S1P and/or ATX modulating agents

Abstract

Compounds of formula (I) wherein: X is —O—, —S(O).sub.r—, —CH.sub.2—, or —NR—, wherein r is 0, 1, or 2; X.sup.1, X.sup.2, and X.sup.5 are each independently CR.sup.7 or N; one of X.sup.3 or X.sup.4 is C and is attached by a single bond to -L-, and the other is CR.sup.7 or N, provided that no more than three of X.sup.1, X.sup.2, X.sup.3, X or X.sup.5 are N; Ring A is monocyclic C.sub.5-6scycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; wherein Ring A is further optionally substituted with from 1 to 3 R.sup.4; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl; L is a bond, —O—, —NR—, —S(O).sub.n—, —CH.sub.2—, or —C(O)—, wherein n is 0, 1, or 2; 1 2 L.sup.1 is an C.sub.1-8alkylene, C.sub.3-scycloalkylene, —CH.sub.2-L.sup.2-, or a 3- to 8-membered heterocyclylene comprising 1 to 5; R.sup.1 is C.sub.6-20alkyl or a monocyclic C.sub.3-8cycloalkyl; wherein said C.sub.3-8cycloalkyl is substituted with at least one R.sup.6 and may be optionally substituted with from 1 to 5 additional R.sup.6 substituents, wherein R.sup.6 for each occurrence is independently selected; and R.sup.2 is —C(O)OR.sup.3, —C(O)N(R.sup.3)—S(O).sub.2R.sup.3, —S(O).sub.2OR.sup.3, —C(O)NHC(O)R.sup.3, —Si(O)OH, —B(OH).sub.2, —N(R.sup.3)S(O).sub.2R.sup.3, —S(O).sub.2N(R.sup.3).sub.2, —O—P(O)(OR.sup.3).sub.2, or —P(O)(OR.sup.3).sub.2, —CN, —S(O).sub.2NHC(O)R.sup.3, —C(O)NHS(O).sub.2R3, —C(O)NHOH, —C(O)NHCN, —CH(CF.sub.3)OH, —C(CF.sub.3).sub.2OH, or a selected heteroaryl or heterocyclyl; and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX). ##STR00001##

Claims

1. A compound represented by formula (I): ##STR00140## or a pharmaceutically acceptable salt thereof, wherein: X is —O—, —S(O).sub.r—, —CH.sub.2—, or —NR—, wherein r is 0, 1, or 2; X.sup.1, X.sup.2, and X.sup.5 are each independently CR.sup.7 or N; X.sup.3 is C and is attached by a single bond to -L-, and X.sup.4 is CR.sup.7 or N, provided that no more than three of X.sup.1, X.sup.2, X.sup.3, X.sup.4 or X.sup.5 are N; Ring A is monocyclic C.sub.5-6cycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; wherein Ring A is further optionally substituted with from 1 to 3 R.sup.4; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl; L is a bond, —O—, —NR—, —S(O).sub.r—, —CH.sub.2—, or —C(O)—, wherein n is 0, 1, or 2; L.sup.1 is an C.sub.1-8alkylene, C.sub.3-8cycloalkylene, —CH.sub.2-L.sup.2-, or a 3- to 8-membered heterocyclylene comprising 1 to 5 heteroatoms selected from N, S, or O; wherein L.sup.1 may be optionally substituted with from 1 to 3 independently selected R.sup.5; L.sup.2 is a divalent bridged ring system comprising 6-10 ring members, wherein the ring members may be all carbon atoms or may comprise 1 to 5 heteroatoms selected from N, S, or O; R, for each occurrence, is independently hydrogen or C.sub.1-8alkyl; R.sup.1 is a monocyclic C.sub.3-8cycloalkyl; wherein said C.sub.3-8cycloalkyl is substituted with at least one R.sup.6 and may be optionally substituted with from 1 to 5 additional R.sup.6 substituents, wherein R.sup.6 for each occurrence is independently selected; R.sup.2 is —C(O)OR.sup.3, —C(O)N(R.sup.3)—S(O).sub.2R.sup.3, —S(O).sub.2OR.sup.3, —C(O)NHC(O)R.sup.3, —Si(O)OH, —B(OH).sub.2, —N(R.sup.3)S(O).sub.2R.sup.3, —S(O).sub.2N(R.sup.3).sub.2, —O—P(O)(OR.sup.3).sub.2, or —P(O)(OR.sup.3).sub.2, —CN, —S(O).sub.2NHC(O)R.sup.3, —C(O)NHS(O).sub.2R.sup.3, —C(O)NHOH, —C(O)NHCN, —CH(CF.sub.3)OH, —C(CF.sub.3).sub.2OH, or a heteroaryl or a heterocyclyl selected from the group consisting of formulae (a)-(i′): ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## R.sup.3 for each occurrence is independently selected from the group consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, C.sub.6-10aryl, a 5 to 12 membered heteroaryl, and a 3 to 12 membered heterocyclyl; wherein the heteroaryl and heterocyclyl independently comprise from 1 to 6 heteroatoms selected from O, N, or S; and wherein R.sup.3 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl, amino, N—C.sub.1-4alkylamino, N,N-di-(C.sub.1-4alkyl) amino, carbamoyl, N—C.sub.1-4alkylcarbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylamido, C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl, N—C.sub.1-4alkylsulfamoyl, and N,N—(C.sub.1-4dialkyl)-sulfamoyl; R.sup.4 and R.sup.5, for each occurrence, are independently halo, hydroxyl, nitro, cyano, C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.1-8alkoxy, C.sub.1-4haloalkoxy, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.3-8cycloalkoxy, C.sub.3-8halocycloalkoxy, —NR.sup.aR.sup.b, —C(O)NR.sup.aR.sup.b, —N(R.sup.a)C(O)R.sup.b, —C(O)R.sup.a, —S(O).sub.pR.sup.a, or —N(R.sup.a)S(O).sub.2R.sup.b, wherein p for each occurrence is independently 0, 1, or 2; R.sup.6, for each occurrence, is independently halo, hydroxyl, mercapto, nitro, C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.1-8alkoxy, C.sub.1-4haloalkoxy, C.sub.1-8 alkylthio, C.sub.2-8alkenyl, C.sub.2-8alkynyl, cyano, —NR.sup.aR.sup.b, C.sub.3-8cycloalkyl, C.sub.3-8halocycloalkyl, C.sub.6-10aryl, 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl comprise 1 to 4 heteroatoms independently selected from O, N, or S; 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, for each occurrence, is independently 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; and R.sup.a and R.sup.b, for each occurrence, are independently hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.6-10aryl, or C.sub.3-8halocycloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is —O—.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is monocyclic C.sub.5-6cycloalkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 2 heteroatoms independently selected from N.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond, or —NR—.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L.sup.1 is an C.sub.1-8alkylene, C.sub.3-8cycloalkylene, —CH.sub.2-L.sup.2-, or a 3- to 8-membered heterocyclylene comprising 1 to 5 N.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L.sup.1 is C.sub.1-8alkylene.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L.sup.2 is a divalent bridged ring system comprising 6-10 ring members, wherein the ring members are all carbon atoms.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R, for each occurrence, is hydrogen.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is monocyclic C.sub.3-8cycloalkyl; wherein said C.sub.3-8cycloalkyl is substituted with at least one R.sup.6 and may be optionally substituted with from 1 to 5 additional R.sup.6 substituents, wherein R.sup.6 for each occurrence is independently selected; and R.sup.6, for each occurrence, is independently C.sub.1-8alkyl; 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.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is —C(O)OR.sup.3.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is —C(O)OR.sup.3, and R.sup.3 is hydrogen.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is —O—; X.sup.1, X.sup.2, and X.sup.5 are each independently CH or N; X.sup.3 is C and is attached by a single bond to -L-, and X.sup.4 is CH or N, provided that no more than three of X.sup.1, X.sup.2, X.sup.3, X.sup.4 or X.sup.5 are N; Ring A is an unsubstituted monocyclic C.sub.5-6cycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl; L is a bond, or —NR—; L.sup.1 is an C.sub.1-8alkylene, C.sub.3-8cycloalkylene, —CH.sub.2-L.sup.2-, or a 3- to 8-membered heterocyclylene comprising 1 to 5 N; L.sup.2 is a divalent bridged ring system comprising 6-10 ring members, wherein the ring members are all carbon atoms; R, for each occurrence, is hydrogen; R.sup.1 is a monocyclic C.sub.3-8cycloalkyl; wherein said C.sub.3-8cycloalkyl is substituted with at least one R.sup.6 and may be optionally substituted with from 1 to 5 additional R.sup.6 substituents, wherein R.sup.6 for each occurrence is independently selected; R.sup.2 is —C(O)OR.sup.3, —C(O)N(R.sup.3)—S(O).sub.2R.sup.3, —S(O).sub.2OR.sup.3, —C(O)NHC(O)R.sup.3, —Si(O)OH, —B(OH).sub.2, —N(R.sup.3)S(O).sub.2R.sup.3, —S(O).sub.2N(R.sup.3).sub.2, —O—P(O)(R.sup.3).sub.2, or —P(O)(OR.sup.3).sub.2, —CN, —S(O).sub.2NHC(O)R.sup.3, —C(O)NHS(O).sub.2R.sup.3, —C(O)NHOH, —C(O)NHCN, —CH(CF.sub.3)OH, —C(CF.sub.3).sub.2OH, or a heteroaryl or a heterocyclyl selected from the group consisting of formulae (a)-(i′): ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## R.sup.3 for each occurrence is independently selected from the group consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, C.sub.6-10aryl, a 5 to 12 membered heteroaryl, and a 3 to 12 membered heterocyclyl; wherein the heteroaryl and heterocyclyl independently comprise from 1 to 6 heteroatoms selected from O, N, or S; and wherein R.sup.3 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C.sub.1-4alkoxy, C.sub.1-4alkyl, cyano, nitro, hydroxyl, amino, N—C.sub.1-4alkylamino, N,N-di-(C.sub.1-4alkyl)amino, carbamoyl, N—C.sub.1-4alkylcarbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4 alkylamido, C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonamido, sulfamoyl, N—C.sub.1-4alkylsulfamoyl, and N,N—(C.sub.1-4dialkyl)-sulfamoyl; and R.sup.6, for each occurrence, is independently C.sub.1-8alkyl; 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.

16. A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of: 3-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperazin-1-yl)propanoic acid; 4-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperazin-1-yl)butanoic acid; 3-(3-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)piperidin-1-yl)propanoic acid; 4-(3-(4-(cis-4-tert-Butylcyclohexyloxy)phenyl)piperidin-1-yl)butanoic acid; 4-((4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperazin-1-yl)methyl)bicyclo[2.2.2]octane-1-carboxylic acid; 1-(3-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)cyclohexyl)piperidine-4-carboxylic acid; 3-(3-(5-(trans-4-tert-butylcyclohexyloxy)pyridin-2-ylamino)piperidin-1-yl)propanoic acid; 3-(3-((4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)amino)piperidin-1-yl)propanoic acid; 3-(3-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)pyrrolidin-1-yl)propanoic acid; 4-(3-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)pyrrolidin-1-yl)butanoic acid; 3-(3-(3-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)propanoic acid; 4-(3-(3-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)butanoic acid; 4-(3-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)cyclohexanecarboxylic acid; 4-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)butanoic acid; 3-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)propanoic acid; 3-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)propanoic acid; 5-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoic acid; 4-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)butanoic acid; 3-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)propanoic acid; 5-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoic acid; 3-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)propanoic acid; 5-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)pentanoic acid; 5-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoic acid; 4-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)butanoic acid; 4-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)butanoic acid; 4-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoic acid; 3-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoic acid; 3-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoic acid; 3-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoic acid; 4-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoic acid; 5-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoic acid; 5-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoic acid; 4-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoic acid; 3-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoic acid; 5-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoic acid; 4-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoic acid; and 5-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoic acid.

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

18. A method of treating, or reducing symptoms of a condition mediated by S1P activity and/or ATX activity 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.

19. The method of claim 18, wherein the condition is selected from the group consisting of multiple sclerosis, an autoimmune disease, a chronic inflammatory disorder, asthma, an inflammatory neuropathy, arthritis, transplantation rejection, Crohn's disease, ulcerative colitis, lupus erythematosis, psoriasis, an ischemia-reperfusion injury, a solid tumor, a tumor metastasis, a disease associated with angiogenesis, a vascular disease, a pain condition, an acute viral disease, an inflammatory bowel condition, insulin-dependent diabetes, non-insulin dependent diabetes, a fibrosis of the lung, or a malignancy of the lung in a mammal.

20. The method of claim 19, further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulating agent, an antipsoriatic, and an antidiabetic.

21. A method of promoting myelination or remyelination in a mammal in need thereof, comprising administering to cells an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

22. 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, L, L.sup.1 and A are as defined herein, Hal is a halogen, and LG is a leaving group, such as a halogen, or a functional group suitable for a coupling reaction, such as a double or triple bond.

(5) ##STR00032##

(6) 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 reacted with an appropriately substituted boronic acid derivative of formula B(OH).sub.2-L-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. Upon reaction completion, compound 1-5 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.

(8) It will be appreciated that the -L-R.sup.2 substitutent can be modified or added to ring A either after (as shown in Scheme 1) or before the addition of the -L-A moiety. The -L-R.sup.2 moiety may be coupled to compound 1-5 under substitution reaction conditions with an appropriate reagent of formula LG-L.sup.1-R.sup.2 (where LG is a leaving group such as a halo, hydroxyl, alkoxy, and the like, or a functional group suitable for a coupling reaction, such as a double or triple bond) as shown in Scheme 1. Typical substitution reaction conditions include the presence of a base, such as cesium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, and the like, in a polar aprotic solvent, such as N,N-dimethylformamide, and optionally an elevated temperature of about 100-150° C., or in a microwave. Upon reaction completion, compounds of formula (I) can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.

(9) TABLE-US-00001 List of Abbreviations and Acronyms Abbreviation Meaning ° C. Degree Celsius Ac Acetate atm Atmosphere ATX Autotaxin BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl BOC tert-Butoxycarbonyl bs Broad singlet BSA Bovine serum albumin Bu Butyl cat Catalytic amount CNTF Ciliary neurotrophic factor conc Concentrated Cy Cyclohexyl d Doublet d day dba dibenzylideneacetone DCE Dichloroethane DCM Dichloromethane dd Doublet of doublets ddH.sub.2O Double-distilled water DIAD Diisopropyl azodicarboxylate DMEM Dulbecco′s modified Eagle′s medium DMF Dimethylformamide 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 ESI-MS Electrospray ionization Et Ethyl g Grams h/H Hours 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 Iu/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 multiplet 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 Mass spectrometry Ms Methanesulfonyl MSD Meso Scale Discovery-R MW Microwave N Normal nL Nanoliter nM Nanometer NMR Nuclear magnetic resonance OPC Oligodendrocyte precursor cells PAGE Polyacrylamide gel electrophoresis PBS Phosphate buffered saline PE Petroleum ether PEA Paraformaldehyde Ph Phenyl pmol Picomole prep Preparative q Quartet rpm Revolutions per minute rpm Revolutions per minute rt Room temperature s Singlet s.c. Subcutaneously SDS Sodium dodecyl sulfate sec Second t Triplet t-Bu tert-Butyl TFA Trifluoroacetic acid THF Tetrahydrofuran Y Yield δ Chemical shift μg Microgram μL Microliter μM Micromolar μm Micrometer

Intermediate 1: 1-Bromo-4-(octyloxy)benzene

(10) ##STR00033##

(11) To a mixture of 4-bromophenol (8.0 g, 46.5 mmol, 1.0 eq), octan-1-ol (7.25 g, 55.8 mmol, 1.2 eq) and PPh.sub.3 (24.4 g, 93.0 mmol, 2.0 eq) in toluene (50 mL) was added dropwise DIAD (18.8 g, 93.0 mmol, 2.0 eq) at 0° C. The reaction mixture was stirred at rt for 3 hours. And then, the solvent was removed under reduced pressure to give the crude title product, which was purified by column chromatography on silica gel, eluting with petroleum ether to furnish the target compound 1-bromo-4-(octyloxy)benzene as a colorless oil (7.0 g, 53% yield). LCMS: m/z 285.1 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ: 7.38-7.34 (m, 2H), 6.79-6.75 (m, 2H), 3.91 (t, J=6.8 Hz, 2H), 1.80-1.73 (m, 2H), 1.46-1.28 (m, 10H), 0.89 (t, J=6.8 Hz, 3H).

Intermediate 2: 1-Bromo-4-(trans-4-tert-butylcyclohexyloxy)benzene

(12) ##STR00034##

(13) 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).

Intermediate 3: 3-(4-(Octyloxy)phenyl)pyridine

(14) ##STR00035##

(15) A mixture of 1-bromo-4-(octyloxy)benzene (1.1 g, 3.87 mmol, 1.0 eq), pyridin-3-ylboronic acid (476 mg, 3.87 mmol, 1.0 eq), Pd(dppf)Cl.sub.2.DCM (310 mg, 0.38 mmol, 0.1 eq) and K.sub.2CO.sub.3 (1.07 g, 7.74 mmol, 2.0 eq) in mixed solvents (1,4-dioxane/H.sub.2O, 4/1, 9 mL) was heated to 90° C. and stirred for 2 h under N.sub.2. After cooling down to rt, the solvents were removed in vacuo, and the residue was suspended with EtOAc (10 mL), followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=10/1) to give the title compound as a white solid (498 mg, 50% yield). LCMS: m/z 284.1 [M+H].sup.+; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 8.84 (s, 1H), 8.56 (d, J=4.0 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.53-7.50 (m, 2H), 7.37-7.33 (m, 1H), 7.01 (d, J=8.4 Hz, 2H), 4.02 (t, J=6.8 Hz, 2H), 1.86-1.79 (m, 2H), 1.51-1.27 (m, 10H), 0.92-0.89 (t, J=6.8 Hz, 3H).

Intermediate 4: 3-(4-(Octyloxy)phenyl)piperidine

(16) ##STR00036##

(17) To a mixture of 3-(4-(octyloxy)phenyl)pyridine (600 mg, 2.12 mmol, 1.0 eq) and conc. HCl (60 mg, 0.6 mmol, 0.3 eq) in MeOH (3 mL) was added PtO.sub.2 (48 mg, 0.2 mmol, 0.1 eq). The mixture was purged with H.sub.2 for three times and then stirred at rt for 4 hours. The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (MeOH/H.sub.2O from 30% to 95%, containing 0.05% TFA) to give the title compound as a white solid (364 mg, 60% yield). .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.08 (d, J=8.0 Hz, 2H), 6.84 (d, J=8.0 Hz, 2H), 3.92 (t, J=6.8 Hz, 2H), 3.44 (bs, 2H), 3.08-3.02 (m, 1H), 2.86 (bs, 2H), 2.08-2.00 (m, 4H), 1.80-1.73 (m, 2H), 1.46-1.28 (m, 10H), 0.90-0.87 (m, 3H).

Intermediate 5: Ethyl 3-(3-(4-(octyloxy)phenyl)piperidin-1-yl)propanoate

(18) ##STR00037##

(19) A stirred mixture of 3-(4-(octyloxy)phenyl)piperidine (140 mg, 0.48 mmol, 1.0 eq), ethyl acrylate (71.5 mg, 0.55 mmol, 1.1 eq) and Cs.sub.2CO.sub.3 (312 mg, 0.96 mol, 2.0 eq) in CH.sub.3CN (3 mL) was heated to reflux for 16 hours. After cooling down to rt, the mixture was filtrated, and the filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC (MeOH/H.sub.2O from 30% to 95%, containing 0.05% TFA) to give the title compound as a colorless oil (56 mg, 30% yield). LCMS: m/z 390.2 [M+H].sup.+.

Example 1

3-(3-(4-(Octyloxy)phenyl)piperidin-1-yl)propanoic acid (Compound 5)

(20) ##STR00038##

(21) To a mixture of ethyl 3-(3-(4-(octyloxy)phenyl)piperidin-1-yl)propanoate (50 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 3-(3-(4-(octyloxy)phenyl)piperidin-1-yl)propanoic acid as a colorless oil (14 mg, 30% yield). LCMS: m/z 362.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.20 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 3.95 (t, J=6.8 Hz, 2H), 3.64-3.53 (m, 2H), 3.40 (t, J=6.8 Hz, 2H), 3.06-2.74 (m, 5H), 2.11-1.72 (m, 6H), 1.49-1.32 (m, 10H), 0.93-0.89 (m, 3H).

Intermediate 6: Ethyl 4-(3-(4-(octyloxy)phenyl)piperidin-1-yl)butanoate

(22) ##STR00039##

(23) To a stirred mixture of 3-(4-(octyloxy)phenyl)piperidine (100 mg, 0.35 mmol, 1.0 eq) and Cs.sub.2CO.sub.3 (228 mg, 0.7 mol, 2.0 eq) in CH.sub.3CN (3 mL) was added ethyl 4-bromobutanoate (74 g, 0.38 mol, 1.1 eq). The mixture was heated to reflux for 16 hours. After cooling down rt, the mixture was filtrated, and the filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC (MeOH/H.sub.2O from 30% to 95%, containing 0.05% TFA) to give the title compound as a yellow oil (56 mg, 40% yield). LCMS: m/z 404.1 [M+H].sup.+.

Example 2

4-(3-(4-(Octyloxy)phenyl)piperidin-1-yl)butanoic acid (Compound 6)

(24) ##STR00040##

(25) Using standard hydrolysis condition as described in example 1, 4-(3-(4-(octyloxy)phenyl)piperidin-1-yl)butanoic acid was obtained as a yellow oil (30 mg, 40% yield). LCMS: m/z 376.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.20 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 3.95 (t, J=6.4 Hz, 2H), 3.65-3.51 (m, 2H), 3.21-3.17 (m, 2H), 3.06-3.00 (m, 3H), 2.46 (t, J=6.8 Hz, 2H), 2.10-1.71 (m, 8H), 1.50-1.31 (m, 10H), 0.92-0.89 (m, 3H).

Intermediate 7: 3-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)pyridine

(26) ##STR00041##

(27) 3-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)pyridine was prepared using the same condition as that of 3-(4-(octyloxy)phenyl)pyridine as in intermediate 3. The title compound was obtained as a white solid (130 mg, 65% yield). LCMS m/z 310.2 [M+H].sup.+; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 8.81 (d, J=2.0 Hz, 1H), 8.54 (dd, J=3.6, 1.2 Hz, 1H), 7.84-7.81 (m, 1H), 7.50-7.48 (dd, J=6.4, 1.6 Hz, 2H), 7.34-7.26 (m, 1H), 6.99 (d, J=2.0 Hz, 2H), 4.18-4.16 (m, 1H), 2.25-2.21 (m, 2H), 1.89-1.87 (m, 2H), 1.44-1.40 (m, 2H), 1.16-1.08 (m, 3H), 0.89 (s, 9H).

Intermediate 8: 3-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)piperidine

(28) ##STR00042##

(29) 3-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)piperidine was prepared using the same condition as that of 3-(4-(octyloxy)phenyl)piperidine in intermediate 4. The title compound was obtained as a white solid (80 mg, 40% yield). LCMS m/z 316.2 [M+H].sup.+; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 8.91 (bs, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 4.11-4.04 (m, 1H), 3.47-3.42 (m, 2H), 3.40-2.84 (m, 3H), 2.18-1.84 (m, 7H), 1.67-1.63 (m, 1H), 1.41-1.32 (m, 2H), 1.17-1.05 (m, 3H), 0.87 (s, 9H).

Example 3

3-(3-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)piperidin-1-yl)propanoic acid (Compound 3)

(30) ##STR00043##

(31) Using the same condition as that of ethyl 4-(3-(4-(octyloxy)phenyl)piperidin-1-yl)butanoate in intermediate 6, ethyl 3-(3-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)piperidin-1-yl)propanoate was obtained as a yellow oil (42 mg, 42% yield). LCMS m/z 416.2 [M+H].sup.+.

(32) Using standard hydrolysis condition, the title compound was obtained as a colorless oil (13 mg, 40% yield). LCMS m/z 388.3 [M+H].sup.+; .sup.1HNMR (400 MHz, CD.sub.3OD) δ: 7.19 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 4.16-4.15 (m, 1H), 3.60-3.37 (m, 2H), 3.36-3.33 (m, 2H), 3.03-2.99 (m, 3H), 2.69-2.65 (m, 2H), 2.18-1.86 (m, 8H), 1.35-1.11 (m, 5H), 0.90 (s, 9H).

Example 4

4-(3-(4-(cis-4-tert-Butylcyclohexyloxy)phenyl)piperidin-1-yl)butanoic acid (Compound 4)

(33) ##STR00044##

(34) Using the same condition as that of ethyl 4-(3-(4-(octyloxy)phenyl)piperidin-1-yl)butanoate in intermediate 6, ethyl 4-(3-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)piperidin-1-yl)butanoate was obtained as a yellow oil (67 mg, 71% yield). LCMS m/z 430.2 [M+H].sup.+.

(35) Using standard hydrolysis condition, the title compound was obtained as a colorless oil (22 mg, 37% yield). LCMS m/z 402.3 [M+H].sup.+; .sup.1HNMR (400 MHz, CD.sub.3OD) δ: 7.19 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.16-4.14 (m, 1H), 3.64-3.53 (m, 2H), 3.19-3.16 (m, 2H), 3.01-2.96 (m, 3H), 2.48-2.45 (m, 2H), 2.18-1.86 (m, 10H), 1.36-1.08 (m, 5H), 0.90 (s, 9H).

Intermediate 9: 1-Bromo-3-(octyloxy)benzene

(36) ##STR00045##

(37) A mixture of 3-bromophenol (1.9 g, 10.9 mmol, 1.0 eq), octan-1-ol (1.4 g, 10.9 mmol, 1.0 eq), Et.sub.3N (1.3 g, 13.1 mmol, 1.2 eq) and PPh.sub.3 (5.7 g, 21.8 mmol, 2.0 eq) in THF (10 mL) was stirred at rt for 1 h. Then DIAD (4.4 g, 21.8 mmol, 2.0 eq) was added dropwise at 0° C. The mixture was stirred at rt for another 16 h. Then the solvent was removed and the residue was purified by column chromatography (PE/EA=8/1) to give the title compound as a yellow oil (2.2 g, 70% yield). LCMS m/z 285.1 [M+H].sup.+.

Intermediate 10: 3-(3-(Octyloxy)phenyl)pyridine

(38) ##STR00046##

(39) A mixture of 1-bromo-3-(octyloxy)benzene (1.4 g, 4.9 mmol, 1.0 eq), pyridin-3-ylboronic acid (723 mg, 5.9 mmol, 1.2 eq), Na.sub.2CO.sub.3 (1.0 g, 9.8 mmol, 2.0 eq) and Pd(dppf)Cl.sub.2.DCM (400 mg, 0.5 mmol, 0.1 eq) in mixed solvents (toluene/EtOH/H.sub.2O, 4/2/1, 10 mL) was heated to 100° C. and stirred for 8 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 (837 mg, 60% yield). LCMS m/z 284.1 [M+H].sup.+.

Intermediate 11: 3-(3-(Octyloxy)phenyl)piperidine

(40) ##STR00047##

(41) To a mixture of 3-(3-(octyloxy)phenyl)pyridine (500 mg, 1.8 mmol, 1.0 eq) and conc. HCl (cat) in MeOH (3 mL) was added PtO.sub.2(43 mg, 0.18 mmol, 0.1 eq). The mixture was purged with H.sub.2 for three times and then stirred at rt for 5 h. The mixture was then filtered, and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (400 mg, 78% yield). LCMS m/z 290.1 [M+H].sup.+.

Example 5

3-(3-(3-(Octyloxy)phenyl)piperidin-1-yl)propanoic acid (Compound 49)

(42) ##STR00048##

(43) A stirred mixture of 3-(3-(octyloxy)phenyl)piperidine (100 mg, 0.35 mmol, 1.0 eq), ethyl acrylate (70 mg, 0.7 mmol, 2.0 eq) and Cs.sub.2CO.sub.3 (228 mg, 0.70 mmol, 2.0 eq) in CH.sub.3CN (3 mL) was heated to reflux for 16 h. After cooling down to rt, the mixture was filtrated. The filtrate was concentrated in vacuo and the residue was purified by prep-HPLC (MeCN/H.sub.2O from 30% to 95%, containing 0.05% TFA) to give ethyl 3-(3-(3-(octyloxy)phenyl)piperidin-1-yl)propanoate as a yellow oil (36 mg, 27% yield). LCMS m/z 390.3 [M+H].sup.+.

(44) Following standard hydrolysis condition, the title compound was obtained as a yellow solid (30 mg, 91% yield). LCMS m/z 362.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.16-7.12 (m, 1H), 6.74-6.70 (m, 3H), 3.85 (t, J=6.4 Hz, 2H), 3.52-3.44 (m, 2H), 3.26 (bs, 2H), 2.97-2.89 (m, 3H), 2.55 (bs, 2H), 1.96-1.89 (m, 3H), 1.69-1.62 (m, 3H), 1.38-1.33 (m, 2H), 1.25-1.21 (m, 8H), 0.80 (t, J=6.4 Hz, 3H).

Example 6

4-(3-(3-(Octyloxy)phenyl)piperidin-1-yl)butanoic acid (Compound 50)

(45) ##STR00049##

(46) Using the same condition as that of ethyl 4-(3-(4-(octyloxy)phenyl)piperidin-1-yl)butanoate in intermediate 6, ethyl 4-(3-(3-(octyloxy)phenyl)piperidin-1-yl)butanoate as a yellow oil (46 mg, 22% yield). LCMS m/z 404.2 [M+H].sup.+.

(47) Following standard hydrolysis condition, the title compound was obtained as a yellow oil (25 mg, 60% yield). LCMS m/z 376.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.26-7.22 (m, 1H), 6.86-6.80 (m, 3H), 3.96 (t, J=6.4 Hz, 2H), 3.60-3.51 (m, 2H), 3.13-2.83 (m, 5H), 2.49-2.46 (m, 2H), 2.07-1.89 (m, 5H), 1.80-1.69 (m, 3H), 1.51-1.44 (m, 2H), 1.37-1.32 (m, 8H), 0.92-0.86 (m, 3H).

Intermediate 12: 3-(3-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)pyridine

(48) ##STR00050##

(49) The title compound was prepared using the same procedure as for intermediate 3, as a yellow oil (200 mg, 61% yield). LCMS m/z 310.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.84 (d, J=2.0 Hz, 1H), 8.59-8.58 (m, 1H), 7.87-7.85 (m, 1H), 7.38-7.34 (m, 2H), 7.14-7.10 (m, 2H), 6.94-6.93 (m, 1H), 4.21-4.16 (m, 1H), 2.25-2.21 (m, 2H), 1.90-1.86 (m, 2H), 1.44-1.38 (m, 2H), 1.17-1.08 (m, 3H), 0.89 (s, 9H).

Intermediate 13: 3-(3-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidine

(50) ##STR00051##

(51) The title compound was prepared using the same procedure as for intermediate 4, as a yellow oil (83 mg, 41% yield). LCMS m/z 316.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 9.38 (bs, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.79-6.72 (m, 3H), 4.13-4.06 (m, 1H), 3.48 (bs, 2H), 3.11-3.09 (m, 1H), 2.89-2.87 (m, 2H), 2.17-2.00 (m, 5H), 1.87-1.84 (m, 2H), 1.67-1.63 (m, 1H), 1.42-1.33 (m, 2H), 1.19-1.03 (m, 3H), 0.89 (s, 9H).

Example 7

3-(3-(3-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)propanoic acid (Compound 18)

(52) ##STR00052##

(53) Using the same procedure as for intermediate 5, ethyl 3-(3-(3-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)propanoate as a yellow oil (237 mg, 62% yield). LCMS m/z 416.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.15 (t, J=8.0 Hz, 1H), 6.75-6.67 (m, 3H), 4.11-4.02 (m, 3H), 3.68-3.59 (m, 2H), 3.36-3.26 (m, 2H), 3.13-3.07 (m, 1H), 2.83-2.80 (m, 2H), 2.64-2.54 (m, 2H), 2.11-1.96 (m, 5H), 1.80-1.78 (m, 2H), 1.60-1.56 (m, 1H), 1.36-1.26 (m, 2H), 1.17 (t, J=8.0 Hz, 3H), 1.11-0.96 (m, 3H), 0.85 (s, 9H).

(54) Using standard hydrolysis condition, the title compound was obtained as a yellow oil (142 mg, 76% yield). LCMS m/z 388.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 7.22 (t, J=8.4 Hz, 1H), 6.83-6.79 (m, 3H), 4.22-4.20 (m, 1H), 3.46-3.42 (m, 2H), 3.26 (t, J=7.6 Hz, 2H), 3.04-2.89 (m, 3H), 2.79-2.74 (m, 2H), 2.12-2.09 (m, 2H), 1.90-1.77 (m, 5H), 1.66-1.64 (m, 1H), 1.30-1.03 (m, 5H), 0.86 (s, 9H).

Example 8

4-(3-(3-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)butanoic acid (Compound 19)

(55) ##STR00053##

(56) Using the same procedure as for intermediate 6, ethyl 4-(3-(3-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)butanoate was obtained as a yellow oil (267 mg, 71% yield). LCMS m/z 430.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.15 (t, J=8.0 Hz, 1H), 6.75-6.68 (m, 3H), 4.08-4.02 (m, 3H), 3.70-3.61 (m, 2H), 3.15-3.01 (m, 3H), 2.59-2.54 (m, 2H), 2.35 (t, J=6.4 Hz, 2H), 2.12-1.95 (m, 7H), 1.81-1.78 (m, 2H), 1.59-1.55 (m, 1H), 1.36-1.26 (m, 2H), 1.17 (t, J=7.2 Hz, 3H), 1.12-0.99 (m, 3H), 0.85 (s, 9H).

(57) Using standard hydrolysis condition the title compound was obtained as a yellow oil (117 mg, 76% yield). LCMS m/z 402.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 7.21 (t, J=8.4 Hz, 1H), 6.83-6.79 (m, 3H), 4.22-4.19 (m, 1H), 3.41-3.35 (m, 2H), 2.98-2.91 (m, 4H), 2.77-2.76 (m, 1H), 2.31 (t, J=7.2 Hz, 2H), 2.12-2.09 (m, 2H), 1.91-1.77 (m, 7H), 1.30-1.28 (m, 1H), 1.26-1.03 (m, 5H), 0.86 (s, 9H).

Intermediate 14: 3-(4-(Octyloxy)phenyl)cyclohex-2-enone

(58) ##STR00054##

(59) To a stirred solution of 1-bromo-4-(octyloxy)benzene (1.4 g, 4.94 mmol, 1.0 eq) in anhydrous THF (25 mL) was added dropwise n-BuLi (3.7 mL, 5.93 mmol, 1.2 eq) at −78° C. under N.sub.2. After addition, the mixture was allowed to stir for 1 h. 3-Ethoxycyclohex-2-enone (761 mg, 5.43 mmol, 1.1 eq) was then added. The resulting mixture was allowed to stir for additional 1 h, and the reaction was then quenched with dilute HCl (6.0 N, 4.9 mL, 29.4 mmol, 6.0 eq), the resulting solution was allowed to warm up to rt and stir for 16 h. The mixture was extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=10:1) to give the title compound as a yellow solid (400 mg, 27% yield). LCMS m/z 301.1 [M+1].sup.+.

Intermediate 15: 3-Ethoxycyclohex-2-enone

(60) ##STR00055##

(61) A mixture of 3-(4-(octyloxy)phenyl)cyclohex-2-enone (250 mg, 0.83 mmol, 1.0 eq) and Pd/C (50 mg, 0.17 mmol, 0.2 eq) in EtOAc (2 mL) was purged with H.sub.2 for three times and then stirred at rt for 2 h under H.sub.2 atmosphere. The mixture was then filtered, and the filtrate was concentrated in vacuo to give the title compound as a white solid (150 mg, 60% yield), which was used in the next step without further purification. LCMS m/z 303.2 [M+1].sup.+.

Intermediate 16: Ethyl 1-(3-(4-(octyloxy)phenyl)cyclohexyl)piperidine-4-carboxylate

(62) ##STR00056##

(63) A mixture of 3-(4-(octyloxy)phenyl)cyclohexanone (150 mg, 0.50 mmol, 1.0 eq), ethyl piperidine-4-carboxylate (94 mg, 0.60 mmol, 1.2 eq) and HOAc (90 mg, 1.5 mmol, 3.0 eq) in DCM (5 mL) was heated to reflux for 30 min. Then NaBH(OAc).sub.3 (212 mg, 1.0 mmol, 2.0 eq) was added and the mixture was reflux for another 16 h. After cooling down to rt, the reaction was quenched with saturated aqueous NaHCO.sub.3 (1 mL) and the mixture was adjusted to pH=8 with saturated aqueous NaHCO.sub.3. The resultant mixture was diluted with DCM (20 mL) and washed with H.sub.2O (10 mL×3), dried over anhydrous Na.sub.2SO.sub.4. The organic phase was concentrated in vacuo and purified by prep-HPLC (MeOH/H.sub.2O from 30% to 95%, containing 0.05% TFA) to give the title compound as a white solid (110 mg, 50% yield). LCMS m/z 444.2 [M+1].sup.+.

Example 9

1-(3-(4-(octyloxy)phenyl)cyclohexyl)piperidine-4-carboxylic acid (Compound 16)

(64) ##STR00057##

(65) Using standard hydrolysis condition, and purified by prep-HPLC (MeOH/H.sub.2O from 30% to 95%, containing 0.05% TFA), the title compound was obtained as a white solid (35 mg, 34% yield). LCMS m/z 416.4 [M+1].sup.+; .sup.1HNMR (400 MHz, CD.sub.3OD) δ: 7.27-7.16 (m, 2H), 6.90-6.84 (m, 2H), 3.97-3.93 (m, 2H), 3.49 (bs, 2H), 3.14-3.06 (m, 3H), 2.68-2.38 (m, 2H), 2.20-1.57 (m, 12H), 1.49-1.31 (m, 12H), 0.93-0.90 (m, 3H).

Intermediate 17: 3-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)cyclohex-2-enone

(66) ##STR00058##

(67) 3-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)cyclohex-2-enone was prepared using the same condition as that for the synthesis of 3-(4-(octyloxy)phenyl)cyclohex-2-enone in intermediate 14. The title compound was obtained as a yellow solid (1.27 g, 65% yield). LCMS m/z 327.2 [M+1].sup.+.

Intermediate 18: 3-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)cyclohexanone

(68) ##STR00059##

(69) 3-(4-(trans-4-tert-Butylcyclohexyloxy)phenyl)cyclohexanone prepared using the same condition as that for the synthesis of 3-ethoxycyclohex-2-enone in intermediate 15. The title compound was obtained as a white solid (220 mg, 50% yield). LCMS m/z 329.1 [M+1].sup.+; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.11-7.09 (m, 2H), 6.86-6.84 (m, 2H), 4.12-4.04 (m, 1H), 2.98-2.91 (m, 1H), 2.59-2.34 (m, 4H), 2.20-2.04 (m, 4H), 1.87-1.73 (m, 4H), 1.42-1.33 (m, 2H), 1.17-1.02 (m, 3H), 0.87 (s, 9H).

Intermediate 19: Ethyl 1-(3-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)cyclohexyl)piperidine-4-carboxylate

(70) ##STR00060##

(71) Ethyl 1-(3-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)cyclohexyl)piperidine-4-carboxylate was prepared using the same condition as that for the synthesis of 1-(3-(4-(octyloxy)phenyl)cyclohexyl)piperidine-4-carboxylic acid in intermediate 16. The title compound was obtained as a yellow solid (90 mg, 56% yield). LCMS m/z 470.1 [M+1].sup.+.

Example 10

1-(3-(4-(trans-4-tert-butylcyclohexyloxy)phenyl)cyclohexyl)piperidine-4-carboxylic acid (Compound 11)

(72) ##STR00061##

(73) Using standard hydrolysis condition, the title compound was obtained as a yellow solid (20 mg, 21% yield). LCMS m/z 442.3 [M+1].sup.+; .sup.1HNMR (400 MHz, CD.sub.3OD) δ: two isomers, 7.26-7.15 (m, 2H), 6.89-6.83 (m, 2H), 4.14-4.13 (m, 1H), 3.62-3.46 (m, 2H), 3.39-3.36 (m, 0.37H), 3.27-3.22 (m, 1.63H), 3.17-3.06 (m, 1.81H), 2.87-2.85 (m, 0.24H), 2.67-2.59 (m, 1H), 2.45-1.55 (m, 16H), 1.39-1.05 (m, 5H), 0.90 (s, 9H).

Intermediate 20: 2-Chloro-5-(octyloxy)pyridine

(74) ##STR00062##

(75) A mixture of 1-bromooctane (390 mg, 3.0 mmol, 1.0 eq), 1-bromooctane (690 mg, 3.6 mmol, 1.2 eq) and K.sub.2CO.sub.3 (840 mg, 6.0 mmol, 2.0 eq) in DMF (10 mL) was heated to 80° C. and stirred for 3 h. After cooling down to rt, the mixture was diluted with H.sub.2O (50 mL) and extracted with EA (50 mL×3). The extracts were combined, dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=50:1) to give the title compound as a yellow oil (570 mg, 65% yield). LCMS: m/z 242.1 [M+H].sup.+.

Intermediate 21: tert-Butyl 3-(5-(octyloxy)pyridin-2-ylamino)piperidine-1-carboxylate

(76) ##STR00063##

(77) A stirred mixture of 2-chloro-5-(octyloxy)pyridine (240 mg, 1.0 mmol, 1.0 eq), tert-butyl 3-aminopiperidine-1-carboxylate (250 mg, 1.2 mmol, 1.2 eq) and NaO.sup.tBu (180 mg, 2.0 mmol, 2.0 eq) in anhydrous toluene (5 mL) was purged with N.sub.2 for 5 minutes, 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (80 mg, 0.2 mmol, 0.2 eq) and Pd.sub.2(dba).sub.3 (92 mg, 0.1 mmol, 0.1 eq) were then added. The mixture was purged with N.sub.2 for three times again and heated to 130° C. for 24 h. After cooling down to rt, the mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether/EtOAc=4:1) to give the title compound as a yellow oil (140 mg, 35% yield). LCMS: m/z 406.4 [M+H].sup.+. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.90 (d, J=3.2 Hz, 1H), 7.13 (dd, J=9.2, 3.2 Hz, 1H), 6.68 (d, J=9.2 Hz, 1H), 4.86 (bs, 1H), 3.91 (t, J=6.4 Hz, 2H), 3.79 (bs, 1H), 3.59-3.21 (m, 4H), 1.84-1.71 (m, 5H), 1.62 (bs, 3H), 1.44 (bs, 11H), 1.31 (bs, 6H), 0.88 (t, J=6.8 Hz, 3H).

Intermediate 22: 5-(Octyloxy)-N-(piperidin-3-yl)pyridin-2-amine

(78) ##STR00064##

(79) A mixture of tert-utyl 3-(5-(octyloxy)pyridin-2-ylamino)piperidine-1-carboxylate (400 mg, 1.0 mmol, 1.0 eq) in a solution of HCl in EtOAc (3 mL, sat.) was stirred at rt for 16 h. The reaction solution was concentrated to yield a crude product, as yellow oil (260 mg, 86% yield), which was used for next step without further purification. LCMS: m/z 306.3 [M+H].sup.+.

Intermediate 23: Ethyl 3-(3-(5-(octyloxy)pyridin-2-ylamino)piperidin-1-yl)propanoate

(80) ##STR00065##

(81) A stirred mixture of 5-(octyloxy)-N-(piperidin-3-yl)pyridin-2-amine (240 mg, 0.8 mmol, 1.0 eq), ethyl acrylate (120 mg, 1.2 mmol, 1.5 eq) and Cs.sub.2CO.sub.3 (510 mg, 1.6 mmol, 2.0 eq) in CH.sub.3CN (2 mL) was heated to refluxed for 16 h. After cooling down to rt, the mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (20 mL×3). The organic layers were combined, dried with Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by prep-TLC (petroleum ether/EtOAc=1:1) to give the title compound as a yellow oil (100 mg, 30% yield). LCMS: m/z 406.4 [M+H].sup.+; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.78 (d, J=3.2 Hz, 1H), 7.08 (dd, J=9.2, 3.2 Hz, 1H), 6.37 (d, J=9.2 Hz, 1H), 4.86 (bs, 1H), 4.15 (q, J=7.6 Hz, 2H), 3.89 (t, J=6.4 Hz, 2H), 3.79 (bs, 1H), 2.71-2.68 (m, 3H), 2.51-2.34 (m, 5H), 1.77-1.70 (m, 4H), 1.55 (bs, 2H), 1.43 (bs, 2H), 1.31-1.24 (bs, 11H), 0.90-0.87 (m, 3H).

Example 11

3-(3-(5-(Octyloxy)pyridin-2-ylamino)piperidin-1-yl)propanoic acid (Compound 12)

(82) ##STR00066##

(83) Using standard hydrolysis condition and purified by prep-HPLC (MeOH and H.sub.2O with 0.05% TFA as mobile phase), the title compound was obtained as a yellow oil (30 mg, 30% yield). LCMS: m/z 378.4 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.70 (dd, J=9.2, 2.8 Hz, 1H), 7.57 (d, J=2.8 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H), 4.17-4.09 (m 1H), 3.99 (t, J=6.4 Hz, 2H), 3.73 (bs, 1H), 3.54-3.41 (m, 3H), 3.10 (bs, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.19-2.11 (m, 2H), 2.02-1.91 (m, 1H), 1.83-1.70 (m, 3H), 1.52-1.45 (m, 2H), 1.37-1.32 (m, 8H), 0.91 (t, J=6.8 Hz, 3H).

Intermediate 24: 5-(trans-4-tert-butylcyclohexyloxy)-2-chloropyridine

(84) ##STR00067##

(85) To a mixture of 6-chloropyridin-3-ol (258 mg, 2.0 mmol, 1.0 eq), cis-4-tert-butylcyclohexanol (374 mg, 2.4 mmol, 1.2 eq), PPh.sub.3 (629 mg, 2.4 mmol, 1.2 eq) and Et.sub.3N (202 mg, 2.0 mmol, 1.0 eq) in THF (5 mL) was added dropwise DIAD (485 mg, 2.4 mmol, 1.2 eq) at 0° C. The reaction mixture was stirred at rt for 16 h. And then, the solvent was removed under reduced pressure to give the crude title product, which was purified by column chromatography on silica gel, eluting with petroleum ether/EtOAc (20/1) to give the title compound as a white solid (150 mg, 24% yield). LCMS: m/z 268.1 [M+H].sup.+. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 8.03 (d, J=2.4 Hz, 1H), 7.21-7.15 (m, 2H), 4.13-4.07 (m, 1H), 2.19-2.15 (m, 2H), 1.89-1.86 (m, 2H), 1.44-1.35 (m, 2H), 1.13-1.05 (m, 3H), 0.88 (s, 9H).

Intermediate 25: tert-butyl 3-(5-(trans-4-tert-butylcyclohexyloxy)pyridin-2-ylamino)piperidine-1-carboxylate

(86) ##STR00068##

(87) Using the same condition as that for the synthesis of tert-Butyl 3-(5-(octyloxy)pyridin-2-ylamino)piperidine-1-carboxylate in intermediate 21, the title compound was obtained as a yellow solid (96 mg, 11% yield). LCMS m/z 432.3 [M+H].sup.+.

Intermediate 26: 5-(trans-4-tert-butylcyclohexyloxy)-N-(piperidin-3-yl)pyridin-2-amine

(88) ##STR00069##

(89) Using the same condition as that for the synthesis of 5-(octyloxy)-N-(piperidin-3-yl)pyridin-2-amine in intermediate 22, the title compound was obtained as a yellow oil (72 mg, 96% yield). LCMS m/z 332.3 [M+H].sup.+.

Example 12

3-(3-(5-(trans-4-tert-butylcyclohexyloxy)pyridin-2-ylamino)piperidin-1-yl)propanoic acid (Compound 13)

(90) ##STR00070##

(91) Using the same procedure as for intermediate 23, ethyl 3-(3-(5-(trans-4-tert-butylcyclohexyloxy)pyridin-2-ylamino)piperidin-1-yl)propanoate was obtained as a white solid (56 mg, 39% yield). LCMS m/z 432.3 [M+H].sup.+.

(92) Using standard hydrolysis condition, the title compound was obtained as a yellow oil (64 mg, 76% yield). LCMS m/z 404.3 [M+H].sup.+; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.71 (m, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.03 (m, 1H), 4.13 (m, 2H), 3.73 (s, 1H), 3.52-3.42 (m, 3H), 3.15-3.02 (m, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.19-2.11 (m, 4H), 1.98-1.88 (m, 3H), 1.72-1.67 (m, 1H), 1.42-1.34 (m, 2H), 1.25-1.09 (m, 3H), 0.90 (s, 9H).

Intermediate 27: tert-Butyl 3-((4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)amino)piperidine-1-carboxylate

(93) ##STR00071##

(94) 1-Bromo-4-((trans-4-(tert-butyl)cyclohexyl)oxy)benzene (620 mg, 2.0 mmol, 1.0 eq), tert-butyl 3-aminopiperidine-1-carboxylate (500 mg, 2.4 mmol, 1.2 eq) and NaOBu.sup.t (360 mg, 4.0 mmol, 2.0 eq) were dissolved in anhydrous toluene (5 mL). The mixture was purged with N.sub.2 for 5 minutes, 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (160 mg, 0.4 mmol, 0.2 eq) and Pd.sub.2(dba).sub.3 (185 mg, 0.2 mmol, 0.1 eq) were added thereto. The stirred mixture was purged with N.sub.2 for three times, and then heated to 130° C. for 24 h. After cooling down to rt, the mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (PE/EA=4:1) to give the title compound as a yellow oil (440 mg, 50% yield). LCMS: m/z 431.4 [M+H].sup.+.

Intermediate 28: N-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperidin-3-amine

(95) ##STR00072##

(96) tert-Butyl 3-((4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)amino)piperidine-1-carboxylate (430 mg, 1.0 mmol, 1.0 eq) was dissolved in a solution of HCl in EtOAc (sat. 3 mL) and stirred at rt for 16 h. The mixture was concentrated to give the crude title compound as a yellow oil (300 mg, 90% yield), which was used for next step without further purification. LCMS: m/z 331.3 [M+H].sup.+.

Example 13

3-(3-((4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)amino)piperidin-1-yl)propanoic acid (Compound 14)

(97) ##STR00073##

(98) Using the same procedure as for intermediate 5, ethyl 3-(3-((4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)amino)piperidin-1-yl)propanoate was obtained as a yellow oil (110 mg, 55% yield). LCMS: m/z 431.4 [M+H].sup.+.

(99) Using standard hydrolysis condition, the title compound as a yellow oil (40 mg, 35% yield). LCMS: m/z 403.4 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 6.66 (d, J=8.4 Hz, 2H), 6.55 (d, J=8.4 Hz, 2H), 3.89-3.81 (m, 1H), 3.56 (bs, 1H), 3.41-3.28 (m, 4H), 2.95 (bs, 1H), 2.80-2.67 (m, 3H), 2.04-1.99 (m, 4H), 1.75 (bs, 3H), 1.48 (bs, 1H), 1.24-1.15 (m, 2H), 1.08-0.95 (m, 3H), 0.78 (s, 9H)

Intermediate 29: tert-Butyl 4-(4-(octyloxy)phenyl)piperazine-1-carboxylate

(100) ##STR00074##

(101) A mixture of 1-bromo-4-(octyloxy)benzene (568 mg, 2.0 mmol, 1.0 eq), tert-butyl piperazine-1-carboxylate (372 mg, 2.0 mmol, 1.0 eq), t-BuOK (448 mg, 4.0 mmol, 2.0 eq) and Pd(dppf)Cl.sub.2.DCM (163 mg, 0.2 mmol, 0.1 eq) in toluene (5 mL) was stirred at 110° C. for 16 h. After cooling down to rt, the mixture was filtrated and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE/EA=8/1) to give the title compound as a white solid (218 mg, 28% yield). LCMS m/z 391.1 [M+1].sup.+.

Intermediate 30: 1-(4-(Octyloxy)phenyl)piperazine

(102) ##STR00075##

(103) To a solution of tert-butyl 4-(4-(octyloxy)phenyl)piperazine-1-carboxylate (600 mg, 1.54 mmol, 1.0 eq) in DCM (2 mL) was added HCl in EA (4M, 3 mL). Then the mixture was stirred at rt for 2 h. Then the solvent was removed in vacuo to give the title compound as a yellow solid (357 mg, 80% yield), which was used in the next step without further purification. LCMS m/z 291.1 [M+1].sup.+; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 6.91-6.83 (m, 4H), 3.92 (t, J=6.8 Hz, 2H), 3.10 (bs, 6H), 2.63 (bs, 2H), 1.80-1.73 (m, 2H), 1.49-1.29 (m, 10H), 0.89 (t, J=6.8 Hz, 3H).

Example 14

3-(4-(4-(Octyloxy)phenyl)piperazin-1-yl)propanoic acid (Compound 7)

(104) ##STR00076##

(105) Using the same procedure as for intermediate 5, ethyl 3-(4-(4-(octyloxy)phenyl)piperazin-1-yl)propanoate was obtained as a yellow solid (120 mg, 74% yield), which was used in the next step without further purification. LCMS m/z 391.1 [M+1].sup.+.

(106) Using standard hydrolysis condition, the title compound as a yellow solid (20 mg, 22% yield). LCMS m/z 363.3 [M+1].sup.+; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 6.89-6.82 (m, 4H), 3.90 (t, J=6.8 Hz, 2H), 3.18 (bs, 4H), 2.88 (bs, 6H), 2.58-2.55 (m, 2H), 1.78-1.71 (m, 2H), 1.45-1.28 (m, 10H), 0.88 (t, J=6.8 Hz, 3H).

Example 15

4-(4-(4-(Octyloxy)phenyl)piperazin-1-yl)butanoic acid (Compound 8)

(107) ##STR00077##

(108) Using the same procedure as for intermediate 6, ethyl 4-(4-(4-(octyloxy)phenyl)piperazin-1-yl)butanoate was obtained as a yellow oil (54 mg, 39% yield). LCMS m/z 405.2 [M+H].sup.+.

(109) Using standard hydrolysis condition, the title compound was obtained as a yellow solid (18 mg, 40% yield). LCMS m/z 377.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 6.87-6.85 (m, 2H), 6.76-6.73 (m, 2H), 3.81 (t, J=6.8 Hz, 2H), 3.16 (bs, 8H), 2.96 (t, J=6.4 Hz, 2H), 2.39-2.36 (m, 2H), 1.87-1.81 (m, 2H), 1.67-1.60 (m, 2H), 1.39-1.32 (m, 2H), 1.25-1.20 (m, 8H), 0.80 (t, J=6.8 Hz, 3H).

Example 16

4-((4-(4-(Octyloxy)phenyl)piperazin-1-yl)methyl)bicyclo[2.2.2]octane-1-carboxylic acid (Compound 9)

(110) ##STR00078##

(111) A mixture of 1-(4-(octyloxy)phenyl)piperazine (100 mg, 0.34 mmol, 1.0 eq), (56 mg, 0.31 mmol, 0.9 eq) and Ti(OEt).sub.4 (155 mg, 0.68 mmol, 2.0 eq) in THF (2 mL) was stirred at 100° C. under MW for 16 h. After cooling to rt, NaBH(OAc).sub.3 (216 mg, 1.02 mmol, 3.0 eq) was added and then the mixture was stirred for another 1 h under same condition. After the mixture was cooled to rt once again, the Celite and water (2 mL) were added, the resulting suspension was filtered through Celite and eluted with EA (10 mL). The filtrate was separated, and the aqueous layer was extracted with EA (10 mL×3). The combined organic phase was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to give the title compound (15 mg, 14% yield) as a white solid. LCMS m/z 457.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 12.01 (bs, 1H), 6.84-6.77 (m, 4H), 3.86 (t, J=6.4 Hz, 2H), 2.95-2.94 (m, 4H), 2.55-2.52 (m, 4H), 2.04 (s, 2H), 1.67-1.63 (m, 8H), 1.41-1.26 (m, 16H), 0.86 (t, J=6.8 Hz, 3H).

Intermediate 31: tert-Butyl 4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperazine-1-carboxylate

(112) ##STR00079##

(113) Using the same condition as in intermediate 29, the title compound was obtained as a white solid (600 mg, 44% yield). LCMS: m/z 417.3 [M+H].sup.+.

Intermediate 32: 1-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperazine

(114) ##STR00080##

(115) Using the same condition as in intermediate 30, the title compound was obtained as a yellow solid (340 mg, 89% yield). LCMS: m/z 317.0 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.83-6.77 (m, 4H), 4.05-4.00 (m, 1H), 2.90-2.88 (m, 4H), 2.82-2.79 (m, 4H), 2.08-2.05 (m, 2H), 1.77-1.74 (m, 2H), 1.25-1.01 (m, 5H), 0.84 (s, 9H).

Example 17

3-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperazin-1-yl)propanoic acid (Compound 1)

(116) ##STR00081##

(117) Using the same procedure as for intermediate 5, ethyl 3-(4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperazin-1-yl)propanoate was obtained as a yellow solid (120 mg, 75% yield). LCMS: m/z 417.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 6.88-6.82 (m, 4H), 4.15 (q, J=6.8 Hz, 2H), 4.01-3.96 (m, 1H), 3.10 (bs, 4H), 2.78-2.55 (m, 7H), 2.17-2.15 (m, 2H), 1.85-1.82 (m, 2H), 1.60 (bs, 1H), 1.39-1.31 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 1.11-1.03 (m, 3H), 0.86 (s, 9H).

(118) Using standard hydrolysis condition, the title compound was obtained as a yellow solid (5 mg, 7% yield). LCMS: m/z 389.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 6.97-6.94 (m, 2H), 6.87-6.85 (m, 2H), 4.10-4.03 (m, 1H), 3.27-3.21 (m, 10H), 2.61-2.57 (m, 2H), 2.18-2.15 (m, 2H), 1.88-1.85 (m, 2H), 1.41-1.30 (m, 1H), 1.25-1.08 (m, 4H), 0.90 (s, 9H).

Example 18

4-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperazin-1-yl)butanoic acid (Compound 2)

(119) ##STR00082##

(120) Using the same procedure as for intermediate 6, ethyl 4-(4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperazin-1-yl)butanoate was obtained as a yellow solid (100 mg, 73% yield). LCMS: m/z 431.3 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ: 6.94-6.92 (m, 2H), 6.88-6.85 (m, 2H), 4.15 (q, J=7.2 Hz, 2H), 4.06-3.99 (m, 1H), 3.70-3.10 (m, 8H), 2.46 (t, J=6.8 Hz, 2H), 2.17-2.08 (m, 6H), 1.87-1.83 (m, 2H), 1.40-1.32 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.15-1.04 (m, 3H), 0.87 (s, 9H).

(121) Using standard hydrolysis condition, the title compound was obtained as a white solid (10 mg, 15% yield). LCMS: m/z 403.3 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 6.97-6.95 (m, 2H), 6.88-6.84 (m, 2H), 4.10-4.04 (m, 1H), 3.27 (bs, 8H), 3.08-3.06 (m, 2H), 2.51-2.48 (m, 2H), 2.18-2.15 (m, 2H), 1.96-1.86 (m, 4H), 1.35-1.30 (m, 2H), 1.19-1.11 (m, 3H), 0.90 (s, 9H).

Example 19

4-((4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperazin-1-yl)methyl)bicyclo[2.2.2]octane-1-carboxylic acid (Compound 10)

(122) ##STR00083##

(123) Using the same procedure as for example 16, the title compound was obtained as a white solid (50 mg, 7% yield). LCMS: m/z 483.4 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 12.16 (s, 1H), 6.91-6.84 (m, 4H), 4.12-4.05 (m, 1H), 3.55-3.48 (m, 4H), 3.26-3.03 (m, 6H), 2.09-2.05 (m, 2H), 1.78-1.70 (m, 8H), 1.59-1.55 (m, 6H), 1.29-1.20 (m, 2H), 1.16-0.98 (m, 3H), 0.85 (s, 9H).

Intermediate 33: 3-Chloro-6-(octyloxy)pyridazine

(124) ##STR00084##

(125) 3,6-Dichloropyridazine (450 mg, 3.0 mmol, 1.0 eq), octan-1-ol (450 mg, 3.3 mmol, 1.1 eq) and K.sub.2CO.sub.3 (840 mg, 6.0 mmol, 2.0 eq) were dissolved in DMF (6 mL). The mixture was heated to 150° C. for 2 h. After cooling down to rt, the mixture was purified by prep-TLC (PE/EA=10/1) to give the title compound as a yellow solid (400 mg, 50% yield). LCMS m/z 243.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.35 (d, J=9.2 Hz, 1H), 6.94 (d, J=9.2 Hz, 1H), 4.47 (t, J=6.4 Hz, 2H), 1.84-1.77 (m, 2H), 1.48-1.41 (m, 2H), 1.37-1.28 (m, 8H), 0.89 (t, J=6.4 Hz, 3H).

Intermediate 34: tert-Butyl 4-(6-(ctyloxy)pyridazin-3-yl)piperazine-1-carboxylate

(126) ##STR00085##

(127) Using the same condition as in intermediate 29, the title compound was obtained as a yellow oil (200 mg, 50% yield). LCMS m/z 393.4 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.02 (d, J=9.6 Hz, 1H), 6.85 (d, J=9.6 Hz, 1H), 4.39 (t, J=6.8 Hz, 2H), 3.56 (bs, 4H), 3.49 (bs, 4H), 1.82-1.75 (m, 2H), 1.49 (s, 9H), 1.45-1.39 (m, 2H), 1.30-1.27 (m, 8H), 0.88 (t, J=6.8 Hz, 3H).

Intermediate 35: 3-(Octyloxy)-6-(piperazin-1-yl)pyridazine

(128) ##STR00086##

(129) Using the same condition as in intermediate 30, the title compound was obtained as a yellow solid (120 mg, 80% yield), which was used for next step without further purification. LCMS m/z 293.2 [M+H].sup.+.

Example 20

3-(4-(6-(Octyloxy)pyridazin-3-yl)piperazin-1-yl)propanoic acid (Compound 22)

(130) ##STR00087##

(131) Using the same procedure as for intermediate 5, ethyl 3-(4-(6-(octyloxy)pyridazin-3-yl)piperazin-1-yl)propanoate was obtained as a yellow solid (80 mg, 60% yield). LCMS m/z 393.3 [M+1].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.00 (d, J=9.6 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 4.38 (t, J=6.8 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.52 (bs, 4H), 2.76 (t, J=7.2 Hz, 2H), 2.61 (bs, 4H), 2.54 (t, J=7.2 Hz, 2H), 1.81-1.74 (m, 2H), 1.46-1.39 (m, 2H), 1.31-1.25 (m, 11H), 0.88 (t, J=6.4 Hz, 3H).

(132) Using standard hydrolysis condition, the title compound was obtained as a yellow oil (65 mg, 90% yield). LCMS m/z 365.3 [M+1].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.50 (d, J=10.0 Hz, 1H), 7.13 (d, J=10.0 Hz, 1H), 4.23 (t, J=6.0 Hz, 2H), 3.77 (bs, 4H), 3.42-3.38 (m, 6H), 2.80 (t, J=7.2 Hz, 2H), 1.74-1.67 (m, 2H), 1.42-1.21 (m, 10H), 0.80 (t, J=7.2 Hz, 3H).

Intermediate 36: 2-Chloro-5-(octyloxy)pyrimidine

(133) ##STR00088##

(134) To a mixture of 2-chloropyrimidin-5-ol (700 mg, 5.4 mmol, 1.0 eq), octan-1-ol (1.05 g, 8.1 mmol, 1.5 eq), PPh.sub.3 (2.8 g, 10.8 mmol, 2.0 eq) and triethylamine (1.63 g, 16.2 mol, 3.0 eq) in THF (14 mL) was added dropwise DIAD (2.18 g, 10.8 mmol, 2.0 eq) at 0° C. The mixture was allowed to warm up to rt and stirred for 16 h. The solvent was then removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EA=10/1) to give the title compound as a yellow oil (847 mg, 65% yield). LCMS m/z 243.1 [M+H].sup.+; 1H NMR (CDCl3, 400 MHz) δ: 8.28 (s, 2H), 4.05 (t, J=6.8 Hz, 2H), 1.85-1.78 (m, 2H), 1.42-1.26 (m, 10H), 0.90-0.86 (m, 3H).

Intermediate 37: 5-(Octyloxy)-2-(piperazin-1-yl)pyrimidine

(135) ##STR00089##

(136) Using the same procedure as for intermediate 29, tert-butyl 4-(5-(octyloxy)pyrimidin-2-yl)piperazine-1-carboxylate was obtained as a yellow oil (290 mg, 40% yield). LCMS m/z 393.4 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.09 (s, 2H), 3.91 (t, J=6.4 Hz, 2H), 3.71-3.69 (m, 4H), 3.51-3.48 (m, 4H), 1.78-1.71 (m, 2H), 1.49 (s, 9H), 1.49-1.40 (m, 2H), 1.31 (bs, 8H), 0.89 (t, J=6.8 Hz, 3H).

(137) Using the same procedure as for intermediate 30, the title compound was obtained as a yellow solid (230 mg, 100% yield). LCMS m/z 293.3 [M+H].sup.+.

Example 21

3-(4-(5-(Octyloxy)pyrimidin-2-yl)piperazin-1-yl)propanoic acid (Compound 23)

(138) ##STR00090##

(139) Using the same procedure as for intermediate 5, ethyl 3-(4-(5-(octyloxy)pyrimidin-2-yl)piperazin-1-yl)propanoate was obtained as a yellow solid (240 mg, 80% yield). LCMS m/z 393.4 [M+1].sup.+.

(140) Using standard hydrolysis condition, the title compound was obtained as a gray solid (160 mg, 80% yield). LCMS m/z 365.3 [M+1].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.09 (s, 2H), 3.91-3.88 (m, 2H), 3.39-3.30 (m, 8H), 2.81-2.78 (m, 2H), 1.65 (bs, 2H), 1.38-1.22 (m, 12H), 0.81 (bs, 3H).

Intermediate 38: 2-Bromo-5-(octyloxy)pyridine

(141) ##STR00091##

(142) Using the same procedure as for intermediate 33, the title compound was obtained as a yellow oil (730 mg, 50% yield). LCMS: m/z 286.1 [M+H].sup.+.

Intermediate 39: 1-(5-(Octyloxy)pyridin-2-yl)piperazine

(143) ##STR00092##

(144) Using the same procedure as for intermediate 29, tert-butyl 4-(5-(octyloxy)pyridin-2-yl)piperazine-1-carboxylate was obtained as a yellow oil (500 mg, 50% yield). LCMS m/z 392.4 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.93 (d, J=2.8 Hz, 1H), 7.16 (d, J=9.2 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 3.92 (t, J=6.4 Hz, 2H), 3.56-3.54 (m, 4H), 3.40-3.37 (m, 4H), 1.78-1.71 (m, 2H), 1.48 (s, 9H), 1.45-1.40 (m, 2H), 1.37-1.28 (m, 8H), 0.88 (t, J=6.8 Hz, 3H).

(145) Using the same procedure as for intermediate 30 the title compound was obtained as a yellow solid, (200 mg, 80% yield). LCMS m/z 292.3 [M+H].sup.+.

Example 22

3-(4-(5-(Octyloxy)pyridin-2-yl)piperazin-1-yl)propanoic acid (Compound 24)

(146) ##STR00093##

(147) Using the same procedure as for intermediate 5, ethyl 3-(4-(5-(octyloxy)pyridin-2-yl)piperazin-1-yl)propanoate was obtained as a yellow solid (240 mg, 80% yield). LCMS m/z 392.4 [M+1].sup.+.

(148) Using standard hydrolysis condition, the title compound was obtained as a yellow oil (80 mg, 35% yield). LCMS m/z 364.3 [M+1].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.87 (d, J=3.2 Hz, 1H), 7.43 (dd, J=3.2, 9.2 Hz, 1H), 7.01 (d, J=9.2 Hz, 1H), 3.98 (t, J=6.4 Hz, 2H), 3.75-3.47 (m, 10H), 2.90 (t, J=6.8 Hz, 2H), 180-1.73 (m, 2H), 1.50-1.32 (m, 10H), 0.91 (t, J=6.8 Hz, 3H).

Intermediate 40: tert-Butyl 3-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

(149) ##STR00094##

(150) To a microwave vial loaded with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (177 mg, 0.600 mmol), 1-bromo-4-(4-tert-butyl-cyclohexyloxy)-benzene (156 mg, 0.500 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) was added 1,2-dimethoxyethane (1.5 mL, 14 mmol), followed by ethanol (1.0 mL, 17 mmol) and saturated aqueous NaHCO.sub.3 solution (0.5 mL). The reaction mixture was heated with microwave irritation at 120° C. for 20 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 get the title compound as a colorless oil (129 mg, 65% yield). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 7.24 (d, J=8.69 Hz, 2H), 6.84 (d, J=8.69 Hz, 2H), 4.06-4.22 (m, 1H), 3.74-3.93 (m, 2H), 2.95 (q, J=9.06 Hz, 2H), 2.17 (d, J=11.71 Hz, 2H), 1.87 (d, J=10.58 Hz, 2H), 1.51 (s, 9H), 1.01-1.43 (m, 5H), 0.89 (s, 9H); LCMS m/z 400.3 [M+H].sup.+.

Intermediate 41: 3-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)pyrrolidine

(151) ##STR00095##

(152) To a solution of tert-butyl 3-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (40 mg, 0.10 mmol) in methanol (4 mL) and EtOAc (2 mL) was added 10% Pd/C (10 mg, 0.09 mmol). The mixture was stirred at rt under H.sub.2 atmosphere overnight. It was filtered through celite and concentrated to get an oil, which was treated with 10% TFA in CH.sub.2Cl.sub.2 (2 mL) at room temperature for 1 h. The reaction mixture was concentrated to give the TFA salt of the desired product (41 mg, yield 98%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.20 (d, J=8.78 Hz, 2H), 6.89 (d, J=8.78 Hz, 2H), 4.00-4.25 (m, 1H), 3.60-3.72 (m, 1H), 3.35-3.58 (m, 3H), 3.12 (t, J=10.92 Hz, 1H), 2.31-2.49 (m, 1H), 1.96-2.24 (m, 3H), 1.80-1.92 (m, 2H), 1.02-1.45 (m, 5H), 0.89 (s, 9H); LCMS m/z 302.2 [M+H].sup.+.

Example 23

3-(3-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)pyrrolidin-1-yl)propanoic acid (Compound 15)

(153) ##STR00096##

(154) To a suspension of 3-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)pyrrolidine TFA salt (18 mg, 0.042 mmol) in acetonitrile (0.5 mL) was added N,N-diisopropylethyl amine (22 μL, 0.13 mmol) and stirred at rt for 2 minutes. 3-Bromopropanoic acid methyl ester (7.0 uL, 0.063 mmol) was then added. The suspension turned to a clear solution after heating with an oil bath (60° C.). The reaction solution was heated at 60° C. for 1 h. It was partitioned between EtOAc and saturated NaHCO.sub.3 solution. The aqueous layer was extracted with EtOAc. The combined organic phases were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography on silica gel column to get the desired methyl ester as a colorless oil (11 mg, yield 67%). LCMS m/z 388.2 [M+H].sup.+.

(155) To a solution of above methyl ester (8.4 mg, 0.022 mmol) in MeOH (0.3 mL) and THF (0.3 mL) was added 3 N NaOH solution (8.7 uL, 0.026 mmol). The reaction mixture was heated with microwave irritation at 80° C. for 30 min. The mixture was then concentrated and lyophilized to get the sodium salt of the desired acid as a white powder (8.9 mg, yield 100%). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 7.16 (d, J=8.69 Hz, 2H), 6.82 (d, J=8.69 Hz, 2H), 4.01-4.20 (m, 1H), 3.12-3.36 (m, 2H), 2.71-3.08 (m, 4H), 2.54 (t, J=9.25 Hz, 1H), 2.44 (t, J=7.93 Hz, 2H), 2.08-2.35 (m, 3H), 1.76-1.97 (m, 3H), 0.99-1.44 (m, 5H), 0.89 (s, 9H); LCMS m/z 374.2 [M+H].sup.+

Example 24

4-(3-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)pyrrolidin-1-yl)butanoic acid (Compound 17)

(156) ##STR00097##

(157) The titled compound was synthesized according to the procedure described in example 23 (9 mg, yield 50%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 7.15 (d, J=8.53 Hz, 2H), 6.82 (d, J=8.53 Hz, 2H), 4.02-4.21 (m, 1H), 3.25-3.35 (m, 1H), 3.12 (t, J=8.66 Hz, 1H), 2.86-3.01 (m, 1H), 2.37-2.75 (m, 4H), 2.10-2.35 (m, 5H), 1.71-1.94 (m, 5H), 1.02-1.44 (m, 5H), 0.89 (s, 9H); LCMS m/z 388.3 [M+H].sup.+

Intermediate 42: Ethyl 4-(3-(4-hydroxyphenyl)piperidin-1-yl)cyclohexanecarboxylate

(158) ##STR00098##

(159) To a mixture of 4-piperidin-3-yl-phenol (89 mg, 0.50 mmol) and 4-oxo-cyclohexanecarboxylic acid ethyl ester (170 mg, 1.00 mmol) in 1,2-dichloroethane (2.5 mL) was added sodium triacetoxyborohydride (212 mg, 1.00 mmol), followed by acetic acid (28 μL, 0.49 mmol). The reaction mixture was stirred at rt for 1 h. It turned to a clear solution after EtOH (2 mL) was added. The reaction solution was stirred at rt overnight, and adjust pH 7 by adding saturated NaHCO.sub.3 solution (˜2 mL) and water. The mixture was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried over MgSO.sub.4, filtered and concentrated in vacuo to get the crude product as a colorless oil (207 mg, 120% yield). It was dissolved in THF (5 mL) to make a 0.1M stock solution for next step. LCMS m/z 332.2 [M+H].sup.+.

Example 25

4-(3-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)cyclohexanecarboxylic acid (Compound 20)

(160) ##STR00099##

(161) To a mixture of ethyl 4-(3-(4-hydroxyphenyl)piperidin-1-yl)cyclohexanecarboxylate stock solution from previous step (1 mL, 0.10 mmol), 4-tert-butyl-cyclohexanol (23 mg, 0.15 mmol), and triphenylphosphine (39 mg, 0.15 mmol) was added diisopropyl azodicarboxylate (31 uL, 0.15 mmol). The reaction mixture was stirred at rt for 3 h, and another portion of reagents were added and stirred overnight. The reaction mixture was purified by flash chromatography on silica gel column to provide desired ester. LCMS m/z 470.3 [M+H].sup.+

(162) To the above ester in MeOH (0.5 mL) and THF (0.5 mL) was added 3 M NaOH (0.1 mL). The mixture was heated at 50° C. for 1 h, and then leave it stirred at rt overnight. It was neutralized with 2N HCl (150 μL) and purified by HPLC (TFA method) to get TFA salt of the desired product as a white powder after lyophilization (7 mg, 13% yield). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 7.19 (dd, J=2.83, 8.88 Hz, 2H), 6.88 (d, J=8.69 Hz, 2H), 4.04-4.24 (m, 1H), 2.88-3.74 (m, 7H), 1.44-2.40 (m, 16H), 0.99-1.42 (m, 5H), 0.89 (s, 9H); LCMS m/z 442.3 [M+H].sup.+

Example 26

4-(3-(4-(Octyloxy)phenyl)piperidin-1-yl)cyclohexanecarboxylic acid (Compound 21)

(163) ##STR00100##

(164) The titled compound was synthesized according to the procedure described in Example 25 (4 mg, yield 7%). .sup.1H NMR (300 MHz, METHANOL-d.sub.4) δ 7.20 (dd, J=2.64, 8.69 Hz, 2H), 6.89 (d, J=8.69 Hz, 2H), 3.95 (t, J=6.42 Hz, 2H), 2.62-3.63 (m, 7H, 1.20-2.41 (m, 24H), 0.83-0.97 (m, 3H); LCMS m/z 416.3 [M+H].sup.+.

Intermediate 43: 1-Bromo-4-((trans-4-ethylcyclohexyl)oxy)benzene

(165) ##STR00101##

(166) To a mixture of 4-bromophenol (0.9 g, 5.23 mmol, 1.0 eq), (cis)-4-ethylcyclohexanol (0.8 g, 6.28 mmol, 1.2 eq), PPh.sub.3 (1.37 g, 5.23 mmol, 1.0 eq) and Et.sub.3N (0.53 g, 5.23 mmol, 1.0 eq) in dry THF (40 mL) was quickly added DIAD (1.06 g, 5.23 mmol, 1.0 eq) in one portion at 0° C. under N.sub.2. Then the reaction mixture was stirred at room temperature for 72 h. The solvent was removed under vacuum and the residue was purified by silica gel column (PE) to give the title compound as a yellow oil (0.62 g, 42% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.34 (dd, J=7.2, 2.4 Hz, 2H), 6.77 (dd, J=7.2, 2.4 Hz, 2H), 4.10-4.05 (m, 1H), 2.13-2.09 (m, 2H), 1.84 (t, J=6.4 Hz, 2H), 1.41-1.38 (m, 2H), 1.26-1.19 (m, 3H), 1.04-0.97 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).

Intermediate 44: tert-Butyl 4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

(167) ##STR00102##

(168) To a solution of 1-bromo-4-((trans-4-ethylcyclohexyl)oxy)benzene (0.6 g, 2.13 mmol, 1.0 eq) in dioxane (30 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.69 g, 2.34 mmol, 1.1 eq), Cs.sub.2CO.sub.3 (2.08 g, 6.39 mmol, 3.0 eq) and PdCl.sub.2(dppf) (0.17 g, 0.21 mmol, 0.1 eq) at room temperature under N.sub.2. Then the reaction mixture was heated to 90° C. with stirring for 16 h. After cooling to room temperature and filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE/EA=15:1) to give the title compound as a white solid (0.66 g, 81% yield). ESI-MS (M+H).sup.+: 385.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.27 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.93-5.91 (m, 1H), 4.16-4.08 (m, 1H), 4.04-4.03 (m, 2H), 3.62-3.59 (m, 2H), 2.49-2.47 (m, 2H), 2.15-2.12 (m, 2H), 1.86-1.83 (m, 2H), 1.48 (s, 9H), 1.42-1.38 (m, 2H), 1.26-1.20 (m, 3H), 1.02-0.98 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).

Intermediate 45: 4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)-1,2,3,6-tetrahydropyridine

(169) ##STR00103##

(170) To the solution of tert-butyl 4-(4-(((trans)-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.65 g, 1.69 mmol, 1.0 eq) in CH.sub.2Cl.sub.2 (25.0 mL) was carefully added TFA (5.0 mL) at room temperature. The reaction solution was stirred at room temperature for 16 h. The solvent was removed to give the title compound (0.43 g, 90% yield) as a crude product, which was directly used for the next step without further purification. ESI-MS (M+H).sup.+: 286.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.27 (m, 2H), 6.84 (m, 2H), 5.95-5.93 (m, 1H), 4.18-4.16 (m, 1H), 3.92-3.45 (m, 2H), 2.81-2.79 (m, 2H), 2.17-2.14 (m, 2H), 1.89-1.86 (m, 2H), 1.47-1.38 (m, 2H), 1.29-1.22 (m, 5H), 1.07-0.96 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

Intermediate 46: Ethyl 3-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoate

(171) ##STR00104##

(172) To the solution of 4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)-1,2,3,6-tetrahydropyridine (250 mg, 0.88 mmol, 1.0 eq) in CH.sub.3CN (20 mL) were added ethyl acrylate (132 mg, 1.32 mmol 1.5 eq) and Cs.sub.2CO.sub.3 (855 mg, 2.63 mmol, 3.0 eq). The mixture was refluxed for 16 h. After cooling to room temperature and filtration, the filtrate was concentrated and purified by silica gel column (PE:EA=2:1) to give the title compound as a yellow solid (260 mg, 77% yield). ESI-MS (M+H).sup.+: 386.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.29 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 5.97-5.95 (m, 1H), 4.17 (q, J=6.8 Hz, 2H), 4.15-4.13 (m, 1H), 3.20-3.18 (m, 2H), 2.86-2.83 (m, 2H), 2.76-2.74 (m, 2H), 2.62-2.55 (m, 4H), 2.16-2.14 (m, 2H), 1.87-1.85 (m, 2H), 1.43-1.39 (m, 2H), 1.29-1.22 (m, 6H), 1.03-0.98 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

Intermediate 47: Ethyl 3-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)propanoate

(173) ##STR00105##

(174) To a solution of ethyl 3-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoate (120 mg, 0.312 mmol, 1.0 eq) in CH.sub.3OH (20 mL) was carefully added Pd/C (24 mg, 20% wt). The reaction solution was stirred at 25° C. under H.sub.2 at 1 atm for 20 h. Then the mixture was filtered and concentrated in vacuo to give the title compound as yellow gum (1.8 g, 82% yield). ESI-MS (M+H).sup.+: 387.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.12 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.13 (q, J=6.8 Hz, 2H), 4.13-4.11 (m, 1H), 3.44-3.42 (m, 2H), 2.84-2.82 (m, 2H), 2.58-2.55 (m, 2H), 2.43 (t, J=7.2 Hz, 3H), 2.13-2.11 (m, 4H), 1.95-1.82 (m, 4H), 1.41-1.36 (m, 2H), 1.28-1.20 (m, 6H), 1.00-0.97 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).

Example 27

3-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoic acid (Compound 45)

(175) ##STR00106##

(176) To the solution of ethyl 3-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)propanoate (90 mg, 0.234 mmol, 1.0 eq) in CH.sub.3OH (20 mL) was added NaOH (94 mg, 2.34 mmol, 10.0 eq) in H.sub.2O (4 ml). The reaction solution was heated to 80° C. for 2 h with stirring. After concentration, the residue was adjusted to pH=6 with 1N HCl, extracted with EtOAc (50 mL×2), washed with H.sub.2O (15 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound as a white solid (45 mg, 54% yield). ESI-MS (M+H).sup.+: 358.2. HPLC: 99.42%-100.00%. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.28 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.94-5.92 (m, 1H), 4.15-4.13 (m, 1H), 3.47-3.45 (m, 2H), 3.04-2.96 (m, 4H), 2.68-2.61 (m, 4H), 2.15-2.13 (m, 2H), 1.87-1.84 (m, 2H), 1.43-1.23 (m, 5H), 1.02-0.98 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

Example 28

3-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)propanoic acid (Compound 30)

(177) ##STR00107##

(178) Using the same procedure as for example 27, the title compound was obtained as a white solid (70 mg, 76% yield). ESI-MS (M+H).sup.+: 360.2; .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.09 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 4.11-4.09 (m, 1H), 3.32-3.29 (m, 2H), 2.89-2.87 (m, 2H), 2.60-2.57 (m, 3H), 2.47-2.45 (m, 2H), 2.14-2.12 (m, 2H), 1.95-1.83 (m, 6H), 1.42-1.23 (m, 5H), 1.01-0.98 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).

Example 29

4-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoic acid (Compound 44)

(179) ##STR00108##

(180) Using the same procedure as for intermediate 6, ethyl 4-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoate was obtained as a yellow solid (240 mg, 58% yield). ESI-MS (M+H).sup.+: 400.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.28 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 5.96-5.94 (m, 1H), 4.14 (q, J=6.8 Hz, 2H), 4.15-4.13 (m, 1H), 3.14-3.13 (m, 2H), 2.70-2.67 (m, 2H), 2.53-2.46 (m, 4H), 2.37 (t, J=7.2 Hz, 2H), 2.15-2.12 (m, 2H), 1.91-1.83 (m, 5H), 1.45-1.27 (m, 2H), 1.26-1.21 (m, 5H), 1.03-0.98 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).

(181) Using standard hydrolysis condition, the title compound was obtained a white solid (52 mg, 62% yield). ESI-MS (M+H).sup.+: 372.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.20 (d, J=7.2 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 5.84-5.82 (m, 1H), 4.08-4.06 (m, 1H), 3.44-3.42 (m, 2H), 3.01-2.99 (m, 2H), 2.82-2.80 (m, 2H), 2.65-2.55 (m, 4H), 2.08-2.06 (m, 2H), 1.89-1.86 (m, 2H), 1.80-1.77 (m, 2H), 1.35-1.17 (m, 5H), 0.93-0.91 (m, 2H), 0.83 (t, J=7.2 Hz, 3H).

Example 30

4-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)butanoic acid (Compound 29)

(182) ##STR00109##

(183) Using the same procedure as for intermediate 47, ethyl 4-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)butanoate was obtained as a yellow gum (125 mg, 83% yield). ESI-MS (M+H).sup.+: 402.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.06 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.10-4.03 (m, 3H), 3.38-3.35 (m, 2H), 2.78-2.76 (m, 2H), 2.52-2.50 (m, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.33-2.05 (m, 5H), 1.88-1.75 (m, 4H), 1.34-1.30 (m, 2H), 1.21-1.12 (m, 8H), 0.98-0.91 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

(184) Using standard hydrolysis condition, the title compound was obtained as a white solid (98 mg, 84% yield). ESI-MS (M+H).sup.+: 374.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.11 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.12-4.10 (m, 1H), 3.35-3.32 (m, 2H), 2.80-2.78 (m, 2H), 2.77-2.63 (m, 5H), 2.16-1.84 (m, 10H), 1.42-1.28 (m, 5H), 1.02-0.99 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

Example 31

5-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoic acid (Compound 43)

(185) ##STR00110##

(186) Using the same procedure as for intermediate 6, ethyl 5-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoate was obtained as a yellow solid (240 mg, 58% yield). ESI-MS (M+H).sup.+: 414.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.21 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 5.89-5.87 (m, 1H), 4.08-4.03 (m, 3H), 3.06-3.05 (m, 2H), 2.62-2.59 (m, 2H), 2.47-2.37 (m, 4H), 2.29-2.26 (m, 2H), 2.08-2.06 (m, 2H), 1.79-1.76 (m, 2H), 1.61-1.53 (m, 4H), 1.37-1.28 (m, 2H), 1.20-1.16 (m, 6H), 0.97-0.86 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

(187) Using standard hydrolysis condition, the title compound was obtained as a pale yellow solid (32 mg, 43% yield). ESI-MS (M+H).sup.+: 386.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.21 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 5.86-5.84 (m, 1H), 4.08-4.06 (m, 1H), 3.39-3.36 (m, 2H), 2.98-2.96 (m, 2H), 2.65-2.59 (m, 3H), 2.20-2.18 (m, 2H), 2.07-2.04 (m, 2H), 1.79-1.76 (m, 2H), 1.56-1.54 (m, 4H), 1.35-1.33 (m, 2H), 1.21-1.14 (m, 4H), 0.96-0.93 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

Example 32

5-(4-(4-((trans-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoic acid (Compound 28)

(188) ##STR00111##

(189) Using the same condition as in intermediate 47, ethyl 5-(4-(4-((trans-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoate was obtained as a yellow gum (104 mg, 69% yield). ESI-MS (M+H).sup.+: 416.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.13 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.16-4.11 (m, 3H), 3.44-3.42 (m, 2H), 2.84-2.82 (m, 2H), 2.59-2.55 (m, 2H), 2.43 (m, 3H), 2.26-2.24 (m, 2H), 2.13-2.11 (m, 4H), 1.95-1.82 (m, 4H), 1.39-1.36 (m, 2H), 1.28-1.20 (m, 8H), 1.01-0.97 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).

(190) Using standard hydrolysis condition, the title compound was obtained as a pale yellow solid (35 mg, 42% yield). ESI-MS (M+H).sup.+: 388.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.03 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 4.03-4.01 (m, 1H), 3.52-3.50 (m, 2H), 2.78-2.76 (m, 2H), 2.51-2.49 (m, 2H), 2.27-2.25 (m, 2H), 2.08-2.03 (m, 4H), 1.86-1.75 (m, 6H), 1.60-1.58 (m, 2H), 1.33-1.14 (m, 7H), 0.91-0.89 (m, 1H), 0.81 (t, J=7.2 Hz, 3H).

Intermediate 48: 1-Bromo-4-((cis-4-ethylcyclohexyl)oxy)benzene

(191) ##STR00112##

(192) Using the same procedure as for intermediate 43, the title compound was obtained as, as yellow oil (2.5 g, 59% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.39-7.36 (m, 2H), 6.83-6.78 (m, 2H), 4.49-4.47 (m, 1H), 2.02-1.98 (m, 1H), 1.60-1.53 (m, 3H), 1.41-1.28 (m, 7H), 0.92 (t, J=7.2 Hz, 3H).

Intermediate 49: tert-Butyl 4-(4-((cis-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

(193) ##STR00113##

(194) Using the same procedure as for intermediate 44, the title compound was obtained, as yellow gum (2.36 g, 82% yield). ESI-MS (M+H).sup.+: 386.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.19 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 5.85-5.83 (m, 1H), 4.42-4.40 (m, 1H), 3.97-3.95 (m, 2H), 3.54-3.52 (m, 2H), 2.41-2.39 (m, 2H), 1.91-1.88 (m, 2H), 1.48-1.42 (m, 4H), 1.40 (s, 9H), 1.34-1.31 (m, 2H), 1.22-1.18 (m, 3H), 0.81 (t, J=7.2 Hz, 3H).

Intermediate 50: 4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)-1,2,3,6-tetrahydropyridine

(195) ##STR00114##

(196) Using the same condition as in intermediate 45, the title compound was obtained as a pale yellow solid (220 mg, 90% yield). ESI-MS (M+H).sup.+: 285.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.20 (br, 1H), 7.17 (d, J=10.0 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 5.82-5.80 (m, 1H), 4.43-4.42 (m, 1H), 3.81-3.79 (m, 2H), 3.41-3.40 (m, 2H), 2.69-2.67 (m, 2H), 1.90-1.86 (m, 2H), 1.49-1.43 (m, 4H), 1.32-1.30 (m, 2H), 1.26-1.15 (m, 3H), 0.79 (t, J=7.2 Hz, 3H).

Example 33

3-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoic acid (Compound 39)

(197) ##STR00115##

(198) Using the same procedure as for intermediate 5, ethyl 3-(4-(4-((cis-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoate was obtained as pale yellow solid (260 mg, 77% yield). ESI-MS (M+H).sup.+: 386.2. .sup.1H NMR (400 MHz, CD.sub.3Cl) δ: 7.21 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 5.89-5.86 (m, 1H), 4.43-4.41 (m, 1H), 4.08 (q, J=6.8 Hz, 2H), 3.12-3.10 (m, 2H), 2.78-2.73 (m, 2H), 2.68-2.66 (m, 2H), 2.54-2.41 (m, 4H), 1.42-1.40 (m, 4H), 1.23-1.15 (m, 10H), 0.80 (t, J=7.2 Hz, 3H).

(199) Using standard hydrolysis condition, the title compound was obtained as a pale yellow solid (40 mg, 74% yield). ESI-MS (M+H).sup.+: 358.2. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ: 7.32 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 6.02-6.00 (m, 1H), 4.56-4.54 (m, 1H), 3.10-3.09 (m, 2H), 2.68-2.65 (m, 4H), 2.43-2.36 (m, 4H), 1.88-1.85 (m, 2H), 1.52-1.48 (m, 4H), 1.25-1.23 (m, 5H), 0.86 (t, J=7.2 Hz, 3H).

Example 34

3-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)propanoic acid (Compound 26)

(200) ##STR00116##

(201) Using the same procedure as for intermediate 47, ethyl 3-(4-(4-((cis-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)propanoate was obtained as yellow gum (91 mg, 70% yield). ESI-MS (M+H).sup.+: 386.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.03 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.39-4.37 (m, 1H), 4.05 (q, J=7.2 Hz, 2H), 3.63-3.62 (m, 2H), 2.95-2.93 (m, 2H), 2.68-2.66 (m, 2H), 2.68-2.47 (m, 2H), 2.05-2.03 (m, 2H), 1.89-1.87 (m, 2H), 1.73-1.70 (m, 3H), 1.49-1.42 (m, 4H), 1.23-1.16 (m, 8H), 0.82 (t, 3H).

(202) Using standard hydrolysis condition, the title compound was obtained as a pale yellow gum (40 mg, 48% yield). ESI-MS (M+H).sup.+: 360.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.01 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.38-4.36 (m, 1H), 3.34-3.31 (m, 2H), 2.96-2.94 (m, 2H), 2.52-2.50 (m, 4H), 1.87-1.85 (m, 6H), 1.47-1.17 (m, 10H), 0.81 (t, J=7.2 Hz, 3H).

Example 35

4-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoic acid (Compound 41)

(203) ##STR00117##

(204) Using the same condition as in intermediate 6, ethyl 4-(4-(4-((cis-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoate was obtained as a yellow solid (180 mg, 64% yield). ESI-MS (M+H).sup.+: 400.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.29 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.95-5.93 (m, 1H), 4.49-4.47 (m, 1H), 4.13-4.10 (m, 2H), 3.16-3.14 (m, 2H), 2.70-2.68 (m, 2H), 2.54-2.47 (m, 4H), 2.39-2.36 (m, 2H), 1.99-1.91 (m, 4H), 1.54-1.50 (m, 4H), 1.29-1.24 (m, 8H), 0.88 (t, J=7.2 Hz, 3H).

(205) Using standard hydrolysis condition, the title compound was obtained as a white solid (40 mg, 61% yield). ESI-MS (M+H).sup.+: 372.2. .sup.1HNMR (400 MHz, MeOD) δ: 7.28 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 5.92-5.90 (m, 1H), 4.48-4.46 (m, 1H), 3.73-3.71 (m, 2H), 3.34-3.33 (m, 2H), 3.10-3.08 (m, 2H), 2.74-2.73 (m, 2H), 2.39-2.36 (m, 2H), 1.89-1.85 (m, 4H), 1.49-1.45 (m, 4H), 1.29-1.18 (m, 5H), 0.80 (t, J=7.2 Hz, 3H).

Example 36

4-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)butanoic acid (Compound 36)

(206) ##STR00118##

(207) Using the same procedure as for intermediate 47, ethyl 4-(4-(4-((cis-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)butanoate was obtained, as a pale yellow gum (104 mg, 69% yield). ESI-MS (M+H).sup.+: 402.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.10 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.45-4.43 (m, 1H), 4.14-4.12 (m, 2H), 3.68-3.67 (m, 1H), 3.06-3.03 (m, 2H), 2.43-2.32 (m, 4H), 2.08-1.76 (m, 10H), 1.52-1.49 (m, 4H), 1.29-1.23 (m, 8H), 0.88 (t, J=7.2 Hz, 3H).

(208) Using standard hydrolysis condition, the title compound was obtained as a yellow solid (33 mg, 40% yield). ESI-MS (M+H).sup.+: 374.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.03 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.40-4.38 (m, 1H), 3.28-3.26 (m, 2H), 2.74-2.72 (m, 2H), 2.54-2.44 (m, 4H), 1.95-1.82 (m, 8H), 1.46-1.43 (m, 4H), 1.32-1.18 (m, 6H), 0.82 (t, J=7.2 Hz, 3H).

Example 37

5-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoic acid (Compound 42)

(209) ##STR00119##

(210) Using the same procedure as for intermediate 6, ethyl 5-(4-(4-((cis-4-ethylcyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoate was obtained, as a pale yellow solid (170 mg, 59% yield). ESI-MS (M+H).sup.+: 414.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.22 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 5.89-5.87 (m, 1H), 4.41-4.40 (m, 1H), 4.05 (q, J=6.8 Hz, 2H), 3.07-3.06 (m, 2H), 2.62-2.60 (m, 2H), 2.47-2.37 (m, 4H), 2.28-2.26 (m, 2H), 1.92-1.90 (m, 2H), 1.63-1.44 (m, 9H), 1.19-1.18 (m, 7H), 0.82 (t, J=7.2 Hz, 3H).

(211) Using standard hydrolysis condition, the title compound was obtained as a pale yellow gum (40 mg, 62% yield). ESI-MS (M+H).sup.+: 386.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.22 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.86-5.84 (m, 1H), 4.44-4.42 (m, 1H), 3.47-3.45 (m, 2H), 3.06-3.04 (m, 2H), 2.72-2.64 (m, 4H), 2.23-2.20 (m, 2H), 1.92-1.88 (m, 2H), 1.71-1.69 (m, 2H), 1.58-1.56 (m, 2H), 1.46-1.43 (m, 3H), 1.31-1.18 (m, 6H), 0.82 (t, J=7.2 Hz, 3H).

Example 38

5-(4-(4-((cis-4-Ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoic acid (Compound 31

(212) ##STR00120##

(213) Using the same procedure as for intermediate 47, ethyl 5-(4-(4-((cis-4-ethylcyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoate was obtained as pale yellow gum (64 mg, 70% yield). ESI-MS (M+H).sup.+: 416.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.10 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.45-4.43 (m, 1H), 4.15-4.12 (m, 2H), 3.06-3.03 (m, 2H), 2.45-2.32 (m, 6H), 2.06-1.76 (m, 11H), 1.52-1.49 (m, 4H), 1.29-1.23 (m, 8H), 0.88 (t, J=7.2 Hz, 3H).

(214) Using standard hydrolysis condition, the title compound was obtained as a pale yellow gum (11 mg, 30% yield). ESI-MS (M+H).sup.+: 388.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.11 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.45-4.43 (m, 1H), 3.59-3.56 (m, 2H), 2.87-2.85 (m, 2H), 2.63-2.61 (m, 2H), 2.37-2.35 (m, 2H), 2.24-2.21 (m, 2H), 1.97-1.94 (m, 4H), 1.86-1.84 (m, 2H), 1.70-1.67 (m, 2H), 1.55-1.49 (m, 4H), 1.39-1.25 (m, 6H), 0.87 (t, J=7.2 Hz, 3H).

Intermediate 51: 8-(4-Bromophenoxyl)spiro[4.5]decane

(215) ##STR00121##

(216) Using the same procedure as for intermediate 43, the title compound was obtained, as yellow oil (2.3 g, 51% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.34 (dd, J=8.8 Hz, 2H), 6.78 (dd, J=8.8 Hz, 2H), 4.20-4.18 (m, 1H), 1.88-1.85 (m, 2H), 1.6-1.55 (m, 8H), 1.47-1.30 (m, 6H).

Intermediate 52: tert-butyl 4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

(217) ##STR00122##

(218) Using the same procedure as for intermediate 44, the title compound was obtained, as a yellow solid (1.77 g, 83% yield). ESI-MS (M+H).sup.+: 412.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.28 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.94-5.92 (m, 1H), 4.25-4.23 (m, 1H), 4.05-4.03 (m, 2H), 3.63-3.61 (m, 2H), 2.50-2.48 (m, 2H), 1.92-1.88 (m, 2H), 1.65-1.55 (m, 8H), 1.49 (s, 9H), 1.46-1.30 (m, 6H).

Intermediate 53: 4-(4-(spiro[4.5]decan-8-yloxy)phenyl)-1,2,3,6-tetrahydropyridine

(219) ##STR00123##

(220) Using the same procedure as for intermediate 45, the title compound was obtained as a yellow solid (1.16 g, 90% yield). ESI-MS (M+H).sup.+: 312.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.81 (br, 1H), 7.27 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 5.91-5.90 (m, 1H), 4.27-4.25 (m, 1H), 3.88-3.86 (m, 2H), 3.47-3.46 (m, 2H), 2.78-2.76 (m, 2H), 1.91-1.88 (m, 2H), 1.63-1.59 (m, 8H), 1.48-1.34 (m, 6H).

Example 39

3-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoic acid (Compound 40)

(221) ##STR00124##

(222) Using the same procedure as for intermediate 5, methyl 3-(4-(4-(spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoate was obtained as a yellow solid (153 mg, 60% yield). ESI-MS (M+H).sup.+: 398.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.28 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 5.95-5.94 (m, 1H), 4.25-4.23 (m, 1H), 3.71-3.69 (m, 3H), 3.21-3.19 (m, 2H), 2.86-2.56 (m, 6H), 1.92-1.88 (m, 2H), 1.65-1.57 (m, 10H), 1.48-1.33 (m, 6H).

(223) Using standard hydrolysis condition, the title compound was obtained as a white solid (70 mg, 75% yield). ESI-MS (M+H).sup.+: 384.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.38 (d, J=4.4 Hz, 2H), 6.90 (d, J=4.4 Hz, 2H), 6.03-6.02 (m, 1H), 4.35-4.31 (m, 1H), 3.95-3.93 (m, 2H), 3.57-3.55 (m, 2H), 3.50 (t, J=7.2 Hz, 2H), 2.85 (t, J=6.4 Hz, 4H), 1.92-1.86 (m, 2H), 1.65-1.56 (m, 8H), 1.49-1.34 (m, 6H).

Example 40

3-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)propanoic acid (Compound 32)

(224) ##STR00125##

(225) Using the same procedure as for intermediate 47, methyl 3-(4-(4-(spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)propanoate was obtained as yellow gum (90 mg, 65% yield). ESI-MS (M+H).sup.+: 400.2.

(226) Using standard hydrolysis condition, the title compound was obtained, as pale yellow gum (25 mg, 30% yield). ESI-MS (M+H).sup.+: 386.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.09 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 4.20-4.18 (m, 1H), 3.35-3.33 (m, 2H), 2.96-2.94 (m, 2H), 2.59-2.52 (m, 5H), 1.95-1.87 (m, 6H), 1.61-1.58 (m, 8H), 1.47-1.25 (m, 6H).

Example 41

4-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoic acid (Compound 47)

(227) ##STR00126##

(228) Using the same procedure as for intermediate 6, ethyl 4-(4-(4-(spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoate was obtained as a yellow solid (260 mg, 64% yield). ESI-MS (M+H).sup.+: 426.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.28 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.96-5.94 (m, 1H), 4.24-4.22 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.15-3.14 (m, 2H), 2.70-2.68 (m, 2H), 2.54-2.47 (m, 4H), 2.37 (t, J=7.2 Hz, 2H), 1.92-1.87 (m, 4H), 1.63-1.26 (m, 14H), 1.25 (t, J=6.8 Hz, 3H).

(229) Using standard hydrolysis condition, the title compound was obtained as a white solid (86 mg, 93% yield). ESI-MS (M+H).sup.+: 398.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.27 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.91-5.90 (m, 1H), 4.25-4.23 (m, 1H), 3.50-3.48 (m, 2H), 3.07-3.05 (m, 2H), 2.88-2.86 (m, 2H), 2.73-2.71 (m, 2H), 2.66-2.63 (m, 2H), 1.95-1.88 (m, 4H), 1.61-1.58 (m, 8H), 1.47-1.34 (m, 6H).

Example 42

4-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)butanoic acid (Compound 35)

(230) ##STR00127##

(231) Using the same procedure as for intermediate 47, ethyl 4-(4-(4-(spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)butanoate was obtained as a yellow gum (98 mg, 65% yield). ESI-MS (M+H).sup.+: 428.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.04 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.13-4.11 (m, 1H), 4.06 (q, J=7.2 Hz, 2H), 3.02-3.00 (m, 2H), 2.40-2.35 (m, 2H), 2.29 (t, J=7.2 Hz, 2H), 2.04-2.02 (m, 2H), 1.84-1.74 (m, 8H), 1.54-1.52 (m, 9H), 1.40-1.24 (m, 6H), 1.19 (t, J=7.2 Hz, 3H).

(232) Using standard hydrolysis condition, the title compound was obtained as a pale yellow solid (80 mg, 84% yield). ESI-MS (M+H).sup.+: 400.2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.10 (d, J=9.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.21-4.18 (m, 1H), 3.34-3.31 (m, 2H), 2.79-2.77 (m, 2H), 2.65-2.48 (m, 5H), 2.01-1.88 (m, 8H), 1.47-1.40 (m, 8H), 1.37-1.25 (m, 6H).

Intermediate 54: Ethyl 5-(4-(4-(spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoate

(233) ##STR00128##

(234) Using the same procedure as for intermediate 6, the title compound was obtained as a yellow solid (260 mg, 71% yield). ESI-MS (M+H).sup.+: 440.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.29 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.96-5.94 (m, 1H), 4.24-4.22 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.17-3.15 (m, 2H), 2.72-2.70 (m, 2H), 2.56-2.49 (m, 4H), 2.35 (t, J=7.2 Hz, 2H), 1.92-1.88 (m, 2H), 1.71-1.48 (m, 12H), 1.46-1.30 (m, 6H), 1.26 (t, J=7.2 Hz, 3H).

Example 43

5-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoic acid (Compound 48)

(235) ##STR00129##

(236) Using standard hydrolysis condition, the title compound was obtained as a white solid (85 mg, 91% yield), ESI-MS (M+H).sup.+: 412.3. .sup.1HNMR (400 MHz, CD.sub.3OD) δ: 7.40 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.05-6.03 (m, 1H), 4.35-4.33 (m, 1H), 3.86-3.84 (m, 2H), 3.47 (t, J=6.0 Hz, 2H), 3.18 (t, J=6.8 Hz, 2H), 2.86-2.84 (m, 2H), 2.32 (t, J=6.8 Hz, 2H), 1.89-1.81 (m, 4H), 1.73-1.62 (m, 10H), 1.49-1.39 (m, 6H).

Example 44

5-(4-(4-(Spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)pentanoic acid (Compound 33)

(237) ##STR00130##

(238) Using the same procedure as for intermediate 47, ethyl 5-(4-(4-(spiro[4.5]decan-8-yloxy)phenyl)piperidin-1-yl)pentanoate was obtained, as yellow gum (98 mg, 75% yield). ESI-MS (M+H).sup.+: 442.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.10 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.20-4.18 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.09-3.06 (m, 2H), 2.46-2.44 (m, 2H), 2.36-2.34 (m, 2H), 2.10-2.08 (m, 2H), 1.88-1.79 (m, 8H), 1.60-1.58 (m, 11H), 1.45-1.31 (m, 6H), 1.25 (t, J=7.2 Hz, 3H).

(239) Using standard hydrolysis condition, the title compound was obtained as a pale yellow solid (80 mg, 88% yield). ESI-MS (M+H).sup.+: 414.3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ: 7.11 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.21-4.19 (m, 1H), 3.60-3.57 (m, 2H), 2.86-2.84 (m, 3H), 2.60-2.58 (m, 2H), 2.36 (t, J=6.4 Hz, 2H), 2.24-2.21 (m, 2H), 2.21-1.84 (m, 6H), 1.69-1.42 (m, 10H), 1.39-1.31 (m, 6H).

Intermediate 55: 1-Bromo-4-((trans-4-(tert-Butyl)cyclohexyl)oxy)benzene

(240) ##STR00131##

(241) Using the same procedure as for intermediate 43, the title compound was obtained, as a white solid (150 mg, 48% yield). ESI-MS (M+H).sup.+: 311.1 .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.29-7.25 (m, 2H), 6.72-6.68 (m, 2H), 4.00-3.96 (m, 1H), 2.11-2.07 (m, 2H), 1.80-1.77 (m, 2H), 1.35-1.17 (m, 2H), 1.06-0.98 (m, 3H), 0.80 (s, 9H).

Intermediate 56: tert-Butyl 4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

(242) ##STR00132##

(243) Using the same procedure as for intermediate 44, the title compound was obtained as a yellow solid (60 mg, 90% yield). ESI-MS (M+H).sup.+: 414.3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.21 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.87-5.86 (m, 1H), 4.03-3.98 (m, 3H), 3.55 (t, J=6.0 Hz, 2H), 2.43-2.41 (m, 2H), 2.13-2.10 (m, 2H), 1.80-1.77 (m, 2H), 1.42 (s, 9H), 1.33-1.27 (m, 2H), 1.07-1.01 (m, 3H), 0.80 (s, 9H).

Intermediate 57: 4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-1,2,3,6-tetrahydropyridine

(244) ##STR00133##

(245) Using the same procedure as for intermediate 45, the title compound was obtained, as a yellow solid (45 mg, 99% yield). ESI-MS (M+H).sup.+: 314.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.28 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.01-5.99 (m, 1H), 4.13-4.08 (m, 1H), 3.58-3.57 (m, 3H), 3.16 (t, J=6.0 Hz, 2H), 2.50-2.49 (m, 2H), 2.20-2.17 (m, 2H), 1.87-1.84 (m, 2H), 1.43-1.33 (m, 2H), 1.14-1.05 (m, 3H), 0.87 (s, 9H).

Example 45

3-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoic acid (Compound 38)

(246) ##STR00134##

(247) Using the same procedure as for intermediate 6, ethyl 3-(4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)propanoate was obtained as a white solid (200 mg, 56% yield). ESI-MS (M+H).sup.+: 414.3.

(248) Using the standard hydrolysis condition, the title compound was obtained as a yellow solid (120 mg, 76% yield). ESI-MS (M+H).sup.+: 386.3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.29 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 5.94-5.92 (m, 1H), 4.13-4.06 (m, 1H), 3.86-3.84 (m, 2H), 3.50-3.47 (m, 2H), 3.41 (t, J=7.2 Hz, 2H), 2.78-2.74 (m, 4H), 2.09-2.06 (m, 2H), 1.80-1.76 (m, 2H), 1.27-1.02 (m, 5H), 0.80 (s, 9H).

Example 46

3-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)propanoic acid (Compound 27)

(249) ##STR00135##

(250) Using the same procedure as for intermediate 47, the title compound was obtained as a yellow solid (40 mg, 71% yield). ESI-MS (M+H).sup.+: 388.3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.05 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.07-4.00 (m, 1H), 3.58-3.55 (m, 2H), 3.34 (t, J=7.2 Hz, 2H), 3.12-3.02 (m, 2H), 2.77-2.70 (m, 3H), 2.05-1.97 (m, 4H), 1.86-1.75 (m, 4H), 1.23-0.95 (m, 5H), 0.79 (s, 9H).

Example 47

4-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoic acid (Compound 37)

(251) ##STR00136##

(252) Using the same procedure as for intermediate 6, ethyl 4-(4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)butanoate was obtained as a white solid (40 mg, 38% yield). ESI-MS (M+H).sup.+: 428.3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.29 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.96-5.94 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 4.13-4.10 (m, 1H), 3.17-3.15 (m, 2H), 2.70 (t, J=5.6 Hz, 2H), 2.54-2.48 (m, 4H), 2.37 (t, J=7.6 Hz, 2H), 2.20-2.17 (m, 2H), 1.92-1.84 (m, 4H), 1.43-1.33 (m, 2H), 1.25 (t, J=7.2, 3H), 1.11-1.07 (m, 3H), 0.87 (s, 9H).

(253) Using standard hydrolysis condition, the title compound was obtained as a white solid (70 mg, 75% yield). ESI-MS (M+H).sup.+: 400.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.26 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.87-5.85 (m, 1H), 4.15-4.08 (m, 2H), 3.67-3.58 (m, 2H), 2.71-2.69 (m, 3H), 2.54-2.45 (m, 4H), 2.18-2.09 (m, 4H), 1.87-1.84 (m, 2H), 1.42-1.33 (m, 2H), 1.17-1.02 (m, 3H), 0.87 (s, 9H).

Example 48

4-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)butanoic acid (Compound 25)

(254) ##STR00137##

(255) Using the same procedure as for intermediate 47, ethyl 4-(4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)butanoate was obtained as a yellow oil (100 mg, 80% yield). ESI-MS (M+H).sup.+: 430.3.

(256) Using standard hydrolysis condition, the title compound was obtained as a white solid (60 mg, 65% yield). ESI-MS (M+H).sup.+: 402.3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.16 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.17-4.12 (m, 1H), 3.69 (d, J=12.0 Hz, 2H), 3.31-3.19 (m, 2H), 3.15-3.12 (m, 2H), 2.84-2.82 (m, 1H), 2.49 (t, J=6.8 Hz, 2H), 2.18-1.86 (m, 10H), 1.36-1.34 (m, 2H), 1.24-1.05 (m, 3H), 0.90 (s, 9H).

Example 49

5-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoic acid (Compound 46)

(257) ##STR00138##

(258) Using the same procedure as for intermediate 6, ethyl 5-(4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)pentanoate was obtained as a yellow oil (440 mg, 50% yield). ESI-MS (M+H).sup.+: 442.3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.28 (dd, J=6.8, 2.0 Hz, 2H), 6.83 (dd, J=7.2, 2.0 Hz, 2H), 5.95-5.94 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 4.10-4.06 (m, 1H), 3.17 (br, 2H), 2.71-2.69 (m, 2H), 2.57-2.53 (m, 2H), 2.51-2.47 (m, 2H), 2.35 (t, J=7.2 Hz, 2H), 2.20-2.16 (m, 2H), 1.87-1.83 (m, 2H), 1.70-1.60 (m, 4H), 1.42-1.33 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 1.16-1.02 (m, 3H), 0.87 (s, 9H).

(259) Using standard hydrolysis condition, the title compound was obtained as a white solid (93 mg, 58% yield). ESI-MS (M+H).sup.+: 414.3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.40 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.05-6.03 (m, 1H), 4.22-4.17 (m, 1H), 4.09-4.05 (m, 2H), 3.80-3.76 (m, 2H), 3.28-3.24 (m, 2H), 2.87-2.84 (m, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.20-2.17 (m, 2H), 1.90-1.82 (m, 4H), 1.75-1.69 (m, 2H), 1.41-1.31 (m, 2H), 1.30-1.19 (m, 2H), 1.16-1.06 (m, 1H), 0.91 (s, 9H).

Example 50

5-(4-(4-((trans-4-(tert-Butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoic acid (Compound 34)

(260) ##STR00139##

(261) Using the same procedure as for intermediate 47, ethyl 5-(4-(4-((trans-4-(tert-butyl)cyclohexyl)oxy)phenyl)piperidin-1-yl)pentanoate was obtained as a yellow oil (200 mg, 81% yield). ESI-MS (M+H).sup.+: 444.3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.11 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.13 (q, J=7.2 Hz, 2H), 4.08-4.03 (m, 1H), 3.07-3.04 (m, 2H), 2.31-2.24 (m, 1H), 2.43-2.38 (m, 2H), 2.35-2.31 (m, 2H), 2.19-2.16 (m, 2H), 2.04-2.01 (m, 2H), 1.82-1.76 (m, 6H), 1.68-1.58 (m, 4H), 1.41-1.32 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 1.15-1.05 (m, 3H), 0.87 (s, 9H).

(262) Using standard hydrolysis condition, the title compound was obtained as a white solid (100 mg, 65% yield). ESI-MS (M+H).sup.+: 416.3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.15 (d, J=9.2 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.17-4.10 (m, 1H), 3.65-3.62 (m, 2H), 3.16-3.07 (m, 4H), 2.83-2.79 (m, 1H), 2.37 (t, J=6.8 Hz, 2H), 2.18-2.14 (m, 2H), 2.08-1.94 (m, 4H), 1.88-1.80 (m, 4H), 1.71-1.68 (m, 2H), 1.37-1.29 (m, 2H), 1.13-1.05 (m, 3H), 0.89 (s, 9H).

Example 51

Activity Measurements

(263) S1P Receptor Activity Assays

(264) Agonist percentage activation determinations were obtained by assaying sample compounds and referencing the Emax control for each receptor profiled. Antagonist percentage inhibition determinations were obtained by assaying sample compounds and referencing the control EC80 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:

(265) Compound Preparation

(266) 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.

(267) 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.

(268) Calcium Flux Assay: Agonist Assay Format

(269) 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.

(270) Reference agonists were handled as mentioned above serving as assay control. The reference agonists were handled as described above for Emax.

(271) Assay was read for 180 seconds using the FLIPRTETRA (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 FLIPRTETRA and placed at 25° C. for seven (7) minutes.

(272) Calcium Flux Assay: Antagonist Assay Format

(273) 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 FLIPRTETRA (This assay added reference agonist to respective wells—then fluorescence measurements were collected to calculate percentage inhibition values).

(274) Data Processing

(275) 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′.

(276) The compounds of examples 37 and 46-48 had an IC.sub.50 of no greater than 2 μM for S1P.sub.1 agonist activity. The compounds of examples 38, 40 and 45 had an IC.sub.50 between 2 μM and 5 μM for S1P.sub.1 agonist activity. The compounds of examples 1, 2, 4-6, 9-36, 39, 41-44, 49 and 50 had an IC.sub.50 of greater than 5 μM for S1P.sub.1.

(277) The compounds of examples 1, 2 and 4-50 had an IC.sub.50 of greater than 5 μM for S1P.sub.3.

(278) The compounds of examples 2, 5-8, 12, 14, 15, 19, 21, 23-25, 29-31, 33, 35, 37, 38, 40 and 44-49 had an IC.sub.50 of no greater than 2 μM for S1P.sub.4 agonist activity. The compounds of examples 13, 17-18, 20, 26, 36, 39 and 41-43 had an IC.sub.50 between 2 μM and 5 μM for S1P.sub.4 agonist activity. The compounds of examples 16 and 50 had an IC.sub.50 of no greater than 5 uM of S1P.sub.4 agonist activity. The compounds of examples 1, 4, 9-11, 22, 27, 28, 32 and 34 had an IC.sub.50 of greater than 5 μM for S1P.sub.4.

(279) The compounds of examples 40, 44, 47 and 48 had an IC.sub.50 of no greater than 2 μM for S1P.sub.5. The compounds of examples 37 and 41 had an IC.sub.50 between 2 μM and 5 μM for S1P.sub.5. The compounds of examples 1, 2, 4-10, 14-24, 26-36, 38, 39, 42, 43, 45, 46, 49 and 50 had an IC.sub.50 of greater than 5 μM for S1P.sub.5.

(280) Autotaxin (ATX) Assay

(281) 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.

(282) Reagents

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

(284) 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.

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

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

(287) 384-well flat bottom plates—Corning #3575.

(288) Assay

(289) 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.

(290) 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.

(291) 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.

(292) 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.

(293) 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.

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

(295) The compounds of examples 16, 19, 32, 37, 40, 41, 47 and 48 had an IC.sub.50 of no greater than 5 μM. The compounds of examples 3-8, 11, 20, 21, 26, 27, 36, 42, 45 and 46 had an IC.sub.50 between 5 μM and 10 μM. The compounds of examples 9, 10, 12-15, 17, 18, 28-31, 33-35, 38, 39, 43 and 44 had an IC.sub.50 greater than 10 μM.

(296) OPC Differentiation Assay

(297) 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+OPCs were collected by shaking the flask overnight at 200 rpm and 37° C., resulting in a 95% pure population.

(298) 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. EC.sub.50 was calculated by Prism using a nonlinear sigmoidal dose-response curvecells. Alternatively, cells were lysed in 80 μL lysis buffer (50 mM HEPES [4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid], pH 7.5, 150 mM NaCl, 1.5 mM MgCl2, 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.

(299) The compounds of examples 14 and 16 were positive in the OPC assay.

(300) OPC Oligodendrocyte Myelination Assay

(301) 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+OPCs are prepared as described above and then added into the cultured neocortical neurons. One day later, different concentrations of an S1P.sub.4 receptor antagonist and control reagents are applied into the co-cultures. Fresh media containing the different concentrations of an S1P.sub.4 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.

(302) Remyelination Assay in Brain Slice Culture

(303) 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 S1P.sub.4 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.

(304) Lysolecithin Demyelination Model

(305) 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.

(306) 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.

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

(308) Three days following the primary surgery, treatments with an S1P.sub.4 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.

(309) For systemic treatment, the animals are administered once daily intraperitoneally with either an S1P.sub.4 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.

(310) Calcium Mobilization

(311) 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 FLIPRTETRA equipped with a 96-well dispense head.

(312) In Vivo Screening Assays

(313) Measurement of circulating lymphocytes: Compounds are dissolved in 30% HPCD. Mice (C57bl/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.

(314) 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.

(315) 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. The dosage required to induce lymphopenia can be 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.

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