintet rpm Revolutions per minute rt Room temperature s Singlet s.c. Subcutaneously SDS Sodium dodecyl sulfate PAGE Polyacrylamide gel electrophoresis sec Second t Triplet t-Bu tert-Butyl TFA Trifluoroacetic acid THF Tetrahydrofuran δ Chemical shift μg Microgram μL Microliter μm Micrometer μM Micromolar

Example 1

1-Bromo-4-(trans-4-tert-butylcyclohexyloxy)benzene

(10) ##STR00024##

(11) To a mixture of 4-bromophenol (11.5 g, 66.9 mmol, 1.0 eq), cis-4-tert-butylcyclohexanol (12.5 g, 80.2 mmol, 1.2 eq), PPh.sub.3 (35 g, 133.8 mmol, 2.0 eq) and triethylamine (8.1 g, 80.3 mol, 1.2 eq) in THF (100 mL) was added dropwise DIAD (27.1 g, 133.8 mmol, 2.0 eq) at 0° C. The mixture was allowed to warm up to rt and stirred for 16 hours. The solvent was then removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with petroleum ether to afford the target compound 1-bromo-4-(trans-4-tert-butylcyclohexyloxy)benzene as a white solid (9.0 g, 43% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) δ: 7.35-7.33 (m, 2H), 6.78-6.76 (m, 2H), 4.06-4.04 (m, 1H), 2.18-2.14 (m, 2H), 1.87-1.84 (m, 2H), 1.38-1.35 (m, 2H), 1.13-1.07 (m, 3H), 0.87 (s, 9H).

Example 2

1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid

(12) ##STR00025##

Step 1: 4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-carbaldehyde

(13) ##STR00026##

(14) To a microwave vial loaded with 1-bromo-4-((trans-4-(tert-butyl)cyclohexyl)oxy)benzene (156 mg, 0.500 mmol), 3-formylphenylboronic acid (90.0 mg, 0.600 mmol), and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) was added 1,2-dimethoxyethane (1 mL), followed by ethanol (0.5 mL) and saturated NaHCO.sub.3 solution (0.5 mL). The reaction mixture was heated with microwave irritation at 120° C. for 10 min. It was then portioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography on silica gel column to provide the aldehyde as a colorless oil (101 mg, 60% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.09 (s, 1H), 8.15 (s, 1H), 7.97 (d, J=7.78 Hz, 1H), 7.84 (d, J=7.53 Hz, 1H), 7.60-7.70 (m, 3H), 7.06 (d, J=8.78 Hz, 2H), 4.16-4.42 (m, 1H), 2.16 (d, J=10.29 Hz, 2H), 1.81 (d, J=12.30 Hz, 2H), 0.97-1.44 (m, 5H), 0.87 (s, 9H); LCMS m/z 337.2 [M+H].sup.+.

Step 2: Methyl 1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylate

(15) ##STR00027##

(16) To a mixture of 4′-((trans-4-(tert-butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-carbaldehyde (27 mg, 0.080 mmol) and piperidine-4-carboxylic acid methyl ester (18 mg, 0.12 mmol) in methylene chloride (1 mL) was added sodium triacetoxyborohydride (20 mg, 0.096 mmol). The reaction mixture was stirred at rt for 1 h. Added more sodium triacetoxyborohydride (5 mg) and stirred at rt overnight. The reaction was quenched with saturated aqueous NaHCO.sub.3, and extracted with EtOAc (×2). The combined organic phases were washed with brine, dried over MgSO.sub.4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel column to provide the ester as a colorless oil (24 mg, 65% yield). LCMS m/z 464.3 [M+H]+.

Step 3: 1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid

(17) ##STR00028##

(18) To the above ester in THF (0.5 mL) and MeOH (0.5 mL) was added 3N NaOH solution (0.08 mL). The reaction mixture was stirred at rt overnight, and adjusted pH-6 by adding 1N HCl and saturated NH.sub.4Cl solution. The mixture was extracted with EtOAc. The organic phase was dried over MgSO.sub.4, filtered and concentrated to give the desired acid as a white solid (23 mg, 96% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.66-7.74 (m, 2H), 7.57 (d, J=8.78 Hz, 2H), 7.52 (t, J=7.66 Hz, 1H), 7.39 (d, J=7.53 Hz, 1H), 7.00 (d, J=8.78 Hz, 2H), 4.27 (s, 2H), 4.18-4.25 (m, 1H), 3.02-3.46 (m, 4H), 2.45-2.58 (m, 1H), 2.16-2.28 (m, 2H), 2.05-2.13 (m, 2H), 1.82-1.95 (m, 4H), 1.04-1.49 (m, 5H), 0.91 (s, 9H); LCMS m/z 450.3 [M+H].sup.+.

Example 3

3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid

(19) ##STR00029##

(20) A mixture of 4′-((trans-4-(tert-butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-carbaldehyde (27 mg, 0.080 mmol) and beta-alanine (11 mg, 0.12 mmol) in methanol (1 mL, 20 mmol) was heated with microwave irritation at 80° C. for 20 min. To the above mixture was added sodium cyanoborohydride (10.0 mg, 0.159 mmol) and acetic acid (9 uL, 0.2 mmol). The mixture was stirred at rt for 1 h. The reaction was partioned between EtOAc and water. The aqueous layer was extracted with EtOAc (×3). The combined organic phases were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by HPLC (TFA method) to collect the desired product as a white powder after lyophilization (19 mg, 45% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.72 (s, 1H), 7.68 (d, J=8.03 Hz, 1H), 7.57 (d, J=8.78 Hz, 2H), 7.51 (t, J=7.78 Hz, 1H), 7.40 (d, J=7.53 Hz, 1H), 6.99 (d, J=8.78 Hz, 2H), 4.30 (s, 2H), 4.18-4.27 (m, 1H), 3.28-3.36 (m, 2H), 2.77 (t, J=6.78 Hz, 2H), 2.18-2.26 (m, 2H), 1.83-1.96 (m, 2H), 1.30-1.47 (m, 2H), 1.15-1.29 (m, 2H), 1.02-1.14 (m, 1H), 0.91 (s, 9H); LCMS m/z 410.3 [M+H].sup.+.

Example 4

3-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid

(21) ##STR00030##

Step 1: 3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-carbaldehyde

(22) ##STR00031##

(23) The titled compound was synthesized according to the procedure described in Example 2, Step 1 (157 mg, 84% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 10.06 (s, 1H), 8.12 (s, 1H), 7.86-7.95 (m, 2H), 7.60-7.67 (m, 1H), 7.33-7.39 (m, 1H), 7.14-7.25 (m, 2H), 6.95 (dd, J=2.01, 8.28 Hz, 1H), 4.14-4.35 (m, 1H), 2.22 (d, J=11.04 Hz, 2H), 1.89 (d, J=12.55 Hz, 2H), 1.32-1.47 (m, 2H), 1.15-1.29 (m, 2H), 1.03-1.14 (m, 1H), 0.90 (s, 9H); LCMS m/z 337.2 [M+H].sup.+.

Step 2: 3-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid

(24) ##STR00032##

(25) The titled compound was synthesized according to the procedure described in Example 3 (33 mg, 64% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.75 (s, 1H), 7.71 (d, J=7.78 Hz, 1H), 7.55 (t, J=7.65 Hz, 1H), 7.44-7.49 (m, 1H), 7.31-7.39 (m, 1H), 7.20 (d, J=7.78 Hz, 1H), 7.15 (t, J=1.88 Hz, 1H), 6.95 (dd, J=2.01, 8.28 Hz, 1H), 4.32 (s, 2H), 4.19-4.30 (m, 1H), 2.77 (t, J=6.78 Hz, 2H), 2.17-2.29 (m, 2H), 1.83-1.96 (m, 2H), 1.32-1.48 (m, 2H), 1.15-1.30 (m, 2H), 1.05-1.15 (m, 1H), 0.91 (s, 9H); LCMS m/z 410.3 [M+H].sup.+.

Example 5

4-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)butanoic acid

(26) ##STR00033##

(27) The titled compound was synthesized according to the procedure described in Example 3 (36 mg, 66% yield). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 7.74 (s, 1H), 7.65-7.72 (m, 1H), 7.54 (t, J=7.55 Hz, 1H), 7.43-7.48 (m, 1H), 7.29-7.39 (m, 1H), 7.11-7.23 (m, 2H), 6.94 (dd, J=1.89, 8.31 Hz, 1H), 4.28 (s, 2H), 4.15-4.33 (m, 1H), 3.10-3.19 (m, 2H), 2.48 (t, J=6.99 Hz, 2H), 2.14-2.31 (m, 2H), 1.82-2.07 (m, 4H), 1.03-1.50 (m, 5H), 0.90 (s, 9H); LCMS m/z 424.3 [M+H].sup.+.

Example 6

(R)-1-((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid

(28) ##STR00034##

(29) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (10 mg, yield 64%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.77 (s, 1H), 7.71 (d, J=7.78 Hz, 1H), 7.52-7.57 (m, 1H), 7.44-7.50 (m, 1H), 7.31-7.39 (m, 1H), 7.11-7.23 (m, 2H), 6.94 (dd, J=2.01, 8.03 Hz, 1H), 4.36-4.49 (m, 2H), 4.19-4.30 (m, 1H), 3.34-3.65 (m, 4H), 3.10-3.22 (m, 1H), 2.15-2.40 (m, 4H), 1.89 (d, J=12.80 Hz, 2H), 1.02-1.48 (m, 5H), 0.90 (s, 9H); LCMS m/z 436.3.3 [M+H].sup.+.

Example 7

(R)-1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid

(30) ##STR00035##

(31) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (25 mg, yield 58%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.73 (s, 1H), 7.67 (d, J=8.03 Hz, 1H), 7.57 (d, J=8.78 Hz, 2H), 7.50 (t, J=7.78 Hz, 1H), 7.37-7.44 (m, 1H), 6.99 (d, J=8.78 Hz, 2H), 4.31-4.46 (m, 2H), 4.16-4.28 (m, 1H), 3.36-3.59 (m, 4H), 3.00-3.17 (m, 1H), 2.14-2.37 (m, 4H), 1.89 (d, J=13.05 Hz, 2H), 1.02-1.46 (m, 5H), 0.91 (s, 9H); LCMS m/z 436.3.3 [M+H].sup.+.

Example 8

3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid

(32) ##STR00036##

(33) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (38 mg, yield 23%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.74 (s, 1H), 7.70 (d, J=8.03 Hz, 1H), 7.59 (d, J=8.78 Hz, 2H), 7.54 (t, J=7.65 Hz, 1H), 7.43 (d, J=7.53 Hz, 1H), 7.02 (d, J=8.53 Hz, 2H), 4.18-4.36 (m, 3H), 3.66-3.88 (m, 1H), 2.93-3.13 (m, 1H), 2.30-2.56 (m, 1H), 2.17-2.29 (m, 3H), 1.72-2.15 (m, 6H), 1.34-1.49 (m, 2H), 1.18-1.33 (m, 2H), 1.05-1.17 (m, 1H), 0.93 (s, 9H); LCMS m/z 450.3 [M+H].sup.+.

Example 9

4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)butanoic acid

(34) ##STR00037##

(35) The titled compound was synthesized according to the procedure described in Example 3 (21 mg, yield 52%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.71 (s, 1H), 7.67 (d, J=7.78 Hz, 1H), 7.56 (d, J=8.78 Hz, 2H), 7.51 (t, J=7.66 Hz, 1H), 7.39 (d, J=7.53 Hz, 1H), 6.99 (d, J=8.78 Hz, 2H), 4.26 (s, 2H), 4.21-4.28 (m, 1H), 3.10-3.18 (m, 2H), 2.48 (t, J=6.90 Hz, 2H), 2.21 (d, J=11.04 Hz, 2H), 1.95-2.05 (m, 2H), 1.90 (d, J=12.80 Hz, 2H), 1.32-1.46 (m, 2H), 1.15-1.30 (m, 2H), 1.03-1.14 (m, 1H), 0.91 (s, 9H); LCMS m/z 424.3 [M+H].sup.+.

Example 10

3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclobutanecarboxylic acid

(36) ##STR00038##

(37) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (30 mg, yield 40%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.05 (br. s., 1H), 7.76 (s, 1H), 7.67 (d, J=7.78 Hz, 1H), 7.61 (d, J=8.78 Hz, 2H), 7.50 (t, J=7.66 Hz, 1H), 7.39 (d, J=7.53 Hz, 1H), 7.06 (d, J=8.78 Hz, 2H), 4.23-4.37 (m, 1H), 4.11 (br. s., 2H), 3.34-3.74 (m, 1H), 2.93 (quin, J=9.04 Hz, 1H), 2.26-2.48 (m, 4H), 2.15 (d, J=10.54 Hz, 2H), 1.81 (d, J=11.80 Hz, 2H), 1.26-1.40 (m, 2H), 1.12-1.25 (m, 2H), 1.04-1.10 (m, 1H), 0.88 (s, 9H); LCMS m/z 436.3 [M+H].sup.+.

Example 11

(1S,4S)-4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexanecarboxylic acid

(38) ##STR00039##

(39) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (27 mg, 40% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.67 (br. s., 1H), 7.78 (s, 1H), 7.67 (d, J=7.78 Hz, 1H), 7.60 (d, J=8.78 Hz, 2H), 7.50 (t, J=7.66 Hz, 1H), 7.38-7.44 (m, 1H), 7.06 (d, J=8.78 Hz, 2H), 4.17-4.35 (m, 3H), 3.04-3.15 (m, 1H), 2.58-2.64 (m, 1H), 2.15 (d, J=10.79 Hz, 2H), 2.07 (d, J=10.29 Hz, 2H), 1.93-2.02 (m, 2H), 1.81 (d, J=12.30 Hz, 2H), 1.47-1.66 (m, 4H), 1.26-1.40 (m, 2H), 1.12-1.25 (m, 2H), 1.01-1.11 (m, 1H), 0.88 (s, 9H); LCMS m/z 464.3 [M+H].sup.+.

Example 12

(1R,4R)-4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexanecarboxylic acid

(40) ##STR00040##

(41) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (33 mg, 50% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.22 (br. s., 1H), 8.75 (br. s., 1H), 7.78 (s, 1H), 7.67 (d, J=7.78 Hz, 1H), 7.60 (d, J=8.78 Hz, 2H), 7.51 (t, J=7.65 Hz, 1H), 7.42 (d, J=7.53 Hz, 1H), 7.06 (d, J=8.78 Hz, 2H), 4.14-4.38 (m, 3H), 3.00-3.19 (m, 1H), 2.08-2.48 (m, 5H), 1.93-2.07 (m, 2H), 1.81 (d, J=12.05 Hz, 2H), 1.25-1.52 (m, 6H), 1.12-1.24 (m, 2H), 1.02-1.11 (m, 1H), 0.88 (s, 9H); LCMS m/z 464.3 [M+H].sup.+.

Example 13

2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)azetidin-3-yl)acetic acid

(42) ##STR00041##

(43) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (15 mg, 30% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.62-7.75 (m, 2H), 7.56 (d, J=8.78 Hz, 2H), 7.51 (t, J=7.65 Hz, 1H), 7.31-7.42 (m, 1H), 6.99 (d, J=8.78 Hz, 2H), 4.36-4.52 (m, 2H), 4.14-4.32 (m, 3H), 3.98-4.12 (m, 2H), 2.68-2.83 (m, 3H), 2.21 (d, J=11.29 Hz, 2H), 1.90 (d, J=13.05 Hz, 2H), 1.32-1.46 (m, 2H), 1.16-1.29 (m, 2H), 1.03-1.15 (m, 1H), 0.91 (s, 9H); LCMS m/z 436.2 [M+H].sup.+.

Example 14

2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)acetic acid

(44) ##STR00042##

(45) The titled compound was synthesized according to the procedure described in Example 2, (5 mg, 10% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.78 (s, 1H), 7.72 (d, J=8.03 Hz, 1H), 7.61 (d, J=8.53 Hz, 2H), 7.53 (t, J=7.66 Hz, 1H), 7.42 (d, J=7.53 Hz, 1H), 7.06 (d, J=8.53 Hz, 2H), 4.23-4.42 (m, 3H), 3.30-3.50 (m, 2H), 2.68-2.93 (m, 2H), 2.25 (d, J=6.78 Hz, 2H), 2.06-2.20 (m, J=9.29 Hz, 3H), 1.72-1.92 (m, 4H), 1.00-1.41 (m, 7H), 0.88 (s, 9H); LCMS m/z 464.3 [M+H].sup.+.

Example 15

2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)acetic acid

(46) ##STR00043##

(47) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (34 mg, 50% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.67-7.81 (m, 2H), 7.60 (d, J=8.53 Hz, 2H), 7.52 (t, J=7.66 Hz, 1H), 7.36-7.45 (m, 1H), 7.05 (d, J=8.53 Hz, 2H), 4.23-4.49 (m, 3H), 3.39 (d, J=11.29 Hz, 2H), 2.92-3.06 (m, 2H), 2.20 (d, J=6.27 Hz, 2H), 1.68-2.15 (m, 7H), 1.26-1.49 (m, 4H), 1.11-1.25 (m, 2H), 1.01-1.10 (m, 1H), 0.87 (s, 9H); LCMS m/z 464.3 [M+H].sup.+.

Example 16

3-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid

(48) ##STR00044##

(49) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (49 mg, 50% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.65-7.84 (m, 2H), 7.51-7.59 (m, J=18.57 Hz, 1H), 7.43-7.49 (m, 1H), 7.29-7.39 (m, 1H), 7.11-7.25 (m, 2H), 6.94 (dd, J=1.63, 8.16 Hz, 1H), 4.18-4.38 (m, 3H), 3.67-3.86 (m, 1H), 2.89-3.11 (m, 1H), 1.72-2.53 (m, 10H), 1.31-1.46 (m, 2H), 1.15-1.29 (m, 2H), 1.03-1.14 (m, 1H), 0.90 (s, 9H); LCMS m/z 450.3 [M+H].sup.+.

Example 17

4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid

(50) ##STR00045##

(51) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (18 mg, 20% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.77 (s, 1H), 7.67 (d, J=8.03 Hz, 1H), 7.60 (d, J=8.53 Hz, 2H), 7.51 (t, J=7.65 Hz, 1H), 7.42 (d, J=7.53 Hz, 1H), 7.06 (d, J=8.78 Hz, 2H), 4.23-4.36 (m, 1H), 4.07-4.20 (m, 2H), 2.15 (d, J=10.29 Hz, 2H), 1.89 (s, 12H), 1.81 (d, J=12.30 Hz, 2H), 1.26-1.42 (m, 2H), 1.12-1.25 (m, 2H), 1.00-1.11 (m, 1H), 0.88 (s, 9H); LCMS m/z 490.3 [M+H].sup.+.

Example 18

1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-ol

(52) ##STR00046##

(53) The titled compound was synthesized according to the procedure described in Example 2, Step 2 (6 mg, 20% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.72 (d, J=7.78 Hz, 2H), 7.49-7.60 (m, 3H), 7.37-7.46 (m, 1H), 7.00 (d, J=8.53 Hz, 2H), 4.36 (d, J=8.78 Hz, 2H), 4.18-4.28 (m, 1H), 4.08 (br. s., 1H), 3.02-3.60 (m, 4H), 2.09-2.32 (m, 3H), 1.82-2.00 (m, 4H), 1.57-1.78 (m, 1H), 1.03-1.49 (m, 5H), 0.91 (s, 9H); LCMS m/z 422.3 [M+H].sup.+.

Example 19

(1R,3S)-3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid

(54) ##STR00047##

(55) The titled compound was synthesized according to the procedure described in Example 3 (21 mg, 62% yield). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 7.72 (s, 1H), 7.67 (d, J=7.93 Hz, 1H), 7.47-7.60 (m, 3H), 7.36-7.44 (m, 1H), 6.95-7.04 (m, 2H), 4.12-4.36 (m, 3H), 3.64-3.80 (m, 1H), 2.97 (quin, J=7.84 Hz, 1H), 2.35-2.50 (m, 1H), 2.15-2.29 (m, 3H), 2.00-2.12 (m, 3H), 1.82-1.96 (m, 3H), 1.04-1.51 (m, 5H), 0.91 (s, 9H); LCMS m/z 450.3 [M+H].sup.+.

Example 20

(1S,3R)-3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid

(56) ##STR00048##

(57) The titled compound was synthesized according to the procedure described in Example 3 (21 mg, 62% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.72 (s, 1H), 7.67 (d, J=8.03 Hz, 1H), 7.57 (d, J=8.53 Hz, 2H), 7.51 (t, J=7.65 Hz, 1H), 7.40 (d, J=7.78 Hz, 1H), 6.99 (d, J=8.78 Hz, 2H), 4.15-4.35 (m, 3H), 3.66-3.77 (m, 1H), 2.97 (quin, J=7.91 Hz, 1H), 2.37-2.50 (m, 1H), 2.16-2.30 (m, 3H), 1.99-2.12 (m, 3H), 1.81-1.95 (m, 3H), 1.03-1.48 (m, 5H), 0.91 (s, 9H); LCMS m/z 450.3 [M+H].sup.+.

Example 21

4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-carbaldehyde

(58) ##STR00049##

(59) A mixture of 1-bromo-4-(trans-4-tert-butylcyclohexyloxy)benzene (500 mg, 1.6 mmol, 1.0 eq), 4-formylphenylboronic acid (241 mg, 1.6 mmol, 1.0 eq), K.sub.2CO.sub.3 (442 mg, 3.2 mmol, 2.0 eq) and Pd(dppf)Cl.sub.2. DCM (130 mg, 0.16 mmol, 0.1 eq) in mixed solvents (toluene/ethanol//H.sub.2O, 5:2:1, 10 mL) was heated to 90° C. and stirred for 16 h under N.sub.2. After cooling down to rt, the resulting mixture was filtered and the filtrate was diluted with water (10 mL), extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was evaporated under reduced pressure to give the residue, which was purified by column chromatography on silica gel (PE/EA=10/1) to give the title compound as a yellow solid (270 mg, 50% yield). LCMS m/z 337.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.06 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 4.21-4.16 (m, 1H), 2.25-2.18 (m, 2H), 1.90-1.87 (m, 2H), 1.47-1.38 (m, 2H), 1.20-1.08 (m, 3H), 0.89 (s, 9H).

Example 22

Ethyl 1-((4′-(trans-4-tert-butylcyclohexyloxy)biphenyl-4-yl)methyl)piperidine-4-carboxylate

(60) ##STR00050##

(61) A mixture of 4′-(trans-4-tert-butylcyclohexyloxy)biphenyl-4-carbaldehyde (160 mg, 0.48 mmol, 1.0 eq), ethyl piperidine-4-carboxylate (83 mg, 0.53 mmol, 1.1 eq), NaBH(OAc).sub.3 (203 mg, 0.96 mmol, 2.0 eq) and CH.sub.3COOH (84 mg, 1.4 mmol, 3.0 eq) in DCE (3 mL) was warmed up to 80° C. for 16 h under N.sub.2. The resulting mixture was then diluted with water (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was evaporated under reduced pressure to give the residue, which was purified by column chromatography on silica gel (DCM/MeOH=20/1) to give the target molecule as a yellow oil (117 mg, 52% yield). LCMS m/z 478.3 [M+H].sup.+.

Example 23

1-((4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-yl)methyl)piperidine-4-carboxylic acid

(62) ##STR00051##

(63) To a mixture of ethyl 1-((4′-(trans-4-tert-butylcyclohexyloxy)biphenyl-4-yl)methyl)piperidine-4-carboxylate (100 mg, 0.21 mmol, 1.0 eq) in mixed solvents (MeOH/H.sub.2O, 4/1, 5 mL) was added LiOH.H.sub.2O (84 mg, 2.1 mmol, 10.0 eq), the resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was then adjusted to pH=6 with dilute aq. HCl (2 M). The resulting suspension was allowed to filter, and the precipitation was collected as crude product, which was purified by column chromatography on silica gel (DCM/MeOH=20:1) to give the title compound as a white solid (50 mg, 53% yield). LCMS m/z 450.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 7.56-7.53 (m, 4H), 7.32 (d, J=8.0 Hz, 2H), 7.83 (d, J=9.2 Hz, 2H), 4.28-4.23 (m, 1H), 3.44 (s, 2H), 2.77-2.74 (m, 2H), 2.15-1.74 (m, 9H), 1.57-1.49 (m, 2H), 1.35-1.02 (m, 5H), 0.86 (s, 9H).

Example 24

3-((4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-yl)methylamino)propanoic acid

(64) ##STR00052##

(65) A mixture of 4′-(trans-4-tert-butylcyclohexyloxy)biphenyl-4-carbaldehyde (120 mg, 0.36 mmol, 1.0 eq) and 3-aminopropanoic acid (38 mg, 0.43 mmol, 1.2 eq) in MeOH (3 mL) was stirred at 50° C. for 1 h. Then NaBH(OAc).sub.3 (229 mg, 1.08 mmol, 3.0 eq) and CH.sub.3COOH (22 mg, 0.36 mmol, 1.0 eq) were added. The mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure to give the residue, which was purified by column chromatography on silica gel (DCM/MeOH=20:1) to give the title compound as a yellow solid (55 mg, 38% yield). LCMS m/z 410.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.67 (d, J=8.4 Hz, 2H), 7.57-7.51 (m, 4H), 6.99 (d, J=8.8 Hz, 2H), 4.26-4.21 (m, 3H), 3.19 (t, J=6.4 Hz, 2H), 2.52 (t, J=6.4 Hz, 2H), 2.24-2.22 (m, 2H), 1.92-1.89 (m, 2H), 1.44-1.07 (m, 5H), 0.92 (s, 9H).

Example 25

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-methylbiphenyl-3-yl)methylamino)propanoic acid

(66) ##STR00053##

(67) Following the same conditions as in Examples 1, 21 and 24, the title compound was prepared. The crude product was purified by prep-HPLC (CH.sub.3CN/H.sub.2O with 10 mM NH.sub.4HCO.sub.3 as mobile phase; from 5% to 95%) to give the target compound as a white solid. (50 mg). LCMS m/z 424.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.71 (s, 1H), 7.66-7.63 (m, 1H), 7.52-7.48 (m, 1H), 7.45-7.43 (m, 1H), 7.02 (s, 1H), 6.94 (s, 1H), 6.75 (s, 1H), 4.25-4.18 (m, 3H), 3.19 (t, J=6.4 Hz, 2H), 2.51 (t, J=6.4 Hz, 2H), 2.36 (s, 3H), 2.22-2.19 (m, 2H), 1.89-1.86 (m, 2H), 1.40-1.31 (m, 2H), 1.28-1.05 (m, 3H), 0.90 (s, 9H).

Example 26

1-Bromo-3-(trans-4-tert-butylcyclohexyloxy)-5-fluorobenzene

(68) ##STR00054##

(69) A mixture of 3-bromo-5-fluorophenol (908 mg, 4.8 mmol, 1.0 eq), 2-methyl-2-(cis-4-(methylsulfonyloxy)cyclohexyl)propan-1-ylium (1.1 g, 4.8 mmol, 1.0 eq) and Cs.sub.2CO.sub.3 (3.1 g, 9.6 mmol, 2.0 eq) in t-BuOH (10 mL) was stirred at 80° C. under N.sub.2 for 16 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (PE, 100%) to give the title compound as a white solid (800 mg, 51% yield).

Example 27

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-fluorobiphenyl-3-yl)methylamino)propanoic acid

(70) ##STR00055##

(71) Following the same conditions as in Examples 21 and 24, the title compound was obtained as a yellow oil (16 mg, 11% yield). LCMS m/z 428.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.62 (s, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.42-7.36 (m, 2H), 6.86-6.82 (m, 2H), 6.59-6.55 (m, 1H), 4.14-4.11 (m, 3H), 3.06 (t, J=6.4 Hz, 2H), 2.41 (t, J=6.4 Hz, 2H), 2.11-2.08 (m, 2H), 1.79-1.76 (m, 2H), 1.32-0.95 (m, 5H), 0.79 (s, 9H).

Example 28

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid

(72) ##STR00056##

(73) Following the same conditions as in Examples 26, 21 and 24, the title compound was prepared. The crude product was purified by pre-HPLC (CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase; from 5% to 95%) to give the target compound as a white solid (140 mg, 90% yield). LCMS m/z 478.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.82 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.62-7.41 (m, 4H), 7.18 (s, 1H), 4.40-4.35 (m, 3H), 3.36-3.34 (m, 2H), 2.79 (t, J=6.8 Hz, 2H), 2.25-2.22 (m, 2H), 1.93-1.90 (m, 2H), 1.45-1.12 (m, 5H), 0.92 (s, 9H).

Example 29

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)propanoic acid

(74) ##STR00057##

(75) Following the same conditions as in Examples 1, 21 and 24, the title compound was prepared as a white solid (90 mg). LCMS m/z 428.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.56 (s, 1H), 7.51-7.50 (m, 1H), 7.44-7.39 (m, 2H), 7.07-7.00 (m, 2H), 6.96-6.90 (m, 1H), 4.17 (s, 2H), 4.13-4.08 (m, 1H), 3.10 (t, J=6.4 Hz, 2H), 2.41 (t, J=6.4 Hz, 2H), 2.13-2.10 (m, 2H), 1.81-1.78 (m, 2H), 1.38-1.29 (m, 2H), 1.15-1.00 (m, 3H), 0.80 (s, 9H).

Example 30

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-2′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid

(76) ##STR00058##

(77) Following the same conditions as in Examples 26, 21 and 24, the title compound was prepared. The crude product was purified by pre-HPLC (CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase; from 5% to 95%) to furnish the target compound (24 mg) as a white solid. LCMS m/z 478.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.53-7.49 (m, 3H), 7.42 (s, 1H), 7.34-7.33 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.80 (d, J=7.2 Hz, 1H), 4.43-4.36 (m, 1H), 4.29 (s, 2H), 3.29 (t, J=6.8 Hz, 2H), 2.75 (t, J=6.8 Hz, 2H), 2.25-2.22 (m, 2H), 1.93-1.90 (m, 2H), 1.50-1.07 (m, 5H), 0.92 (s, 9H).

Example 31

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)propanoic acid

(78) ##STR00059##

(79) Following the same conditions as in Examples 26, 21 and 24, the title compound was prepared. The crude product was purified by prep-HPLC (CH.sub.3CN/H.sub.2O with 10.05% TFA as mobile phase; from 5% to 95%) to give the target compound as a yellow oil (100 mg). LCMS m/z 428.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.66 (s, 1H), 7.62-7.39 (m, 4H), 6.83 (dd, J=2.4, 8.8 Hz, 1H), 6.77 (dd, J=2.4, 8.8 Hz, 1H), 4.30 (s, 2H), 4.28-4.20 (m, 1H), 3.34-3.31 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.23-2.20 (m, 2H), 1.92-1.88 (m, 2H), 1.41-1.10 (m, 5H), 0.91 (s, 9H).

Example 32

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)cyclopentanecarboxylic acid

(80) ##STR00060##

(81) Following the same conditions as in Examples 22 and 23, the title compound was obtained as a white solid (30 mg). LCMS m/z 468.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.69-7.41 (m, 5H), 6.85-6.75 (m, 2H), 4.26-4.22 (m, 3H), 3.82-3.64 (m, 1H), 3.14-2.90 (m, 1H), 2.47-1.78 (m, 9H), 1.44-1.07 (m, 6H), 0.91 (s, 9H).

Example 33

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-fluorobiphenyl-3-yl)methylamino)propanoic acid

(82) ##STR00061##

(83) Following the same conditions as in Examples 26, 21 and 24, the title compound was obtained as a yellow oil, 70 mg. LCMS m/z 428.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.75 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.52-7.38 (m, 4H), 7.18-7.14 (m, 1H), 4.29 (s, 2H), 4.23-4.17 (m, 1H), 3.32-3.29 (m, 2H), 2.77 (t, J=6.8 Hz, 2H), 2.21-2.18 (m, 2H), 1.88-1.86 (m, 2H), 1.43-1.08 (m, 5H), 0.89 (s, 9H).

Example 34

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-fluorobiphenyl-3-yl)methylamino)cyclopentanecarboxylic acid

(84) ##STR00062##

(85) Following the same conditions as in Examples 22 and 23, the title compound was obtained as a yellow solid (43 mg). LCMS m/z 468.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD+CDCl.sub.3) δ: 7.68 (bs, 1H), 7.64-7.61 (m, 1H), 7.53-7.48 (m, 1H), 7.44-7.35 (m, 3H), 7.16-7.12 (m, 1H), 4.26-4.09 (m, 3H), 3.70-3.64 (m, 1H), 2.95-2.82 (m, 1H), 2.36-1.10 (m, 15H), 0.90 (s, 9H).

Example 35

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid

(86) ##STR00063##

(87) Following the same conditions as in Examples 26, 21 and 24, the title compound was obtained as a yellow solid. LCMS m/z 449.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.73-7.71 (m, 2H), 7.65 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.44-7.34 (m, 2H), 7.20-7.17 (m, 1H), 4.30-4.25 (m, 1H), 4.18 (s, 2H), 3.13 (t, J=6.8 Hz, 2H), 2.50 (t, J=6.8 Hz, 2H), 2.13-2.10 (m, 2H), 1.81-1.78 (m, 2H), 1.38-0.97 (m, 5H), 0.80 (s, 9H).

Example 36

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-(trifluoromethyl)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid

(88) ##STR00064##

(89) Following the same conditions as in Examples 22 and 23, the title compound was obtained as a yellow oil (15 mg). LCMS m/z 518.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.85 (bs, 2H), 7.78 (s, 1H), 7.71 (d, J=6.8 Hz, 1H), 7.58-7.45 (m, 2H), 7.33-7.31 (m, 1H), 4.43-4.27 (m, 3H), 3.75-3.71 (m, 1H), 3.02-2.94 (m, 1H), 2.49-2.42 (m, 1H), 2.28-1.84 (m, 9H), 1.50-1.08 (m, 5H), 0.92 (s, 9H).

Example 37

8-(4-Bromophenoxyl)spiro[4.5]decane

(90) ##STR00065##

(91) A mixture of spiro[4.5]decan-8-ol (1.08 g, 7.0 mmol, 1.0 eq), 4-bromophenol (1.80 g, 10.5 mmol, 1.5 eq) and PPh.sub.3 (3.66 g, 14.0 mmol, 2.0 eq) in THF (10 mL) was stirred at rt for 15 min. Then DIAD (2.82 g, 14.0 mmol, 2.0 eq) was added slowly. The mixture was then stirred at rt for 16 h. The organic solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (100% PE) to give the title compound as a yellow oil (755 mg, 35% yield). LCMS m/z 309.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3Cl.sub.3) δ: 7.34 (d, J=9.2 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.20-4.18 (m, 1H), 1.89-1.54 (m, 6H), 1.47-0.86 (m, 10H).

Example 38

4′-(Spiro[4.5]decan-8-yloxy)biphenyl-3-carbaldehyde

(92) ##STR00066##

(93) A mixture of 8-(4-bromophenoxyl)spiro[4.5]decane (308 mg, 1.0 mmol, 1.0 eq), 3-formylphenylboronic acid (180 mg, 1.2 mmol, 1.2 eq), Pd(dppf)Cl.sub.2 (80 mg, 0.1 mmol, 0.1 eq) and Na.sub.2CO.sub.3 (212 mg, 2.0 mmol, 2.0 eq) in toluene/EtOH/H.sub.2O (5/2/2, 9 mL) was stirred at 80° C. under N.sub.2 for 16 h. The solvent was removed in vacuo, and the residue was suspended in DCM (10 mL). After filtration, the organic solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (PE/EA=10/1) to give the title compound as a yellow oil (217 mg, 65% yield). LCMS m/z 335.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3Cl.sub.3) δ: 10.1 (s, 1H), 8.05 (s, 1H), 7.81-7.79 (m, 2H), 7.59-7.46 (m, 3H), 6.99-6.98 (m, 2H), 4.33-4.28 (m, 1H) 0.1.96-1.91 (m, 2H), 1.71-1.57 (m, 8H), 1.50-1.37 (m, 6H).

Example 39

3-((4′-(Spiro[4.5]decan-8-yloxy)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid

(94) ##STR00067##

(95) Following the same conditions as in Examples 22 and 23, the title compound was obtained as a yellow oil (76 mg). LCMS m/z 448.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 12.34 (bs, 1H), 9.06 (bs, 1H), 7.80 (s, 1H), 7.67-7.60 (m, 3H), 7.51-7.42 (m, 2H), 7.05 (d, J=8.4 Hz, 2H), 4.41 (bs, 1H), 4.22 (s, 2H), 3.62-3.61 (m, 1H), 2.95-2.93 (m, 1H), 2.22-1.71 (m, 8H), 1.59-1.53 (m, 8H), 1.45-1.35 (m, 6H).

Example 40

3-((4′-(4,4-Dimethylcyclohexyloxyl)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid

(96) ##STR00068##

(97) Following the same condition as Examples 37, 38 and 39, the title compound was obtained as a white solid (20 mg, 1.5% yield for 4 steps). LCMS m/z 422.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.72 (s, 1H), 7.67-7.63 (m, 1H), 7.58 (d, J=6.8 Hz, 2H), 7.53-7.47 (m, 1H), 7.43-7.40 (m, 1H), 7.03-6.99 (m, 2H), 4.40-4.34 (m, 1H), 4.22 (s, 2H), 3.74-3.71 (m, 1H), 2.92-2.83 (m, 1H), 2.40-2.11 (m, 4H), 1.93-1.64 (m, 6H), 1.58-1.52 (m, 2H), 1.37-1.30 (m, 2H), 0.99 (d, J=6.8 Hz, 6H).

Example 41

3-((4′-(cis-4-Ethylcyclohexyloxy)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid

(98) ##STR00069##

(99) Following the same condition as Examples 37, 38 and 39, the title compound was obtained as a yellow oil (76 mg, 1.3% for 4 steps). LCMS m/z 422.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.63 (bs, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.42-7.38 (m, 1H), 7.31 (d, J=7.2 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.51-4.50 (bs, 1H), 4.17-4.15 (m, 2H), 3.67-3.64 (m, 1H), 2.96-2.83 (m, 1H), 2.37-1.66 (m, 8H), 1.55-1.46 (m, 4H), 1.34-1.18 (m, 5H), 0.82 (t, J=6.8 Hz, 3H).

Example 42

1-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzyl)piperidine-4-carboxylic acid

(100) ##STR00070##

(101) Following the same conditions as in Examples 1, 21, 22 and 23, the title compound was obtained as a white solid (80 mg), LCMS m/z 451.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.28 (d, J=6.8 Hz, 1H), 8.01 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.50-7.47 (m, 2H), 4.37-4.30 (m, 1H), 4.19 (s, 2H), 2.91-2.86 (m, 2H), 2.40-2.35 (m, 1H), 2.25-2.22 (m, 2H), 2.07-2.04 (m, 2H), 1.94-1.87 (m, 4H), 1.49-1.40 (m, 4H), 1.30-1.20 (m, 2H), 1.16-1.10 (m, 1H), 0.92 (s, 9H).

Example 43

3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzylamino)propanoic acid

(102) ##STR00071##

(103) Following the same condition as in Example 24, the title compound was obtained as a yellow solid (20 mg, 8% yield). LCMS m/z 411.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.33 (d, J=2.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.50 (dd, J=2.8, 8.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 4.40-4.33 (m, 1H), 3.87 (s, 2H), 2.80 (t, J=6.4 Hz, 2H), 2.32 (t, J=6.8 Hz, 2H), 2.16-2.13 (m, 1H), 1.81-1.78 (m, 2H), 1.38-1.29 (m, 2H), 1.23-1.13 (m, 3H), 1.08-1.05 (m, 1H), 0.87 (s, 9H).

Example 44

3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzylamino)cyclopentanecarboxylic acid

(104) ##STR00072##

(105) Following the same conditions as in Examples 22 and 23, the title compound was obtained as a white solid 40 mg. LCMS m/z 451.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.35 (s, 1H), 8.06 (s, 1H), 7.98-7.90 (m, 2H), 7.66-7.59 (m, 3H), 4.40-4.32 (m, 3H), 3.83-3.71 (m, 1H), 3.10-2.95 (m, 1H), 2.51-1.78 (m, 10H), 1.50-1.41 (m, 2H), 1.33-1.21 (m, 2H), 1.16-1.09 (m, 1H), 0.92 (s, 9H).

Example 45

3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-3-yl)benzylamino)propanoic acid

(106) ##STR00073##

(107) Following the same conditions as in Examples 1, 21 and 24, the title compound was obtained as a yellow oil (40 mg). LCMS m/z 411.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.27 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.62-7.61 (m, 1H), 7.49-7.43 (m, 3H), 4.28-4.27 (m, 1H), 4.19 (s, 2H), 3.10 (t, J=6.4 Hz, 2H), 2.42 (t, J=6.4 Hz, 2H), 2.14-2.11 (m, 2H), 1.81-1.78 (m, 2H), 1.33-1.00 (m, 5H), 0.79 (s, 9H).

Example 46

3-(trans)-4-tert-Butylcyclohexyloxy)-6-chloropyridazine (A) 2-(trans)-4-tert-Butylcyclohexyl)-6-chloropyridazin-3(2H)-one (B)

(108) ##STR00074##

(109) To a mixture of 6-chloropyridazin-3-ol (1.30 g, 10.0 mmol, 1.0 eq), trans-4-tert-butylcyclohexanol (1.56 g, 10.0 mmol, 1.2 eq), PPh.sub.3 (5.25 g, 20.0 mmol, 2.0 eq) and TEA (1.20 g, 12.0 mol, 1.2 eq) in THF (15 mL) was added dropwise DIAD (4.04 g, 20.0 mmol, 2.0 eq) at rt. The mixture was stirred for 2 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EA=100/1) to afford 3-(trans-4-tert-butylcyclohexyloxy)-6-chloropyridazine (A) as a yellow solid (1.05 g, 40% yield). LCMS m/z 269.2 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ: 7.33 (d, J=9.2 Hz, 1H), 6.88 (d, J=9.2 Hz, 1H), 5.19-5.11 (m, 1H), 2.28 (bs, 2H), 1.84 (bs, 2H), 1.42-1.39 (m, 2H), 1.09-1.03 (m, 3H), 0.87 (s, 9H). 2-(trans-4-tert-butylcyclohexyl)-6-chloropyridazin-3(2H)-one (B) as a yellow solid (600 mg, 25% yield) LCMS m/z 269.1 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ: 7.12 (d, J=9.6 Hz, 1H), 6.88 (d, J=9.6 Hz, 1H), 4.84-4.76 (m, 1H), 1.92-1.89 (m, 4H), 1.79-1.71 (m, 2H), 1.28-1.08 (m, 3H), 0.88 (s, 9H).

Example 47

3-(1-(trans-4-(tert-butyl)cyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzaldehyde

(110) ##STR00075##

(111) 2-(trans-4-(tert-butyl)cyclohexyl)-6-chloropyridazin-3(2H)-one (400 mg, 1.5 mmol, 1.0 eq), 3-formylphenylboronic acid (270 mg, 1.8 mmol, 1.2 eq) and Na.sub.2CO.sub.3 (318 mg, 3.0 mmol, 2.0 eq) were dissolved in mixed solvents (toluene/EtOH/H.sub.2O, 8/2/1, 5.5 mL). The mixture was purged with N.sub.2 for 3 times, Pd(dppf)Cl.sub.2. DCM (120 mg, 0.15 mmol, 0.1 eq) was added. The mixture was purged with N.sub.2 for 3 times, and then heated to 100° C. for 16 h under N.sub.2. After cooling down to rt, the resulting mixture was concentrated to yield a crude product, which was purified by pre-TLC (PE/EA=10/1) to afford the target molecule as a yellow oil (200 mg, 40% yield). LCMS m/z 339.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.11 (s, 1H), 8.29 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.04 (d, J=9.2 Hz, 1H), 5.01-4.93 (m, 1H), 2.02-1.83 (m, 6H), 1.35-1.28 (m, 2H), 1.21-1.14 (m, 1H), 0.91 (s, 9H).

Example 48

3-((3-(1-(trans-4-(tert-butyl)cyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl)amino)propanoic acid

(112) ##STR00076##

(113) Following the same condition as in Example 24, the title compound was obtained as a yellow oil (80 mg, 40%). LCMS m/z 412.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.03-7.96 (m, 3H), 7.58 (d, J=4.4 Hz, 2H), 7.06 (d, J=9.6 Hz, 1H), 4.86-4.85 (m, 1H), 4.27 (s, 2H), 3.18 (t, J=6.4 Hz, 2H), 2.51 (t, J=6.4 Hz, 2H), 2.00-1.90 (m, 6H), 1.35-1.31 (m, 2H), 1.21-1.15 (m, 1H), 0.93 (s, 9H).

Example 49

3-(3-(6-(trans-4-tert-Butylcyclohexyloxy)pyridazin-3-yl)benzylamino)propanoic acid

(114) ##STR00077##

(115) Following the same condition as in Example 21 and 24, the title compound was obtained as a white solid (80 mg). LCMS m/z 412.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.13-8.06 (m, 3H), 7.64 (d, J=4.8 Hz, 2H), 7.26 (d, J=9.6 Hz, 1H), 4.17-5.10 (m, 1H), 4.37 (s, 2H), 3.36 (t, J=6.8 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 2.35 (bs, 2H), 1.95 (bs, 2H), 1.52-1.45 (m, 2H), 1.31-1.25 (m, 2H), 1.16-1.07 (m, 1H), 0.92 (s, 9H).

Example 50

3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyrimidin-2-yl)benzylamino)propanoic acid

(116) ##STR00078##

(117) Following the same condition as in Examples 1, 21 and 24, the title compound was obtained as a white solid (132 mg). LCMS m/z 412.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.53 (s, 2H), 8.46 (s, 1H), 8.40-8.37 (m, 1H), 7.57-7.55 (m, 2H), 4.45-4.40 (m, 1H), 4.29 (s, 2H), 3.22 (t, J=6.4 Hz, 2H), 2.52 (t, J=6.4 Hz, 2H), 2.27-2.24 (m, 2H), 1.94-1.91 (m, 2H), 1.47-1.44 (m, 2H), 1.28-1.24 (m, 2H), 1.16-1.13 (m, 1H), 0.92 (s, 9H).

Example 51

3-(3-(2-(trans-4-tert-Butylcyclohexyloxy)pyrimidin-5-yl)benzylamino) propanoic acid

(118) ##STR00079##

(119) Following the same condition as in Examples 1, 21 and 24, the title compound was obtained as a yellow solid (96 mg). LCMS m/z 412.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.85 (s, 2H), 7.80 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 5.02-4.96 (m, 1H), 4.34 (s, 2H), 3.34 (t, J=6.8 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 2.29-2.24 (m, 2H), 1.95-1.92 (m, 2H), 1.55-1.45 (m, 2H), 1.30-1.20 (m, 2H), 1.17-1.14 (m, 1H), 0.92 (s, 9H).

Example 52

3-(3-(6-(trans-4-tert-Butylcyclohexyloxy)pyrimidin-4-yl)benzylamino)propanoic acid

(120) ##STR00080##

(121) Following the same condition as in Examples 1, 21 and 24, the title compound was obtained as a white solid (31 mg). LCMS m/z 412.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.77 (s, 1H), 8.18 (s, 1H), 8.13-8.11 (m, 1H), 7.64-7.61 (m, 2H), 7.28 (s, 1H), 5.11-5.06 (m, 1H), 4.28 (s, 2H), 3.19 (t, J=6.8 Hz, 2H), 2.52 (t, J=6.4 Hz, 2H), 2.26-2.24 (m, 2H), 1.94-1.91 (m, 2H), 1.49-1.45 (m, 2H), 1.27-1.23 (m, 2H), 1.16-1.13 (m, 1H), 0.92 (s, 9H).

Example 53

2-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(122) ##STR00081##

(123) A mixture of 1-bromo-4-(trans-4-tert-butylcyclohexyloxy)benzene (5.0 g, 6.5 mmol, 1.0 eq), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.3 g, 13.0 mmol, 2.0 eq), KOAc (1.3 g, 13.0 mmol, 2.0 eq) and Pd(dppf)Cl.sub.2. DCM (1.1 g, 1.3 mmol, 0.2 eq) in mixed solvents (1,4-dioxane/DMSO, 4/1, 10 mL) was heated to 90° C. and stirred for 4 h under N.sub.2. After cooling down to rt, the resulting mixture was filtrated and the filtrate was diluted with water (10 mL), extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was evaporated under reduced pressure to give the residue, which was purified by column chromatography on silica gel (PE/EA=20/1) to give the title compound as a yellow solid (4.6 g, 80% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.65 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 4.13-4.05 (m, 1H), 2.13-2.08 (m, 2H), 1.79-1.76 (m, 2H), 1.35-1.29 (m, 2H), 1.24 (s, 12H), 1.10-0.95 (m, 3H), 0.79 (s, 9H).

Example 54

6-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)picolinaldehyde

(124) ##STR00082##

(125) A mixture of 2-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 0.84 mmol, 1.2 eq), 6-bromopicolinaldehyde (130 mg, 0.70 mmol, 1.0 eq), Na.sub.2CO.sub.3 (148 mg, 1.40 mmol, 2.0 eq) and Pd(dppf)Cl.sub.2. DCM (114 mg, 0.14 mmol, 0.2 eq) in mixed solvents (toluene/EtOH/H.sub.2O, 5/2/1, 1.6 mL) was heated to 95° C. and stirred for 4 h under N.sub.2. After cooling down to rt, the resulting mixture was filtrated and the filtrate was diluted with water (10 mL), extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was evaporated under reduced pressure to give the residue, which was purified by column chromatography on silica gel (PE/EA=20/1) to yield the title compound as a yellow oil (100 mg, 42% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.16 (s, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.89 (d, J=4.0 Hz, 2H), 7.85-7.83 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 4.25-4.18 (m, 1H), 2.26-2.22 (m, 2H), 1.91-1.87 (m, 2H), 1.44-1.41 (m, 2H), 1.18-1.08 (m, 3H), 0.89 (s, 9H).

Example 55

3-((6-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)pyridin-2-yl)methylamino)propanoic acid

(126) ##STR00083##

(127) Following the same condition as in Example 24, the title compound was obtained as a white solid (19 mg, 16%). LCMS m/z 411.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.10 (d, J=8.8 Hz, 2H), 7.89-7.83 (m, 2H), 7.30 (d, J=7.2 Hz, 1H), 7.00 (d, J=9.2 Hz, 2H), 4.45 (s, 2H), 4.29-4.22 (m, 1H), 3.44 (t, J=6.6 Hz, 2H), 2.87 (t, J=6.8 Hz, 2H), 2.23-2.21 (m, 2H), 1.91-1.88 (m, 2H), 1.44-1.34 (m, 2H), 1.27-1.17 (m, 2H), 1.14-1.06 (m, 1H), 0.91 (s, 9H).

Example 56

3-((2-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)pyridin-4-yl)methylamino)propanoic acid

(128) ##STR00084##

(129) Following the same condition as in Examples 54 and 24, the title compound was obtained as a yellow solid (28 mg). LCMS m/z 411.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.68 (d, J=5.6 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=14.4 Hz, 2H), 7.42 (dd, J=1.2, 5.2 Hz, 1H), 7.06 (d, J=14.8 Hz, 2H), 4.42 (s, 2H), 4.33-4.28 (m, 1H), 3.39 (t, J=6.8 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H), 2.24-2.21 (m, 2H), 1.92-1.89 (m, 2H), 1.43-1.36 (m, 2H), 1.28-1.19 (m, 2H), 1.15-1.11 (m, 1H), 0.91 (s, 9H).

Example 57

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-6-fluorobiphenyl-3-yl)methylamino) propanoic acid

(130) ##STR00085##

(131) Following the same condition as in Examples 54 and 24, the title compound was obtained as a yellow oil (66 mg, 42%). LCMS m/z 428.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.64-7.62 (m, 1H), 7.49-7.42 (m, 3H), 7.25-7.20 (m, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.24 (s, 2H), 4.22-4.17 (m, 1H), 3.27 (t, J=6.6 Hz, 2H), 2.72 (t, J=6.6 Hz, 2H), 2.21-2.18 (m, 2H), 1.88-1.85 (m, 2H), 1.38-1.35 (m, 2H), 1.20-1.17 (m, 2H), 1.10-1.08 (m, 1H), 0.89 (s, 9H).

Example 58

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-4-fluorobiphenyl-3-yl)methylamino)propanoic acid

(132) ##STR00086##

(133) Following the same condition as in Examples 54 and 24, the title compound was obtained as a yellow solid (120 mg). LCMS m/z 428.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.76-7.68 (m, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.32-7.27 (m, 1H), 6.99 (d, J=8.0 Hz, 2H), 4.37 (s, 2H), 4.26-4.19 (m, 1H), 3.34-3.32 (m, 2H), 2.71 (t, J=6.6 Hz, 2H), 2.23-2.19 (m, 2H), 1.91-1.88 (m, 2H), 1.43-1.33 (m, 2H), 1.27-1.17 (m, 2H), 1.13-1.06 (m, 1H), 0.91 (s, 9H).

Example 59

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-2,4-difluorobiphenyl-3-yl)methylamino)propanoic acid

(134) ##STR00087##

(135) Following the same condition as in Examples 54 and 24, the title compound was obtained as a yellow oil (50 mg). LCMS m/z 446.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.56-7.49 (m, 1H), 7.34 (d, J=7.6 Hz, 2H), 7.12-7.07 (m, 1H), 6.89 (d, J=8.8 Hz, 2H), 4.33 (s, 2H), 4.18-4.10 (m, 1H), 3.27 (t, J=6.8 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H), 2.13-2.10 (m, 2H), 1.81-1.78 (m, 2H), 1.33-1.24 (m, 2H), 1.17-1.07 (m, 2H), 1.04-0.96 (m, 1H), 0.81 (s, 9H).

Example 60

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-5-fluorobiphenyl-3-yl)methylamino)propanoic acid

(136) ##STR00088##

(137) Following the same condition as in Examples 54 and 24, the title compound was obtained as a yellow oil (26 mg). LCMS m/z 428.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.60-7.58 (m, 3H), 7.44-7.41 (m, 1H), 7.21-7.18 (m, 1H), 7.00 (d, J=8.8 Hz, 2H), 4.29 (s, 2H), 4.28-4.20 (m, 1H), 3.31-3.28 (m, 2H), 2.71 (t, J=6.4 Hz, 2H), 2.23-2.20 (m, 2H), 1.91-1.88 (m, 2H), 1.44-1.34 (m, 2H), 1.27-1.17 (m, 2H), 1.14-1.07 (m, 1H), 0.91 (s, 9H).

Example 61

3-((4′-(trans-4-tert-Butylcyclohexyloxy)-5-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid

(138) ##STR00089##

(139) Following the same condition as in Examples 54 and 24, the title compound was obtained as a yellow oil (31 mg). LCMS m/z 478.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.02 (s, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.38 (s, 2H), 4.29-4.21 (m, 1H), 3.34-3.32 (m, 1H), 3.31-3.29 (m, 1H), 2.73 (t, J=6.8 Hz, 2H), 2.24-2.21 (m, 2H), 1.92-1.88 (m, 2H), 1.44-1.35 (m, 2H), 1.28-1.18 (m, 2H), 1.14-1.07 (m, 1H), 0.91 (s, 9H).

Example 62

3-(((4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)methyl)amino)propanoic acid

(140) ##STR00090##

(141) Following the same condition as in Examples 21 and 24, the title compound was obtained (27 mg). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.91 (d, J=8.78 Hz, 2H), 7.80 (s, 1H), 6.98 (d, J=8.78 Hz, 2H), 4.69 (s, 2H), 4.12-4.35 (m, 1H), 3.49 (t, J=6.65 Hz, 2H), 2.85 (t, J=6.65 Hz, 2H), 2.23 (d, J=10.54 Hz, 2H), 1.92 (d, J=12.80 Hz, 2H), 1.41 (q, J=12.63 Hz, 2H), 1.17-1.30 (m, 2H), 1.06-1.17 (m, 1H), 0.93 (s, 9H); LCMS m/z 417.2 [M+H].sup.+.

Example 63

4-(((4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)methyl)amino)butanoic acid

(142) ##STR00091##

(143) The titled compound was synthesized according to the procedure described in Example 62 (10 mg, 30% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.91 (d, J=8.78 Hz, 2H), 7.80 (s, 1H), 6.98 (d, J=8.78 Hz, 2H), 4.67 (s, 2H), 4.17-4.33 (m, 1H), 3.29 (t, J=7.03 Hz, 2H), 2.53 (t, J=7.03 Hz, 2H), 2.23 (d, J=11.55 Hz, 2H), 2.01-2.12 (m, 2H), 1.92 (d, J=11.80 Hz, 2H), 1.35-1.48 (m, 2H), 1.17-1.31 (m, 2H), 1.08-1.16 (m, 1H), 0.93 (s, 9H); LCMS m/z 431.2 [M+H].sup.+.

Example 64

1-((4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)methyl)piperidine-4-carboxylic acid

(144) ##STR00092##

(145) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (18 mg, yield 24%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.90 (d, J=8.78 Hz, 2H), 7.86 (s, 1H), 6.99 (d, J=8.78 Hz, 2H), 4.77 (s, 2H), 4.20-4.31 (m, 1H), 3.70-3.81 (m, 2H), 3.15-3.30 (m, 2H), 2.58-2.78 (m, 1H), 2.18-2.26 (m, 4H), 1.88-2.00 (m, 4H), 1.06-1.48 (m, 5H), 0.93 (s, 9H); LCMS m/z 457.3 [M+H].sup.+.

Example 65

2-(1-((4-(4-((trans)-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)methyl)azetidin-3-yl)acetic acid

(146) ##STR00093##

(147) The titled compound was synthesized according to the procedure described in Example 2, Step 2-3 (15 mg, yield 30%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.05 (s, 1H), 7.87 (d, J=8.78 Hz, 2H), 7.02 (d, J=8.78 Hz, 2H), 4.72-4.96 (m, 2H), 4.19-4.36 (m, 3H), 3.95-4.12 (m, 2H), 2.63-3.10 (m, 3H), 2.13 (d, J=10.04 Hz, 2H), 1.80 (d, J=12.30 Hz, 2H), 1.00-1.41 (m, 5H), 0.87 (s, 9H); LCMS m/z 443.2 [M+H].sup.+.

Example 66

3-(((6-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)quinolin-2-yl)methyl)amino)propanoic acid

(148) ##STR00094##

(149) Following the same condition as in Examples 54 and 24, the title compound was obtained (15 mg, yield 23%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.45 (d, J=8.53 Hz, 1H), 8.06-8.21 (m, 3H), 7.73 (d, J=8.78 Hz, 2H), 7.53 (d, J=8.53 Hz, 1H), 7.07 (d, J=8.53 Hz, 2H), 4.64 (s, 2H), 4.21-4.34 (m, 1H), 3.47-3.57 (m, 2H), 2.92 (t, J=6.78 Hz, 2H), 2.26 (d, J=10.04 Hz, 2H), 1.84-1.98 (m, 2H), 1.36-1.52 (m, 2H), 1.19-1.33 (m, 2H), 1.08-1.18 (m, 1H), 0.94 (s, 9H); LCMS m/z 461.3 [M+H].sup.+.

Example 67

2-(5-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)isoindolin-2-yl)acetic acid

Step 1: tert-butyl 5-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)isoindoline-2-carboxylate

(150) ##STR00095##

(151) The titled compound was synthesized according to the procedure described in Example 13, Step 1 (80 mg, yield 60%). LCMS m/z 350.2 [M+H—BOC].sup.+.

Step 2 5-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)isoindoline

(152) ##STR00096##

(153) tert-Butyl 5-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)isoindoline-2-carboxylate (75 mg, 0.17 mmol) from previous step was dissolved in CH.sub.2Cl.sub.2 (1 mL). TFA (100 μL, 0.6 mmol) was added, and the reaction was stirred at rt overnight. Reaction mixture was then concentrated to get the TFA salt of the desired amine (59 mg, yield 76%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.64 (s, 1H), 7.61 (d, J=8.03 Hz, 1H), 7.56 (d, J=8.78 Hz, 2H), 7.45 (d, J=8.03 Hz, 1H), 7.03 (d, J=8.78 Hz, 2H), 4.46-4.59 (m, 4H), 4.18-4.34 (m, 1H), 2.13 (d, J=10.79 Hz, 2H), 1.80 (d, J=13.05 Hz, 2H), 0.98-1.40 (m, 5H), 0.87 (s, 9H); LCMS m/z 350.2 [M+H].sup.+.

Step 3 2-(5-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)isoindolin-2-yl)acetic acid

(154) ##STR00097##

(155) The titled compound was synthesized according to the procedure described in Example 8, Step 3 (7 mg, yield 41%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.49 (d, J=8.53 Hz, 2H), 7.40-7.46 (m, 2H), 7.27 (d, J=7.78 Hz, 1H), 6.95 (d, J=8.78 Hz, 2H), 4.15-4.33 (m, 5H), 3.54 (s, 2H), 2.16-2.29 (m, 2H), 1.83-1.96 (m, 2H), 1.05-1.45 (m, 5H), 0.91 (s, 9H); LCMS m/z 408.2 [M+H].sup.+.

Example 68

2-(3-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(156) ##STR00098##

(157) A mixture of 1-bromo-3-(trans-4-tert-butylcyclohexyloxy)benzene (5.0 g, 6.5 mmol, 1.0 eq), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.3 g, 13.0 mmol, 2.0 eq), KOAc (1.3 g, 13.0 mmol, 2.0 eq) and Pd(dppf)Cl.sub.2. DCM (1.1 g, 1.3 mmol, 0.2 eq) in mixed solvents (1,4-dioxane/DMSO, 4/1, 10 mL) was heated to 90° C. and stirred for 4 h under N.sub.2. The mixture was concentrated under reduced pressure to give the residue, which was purified by column chromatography on silica gel (PE/EA=20/1) to yield the title compound as a yellow solid (4.0 g, 70%).

Example 69

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-6-fluorobiphenyl-3-yl)methylamino)propanoic acid

(158) ##STR00099##

(159) Following the same condition as in Examples 54 and 24, the title compound was obtained as a white solid (100 mg). LCMS m/z 428.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.66 (dd, J=2.0, 7.2 Hz, 1H), 7.52-7.28 (m, 3H), 7.12-7.08 (m, 2H), 6.97 (dd, J=1.6, 7.6 Hz, 1H), 4.30 (s, 2H), 4.22-4.20 (m, 1H), 3.34 (bs, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.24-2.21 (m, 2H), 1.91-1.88 (m, 2H), 1.44-1.08 (m, 5H), 0.91 (s, 9H).

Example 70

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-4-fluorobiphenyl-3-yl)methylamino)propanoic acid

(160) ##STR00100##

(161) Following the same condition as in Examples 54 and 24, the title compound was obtained as a yellow solid (100 mg). LCMS m/z 428.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.82-7.69 (m, 2H), 7.35-7.13 (m, 4H), 6.93-6.90 (m, 1H), 4.38 (s, 2H), 4.25-4.22 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 2.22-2.19 (m, 2H), 1.88-1.85 (m, 2H), 1.42-1.04 (m, 5H), 0.89 (s, 9H).

Example 71

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-2,4-difluorobiphenyl-3-yl)methylamino)propanoic acid

(162) ##STR00101##

(163) Following the same condition as in Examples 54 and 24, the title compound was obtained as a yellow oil (120 mg). LCMS m/z 446.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.65-7.63 (m, 1H), 7.37-6.95 (m, 5H), 4.45 (s, 2H), 4.26-4.20 (m, 1H), 3.40 (t, J=6.8 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H), 2.23-2.20 (m, 2H), 1.89-1.86 (m, 2H), 1.39-1.09 (m, 5H), 0.90 (s, 9H).

Example 72

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5-fluorobiphenyl-3-yl)methylamino)propanoic acid

(164) ##STR00102##

(165) Following the same condition as in Examples 54 and 24, the title compound was obtained as a white solid (213 mg). LCMS m/z 428.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.61 (s, 1H), 7.48 (d, J=6.4 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.17 (s, 1H), 6.98 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 4.34 (s, 2H), 4.32-4.25 (m, 1H), 3.34 (d, J=6.8 Hz, 2H), 2.79 (t, J=6.8 Hz, 2H), 2.24-2.21 (m, 2H), 1.92-1.88 (m, 2H), 1.44-1.34 (m, 2H), 1.28-1.18 (m, 2H), 1.14-1.07 (m, 1H), 0.91 (s, 9H).

Example 73

3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid

(166) ##STR00103##

(167) Following the same condition as in Examples 54 and 24, the title compound was obtained as a white solid (156 mg). LCMS m/z 478.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.05 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 4.43 (s, 2H), 4.32-4.26 (m, 1H), 3.37 (t, J=6.8 Hz, 2H), 2.80 (t, J=6.8 Hz, 2H), 2.25-2.22 (m, 2H), 1.92-1.88 (m, 2H), 1.45-1.35 (m, 2H), 1.28-1.18 (m, 2H), 1.14-1.08 (m, 1H), 0.91 (s, 9H).

Example 74

3-(((4-(3-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)methyl)amino)propanoic acid

(168) ##STR00104##

(169) Following the same condition as in Examples 54 and 24, the title compound was obtained (18 mg, 38% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.95 (s, 1H), 7.47-7.59 (m, 2H), 7.32 (t, J=7.91 Hz, 1H), 6.92 (dd, J=1.76, 8.28 Hz, 1H), 4.69 (s, 2H), 4.15-4.31 (m, 1H), 3.47 (t, J=6.65 Hz, 2H), 2.83 (t, J=6.65 Hz, 2H), 2.21 (d, J=10.54 Hz, 2H), 1.89 (d, J=12.80 Hz, 2H), 1.38 (d, J=13.30 Hz, 2H), 1.15-1.30 (m, 2H), 1.07-1.13 (m, 1H), 0.91 (s, 9H); LCMS m/z 417.2 [M+H].sup.+.

Example 75

3-(3-(5-(cis-4-(Trifluoromethyl)cyclohexyloxy)pyridin-2-yl)benzylamino)propanoic acid

(170) ##STR00105##

(171) Following the same condition as in Example 1, 21 and 24, the title compound was obtained as a yellow oil (150 mg, 70% yield). LCMS m/z 423.2 [M+1].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.49 (s, 1H), 8.06-7.90 (m, 4H), 7.67-7.64 (m, 2H), 4.88 (bs, 1H), 4.31 (s, 2H), 3.35 (t, J=6.4 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H), 2.30 (bs, 1H), 2.19 (bs, 2H), 1.82-1.75 (m, 6H).

Example 76

3-(3-(5-(cis-4-(Trifluoromethyl)cyclohexyloxy)pyrimidin-2-yl)benzylamino)propanoic acid

(172) ##STR00106##

(173) Following the same condition as in Example 1, 21 and 24, the title compound was obtained as a yellow oil (160 mg, 65% yield). LCMS m/z 424.2 [M+1].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.56 (s, 2H), 8.49 (s, 1H), 8.40 (d, J=7.2 Hz, 1H), 7.60-7.54 (m, 2H), 4.84 (bs, 1H), 4.33 (s, 2H), 3.34 (t, J=6.8 Hz, 2H), 2.80 (t, J=6.8 Hz, 2H), 2.28-2.15 (m, 3H), 1.80-1.72 (m, 6H).

Example 77

2-(1-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)azetidin-3-yl)acetic acid

Step 1 Methyl 2-(1-(4-bromothiazol-2-yl)azetidin-3-yl)acetate

(174) ##STR00107##

(175) To a mixture of 2,4-dibromo-thiazole (190 mg, 0.78 mmol) and azetidin-3-yl-acetic acid methyl ester HCl salt (130 mg, 0.78 mmol) in acetonitrile (1.0 mL) was added N, N-diisopropylethylamine (273 μL, 1.57 mmol). The reaction mixture was heated with microwave irritation at 120° C. for 30 min. More azetidin-3-yl-acetic acid methyl ester HCl salt (170 mg) and N,N-diisopropylethylamine (300 μL) were added, and the mixture was heated with microwave irritation at 120° C. for 1 hr. The reaction mixture was partitioned between EtOAc and saturated aqueous NH.sub.4Cl. The organic phase was dried over MgSO.sub.4, filtered, and concentrated. The residue was purified by silica gel column to give the desired product as a tan colored solid (189 mg, 83% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.85 (s, 1H), 4.11 (t, J=8.16 Hz, 2H), 3.71 (dd, J=6.02, 8.03 Hz, 2H), 3.60 (s, 3H), 2.99-3.15 (m, 1H), 2.76 (d, J=7.78 Hz, 2H); LCMS m/z 290.9; 293.0 [M+H].sup.+.

Step 2 2-(1-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)azetidin-3-yl)acetic acid

(176) ##STR00108##

(177) 2-[4-(4-tert-Butyl-cyclohexyloxy)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg, 0.1 mmol), [1-(4-bromo-thiazol-2-yl)-azetidin-3-yl]-acetic acid methyl ester (48.8 mg, 0.167 mmol), and tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol) were added to microwave vial. Under nitrogen, 1,2-dimethoxyethane (0.5 mL), ethanol (0.25 mL), and saturated aqueous sodium bicarbonate solution (137 μL, 1.40 mmol) were added. The mixture was heated with microwave irritation at 120° C. for 45 min. The reaction mixture was filtered through celite and concentrated. It was purified by HPLC (TFA method) to collect desired acid as an off-white powder after lyophilization (15 mg, 20% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.59 (d, J=8.78 Hz, 2H), 6.97 (d, J=8.78 Hz, 2H), 6.86 (s, 1H), 4.46 (t, J=8.78 Hz, 2H), 4.18-4.31 (m, 1H), 3.99-4.11 (m, 2H), 2.79 (d, J=7.78 Hz, 2H), 2.20 (d, J=10.79 Hz, 2H), 1.89 (d, J=13.05 Hz, 2H), 1.03-1.46 (m, 5H), 0.90 (s, 9H); LCMS m/z 429.2 [M+H].sup.+.

Example 78

1-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)piperidine-4-carboxylic acid

Step 1 Methyl 1-(4-bromothiazol-2-yl)piperidine-4-carboxylate

(178) ##STR00109##

(179) To a mixture of 2,4-dibromo-thiazole (121 mg, 0.50 mmol) and piperidine-4-carboxylic acid methyl ester (72 mg, 0.50 mmol) in acetonitrile (0.5 mL) was added N,N-diisopropylethylamine (87 μL, 0.50 mmol). The reaction mixture was heated with microwave irritation at 120° C. for 20 min. The reaction mixture was partitioned between EtOAc and saturated aqueous NH.sub.4Cl. The organic phase was dried over MgSO.sub.4, filtered, and concentrated. The residue was purified by silica gel column to give the desired product as a white solid (85 mg, 56% yield). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 6.61 (s, 1H), 3.89 (td, J=3.82, 13.50 Hz, 2H), 3.71 (s, 3H), 3.10-3.24 (m, 2H), 2.57-2.74 (m, 1H), 1.93-2.09 (m, 2H), 1.64-1.86 (m, 2H); LCMS m/z 305.0; 307.0 [M+H].sup.+.

Step 2 1-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)thiazol-2-yl)piperidine-4-carboxylic acid

(180) ##STR00110##

(181) The titled compound was synthesized according to the procedure described in Example 21, Step 2 (14 mg, 30% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.32 (m, 1H), 7.74 (d, J=8.78 Hz, 2H), 7.06 (s, 1H), 6.93 (d, J=8.78 Hz, 2H), 4.15-4.22 (m, OH), 4.27 (br. s., OH), 3.89 (d, J=13.05 Hz, 2H), 2.99-3.22 (m, 2H), 2.13 (d, J=10.29 Hz, 2H), 1.95 (dd, J=2.64, 13.18 Hz, 2H), 1.79 (d, J=12.05 Hz, 2H), 1.52-1.69 (m, J=9.29 Hz, 1H), 1.00-1.39 (m, 5H), 0.87 (s, 9H); LCMS m/z 443.2 [M+H].sup.+.

Example 79

Ethyl 3-((4-bromothiazol-2-yl)methylamino)propanoate

(182) ##STR00111##

(183) A mixture of 4-bromothiazole-2-carbaldehyde (1.91 g, 10.0 mmol, 1.0 eq), ethyl 3-aminopropanoate HCl (1.75 g, 15.0 mmol, 1.5 eq) in DCE (30 mL) was stirred at 80° C. for 2 h. The mixture was cooled down to rt, and NaBH(AcO).sub.3 (5.3 g, 25.0 mmol, 2.5 eq) was added, the resultant mixture was stirred at rt for 2 h. The reaction mixture was diluted with EA (60 mL), followed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE/EA=5/1) to give the title compound as a yellow oil (1.1 g, 37% yield). LCMS m/z 293.0 [M+H].sup.+.

Example 80

Ethyl 3-((4-(4-hydroxyphenyl)thiazol-2-yl)methylamino)propanoate

(184) ##STR00112##

(185) A mixture of ethyl 3-((4-bromothiazol-2-yl)methylamino)propanoate (2.2 g, 7.53 mmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.4 g, 11.3 mmol, 1.5 eq), Pd(dppf)Cl.sub.2 (610 mg, 0.75 mmol, 0.1 eq) and K.sub.2CO.sub.3 (2.1 g, 16.6 mmol, 2.0 eq) in mixed solvents (toluene/EtOH/H.sub.2O, 5/2/2, 9 mL) was stirred at 80° C. under N.sub.2 for 16 h. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (PE/EA=1/1) to give the title compound as a yellow solid (1.02 g, 45% yield). LCMS m/z 306.9 [M+H].sup.+.

Example 81

3-((4-(4-(cis-4-tert-Butylcyclohexyloxy)phenyl)thiazol-2-yl)methylamino)propanoic acid

(186) ##STR00113##

(187) A mixture of ethyl 3-((4-(4-hydroxyphenyl)thiazol-2-yl)methylamino)propanoate (120 mg, 0.40 mmol, 1.0 eq), trans-4-tert-butylcyclohexanol (125 mg, 0.8 mmol, 2.0 eq) and PPh.sub.3 (210 mg, 0.8 mmol, 2.0 eq) in THF (0.8 mL) was stirred at rt for 15 min. Then DIAD (161 mg, 0.8 mmol, 2.0 eq) was added dropwise and the resulting mixture was stirred at rt for 16 h. The organic solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (PE/EA=2/1) to give ethyl 3-((4-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)thiazol-2-yl)methylamino)propanoic acid as a white solid (100 mg, 57%). LCMS m/z 445.0 [M+H].sup.+.

(188) A mixture of ethyl 3-((4-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)thiazol-2-yl)methylamino)propanoic acid (100 mg, 0.22 mmol, 1.0 eq) and LiOH H.sub.2O (37 mg, 0.88 mmol, 4 eq) in EtOH/H.sub.2O (4/1, 2.5 mL) was stirred at rt for 16 h. The mixture was then adjusted to pH=6 with dilute HCl solution (2 N), and the resulting mixture was purified with pre-HPLC (CH.sub.3CN/H.sub.2O with 0.05% TFA as mobile phase; from 5% to 95%) to give the title compound as a white solid (14 mg, 14% yield). LCMS m/z 416.9 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 8.89 (bs, 1H), 7.89-7.85 (m, 3H), 6.99 (d, J=9.2 Hz, 2H), 4.64 (s, 1H), 4.26 (s, 2H), 3.00 (t, J=7.2 Hz, 2H), 2.54-2.53 (m, 2H), 2.03-1.99 (m, 2H), 1.54-1.48 (m, 4H), 1.38-1.28 (m, 2H), 1.11-1.05 (m, 1H), 0.86 (s, 9H).

Example 82

3-((4-(4-(cis-4-Methylcyclohexyloxy)phenyl)thiazol-2-yl)methylamino)propanoic acid

(189) ##STR00114##

(190) Following the same conditions as in Example 83, the title compound was obtained as a white solid (80 mg, 43%). LCMS m/z 374.9 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.91 (d, J=8.8 Hz, 2H), 7.79 (s, 1H), 6.99 (s, J=8.8 Hz, 2H), 4.67 (s, 2H), 4.62-4.61 (m, 1H), 3.46 (t, d, J=6.4 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H), 2.03-1.99 (m, 2H), 1.67-1.60 (m, 2H), 1.55-1.51 (m, 3H), 1.46-1.37 (m, 2H), 0.96 (d, J=6.0 Hz, 3H).

Example 83

3-((4-(4-(cis-4-(Trifluoromethyl)cyclohexyloxy)phenyl)thiazol-2-yl)methylamino)propanoic acid

(191) ##STR00115##

(192) Following the same conditions as in Example 83, the title compound was obtained as a yellow oil (17 mg, 25% yield). LCMS m/z 429.2 [M+H].sup.+; .sup.1H NMR (CD.sub.3OD, 400 MHz) δ: 7.92 (d, J=8.8 Hz, 2H), 7.78 (s, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.69-4.68 (m, 1H), 4.66 (s, 2H), 3.44 (t, J=6.6 Hz, 2H), 2.79 (t, J=6.6 Hz, 2H), 2.30-2.22 (m, 1H), 2.16-2.12 (m, 2H), 1.78-1.61 (m, 6H).

Example 84

3-((4-(4-(trans-4-Methylcyclohexyloxy)phenyl)thiazol-2-yl)methylamino)propanoic acid

(193) ##STR00116##

(194) Following the same conditions as in Example 83, the title compound was obtained as a white solid (60 mg, 24%). LCMS m/z 374.9 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.90 (d, J=8.8 Hz, 2H), 7.77 (s, 1H), 6.96 (d, J=8.8 Hz, 2H), 4.65 (s, 2H), 4.30-4.23 (m, 1H), 3.43 (t, d, J=6.8 Hz, 2H), 2.76 (t, J=6.8 Hz, 2H), 2.16-2.13 (m, 2H), 1.82-1.79 (m, 2H), 1.49-1.39 (m, 3H), 1.19-1.09 (m, 2H), 0.95 (d, J=5.6 Hz, 3H).

Example 85

3-((4-(4-(4,4-Dimethylcyclohexyloxyl)phenyl)thiazol-2-yl)methylamino)propanoic acid

(195) ##STR00117##

(196) Following the same conditions as in Example 83, the title compound was obtained as a white solid (80 mg, 42%). LCMS m/z 388.9 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 10.38 (bs, 1H), 8.04 (s, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.62 (s, 2H), 4.42-4.36 (m, 1H), 3.28 (t, d, J=7.2 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 1.86-1.81 (m, 2H), 1.64-1.55 (m, 2H), 1.48-1.44 (m, 2H), 1.33-1.26 (m, 2H), 0.94 (d, J=4.0 Hz, 6H).

Example 86

3-((4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)thiazol-2-yl)methylamino)propanoic acid

(197) ##STR00118##

(198) Following the same conditions as in Example 83, the title compound was obtained as a white solid (85 mg, 42%). LCMS m/z 415.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 10.33 (bs, 1H), 8.05 (s, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.65 (s, 2H), 4.45-4.39 (m, 1H), 3.30 (t, d, J=7.2 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 1.88-1.84 (m, 2H), 1.59-1.53 (m, 8H), 1.45-1.34 (m, 6H).

Example 87

Ethyl 1-(6-chloropyrimidin-4-yl)piperidine-4-carboxylate

(199) ##STR00119##

(200) A mixture of 4,6-dichloropyrimidine (600 mg, 4.0 mmol, 1.0 eq), ethyl piperidine-4-carboxylate (636 mg, 4.0 mmol, 1.0 eq) and NaHCO.sub.3 (672 mg, 8.0 mmol, 2.0 eq) in 1,4-dioxane (10 mL) was heated to 60° C. and stirred for 16 h. After cooling down to rt, the resulting mixture was filtered and the filtrate was evaporated under reduced pressure to give the residue, which was purified by column chromatography on silica gel (PE/EA=10/1) to give the title compound as a yellow solid (896 mg, 82% yield). LCMS m/z 270.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.36 (d, J=0.4 Hz, 1H), 6.52 (d, J=0.8 Hz, 1H), 4.26-4.24 (m, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.15-3.08 (m, 2H), 2.64-2.59 (m, 1H), 2.03-1.98 (m, 2H), 1.79-1.70 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).

Example 88

1-(6-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)pyrimidin-4-yl)piperidine-4-carboxylic acid

(201) ##STR00120##

(202) Following the same conditions as in Examples 54 and 23, the title compound was obtained as a white solid (67 mg, 35% yield). LCMS m/z 438.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.62 (s, 1H), 7.73 (d, J=9.2 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.75 (s, 1H), 4.34-4.16 (m, 3H), 3.38-3.28 (m, 2H), 2.64-2.63 (m, 1H), 2.14-1.96 (m, 4H), 1.82-1.75 (m, 4H), 1.35-0.99 (m, 5H), 0.79 (s, 9H).

Example 89

1-(6-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)-5-chloropyrimidin-4-yl)piperidine-4-carboxylic acid

(203) ##STR00121##

(204) Following the same conditions as in Examples 90, 54 and 23, the title compound was obtained as a yellow solid (42 mg, 35% yield). LCMS m/z 472.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.47 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.29-4.25 (m, 3H), 3.22-3.15 (m, 2H), 2.63-2.62 (m, 1H), 2.25-2.22 (m, 2H), 2.08-2.03 (m, 2H), 1.92-1.84 (m, 4H), 1.42-1.10 (m, 5H), 0.90 (s, 9H).

Example 90

1-((6-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)imidazo[1,2-b]pyridazin-2-yl)methyl)piperidine-4-carboxylic acid

(205) ##STR00122##

Step 1 Methyl 1-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)piperidine-4-carboxylate

(206) ##STR00123##

(207) To a mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (101 mg, 0.500 mmol), sodium carbonate (53.0 mg, 0.500 mmol) and piperidine-4-carboxylic acid methyl ester (71.6 mg, 0.500 mmol) was added methanol (2 mL). The mixture was heated with microwave irritation at 100° C. for 40 min, and then partitioned between EtOAc and saturated NaHCO.sub.3 Solution. The organic phase was dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography on silica gel column to give the title compound as a pale yellow oil (101 mg, 65% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.08 (s, 1H), 7.97 (d, J=9.54 Hz, 1H), 7.28 (d, J=9.54 Hz, 1H), 3.74 (s, 2H), 3.65 (s, 3H), 2.96 (d, J=11.80 Hz, 2H), 2.30-2.41 (m, 1H), 2.16-2.27 (m, 2H), 1.84-1.97 (m, 2H), 1.64-1.81 (m, 2H); LCMS m/z 309.1 [M+H].sup.+.

Step 2 1-((6-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)imidazo[1,2-b]pyridazin-2-yl)methyl)piperidine-4-carboxylic acid

(208) ##STR00124##

(209) To a mixture of 2-[4-(4-tert-butyl-cyclohexyloxy)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (35.8 mg, 0.100 mmol), 1-(6-chloro-imidazo[1,2-b]pyridazin-2-ylmethyl)-piperidine-4-carboxylic acid methyl ester (30.9 mg, 0.100 mmol) and tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol) were added ethanol (200 μL), followed by 1,2-dimethoxyethane (300 μL), and saturated aqueous sodium bicarbonate solution (100 μL). The reaction mixture was heated with microwave irritation at 130° C. for 30 min. The mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography on silica gel column to obtain the desired ester as a white solid (28 mg, 56% yield). LCMS m/z 505.3 [M+H].sup.+

(210) To the above ester in methanol (2 mL) and THF (2 mL) was added 3 N of NaOH in water (50 μL). The mixture was heated at 80° C. for 30 min. It was neutralized with 1N HCl (150 μL), partitioned between EtOAc and saturated NH.sub.4Cl solution. The aqueous layer was extracted with EtOAc (×3). The combined organic phases were dried over MgSO.sub.4, filtered and concentrated. It was purified by HPLC (TFA method) to the TFA salt of the desired product as a white solid (18 mg, 30% yield). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 8.33 (s, 1H), 8.08 (d, J=9.82 Hz, 1H), 8.01 (d, J=8.69 Hz, 2H), 7.84 (d, J=9.82 Hz, 1H), 7.08 (d, J=9.06 Hz, 2H), 4.52 (s, 2H), 4.22-4.42 (m, 1H), 3.48-3.93 (m, 2H), 3.04-3.28 (m, 2H), 2.51-2.86 (m, 1H), 2.12-2.45 (m, 4H), 1.73-2.12 (m, 4H), 1.03-1.60 (m, 5H), 0.93 (s, 9H); LCMS m/z 491.3 [M+H].sup.+.

Example 91

1-Azido-4-(trans-4-tert-butylcyclohexyloxy)benzene

(211) ##STR00125##

(212) A mixture of 1-bromo-4-(trans-4-tert-butylcyclohexyloxy)benzene (508 mg, 1.64 mmol, 1.0 eq), NaN.sub.3 (213 mg, 3.28 mmol, 2.0 eq), N1,N2-dimethylethane-1,2-diamine (43 mg, 0.49 mmol, 0.3 eq) and CuI (31 mg, 0.16 mmol, 0.1 eq) in mixed solvents (EtOH/H.sub.2O, 7/3, 5 mL) was heated to 100° C. and stirred for 1 h under N.sub.2. After cooling down to rt, the mixture was diluted with DCM (20 mL), washed with water (20 mL X 2) and brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure. And the residue was purified by Prep-TLC (PE/EA=20/1) to give the title compound as a yellow solid (317 mg, 71% yield). LCMS: m/z 276.0 [M+3H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 6.95-6.86 (m, 4H), 4.09-4.01 (m, 1H), 2.18-2.15 (m, 2H), 1.87-1.84 (m, 2H), 1.42-1.33 (m, 2H), 1.16-1.03 (m, 3H), 0.87 (s, 9H).

Example 92

Ethyl 1-((1-(4-(trans4-tert-butylcyclohexyloxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)piperidine-4-carboxylate

(213) ##STR00126##

(214) A mixture of 3-bromoprop-1-yne (142 mg, 1.2 mmol, 1.2 eq), ethyl piperidine-4-carboxylate (188 mg, 1.2 mmol, 1.2 eq) and TEA (202 mg, 2.0 mmol, 2.0 eq) in H.sub.2O (4 mL) was stirred vigorously for 1 h at rt. Then, 1-azido-4-((1R,4R)-4-tert-butylcyclohexyloxy)benzene (273 mg, 1.0 mmol, 1.0 eq) and CuI (19 mg, 0.1 mmol, 0.1 eq) were added into the mixture. The resulting mixture was then stirred at rt for additional 16 h. The reaction was diluted with water (20 mL), and extracted with DCM (25 mL X 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by pre-TLC (DCM/MeOH=10/1) to give the title compound as a yellow solid (300 mg, 32% yield). LCMS: m/z 496.4 [M+H].sup.+.

Example 93

1-((1-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)piperidine-4-carboxylic acid

(215) ##STR00127##

(216) To a stirred mixture of ethyl 1-((1-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)piperidine-4-carboxylate (60 mg, 0.13 mmol, 1.0 eq) in mixed solvents (THF/H.sub.2O, 8/1, 2 mL) was added LiOH H.sub.2O (10 mg, 0.26 mmol, 2.0 eq). The mixture was stirred at rt for 16 h. The reaction mixture was then adjusted to pH=6 with dilute aq. HCl. The solvent was removed in vacuo and the residue was purified by pre-HPLC (MeOH/H.sub.2O from 30% to 95%, containing 0.05% TFA) to give the title compound as a yellow solid (10 mg, 18% yield). LCMS: m/z 441.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 8.63 (s, 1H), 7.77 (d, J=9.2 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 4.35-4.28 (m, 1H), 3.73 (bs, 2H), 2.91 (bs, 2H), 2.23-2.13 (m, 4H), 1.84-1.78 (m, 4H), 1.62-1.54 (m, 2H), 1.36-1.02 (m, 6H), 0.86 (m, 9H).

Example 94

4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid

(217) ##STR00128##

(218) The titled compound was synthesized according to the procedure described in Example 78 (12 mg, yield 27%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.30-7.38 (m, 2H), 7.18-7.28 (m, 1H), 6.94 (s, 1H), 6.84 (dd, J=1.51, 8.03 Hz, 1H), 4.13-4.29 (m, 1H), 4.01 (td, J=3.67, 12.99 Hz, 2H), 3.10-3.25 (m, 2H), 2.60 (tt, J=3.76, 10.92 Hz, 1H), 2.21 (d, J=10.04 Hz, 2H), 1.99-2.11 (m, 2H), 1.74-1.92 (m, 4H), 1.14-1.45 (m, 4H), 1.03-1.13 (m, 1H), 0.90 (s, 9H); LCMS m/z 443.2 [M+H].sup.+

Example 95

3-4(4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid

(219) ##STR00129##

(220) The titled compound was synthesized according to the procedure described in Example 57 (14 mg, yield 53%). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 7.58 (dt, J=1.89, 7.74 Hz, 1H), 7.41-7.51 (m, 3H), 7.28-7.38 (m, 1H), 6.93-7.04 (m, 2H), 4.38 (s, 2H), 4.16-4.31 (m, 1H), 3.33-3.39 (m, 2H), 2.78 (t, J=6.61 Hz, 2H), 2.16-2.30 (m, 2H), 1.80-1.97 (m, 2H), 1.03-1.49 (m, 5H), 0.91 (s, 9H); LCMS m/z 428.3 [M+H].sup.+

Example 96

(S)-1-(4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenylcarbonyl)pyrrolidine-3-carboxylic acid

Step 1: 4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenyl-4-carbaldehyde

(221) ##STR00130##

(222) Into a solution of 4′-hydroxybiphenyl-4-carbaldehyde (6.0 g, 30 mmol) in t-BuOH (50 mL) was added Cs.sub.2CO.sub.3 (19.8 g, 61 mmol, 2.0 eq) and 4-(trifluoromethyl)cyclohexyl methanesulfonate (15.0 g, 61 mmol, 2.0 eq). The reaction mixture was heated at reflux for 48 h and cooled down. The mixture was filtered and cake was washed with THF. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=10/1) to give the title compound as a gray solid (4.3 g, 41% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) δ: 10.04 (s, 1H), 7.92 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 4.25 (s, 1H), 2.31-2.28 (m, 2H), 2.09-2.04 (m, 2H), 1.52-1.46 (m, 5H).

Step 2: 4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenyl-4-carboxylic acid

(223) ##STR00131##

(224) Into a solution of 4′-(4-(trifluoromethyl)cyclohexyloxy)biphenyl-4-carbaldehyde

(225) (3.9 g, 11 mmol) in 21 mL of EtOH/H.sub.2O (6:1) was added NaOH (3.1 g, 77 mmol, 7.0 eq) and AgNO.sub.3 (2.8 g, 16.5 mmol, 1.5 eq). The resulting mixture was stirred for 1 h at rt and filtered. The filtrate was concentrated and the resulting aqueous layer was acidified to pH=4 with 1N HCl. The white solid was collected by filtration to give the title compound as a white solid (4.0 g, 93% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ: 12.45 (br s, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 4.73 (s, 1H), 2.45-2.33 (m, 1H), 2.15-1.96 (m, 3H), 1.71-1.60 (m, 5H).

Step 3: (S)-1-(4′-(4-(Trifluoromethyl)cyclohexyloxy)biphenylcarbonyl) pyrrolidine-3-carboxylic acid

(226) ##STR00132##

(227) Into a solution of 4′-(4-(trifluoromethyl)cyclohexyloxy)biphenyl-4-carboxylic acid (80 mg) in DCM (3 mL) was added DIPEA (2.5 eq), HATU (1.5 eq). The mixture was stirred at rt for 2 h and (S)-methyl pyrrolidine-3-carboxylate (1.2 eq) was added. The mixture was stirred at rt for 16 h and concentrated. The residue was purified by preparative HPLC to give the title condensation product.

(228) The condensation product was dissolved in 6 mL of THF/H.sub.2O (2/1) and NaOH (3.0 eq) was added. The resulting mixture was stirred at 78° C. until the ester was completely converted to corresponding acid. THF was removed and the aqueous solution was acidified to adjusted pH=6 with 1N HCl. The solid was collected by filtration and washed with water to give the title compound (31 mg) LCMS [M+H].sup.+: 462.2. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ: 7.69-7.55 (m, 6H), 7.07 (d, J=8.7 Hz, 2H), 4.72 (s, 1H), 3.67-3.62 (m, 2H), 3.54-3.49 (m, 2H), 3.10-3.06 (m, 2H), 2.50-2.40 (m, 1H), 2.17-1.99 (m, 4H), 1.71-1.62 (m, 5H).

(229) The following examples of Table 1 were prepared according to the procedures substantially as described in Example 96.

(230) TABLE-US-00002 TABLE 1 LCMS [M + No. Name Structure H].sup.+ 97 1-(4′-(4- (Trifluoro- methyl) cyclohexyl- oxy)biphenyl- carbonyl) piperidine-4- carboxylic acid 476.3 1H NMR (400 MHz, METHANOL-d4) d ppm 7.57 (dd, J = 8.16, 2.64 Hz, 2 H) 7.48 (t, J = 8.50 Hz, 2 H) 7.35 (d, J = 8.03 Hz, 2 H) 6.93 (t, J = 9.04 Hz, 2 H) 4.58 (t, J = 2.00 Hz, 1 H) 4.28-4.46 (m, 1 H) 4.12-4.28 (m, 1 H) 3.70 (br.s, 1 H) 2.88- 3.17 (m, 2 H) 2.43-2.64 (m, 1 H) 2.00-2.24 (m, 2 H) 1.74-1.99 (m, 2 H) 1.49-1.73 (m, 7 H) 1.40 (s, 1 H) 98 2-(1-(4′-(4- (Trifluoro- methyl) cyclohexyl- oxy)biphenyl- carbonyl) azetidin-3- yl)acetic acid 462.3 1H NMR (400 MHz, METHANOL-d4) d ppm 7.66- 7.77 (m, 4 H) 7.58-7.66 (m, 2 H) 7.00-7.12 (m, 2 H) 4.71 (d, J = 2.51 Hz, 1 H) 4.57 (t, J = 8.78 Hz, 1 H) 4.28-4.42 (m, 1 H) 4.16 (dd, J = 8.78, 6.02 Hz, 1 H) 3.91 (dd, J = 10.16, 5.90 Hz, 1 H) 2.99-3.13 (m, 1 H) 2.73 (d, J = 7.78 Hz, 2 H) 1.99-2.38 (m, 3 H) 1.40-1.89 (m, 6 H) 99 3-(4′-(4- (Trifluoro- methyl) cyclohexyl- oxy)biphenyl- 4-yl- carboxamido) propanoic acid 436.2 100 1-(4′-(4- (Trifluoro- methyl) cyclohexyl- oxy)biphenyl- carbonyl) azetidine-3- carboxylic acid 448.3 1H NMR (400 MHz, METHANOL-d4) d ppm 7.60 (s, 4 H) 7.50 (s, 2 H) 6.88-6.99 (m, 2 H) 4.55-4.63 (m, 1 H) 4.36-4.53 (m, 2 H) 4.14-4.34 (m, 2 H) 3.38-3.54 (m, 1 H) 1.87- 2.23 (m, 3 H) 1.29-1.76 (m, 6 H)

Example 101

(4-bromophenoxy)(tert-butyl)dimethylsilane

(231) ##STR00137##

(232) To a solution of 4-bromophenol (15.5 g, 90.1 mmol) in 60 mL of DMF were added imidazole (12.26 g, 180.2 mmol, 2.0 eq) and TBSCl (2.03 g, 135.2 mmol, 1.5 eq). The mixture was stirred at rt for 16 h. The mixture was diluted with 200 mL of water and extracted with DCM (2×200 mL). The combined organic phase was dried over Na.sub.2SO.sub.4. After concentration, the residue was purified by column chromatography on silica gel (PE/EA=10/1) to afford (4-bromophenoxy)(tert-butyl)dimethylsilane as a yellow solid (23.3 g, yield: 90%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.23-7.20 (m, 2H), 6.63-6.60 (m, 2H), 0.88 (s, 9H), 0.09 (s, 6H).

Example 102

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

(233) ##STR00138##

(234) A mixture of (4-bromophenoxy)(tert-butyl)dimethylsilane (10.0 g, 34.9 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (17.8 g, 69.8 mmol, 2.0 eq), KOAc (6.85 g, 69.8 mmol, 2.0 eq) and Pd(dppf)Cl.sub.2 DCM (5.11 g, 6.98 mmol, 0.2 eq) in 1,4-dioxane/DMSO (4/1, 30 mL) was stirred at 90° C. for 16 h under N.sub.2. After cooling down to rt, the resulting mixture was filtrated and the filtrate was diluted with water (15 mL), extracted with EA (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (PE/EA=20/1) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol as a yellow solid (7.3 g, yield: 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.71 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 1.33 (s, 12H).

Example 103

2-fluoro-4′-hydroxy-[1,1′-biphenyl]-3-carbaldehyde

(235) ##STR00139##

(236) A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.2 g, 5.45 mmol), 3-bromo-2-fluorobenzaldehyde (1.1 g, 5.4 5 mmol, 1.0 eq), K.sub.2CO.sub.3 (1.5 g, 10.9 mmol, 2.0 eq) and Pd(PPh.sub.3).sub.4 (314 mg, 0.27 mmol, 0.05 eq) in 1,4-dioxane/H.sub.2O (6/1, 14 mL) was stirred at 95° C. for 2 h under microwave. After cooling down to rt, the resulting mixture was filtrated and the filtrate was diluted with water (30 mL), extracted with EA (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (PE/EA=10/1) to give 2-fluoro-4′-hydroxy-[1,1′-biphenyl]-3-carbaldehyde as yellow oil (883 mg, yield: 75%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.44 (s, 1H), 7.85-7.81 (m, 1H), 7.69-7.67 (m, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.34-7.29 (m, 1H), 6.96 (d, J=8.4 Hz, 2H), 5.10 (br, 1H).

Example 104

2-fluoro-4′-3-carbaldehyde

(237) ##STR00140##

(238) To a mixture of 2-fluoro-4′-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (600 mg, 2.78 mmol) and K.sub.2CO.sub.3 (767 mg, 5.56 mmol, 2.0 eq) in 5 mL of DMF was added spiro[3.5]nonan-7-yl methanesulfonate (727 mg, 3.34 mmol, 1.2 eq). The reaction mixture was stirred at 100° C. for 16 h and diluted with 15 mL of water. The resulting mixture was extracted with DCM (2×30 mL). The combined organic phase was dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (PE/EA=20/1) to afford 2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-carbaldehyde as yellow oil (252 mg, yield: 27%).

Example 105

1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid

(239) ##STR00141##

(240) A mixture of 2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-carbaldehyde (80 mg, 0.24 mmol) and methyl azetidine-3-carboxylate (33 mg, 0.28 mmol, 1.2 eq) in DCE (5 mL) was stirred at 60° C. for 2 h. Then, NaBH(OAc).sub.3 (102 mg, 0.48 mmol, 2.0 eq) was added. The mixture was stirred at rt for another 2 h. After the solvent was removed in vacuo, the residue was dissolved in MeOH/H.sub.2O (2 mL/6 mL). NaOH (19 mg, 0.48 mmol, 2.0 eq) was added. The mixture was stirred at 100° C. for 16 h. The resulting mixture was adjusted to PH=6 with 3 N HCl and extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4. After concentration, the residue was purified by pre-HPLC (CH.sub.3CN/water, 0.5% TFA) to give 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid as a white solid (41 mg, yield: 34%). ESI-MS (M+H).sup.+: 424.2. HPLC: 98.29%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.61-7.57 (m, 1H), 7.48-7.44 (m, 3H), 7.36-7.31 (m, 1H), 7.00 (d, J=8.8 Hz, 2H), 4.58 (s, 2H), 4.45-4.34 (m, 5H), 3.75-3.71 (m, 1H), 1.91-1.76 (m, 10H), 1.61-1.33 (m, 4H).

Example 106

1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid

(241) ##STR00142##

(242) The preparation of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl pyrrolidine-3-carboxylate as the starting amine. 50 mg, yellow solid, yield: 51%. ESI-MS (M+H).sup.+: 438.2. HPLC: 94.06%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.61-7.57 (m, 1H), 7.53-7.46 (m, 3H), 7.36-7.31 (m, 1H), 6.99 (d, J=8.0 Hz, 2H), 4.55 (s, 2H), 4.35-4.30 (m, 1H), 3.70-3.31 (m, 5H), 2.45-2.35 (m, 2H), 1.92-1.75 (m, 10H), 1.60-1.43 (m, 4H).

Example 107

1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid

(243) ##STR00143##

(244) The preparation of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-3-carboxylate as the starting amine. 38 mg, white solid, yield: 36%. ESI-MS (M+H).sup.+: 452.3. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.46-7.42 (m, 1H), 7.37-7.34 (m, 3H), 7.21-7.17 (m, 1H), 6.84 (d, J=8.4 Hz, 2H), 4.24-4.18 (m, 3H), 3.09-3.05 (m, 4H), 2.56-2.54 (m, 1H), 1.81-1.64 (m, 14H), 1.49-1.32 (m, 4H).

Example 108

1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid

(245) ##STR00144##

(246) The preparation of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-4-carboxylate as the starting amine. 49 mg, yellow solid, yield: 46%. ESI-MS (M+H).sup.+: 452.3. HPLC: 97.42%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.65-7.60 (m, 1H), 7.52-7.48 (m, 3H), 7.38-7.34 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.46 (s, 2H), 4.38-4.33 (m, 1H), 3.63-3.61 (m, 2H), 3.16-3.14 (m, 2H), 2.66-2.64 (m, 1H), 2.25-2.22 (m, 2H), 1.95-1.77 (m, 12H), 1.62-1.44 (m, 4H).

Example 109

2-(((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid

(247) ##STR00145##

(248) The preparation of 2-(((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl 2-aminoacetate as the starting amine. 78 mg, white solid, yield: 48%. ESI-MS (M+H).sup.+: 397.9. HPLC: 96.07%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.44-7.40 (m, 1H), 7.38-7.32 (m, 3H), 7.20 (t, J=8.0 H, 1H), 6.89 (d, J=8.8 Hz, 2H), 4.26-4.22 (m, 1H), 4.19 (s, 2H), 3.44 (s, 2H), 1.83-1.66 (m, 10H), 1.51-1.33 (m, 4H).

Example 110

8-(4-bromophenoxyl)spiro[4.5]decane

(249) ##STR00146##

(250) To a solution of spiro[4.5]decan-8-ol (2.0 g, 13.0 mmol) in toluene (20 mL) were added PPh.sub.3 (4.4 g, 16.9 mmol, 1.3 eq), 4-bromophenol (2.2 g, 13.0 mmol, 1.0 eq) and DIAD (5.2 g, 26.0 mmol, 2.0 eq). The mixture was stirred at room temperature for 3 h under N.sub.2. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (PE) to afford 8-(4-bromophenoxyl)spiro[4.5]decane as yellow oil (2.9 g, yield: 72%). ESI-MS (M+H).sup.+: 309.1.

Example 111

4,4,5,5-tetramethyl-2-(4-(spiro[4.5]decan-8-yloxy)phenyl)-1,3,2-dioxaborolane

(251) ##STR00147##

(252) The preparation of 4,4,5,5-tetramethyl-2-(4-(spiro[4.5]decan-8-yloxy)phenyl)-1,3,2-dioxaborolane was the same as that of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. 2.8 g, yellow oil, yield: 83%. ESI-MS (M+H).sup.+: 357.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.72 (d, J=9.2 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 4.32-4.30 (m, 1H), 1.90-1.87 (m, 2H), 1.62-1.57 (m, 8H), 1.47-1.34 (m, 6H), 1.32 (s, 12H).

Example 112

2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-carbaldehyde

(253) ##STR00148##

(254) The preparation of 2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-carbaldehyde was the same as that of 2-fluoro-4′-hydroxy-[1,1′-biphenyl]-3-carbaldehyde. 1.2 g, yellow oil, yield: 61%. ESI-MS (M+H).sup.+: 353.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.44 (s, 1H), 7.83-7.78 (m, 1H), 7.74-7.64 (m, 2H), 7.47-7.45 (m, 1H), 7.32-7.28 (m, 1H), 7.01-6.98 (m, 1H), 6.89-6.87 (m, 1H), 4.33-4.28 (m, 1H), 1.96-1.87 (m, 2H), 1.68-1.57 (m, 8H), 1.50-1.38 (m, 6H).

Example 113

1-((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid

(255) ##STR00149##

(256) The preparation of 1-((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl azetidine-3-carboxylate as the starting amine. 91 mg, white solid, yield: 33%. ESI-MS (M+H).sup.+: 438.3. HPLC: 94.03%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.63-7.59 (m, 1H), 7.49-7.44 (m, 3H), 7.37-7.33 (m, 1H), 7.02 (d, J=9.2 Hz, 2H), 4.58 (s, 2H), 4.42-4.39 (m, 5H), 3.74-3.69 (m, 1H), 1.95-1.93 (m, 2H), 1.70-1.62 (m, 8H), 1.53-1.36 (m, 6H).

Example 114

1-((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid

(257) ##STR00150##

(258) The preparation of 1-((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl pyrrolidine-3-carboxylate as the starting amine. 83 mg, white solid, yield: 35%. ESI-MS (M+H).sup.+: 452.3. HPLC: 96.61%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.65-7.61 (m, 1H), 7.51-7.48 (m, 3H), 7.39-7.35 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 4.58 (s, 2H), 4.42-4.39 (m, 1H), 3.76-3.43 (m, 5H), 2.47-2.36 (m, 2H), 1.96-1.93 (m, 2H), 1.66-1.62 (m, 8H), 1.53-1.38 (m, 6H).

Example 115

1-((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid

(259) ##STR00151##

(260) The preparation of 1-((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-3-carboxylate as the starting amine. 87 mg, white solid, yield: 42%. ESI-MS (M+H).sup.+: 466.2. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.59-7.47 (m, 4H), 7.33 (t, J=7.6 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.58 (s, 2H), 4.36-4.34 (m, 1H), 3.77-3.54 (m, 2H), 3.12-2.90 (m, 3H), 2.18-1.90 (m, 5H), 1.63-1.58 (m, 9H), 1.49-1.38 (m, 6H).

Example 116

1-((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid

(261) ##STR00152##

(262) The preparation of 1-((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-4-carboxylate as the starting amine. 63 mg, white solid, yield: 24%. ESI-MS (M+H).sup.+: 466.3. HPLC: 96.67%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.64 (t, J=7.2 Hz, 1H), 7.51-7.48 (m, 3H), 7.40-7.35 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 4.46 (s, 2H), 4.42-4.38 (m, 1H), 3.66-3.43 (m, 2H), 3.19-3.13 (m, 2H), 2.65-2.62 (m, 1H), 2.33-2.24 (m, 2H), 1.96-1.83 (m, 4H), 1.67-1.63 (m, 8H), 1.52-1.39 (m, 6H).

Example 117

2-(((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid

(263) ##STR00153##

(264) The preparation of 2-(((2-fluoro-4′-(spiro[4.5]decan-8-yloxy)-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl 2-aminoacetate as the starting amine. 27 mg, white solid, yield: 18%. ESI-MS (M+H).sup.+: 412.2. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.56-7.47 (m, 4H), 7.32 (t, J=7.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 2H), 4.40-4.37 (m, 3H), 3.90 (s, 2H), 1.94-1.92 (m, 2H), 1.68-1.63 (m, 8H), 1.51-1.37 (m, 6H).

Example 118

1-bromo-4-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)benzene

(265) ##STR00154##

(266) The preparation of 1-bromo-4-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)benzene was the same as that of 8-(4-bromophenoxyl)spiro[4.5]decane. 4.2 g, white solid, yield: 70%. ESI-MS (M+H).sup.+: 311.1.

Example 119

2-(4-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(267) ##STR00155##

(268) The preparation of 2-(4-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was the same as that of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. 3.6 g, yellow oil, yield: 74%. ESI-MS (M+H).sup.+: 359.1.

Example 120

4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-carbaldehyde

(269) ##STR00156##

(270) The preparation of 4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-carbaldehyde was the same as that of 2-fluoro-4′-hydroxy-[1,1′-biphenyl]-3-carbaldehyde. 1.3 g, yellow oil, yield: 65%. ESI-MS (M+H).sup.+: 355.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.44 (s, 1H), 7.83-7.64 (m, 3H), 7.48-7.45 (m, 1H), 7.32-7.25 (m, 1H), 7.03-6.99 (m, 1H), 6.92-6.88 (m, 1H), 4.59-4.57 (m, 1H), 2.17-2.08 (m, 2H), 1.59-1.42 (m, 6H), 1.09-1.01 (m, 1H), 0.88 (s, 9H).

Example 121

1-((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid

(271) ##STR00157##

(272) The preparation of 1-((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl azetidine-3-carboxylate as the starting amine. 46 mg, white solid, yield: 18%. ESI-MS (M+H).sup.+: 440.2. HPLC: 92.33%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.63-7.59 (m, 1H), 7.50-7.44 (m, 3H), 7.37-7.33 (m, 1H), 7.03 (d, J=8.8 Hz, 2H), 4.65-4.64 (m, 1H), 4.58 (s, 2H), 4.45-4.36 (m, 4H), 3.74-3.69 (m, 1H), 2.16-2.11 (m, 2H), 1.62-1.46 (m, 6H), 1.18-1.11 (m, 1H), 0.91 (s, 9H).

Example 122

1-((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid

(273) ##STR00158##

(274) The preparation of 1-((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl pyrrolidine-3-carboxylate as the starting amine. 65 mg, white solid, yield: 25%. ESI-MS (M+H).sup.+: 454.2. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.65-7.61 (m, 1H), 7.54-7.49 (m, 3H), 7.39-7.34 (m, 1H), 7.03 (d, J=8.4 Hz, 2H), 4.65-4.64 (m, 1H), 4.57 (s, 2H), 3.81-3.67 (m, 2H), 3.51-3.40 (m, 3H), 2.46-2.36 (m, 2H), 2.14-2.11 (m, 2H), 1.62-1.42 (m, 6H), 1.17-1.11 (m, 1H), 0.91 (s, 9H).

Example 123

1-((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid

(275) ##STR00159##

(276) The preparation of 1-((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-3-carboxylate as the starting amine. 50 mg, white solid, yield: 19%. ESI-MS (M+H).sup.+: 468.2. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.67-7.62 (m, 1H), 7.52-7.49 (m, 3H), 7.40-7.36 (m, 1H), 7.03 (d, J=8.4 Hz, 2H), 4.65-4.64 (m, 1H), 4.50 (s, 2H), 3.81-3.52 (m, 2H), 3.22-3.06 (m, 2H), 2.87-2.82 (m, 1H), 2.24-1.80 (m, 5H), 1.62-1.47 (m, 7H), 1.18-1.11 (m, 1H), 0.91 (s, 9H).

Example 124

1-((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid

(277) ##STR00160##

(278) The preparation of 1-((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-4-carboxylate as the starting amine. 52 mg, white solid, yield: 25%. ESI-MS (M+H).sup.+: 468.2. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.66-7.62 (m, 1H), 7.52-7.49 (m, 3H), 7.39-7.35 (m, 1H), 7.03 (d, J=8.8 Hz, 2H), 4.65-4.64 (m, 1H), 4.46 (s, 2H), 3.66-3.48 (m, 2H), 3.19-3.13 (m, 2H), 2.65-2.62 (m, 1H), 2.29-1.86 (m, 6H), 1.62-1.44 (m, 6H), 1.18-1.11 (m, 1H), 0.91 (s, 9H).

Example 125

2-(((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid

(279) ##STR00161##

(280) The preparation of 2-(((4′-(((1s,4s)-4-(tert-butyl)cyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl 2-aminoacetate as the starting amine. 20 mg, white solid, yield: 15%. ESI-MS (M+H).sup.+: 414.2. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.47 (t, J=7.6 Hz, 1H), 7.40-7.38 (m, 3H), 7.24-7.20 (m, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.86-4.84 (m, 1H), 4.30 (s, 2H), 3.79 (s, 2H), 2.03-2.00 (m, 2H), 1.50-1.35 (m, 6H), 1.05-1.00 (m, 1H), 0.80 (s, 9H).

Example 126

1-bromo-4-(((1s,4s)-4-ethylcyclohexyl)oxy)benzene

(281) ##STR00162##

(282) The preparation of 1-bromo-4-(((1s,4s)-4-ethylcyclohexyl)oxy)benzene was the same as that of 8-(4-bromophenoxyl)spiro[4.5]decane. 2.3 g, white solid, yield: 48%. ESI-MS (M+H).sup.+: 283.1.

Example 127

2-(4-(((1s,4s)-4-ethylcyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(283) ##STR00163##

(284) The preparation of 2-(4-(((1s,4s)-4-ethylcyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was the same as that of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. 1.9 g, yellow oil, yield: 73%. ESI-MS (M+H).sup.+: 331.2.

Example 128

4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-carbaldehyde

(285) ##STR00164##

(286) The preparation of 4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-carbaldehyde was the same as that of 2-fluoro-4′-hydroxy-[1,1′-biphenyl]-3-carbaldehyde. 1.3 g, yellow oil, yield: 58%. ESI-MS (M+H).sup.+: 327.1.

Example 129

1-((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid

(287) ##STR00165##

(288) The preparation of 1-((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl pyrrolidine-3-carboxylate as the starting amine. 48 mg, white solid, yield: 25%. ESI-MS (M+H).sup.+: 426.2. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.52-7.49 (m, 1H), 7.43-7.37 (m, 3H), 7.27-7.23 (m, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.54-4.51 (m, 1H), 4.35 (s, 2H), 3.64-3.61 (m, 1H), 3.58-3.55 (m, 1H), 3.41-3.37 (m, 2H), 3.33-3.29 (m, 1H), 2.34-2.22 (m, 2H), 2.08-1.76 (m, 3H), 1.54-1.46 (m, 3H), 1.33-1.17 (m, 5H), 0.82 (t, J=7.2 Hz, 3H).

Example 130

1-((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid

(289) ##STR00166##

(290) The preparation of 1-((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl azetidine-3-carboxylate as the starting amine. 35 mg, white solid, yield: 18%. ESI-MS (M+H).sup.+: 412.2. HPLC: 92.91%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.47-7.45 (m, 1H), 7.37-7.33 (m, 3H), 7.22 (t, J=7.6 Hz, 1H), 6.90 (d, J=8.4 Hz, 2H), 4.52-4.49 (m, 1H), 4.44 (s, 2H), 4.29-4.27 (m, 4H), 3.58-3.56 (m, 1H), 2.06-1.75 (m, 3H), 1.50-1.45 (m, 3H), 1.30-1.19 (m, 5H), 0.82 (t, J=6.8 Hz, 3H).

Example 131

1-((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid

(291) ##STR00167##

(292) The preparation of 1-((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-3-carboxylate as the starting amine. 95 mg, white solid, yield: 56%. ESI-MS (M+H).sup.+: 440.2. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.51 (t, J=7.6 Hz, 1H), 7.43-7.37 (m, 3H), 7.25 (t, J=7.6 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.52-4.50 (m, 1H), 4.37 (s, 2H), 3.65-3.44 (m, 2H), 3.03-2.79 (m, 4H), 2.08-2.05 (m, 1H), 1.92-1.75 (m, 4H), 1.54-1.46 (m, 4H), 1.30-1.18 (m, 5H), 0.82 (t, J=7.2 Hz, 3H).

Example 132

1-((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid

(293) ##STR00168##

(294) The preparation of 1-((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-4-carboxylate as the starting amine. 35 mg, white solid, yield: 18%. ESI-MS (M+H).sup.+: 440.2. HPLC: 97.71%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.51 (t, J=7.6 Hz, 1H), 7.41-7.37 (m, 3H), 7.25 (t, J=8.0 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.35-4.33 (m, 1H), 4.34 (s, 2H), 3.50-3.48 (m, 2H), 3.09-3.07 (m, 2H), 2.58-2.57 (m, 1H), 2.10-2.05 (m, 2H), 1.93-1.75 (m, 4H), 1.54-1.27 (m, 3H), 1.22-1.17 (m, 6H), 0.82 (t, J=7.2 Hz, 3H).

Example 133

2-4(4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid

(295) ##STR00169##

(296) The preparation of 2-(((4′-(((1s,4s)-4-ethylcyclohexyl)oxy)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl 2-aminoacetate as the starting amine. 39 mg, white solid, yield: 19%. ESI-MS (M+H).sup.+: 386.2. HPLC: 96.17%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.49-7.46 (m, 1H), 7.40-7.37 (m, 3H), 7.25 (t, J=7.6 Hz, 1H), 6.92 (d, J=8.4 Hz, 2H), 4.54-4.52 (m, 1H), 4.30 (s, 2H), 3.82 (s, 2H), 1.93-1.79 (m, 2H), 1.52-1.47 (m, 3H), 1.32-1.19 (m, 6H), 0.83 (t, J=7.2 Hz, 3H).

Example 134

1-bromo-4-(((1r,4r)-4-isopropylcyclohexyl)oxy)benzene

(297) ##STR00170##

(298) The preparation of 1-bromo-4-(((1r,4r)-4-isopropylcyclohexyl)oxy)benzene was the same as that of 8-(4-bromophenoxyl)spiro[4.5]decane. 1.9 g, white solid, yield: 57%. ESI-MS (M+H).sup.+: 297.1.

Example 135

2-(4-(((1r,4r)-4-isopropylcyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(299) ##STR00171##

(300) The preparation of 2-(4-(((1r,4r)-4-isopropylcyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was the same as that of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. 1.9 g, yellow oil, yield: 86%. ESI-MS (M+H).sup.+: 345.2.

Example 136

2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-carbaldehyde

(301) ##STR00172##

(302) The preparation of 2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-carbaldehyde was the same as that of 2-fluoro-4′-hydroxy-[1,1′-biphenyl]-3-carbaldehyde. 1.4 g, yellow oil, yield: 64%. ESI-MS (M+H).sup.+: 341.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.44 (s, 1H), 7.82-7.64 (m, 3H), 7.48-7.45 (m, 1H), 7.32-7.27 (m, 1H), 7.03-6.99 (m, 1H), 6.92-6.88 (m, 1H), 4.59-4.57 (m, 1H), 2.10-2.02 (m, 2H), 1.60-1.42 (m, 7H), 1.17-1.09 (m, 1H), 0.88 (t, J=8.8 Hz, 6H).

Example 137

1-((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid

(303) ##STR00173##

(304) The preparation of 1-((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl azetidine-3-carboxylate as the starting amine. 53 mg, white solid, yield: 21%. ESI-MS (M+H).sup.+: 426.2. HPLC: 97.37%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.49-7.44 (m, 1H), 7.40-7.34 (m, 3H), 7.24-7.20 (m, 1H), 6.93 (d, J=8.8 Hz, 2H), 4.55-4.53 (m, 1H), 4.35 (s, 2H), 4.16-4.06 (m, 4H), 3.39-3.32 (m, 1H), 2.00-1.96 (m, 2H), 1.55-1.35 (m, 7H), 1.13-1.06 (m, 1H), 0.84 (d, J=6.8 Hz, 6H).

Example 138

1-((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid

(305) ##STR00174##

(306) The preparation of 1-((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing methyl pyrrolidine-3-carboxylate as the starting amine. 66 mg, white solid, yield: 25%. ESI-MS (M+H).sup.+: 440.2. HPLC: 90.81%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.58-7.45 (m, 4H), 7.32-7.28 (m, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.59-4.58 (m, 1H), 4.52 (s, 2H), 3.72-3.59 (m, 2H), 3.49-3.45 (m, 2H), 3.32-3.31 (m, 1H), 2.42-2.28 (m, 2H), 2.06-2.02 (m, 2H), 1.60-1.35 (m, 7H), 1.18-1.11 (m, 1H), 0.90 (d, J=6.8 Hz, 6H).

Example 139

1-((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid

(307) ##STR00175##

(308) The preparation of 1-((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-3-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-3-carboxylate as the starting amine. 80 mg, white solid, yield: 46%. ESI-MS (M+H).sup.+: 454.3. HPLC: 100.00%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.59 (t, J=7.2 Hz, 1H), 7.50-7.44 (m, 3H), 7.35-7.31 (m, 1H), 6.98 (d, J=8.8 Hz, 2H), 4.61-4.58 (m, 1H), 4.45 (s, 2H), 3.75-3.51 (m, 2H), 3.14-2.98 (m, 2H), 2.85-2.75 (m, 1H), 2.19-1.72 (m, 6H), 1.59-1.42 (m, 7H), 1.16-1.12 (m, 1H), 0.88 (d, J=6.8 Hz, 6H).

Example 140

1-((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid

(309) ##STR00176##

(310) The preparation of 1-((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl piperidine-4-carboxylate as the starting amine. 36 mg, white solid, yield: 14%. ESI-MS (M+H).sup.+: 454.2. HPLC: 94.76%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.66-7.56 (m, 1H), 7.51-7.48 (m, 3H), 7.39-7.35 (m, 1H), 7.04-6.89 (m, 2H), 4.64-4.60 (m, 1H), 4.46-4.38 (m, 2H), 3.77-3.38 (m, 2H), 3.19-3.11 (m, 1H), 2.72-2.67 (m, 1H), 2.22-1.86 (m, 5H), 1.64-1.44 (m, 9H), 1.23-1.14 (m, 1H), 0.93 (d, J=6.8 Hz, 6H).

Example 141

2-(((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid

(311) ##STR00177##

(312) The preparation of 2-(((2-fluoro-4′-(((1r,4r)-4-isopropylcyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)acetic acid was the same as that of 1-((2-fluoro-4′-(spiro[3.5]nonan-7-yloxy)-[1,1′-biphenyl]-3-yl)methyl)azetidine-3-carboxylic acid utilizing ethyl 2-aminoacetate as the starting amine. 57 mg, white solid, yield: 24%. ESI-MS (M+H).sup.+: 400.2. HPLC: 96.49%. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.49-7.44 (m, 1H), 7.39-7.35 (m, 3H), 7.24-7.19 (m, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.52-4.50 (m, 1H), 4.30 (s, 2H), 3.88 (s, 2H), 1.97-1.92 (m, 2H), 1.52-1.33 (m, 7H), 1.09-1.04 (m, 1H), 0.81 (d, J=6.8 Hz, 6H).

Example 142

Activity Measurements

(313) S1P Receptor Activity Assays

(314) Agonist percentage activation determinations were obtained by assaying sample compounds and referencing the E.sub.max control for each receptor profiled. Antagonist percentage inhibition determinations were obtained by assaying sample compounds and referencing the control EC.sub.80 wells for each receptor profiled. The samples were run using a “Single Addition” assay protocol for the agonist and antagonist assay run. The protocol design was as follows:

(315) Compound Preparation

(316) Master stock solution: Unless specified otherwise, all sample compounds were diluted in 100% anhydrous DMSO including all serial dilutions. All control wells contained identical solvent final concentrations as did the sample compound wells.

(317) Compound plate for assay: The sample compounds were transferred from a master stock solution into a daughter plate that was used in the assay. Each sample compound was diluted into assay buffer (1×HBSS with 20 mM HEPES and 2.5 mM Probenecid) at an appropriate concentration to obtain final concentrations.

(318) Calcium Flux Assay: Agonist Assay Format

(319) Sample compounds were plated in an eight-point, four-fold dilution series in duplicate with a top concentration of 10 μM. The concentrations described here reflect the final concentration of the compounds during the antagonist assay. During the agonist assay the compound concentrations were 1.25 fold higher to allow for the final desired concentration to be achieved with further dilution by EC.sub.80 of reference agonists during the antagonist assay.

(320) Reference agonists were handled as mentioned above serving as assay control. The reference agonists were handled as described above for E.sub.max.

(321) Assay was read for 180 seconds using the FLIPR.sup.TETRA (This assay run added sample compounds and reference agonist to respective wells). At the completion of the first “Single Addition” assay run, assay plate was removed from the FLIPR.sup.TETRA and placed at 25° C. for seven (7) minutes.

(322) Calcium Flux Assay: Antagonist Assay Format

(323) Using the EC.sub.80 values determined during the agonist assay, stimulated all pre-incubated sample compound and reference antagonist (if applicable) wells with EC.sub.80 of reference agonist. Read for 180 seconds using the FLIPR.sup.TETRA (This assay added reference agonist to respective wells—then fluorescence measurements were collected to calculate percentage inhibition values).

(324) Data Processing

(325) All plates were subjected to appropriate baseline corrections. Once baseline corrections were processed, maximum fluorescence values were exported and data manipulated to calculate percentage activation, percentage inhibition and Z′.

(326) With regard to S1P1 agonist activity, the compounds of examples 4, 29, 41, 52, 58, 69, 70, and 72 had EC.sub.50 values in the range of 50 nM to 5 μM. With regard to S1P3 agonist activity, the compound of example 50 had EC.sub.50 values in the range of 50 nM to 5 μM. With regard to S1P4 antagonist activity, the compounds of examples 2-8, 10-20, 23-25, 27-29, 32, 34, 39-41, 43-45, 49, 50, 52, 55-63, 66, 67, 70-78, 81, 84, 90, 93, 95, 105, 106, 107, 108, 113, 114, 115, 116, 117,121, 122, 123, 124, 125, 129, 130, 131, 132, 133, 137, 138, 139, 140 and 141 had IC.sub.50 values in the range of 5 nM to 5 μM. With regard to S1P4 agonist activity, the compound of example 48 had EC50 value of 1 nM to 5 uM. With regard to S1P5 antagonist activity, the compounds of examples 6-7, 11, 27, 28, 39, 41 and 59 had IC.sub.50 values in the range of 50 nM to 5 μM. With regard to S1P5 agonist activity, the compounds of examples 3, 10, 24, 29, 31-33, 45, 50-52, 56-58, 60, 61, 69, 72, and 73 had IC.sub.50 values in the range of 50 nM to 5 μM.

(327) Autotaxin (ATX) Assay

(328) ATX (Autotaxin) is a 125 KDa glycoprotein with lysophospholipase D (LPLD) activity that generates the bioactive lipid lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). The ATX biochemical assay utilizes a FRET (fluorescence resonance energy transfer) technology platform. The fluorescence signal of FRET substrate FS-3 is quenched due to intra-molecular FRET of a fluorophore to a non-fluorescing quencher (Ferguson, C. G., et al., Org Lett. 2006 May 11; 8(10): 2023-2026, which is incorporated by reference in its entirety). ATX catalyzes the hydrolysis of the substrate which separates the dabsyl quencher from the fluorescein reporter, which becomes fluorescent. The reaction is monitored by a SpectraMax M5 (Molecular Devices, Sunnyvale, Calif.) with at excitation wavelength 485 nm and emission wavelength 535 nm.

(329) Reagents

(330) Fatty acid free-BSA (Sigma A8806): 10 mg/mL in H.sub.2O, stored at 4° C.

(331) 2×ATX assay buffer: 100 mM Tris, 280 mM NaCl, 10 mM KCl, 2 mM CaCl.sub.2, 2 mM MgCl.sub.2, pH 7.4.

(332) Human ATX protein: expressed and purified in house. Stored at −80° C.

(333) Substrate FS-3 (Echelon, L-2000): 100 μg in 77.74 □L H.sub.2O (1 mM stock), stored at −20° C.

(334) 384-well flat bottom plates—Corning #3575.

(335) Assay

(336) Compound dilution—All compounds were provided at 10 mM in 100% DMSO. In the first well, 2 μL of 10 mM compound was added to 78 μL of DMSO (1:40 dilution). In subsequent wells 3-fold dilution (total 10 dilutions) were performed.

(337) 1×ATX assay buffer was made up with a final concentration of 1 mg/mL fatty acid free-BSA using 2×ATX assay buffer, 10 mg/ml fatty acid free-BSA and ddH.sub.2O.

(338) ATX protein was diluted with 1×ATX assay buffer to a concentration of 1.32 μg/mL (1.32×). 38 μL was added per well to the assay plate. The final concentration of ATX in the reaction as 1.0 μg/mL.

(339) 2 μL per well of compounds was transferred to provide the desired concentration. The plate was centrifuged, then incubated at room temperature for 30 minutes on the shaker.

(340) FS-3 was diluted with 1×ATX assay buffer to a concentration of FS-3 of 10 μM (5×). Then, 10 μL was added per well to the assay plate. The final concentration of FS-3 in the reaction was 2 μM. The plate was centrifuged. The plate was kept shaking at room temperature for 2 hours. Because FS-3 substrate is light sensitive, plates were kept covered and protected from light.

(341) Fluorescence was measured using SpectraMax M5 (excitation at 485 nm/emission at 538 nm, top read).

(342) With regard to ATX activity, the compounds of examples 4, 5, 12, 15, 16, 29, 31-33, 35, 36, 43, 45, 50-52, 55, 57-61, 69-73, 75, 76, 81, 83-86, 88, 89, 93, and 96-100 had IC.sub.50 values in the range of 10 nM to 10 μM.

(343) OPC Differentiation Assay

(344) Enriched populations of oligodendrocytes were grown from post-natal day 2 (P2) female Sprague Dawley rats. The forebrain was dissected out and placed in Hank's buffered saline solution (HBSS; Invitrogen, Grand Island, N.Y.). The tissue was cut into 1 mm fragments and incubated at 37° C. for 15 minutes in 0.01% trypsin and 10 μg/mL DNase. Dissociated cells were plated on poly-L-lysine-coated T75 tissue culture flasks and grown at 37° C. for 10 days in Dulbecco's modified Eagle's medium (DMEM) with 20% fetal calf serum (Invitrogen). A2B5.sup.+ OPCs were collected by shaking the flask overnight at 200 rpm and 37° C., resulting in a 95% pure population.

(345) For the differentiation assay, 2 μM and 20 μM antagonist or the same concentrations of vehicle (DMSO) were applied to OPCs cultured in CNTF/T3 containing media. After a 3-day incubation, after a 3-day incubation, cell were lysed and then subjected to MSD (Meso Scale Discovery-R) analysis. EC50 was calculated by Prism using a nonlinear sigmoidal dose-response curve cells. Alternatively, cells were lysed in 80 μL lysis buffer (50 mM HEPES [4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid], pH 7.5, 150 mM NaCl, 1.5 mM MgCl.sub.2, 1 mM ethylene glycol tetraacetic acid [EGTA], 1% Triton X-100 and 10% glycerol) for 30 minutes at 4° C. After centrifugation at 14,000 g for 15 minutes, the supernatants were boiled in Laemmli sample buffer, subjected to 4-20% SDS-PAGE, and analyzed by Western blotting with anti-MBP, anti-myelin-associated glycoprotein (MAG), or anti-beta actin antibodies. The secondary antibodies used were anti-mouse IgG-HRP (horseradish peroxidase) and anti-rabbit IgG-HRP respectively.

(346) The compounds of examples 4, 10, 24, 62, 93, 95, 106, 114, 115, 138, 139, and 140 were positive at between 0.5 and 5 micromolar in the OPC assay.

(347) OPC Oligodendrocyte Myelination Assay

(348) Embryonic neocortical neurons are dissected from embryonic day 18 (E18) Sprague Dawley rats, and then plated on poly-D-lysine (100 μg/mL)-coated cover slips and grown in neurobasal medium supplemented with B27 (Invitrogen) for one week. A2B5.sup.+ OPCs are prepared as described above and then added into the cultured neocortical neurons. One day later, different concentrations of an S1P4 receptor antagonist and control reagents are applied into the co-cultures. Fresh media containing the different concentrations of an S1P4 receptor antagonist or control compounds are supplied every three days. After ten days, co-cultures are subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)/Western blot analyses to quantify MAG, MBP, and MOG.

(349) Remyelination Assay in Brain Slice Culture

(350) Approximately three to four consecutive 300 μm slices are taken from the junction of the corpus callosum to the hippocampus in post-natal, day 17 Sprague Dawley rats (Charles River, Willmington, Mass.). Slices are cultured in basal DMEM supplemented with 25% horse serum for three days, before being treated with 6 mg/mL LPC (Sigma L-4129) for a further three days. The medium is then changed, and slices incubated with medium containing an S1P4 receptor antagonist or vehicle control for a final period of three days, after which myelination is visualized by black gold staining (Millipore, Bedford, Mass.) following the manufacture's protocol. Images are acquired using a Leica M420 microscope (Bannockburn, Ill.) and the staining intensity of corpus callosum is analyzed using Metamorph software (Molecular Devices, Downingtown, Pa.). Three or four brain slices are used for each treatment group.

(351) Lysolecithin Demyelination Model

(352) Adult Sprague Dawley rats (220-260 g) are anesthetized by intraperitoneal injection of a cocktail, consisting of Ketamine (35 mg/kg), Xylazine (6 mg/kg) and Acepromazine (1 mg/kg). The back of the animal is shaved from the lower thoracic to the lumbar region, subsequently sanitized with 70% isopropanol, Betadine Scrub solution, and 70% isopropanol again. The animal is then placed onto stereotaxic frame.

(353) After ensuring an adequate anesthetic level, the skin is incised along the midline over the thoracic region. The dorsal fascia is incised and the paraspinal muscles separated from the spinous processes of the thoracic vertebrae T-9 through T-11. The T-10 vertebra is demolished, and the lamina removed with micro-rongeurs. Once the dorsal spinal cord region is exposed, a microcapillary glass needle is inserted into the dorsal column to a depth of 0.6 mm. The demyelinating reagent, 1.5 μL of 1% Lysolecithin (LPC, Sigma# L1381) in saline is injected with the infusion rate of 2 nL/sec controlled by a micro-pump (World Precision Instrument #micro4). Once the injection is completed, the needle is placed for additional 1 min before removal. The paraspinal muscles and the lumbar fascia are closed with suture (#5, silk). The skin incision is closed with wound clips. Animals are allowed to recover from the anesthesia and are observed in the humidified incubator.

(354) Buprenorphine (0.05 mg/kg) is administrated subcutaneously (s.c.) twice a day for additional two days following operation.

(355) Three days following the primary surgery, treatments with an S1P4 receptor antagonist (30 pmol), LPA (30 pmol) or control (0.1% DMSO in saline) are injected at the primary injection region in a volume of 1.5 μL with the same infusion speed as indicated above. Nine days following the primary surgery, the animals are anesthetized and perfused trans-cardially with heparin (10 iu/mL) in saline followed by 4% PFA in PBS. The spinal cords are removed and post fixed in PFA overnight. Then the cords are cut into 100 μM thickness longitudinally and then 1% loxuol fast blue is stained and histological evaluation for remyelination and repair is assessed under microscope.

(356) For systemic treatment, the animals are administered once daily intraperitoneally with either an S1P4 receptor antagonist (10 mg/kg) or control (15% HPCD (hydroxypropyl-β-cyclodextrin)) 2 days following the primary surgery. Nine days after the primary surgery, animals are sacrificed and the spinal cords were processed as indicated above.

(357) Calcium Mobilization

(358) Compounds that are not specific for a particular S1P receptor can cause undesirable side effects. Accordingly, compounds are tested to identify those that are specific. Accordingly, the test compounds are tested in a calcium mobilization assay. The procedure is essentially as described in Davis et al. (2005) Journal of Biological Chemistry, vol. 280, pp. 9833-9841, which is incorporated by reference in its entirety with the following modifications. Calcium mobilization assays are performed in recombinant CHEM cells expressing human S1P.sub.1, S1P.sub.2, S1P.sub.3, S1P.sub.4, or S1P.sub.5 purchased from Millipore (Billerica, Mass.). To detect free intracellular calcium, S1P.sub.1, S1P.sub.2, S1P.sub.3, S1P.sub.4, or S1P.sub.5 cells are loaded with FLIPR Calcium 4 dye from Molecular Devices (Sunnyvale, Calif.). Cells are imaged for calcium mobilization using a FLIPR.sup.TETRA equipped with a 96-well dispense head.

(359) In vivo Screening Assays

(360) Measurement of circulating lymphocytes: Compounds are dissolved in 30% HPCD. Mice (C57b1/6 male, 6-10 week-old) are administered 0.5 and 5 mg/kg of a compound via oral gavage 30% HPCD is included as a negative control.

(361) Blood is collected from the retro-orbital sinus 5 and 24 hours after drug administration under short isoflurane anesthesia. Whole blood samples are subjected to hematology analysis. Peripheral lymphocyte counts are determined using an automated analyzer (HEMAVET™ 3700). Subpopulations of peripheral blood lymphocytes are stained by fluorochrome-conjugated specific antibodies and analyzed using a fluorescent activating cell sorter (FACSCALIBUR™). Three mice are used to assess the lymphocyte depletion activity of each compound screened.

(362) Compounds of formula (I), or pharmaceutically acceptable salts thereof, can induce full lymphopenia at times as short as 4 hours or less to as long as 48 hours or more; for example, 4 to 36 hours, or 5 to 24 hours. In some cases, a compound of formula can induce full lymphopenia at 5 hours and partial lymphopenia at 24 hours. In some embodiments, the dosage required to induce lymphopenia is in the range of, e.g., 0.001 mg/kg to 100 mg/kg; or 0.01 mg/kg to 10 mg/kg. The dosage can be 10 mg/kg or less, such as 5 mg/kg or less, 1 mg/kg or less, or 0.1 mg/kg or less.

(363) Other embodiments are within the scope of the following claims.