Selective FKBP51 ligands for treatment of psychiatric disorders

Abstract

The present invention relates to compounds of the general formula (I) having a selective FKBP51 ligand scaffold, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said selective FKBP51 ligand compounds can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions. ##STR00001##

Claims

1. Compound of the general formula (I): ##STR00306## wherein X represents —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2SCH.sub.2—, —CH.sub.2OCH.sub.2—, or —SCH.sub.2CH.sub.2—; Y represents —NH—, or —O—; Z represents a covalent bond, —NHCO—, —CHR.sup.39—NHCO—, or —CH(NHCOR.sup.39)—; R* represents —R.sup.18, —CH.sub.2—R.sup.18, —R**, —CH.sub.2—R**, —CH(OR′)R″, —CH.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3).sub.3, —C.sub.5H.sub.11, —CH(CH.sub.3)—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3).sub.3, —CH(C.sub.2H.sub.5).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3).sub.2, —C.sub.6H.sub.13, —CH.sub.2-cyclo-C.sub.3H.sub.5, —CH.sub.2-cyclo-C.sub.6H.sub.11, —CH.sub.2—CH═CH.sub.2, —CH.sub.2-cyclo-C.sub.6H.sub.9, -Ph, —CH.sub.2-Ph, -cyclo-C.sub.6H.sub.11, -cyclo-C.sub.5H.sub.9, —CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)-cyclo-C.sub.3H.sub.5, or —CH(CH.sub.3)—CH═CH.sub.2; R** represents ##STR00307## ##STR00308## ##STR00309## R′ and R″ represent independently of each other —CH.sub.3, —C.sub.2H.sub.5, —CH(CH.sub.3).sub.2, —CH.sub.2CH═CH.sub.2, -cyclo-C.sub.3H.sub.5, or —C(CH.sub.3).sub.3; R.sup.A represents: ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## R.sup.B represents: —R.sup.26 or ##STR00318## ##STR00319## ##STR00320## R.sup.C represents: —R.sup.27 or ##STR00321## ##STR00322## ##STR00323## R.sup.D represents: —R.sup.28 or ##STR00324## ##STR00325## ##STR00326## R.sup.1-R.sup.22, R.sup.18′-R.sup.22′, R.sup.26-R.sup.39 represent independently of each other —H, —OH, —OCH.sub.3, —OC.sub.2H.sub.5, —OC.sub.3H.sub.7, —O-cyclo-C.sub.3H.sub.5, —OCH(CH.sub.3).sub.2, —OC(CH.sub.3).sub.3, —OC.sub.4H.sub.9, —OCH.sub.2—COOH, —OPh, —OCH.sub.2-Ph, —OCPh.sub.3, —CH.sub.2—OH, —C.sub.2H.sub.4—OH, —C.sub.3H.sub.6—OH, —CH(OH)—CH.sub.2—OH, —CH.sub.2—OCH.sub.3, —C.sub.2H.sub.4—OCH.sub.3, —C.sub.4H.sub.8—OCH.sub.3, —C.sub.3H.sub.6—OCH.sub.3, —CH.sub.2—OC.sub.2H.sub.5, —C.sub.2H.sub.4—OC.sub.2H.sub.5, —C.sub.3H.sub.6—OC.sub.2H.sub.5, —C.sub.4H.sub.8—OC.sub.2H.sub.5, —CH.sub.2—OC.sub.3H.sub.7, —C.sub.2H.sub.4—OC.sub.3H.sub.7, —C.sub.3H.sub.6—OC.sub.3H.sub.7, —CH.sub.2—O-cyclo-C.sub.3H.sub.5, —C.sub.2H.sub.4—O-cyclo-C.sub.3H.sub.5, —C.sub.3H.sub.6—O-cyclo-C.sub.3H.sub.5, —C.sub.4H.sub.8—O-cyclo-C.sub.3H.sub.5, —CH.sub.2—OCH(CH.sub.3).sub.2, —C.sub.2H.sub.4—OCH(CH.sub.3).sub.2, —C.sub.3H.sub.6—OCH(CH.sub.3).sub.2, —C.sub.4H.sub.8—OCH(CH.sub.3).sub.2, —CH.sub.2—OC(CH.sub.3).sub.3, —C.sub.2H.sub.4—OC(CH.sub.3).sub.3, —C.sub.3H.sub.6—OC(CH.sub.3).sub.3, —C.sub.4H.sub.8—OC(CH.sub.3).sub.3, —CH.sub.2—OC.sub.4H.sub.9, —C.sub.2H.sub.4—OC.sub.4H.sub.9, —C.sub.3H.sub.6—OC.sub.4H.sub.9, —C.sub.4H.sub.8—OC.sub.4H.sub.9, —CH.sub.2—OPh, —C.sub.2H.sub.4—OPh, —C.sub.3H.sub.6—OPh, —C.sub.4H.sub.8—OPh, —CH.sub.2—OCH.sub.2-Ph, —C.sub.2H.sub.4—OCH.sub.2-Ph, —C.sub.3H.sub.6—OCH.sub.2-Ph, —C.sub.4H.sub.8—OCH.sub.2-Ph, —SH, —SCH.sub.3, —SC.sub.2H.sub.5, —SC.sub.3H.sub.7, —S-cyclo-C.sub.3H.sub.5, —SCH(CH.sub.3).sub.2, —SC(CH.sub.3).sub.3, —NO.sub.2, —F, —Cl, —Br, —I, —P(O)(OH).sub.2, —P(O)(OCH.sub.3).sub.2, —P(O)(OC.sub.2H.sub.5).sub.2, —P(O)(OCH(CH.sub.3).sub.2).sub.2, —C(OH)[P(O)(OH).sub.2].sub.2, —Si(CH.sub.3).sub.2(C(CH.sub.3).sub.3), —Si(C.sub.2H.sub.5).sub.3, —Si(CH.sub.3).sub.3, —N.sub.3, —CN, —OCN, —NCO, —SCN, —NCS, —CHO, —COCH.sub.3, —COC.sub.2H.sub.5, —COC.sub.3H.sub.7, —CO-cyclo-C.sub.3H.sub.5, —COCH(CH.sub.3).sub.2, —COC(CH.sub.3).sub.3, —COOH, —COCN, —COOCH.sub.3, —COOC.sub.2H.sub.5, —COOC.sub.3H.sub.7, —COO-cyclo-C.sub.3H.sub.5, —COOCH(CH.sub.3).sub.2, —COOC(CH.sub.3).sub.3, —OOC—CH.sub.3, —OOC—C.sub.2H.sub.5, —OOC—C.sub.3H.sub.7, —OOC-cyclo-C.sub.3H.sub.5, —OOC—CH(CH.sub.3).sub.2, —OOC—C(CH.sub.3).sub.3, —CONH.sub.2, —CH.sub.2—CONH.sub.2, —CONHCH.sub.3, —CONHC.sub.2H.sub.5, —CONHC.sub.3H.sub.7, —CONH-cyclo-C.sub.3H.sub.5, —CONH[CH(CH.sub.3).sub.2], —CONH[C(CH.sub.3).sub.3], —CON(CH.sub.3).sub.2, —CON(C.sub.2H.sub.5).sub.2, —CON(C.sub.3H.sub.7).sub.2, —CON(cyclo-C.sub.3H.sub.5).sub.2, —CON[CH(CH.sub.3).sub.2].sub.2, —CON[C(CH.sub.3).sub.3].sub.2, —NHCOCH.sub.3, —NHCOC.sub.2H.sub.5, —NHCOC.sub.3H.sub.7, —NHCO-cyclo-C.sub.3H.sub.5, —NHCO—CH(CH.sub.3).sub.2, —NHCO—C(CH.sub.3).sub.3, —NHCO—OCH.sub.3, —NHCO—OC.sub.2H.sub.5, —NHCO—OC.sub.3H.sub.7, —NHCO—O-cyclo-C.sub.3H.sub.5, —NHCO—OCH(CH.sub.3).sub.2, —NHCO—OC(CH.sub.3).sub.3, —NH.sub.2, —NHCH.sub.3, —NHC.sub.2H.sub.5, —NHC.sub.3H.sub.7, —NH-cyclo-C.sub.3H.sub.5, —NHCH(CH.sub.3).sub.2, —NHC(CH.sub.3).sub.3, —N(CH.sub.3).sub.2, —N(C.sub.2H.sub.5).sub.2, —N(C.sub.3H.sub.7).sub.2, —N(cyclo-C.sub.3H.sub.5).sub.2, —N[CH(CH.sub.3).sub.2].sub.2, —N[C(CH.sub.3).sub.3].sub.2, —SOCH.sub.3, —SOC.sub.2H.sub.5, —SOC.sub.3H.sub.7, —SO-cyclo-C.sub.3H.sub.5, —SOCH(CH.sub.3).sub.2, —SOC(CH.sub.3).sub.3, —SO.sub.2CH.sub.3, —SO.sub.2C.sub.2H.sub.5, —SO.sub.2C.sub.3H.sub.7, —SO.sub.2-cyclo-C.sub.3H.sub.5, —SO.sub.2CH(CH.sub.3).sub.2, —SO.sub.2C(CH.sub.3).sub.3, —SO.sub.3H, —SO.sub.3CH.sub.3, —SO.sub.3C.sub.2H.sub.5, —SO.sub.3C.sub.3H.sub.7, —SO.sub.3-cyclo-C.sub.3H.sub.5, —SO.sub.3CH(CH.sub.3).sub.2, —SO.sub.3C(CH.sub.3).sub.3, —SO.sub.2NH.sub.2, —SO.sub.2NHCH.sub.3, —SO.sub.2NHC.sub.2H.sub.5, —SO.sub.2NHC.sub.3H.sub.7, —SO.sub.2NH-cyclo-C.sub.3H.sub.5, —SO.sub.2NHCH(CH.sub.3).sub.2, —SO.sub.2NHC(CH.sub.3).sub.3, —SO.sub.2N(CH.sub.3).sub.2, —SO.sub.2N(C.sub.2H.sub.5).sub.2, —SO.sub.2N(C.sub.3H.sub.7).sub.2, —SO.sub.2N(cyclo-C.sub.3H.sub.5).sub.2, —SO.sub.2N[CH(CH.sub.3).sub.2].sub.2, —SO.sub.2N[C(CH.sub.3).sub.3].sub.2, —O—S(═O)CH.sub.3, —O—S(═O)C.sub.2H.sub.5, —O—S(═O)C.sub.3H.sub.7, —O—S (═O)-cyclo-C.sub.3H.sub.5, —O—S(═O)CH(CH.sub.3).sub.2, —O—S(═O)C(CH.sub.3).sub.3, —S(═O)(═NH)CH.sub.3, —S(═O)(═NH)C.sub.2H.sub.5, —S(═O)(═NH)C.sub.3H.sub.7, —S(═O)(═NH)-cyclo-C.sub.3H.sub.5, —S(═O)(═NH)CH(CH.sub.3).sub.2, —S(═O)(═NH)C(CH.sub.3).sub.3, —NH—SO.sub.2—CH.sub.3, —NH—SO.sub.2—C.sub.2H.sub.5, —NH—SO.sub.2—C.sub.3H.sub.7, —NH—SO.sub.2-cyclo-C.sub.3H.sub.5, —NH—SO.sub.2—CH(CH.sub.3).sub.2, —NH—SO.sub.2—C(CH.sub.3).sub.3, —O—SO.sub.2—CH.sub.3, —O—SO.sub.2—C.sub.2H.sub.5, —O—SO.sub.2—C.sub.3H.sub.7, —O—SO.sub.2-cyclo-C.sub.3H.sub.5, —O—SO.sub.2—CH(CH.sub.3).sub.2, —O—SO.sub.2—C(CH.sub.3).sub.3, —OCF.sub.3, —CH.sub.2—OCF.sub.3, —C.sub.2H.sub.4—OCF.sub.3, —C.sub.3H.sub.6—OCF.sub.3, —OC.sub.2F.sub.5, —CH.sub.2—OC.sub.2F.sub.5, —C.sub.2H.sub.4—OC.sub.2F.sub.5, —C.sub.3H.sub.6—OC.sub.2F.sub.5, —O—COOCH.sub.3, —O—COOC.sub.2H.sub.5, —O—COOC.sub.3H.sub.7, —O—COO-cyclo-C.sub.3H.sub.5, —O—COOCH(CH.sub.3).sub.2, —O—COOC(CH.sub.3).sub.3, —NH—CO—NH.sub.2, —NH—CO—NHCH.sub.3, —NH—CO—NHC.sub.2H.sub.5, —NH—CS—N(C.sub.3H.sub.7).sub.2, —NH—CO—NHC.sub.3H.sub.7, —NH—CO—N(C.sub.3H.sub.7).sub.2, —NH—CO—NH[CH(CH.sub.3).sub.2], —NH—CO—NH[C(CH.sub.3).sub.3], —NH—CO—N(CH.sub.3).sub.2, —NH—CO—N(C.sub.2H.sub.5).sub.2, —NH—CO—NH-cyclo-C.sub.3H.sub.5, —NH—CO—N(cyclo-C.sub.3H.sub.5).sub.2, —NH—CO—N[CH(CH.sub.3).sub.2].sub.2, —NH—CS—N(C.sub.2H.sub.5).sub.2, —NH—CO—N[C(CH.sub.3).sub.3].sub.2, —NH—CS—NH.sub.2, —NH—CS—NHCH.sub.3, —NH—CS—N(CH.sub.3).sub.2, —NH—CS—NHC.sub.2H.sub.5, —NH—CS—NHC.sub.3H.sub.7, —NH—CS—NH-cyclo-C.sub.3H.sub.5, —NH—CS—NH[CH(CH.sub.3).sub.2], —NH—CS—NH[C(CH.sub.3).sub.3], —NH—CS—N(cyclo-C.sub.3H.sub.5).sub.2, —NH—CS—N[CH(CH.sub.3).sub.2].sub.2, —NH—CS—N[C(CH.sub.3).sub.3].sub.2, —NH—C(═NH)—NH.sub.2, —NH—C(═NH)—NHCH.sub.3, —NH—C(═NH)—NHC.sub.2H.sub.5, —NH—C(═NH)—NHC.sub.3H.sub.7, —O—CO—NH-cyclo-C.sub.3H.sub.5, —NH—C(═NH)—NH-cyclo-C.sub.3H.sub.5, —NH—C(═NH)—NH[CH(CH.sub.3).sub.2] —O—CO—NH[CH(CH.sub.3).sub.2], —NH—C(═NH)—NH[C(CH.sub.3).sub.3], —NH—C(═NH)—N(CH.sub.3).sub.2, —NH—C(═NH)—N(C.sub.2H.sub.5).sub.2, —NH—C(═NH)—N(C.sub.3H.sub.7).sub.2, —NH—C(═NH)—N(cyclo-C.sub.3H.sub.5).sub.2, —O—CO—NHC.sub.3H.sub.7, —NH—C(═NH)—N[CH(CH.sub.3).sub.2].sub.2, —NH—C(═NH)—N[C(CH.sub.3).sub.3].sub.2, —O—CO—NH.sub.2, —O—CO—NHCH.sub.3, —O—CO—NHC.sub.2H.sub.5, —O—CO—NH[C(CH.sub.3).sub.3], —O—CO—N(CH.sub.3).sub.2, —O—CO—N(C.sub.2H.sub.5).sub.2, —O—CO—N(C.sub.3H.sub.7).sub.2, —O—CO—N(cyclo-C.sub.3H.sub.5).sub.2, —O—CO—N[CH(CH.sub.3).sub.2].sub.2, —O—CO—N[C(CH.sub.3).sub.3].sub.2, —O—CO—OCH.sub.3, —O—CO—OC.sub.2H.sub.5, —O—CO—OC.sub.3H.sub.7, —O—CO—O-cyclo-C.sub.3H.sub.5, —O—CO—OCH(CH.sub.3).sub.2, —O—CO—OC(CH.sub.3).sub.3, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —CH.sub.2Cl, —CH.sub.2Br, —CH.sub.2I, —CH.sub.2—CH.sub.2F, —CH.sub.2—CHF.sub.2, —CH.sub.2—CF.sub.3, —CH.sub.2—CH.sub.2Cl, —CH.sub.2—CH.sub.2Br, —CH.sub.2—CH.sub.2I, -cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11, —CH.sub.2-cyclo-C.sub.6H.sub.11, —CH.sub.2—CH.sub.2-cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13, -cyclo-C.sub.8H.sub.15, -Ph, —CH.sub.2-Ph, —CH.sub.2—CH.sub.2-Ph, —CH═CH-Ph, —CPh.sub.3, —CH.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3).sub.3, —C.sub.5H.sub.11, —CH(CH.sub.3)—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3).sub.3, —CH(C.sub.2H.sub.5).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3).sub.2, —C.sub.6H.sub.13, —C.sub.7H.sub.15, —C.sub.8H.sub.17, —C.sub.3H.sub.6—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3)—C.sub.3H.sub.7, —CH(CH.sub.3)—CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—CH(CH.sub.3)—C.sub.2H.sub.5, —CH.sub.2—CH(CH.sub.3)—CH(CH.sub.3).sub.2, —CH.sub.2—C(CH.sub.3).sub.2—C.sub.2H.sub.5, —C(CH.sub.3).sub.2—C.sub.3H.sub.7, —C(CH.sub.3).sub.2—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—C(CH.sub.3).sub.3, —CH(CH.sub.3)—C(CH.sub.3).sub.3, —CH═CH.sub.2, —CH.sub.2—CH═CH.sub.2, —C(CH.sub.3)═CH.sub.2, —CH═CH—CH.sub.3, —C.sub.2H.sub.4—CH═CH.sub.2, —CH.sub.2—CH═CH—CH.sub.3, —CH═CH—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—CH═CH, —CH═C(CH.sub.3).sub.2, —C(CH.sub.3)═CH—CH.sub.3, —CH═CH—CH═CH.sub.2, —C.sub.3H.sub.6—CH═CH.sub.2, —C.sub.2H.sub.4—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—C.sub.2H.sub.5, —CH═CH—C.sub.3H.sub.7, —CH.sub.2—CH═CH—CH═CH.sub.2, —CH═CH—CH═CH—CH.sub.3, —CH═CH—CH.sub.2—CH═CH.sub.2, —C(CH.sub.3)═CH—CH═CH.sub.2, —CH═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—C(CH.sub.3)═CH.sub.2, —C.sub.2H.sub.4—C(CH.sub.3)═CH.sub.2, —CH.sub.2—CH(CH.sub.3)—CH═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —CH.sub.2—CH═C(CH.sub.3).sub.2, —CH.sub.2—C(CH.sub.3)═CH—CH.sub.3, —CH(CH.sub.3)—CH═CH—CH.sub.3, —CH═CH—CH(CH.sub.3).sub.2, —CH═C(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3)═CH—C.sub.2H.sub.5, —C(CH.sub.3)═C(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—CH═CH.sub.2, —CH(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═CH—CH═CH.sub.2, —CH═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—C(CH.sub.3)═CH.sub.2, —C.sub.4H.sub.8—CH═CH.sub.2, —C.sub.3H.sub.6—CH═CH—CH.sub.3, —C.sub.2H.sub.4—CH═CH—C.sub.2H.sub.5, —CH.sub.2—CH═CH—C.sub.3H.sub.7, —CH═CH—C.sub.4H.sub.9, —C.sub.3H.sub.6—C(CH.sub.3)═CH.sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—CH═CH.sub.2, —CH.sub.2—CH(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —C.sub.2H.sub.4—CH═C(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.4—CH═CH.sub.2, —C.sub.2H.sub.4—C(CH.sub.3)═CH—CH.sub.3, —CH.sub.2—CH(CH.sub.3)—CH═CH—CH.sub.3, —CH(CH.sub.3)—CH.sub.2—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—CH(CH.sub.3).sub.2, —CH.sub.2—CH═C(CH.sub.3)—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3)═CH—C.sub.2H.sub.5, —CH(CH.sub.3)—CH═CH—C.sub.2H.sub.5, —CH═CH—CH.sub.2—CH(CH.sub.3).sub.2, —CH═CH—CH(CH.sub.3)—C.sub.2H.sub.5, —CH═C(CH.sub.3)—C.sub.3H.sub.7, —C(CH.sub.3)═CH—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C[C(CH.sub.3).sub.3]═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—CH(CH.sub.3)—CH═CH.sub.2, —CH═CH—C.sub.2H.sub.4—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3).sub.2—CH═CH.sub.2, —C(CH.sub.3).sub.2—CH.sub.2—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═C(CH.sub.3).sub.2, —CH(CH.sub.3)—CH═C(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—CH═CH—CH.sub.3, —CH═CH—CH.sub.2—CH═CH—CH.sub.3, —CH(CH.sub.3)—C(CH.sub.3)═CH—CH.sub.3, —CH═C(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3)═CH—CH(CH.sub.3).sub.2, —C(CH.sub.3)═C(CH.sub.3)—C.sub.2H.sub.5, —CH═CH—C(CH.sub.3).sub.3, —C(CH.sub.3).sub.2—C(CH.sub.3)═CH.sub.2, —CH(C.sub.2H.sub.5)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)(C.sub.2H.sub.5)—CH═CH.sub.2, —CH(CH.sub.3)—C(C.sub.2H.sub.5)═CH.sub.2, —CH.sub.2—C(C.sub.3H.sub.7)═CH.sub.2, —CH.sub.2—C(C.sub.2H.sub.5)═CH—CH.sub.3, —CH(C.sub.2H.sub.5)—CH═CH—CH.sub.3, —C(C.sub.4H.sub.9)═CH.sub.2, —C(C.sub.3H.sub.7)═CH—CH.sub.3, —C(C.sub.2H.sub.5)═CH—C.sub.2H.sub.5, —C(C.sub.2H.sub.5)═C(CH.sub.3).sub.2, —C[CH(CH.sub.3)(C.sub.2H.sub.5)]═CH.sub.2, —C[CH.sub.2—CH(CH.sub.3).sub.2]═CH.sub.2, —C.sub.2H.sub.4—CH═CH—CH═CH.sub.2, —CH.sub.2—CH═CH—CH.sub.2—CH═CH.sub.2, —C.sub.3H.sub.6—C≡C—CH.sub.3, —CH.sub.2—CH═CH—CH═CH—CH.sub.3, —CH═CH—CH═CH—C.sub.2H.sub.5, —CH.sub.2—CH═CH—C(CH.sub.3)═CH.sub.2, —CH.sub.2—CH═C(CH.sub.3)—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═CH—CH═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—C≡CH, —CH(CH.sub.3)—CH═CH—CH═CH.sub.2, —CH═CH—CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—C≡C—CH.sub.3, —CH═CH—CH(CH.sub.3)—CH═CH.sub.2, —CH═C(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—C≡CH, —C(CH.sub.3)═CH—CH.sub.2—CH═CH.sub.2, —CH═CH—CH═C(CH.sub.3).sub.2, —CH.sub.2—CH(CH.sub.3)—CH.sub.2—C≡CH, —CH═CH—C(CH.sub.3)═CH—CH.sub.3, —CH═C(CH.sub.3)—CH═CH—CH.sub.3, —CH.sub.2—CH(CH.sub.3)—C≡CH, —C(CH.sub.3)═CH—CH═CH—CH.sub.3, —CH═C(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═CH—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—CH═CH—CH═CH.sub.2, —C≡CH, —C≡C—CH.sub.3, —CH.sub.2—C≡CH, —C.sub.2H.sub.4—C≡CH, —CH.sub.2—C≡C—CH.sub.3, —C≡C—C.sub.2H.sub.5, —C.sub.3H.sub.6—C≡CH, —C.sub.2H.sub.4—C≡C—CH.sub.3, —CH.sub.2—C≡C—C.sub.2H.sub.5, —C≡C—C.sub.3H.sub.7, —CH(CH.sub.3)—C≡CH, —C.sub.4H.sub.8—C≡CH, —C.sub.2H.sub.4—C≡C—C.sub.2H.sub.5, —CH.sub.2—C≡C—C.sub.3H.sub.7, —C≡C—C.sub.4H.sub.9, —C≡C—C(CH.sub.3).sub.3, —CH(CH.sub.3)—C.sub.2H.sub.4—C≡CH, —CH.sub.2—CH(CH.sub.3)—C≡C—CH.sub.3, —CH(CH.sub.3)—CH.sub.2—C≡C—CH.sub.3, —CH(CH.sub.3)—C≡C—C.sub.2H.sub.5, —CH.sub.2—C≡C—CH(CH.sub.3).sub.2, —C≡C—CH(CH.sub.3)—C.sub.2H.sub.5, —C≡C—CH.sub.2—CH(CH.sub.3).sub.2, —CH(C.sub.2H.sub.5)—C≡C—CH.sub.3, —C(CH.sub.3).sub.2—C≡C—CH.sub.3, —CH(C.sub.2H.sub.5)—CH.sub.2—C≡CH, —CH.sub.2—CH(C.sub.2H.sub.5)—C≡CH, —C(CH.sub.3).sub.2—CH.sub.2—C≡CH, —CH.sub.2—C(CH.sub.3).sub.2—C≡CH, —CH(CH.sub.3)—CH(CH.sub.3)—C≡CH, —CH(C.sub.3H.sub.7)—C≡CH, —C(CH.sub.3)(C.sub.2H.sub.5)—C≡CH, —CH.sub.2—CH(C≡CH).sub.2, —C≡C—C≡CH, —CH.sub.2—C≡C—C≡CH, —C≡C—C≡C—CH.sub.3, —CH(C≡CH).sub.2, —C.sub.2H.sub.4—C≡C—C≡CH, —CH.sub.2—C≡C—CH.sub.2—C≡CH, —C≡C—C.sub.2H.sub.4—C≡CH, —CH.sub.2—C≡C—C≡C—CH.sub.3, —C≡C—CH.sub.2—C≡C—CH.sub.3, —C≡C—C≡C—C.sub.2H.sub.5, —C(C≡CH).sub.2—CH.sub.3, —C≡C—CH(CH.sub.3)—C≡CH, —CH(CH.sub.3)—C≡C—C≡CH, —CH(C≡CH)—CH.sub.2—C≡CH, —CH(C≡CH)—C≡C—CH.sub.3, ##STR00327##  or R.sup.18 and R.sup.18′ or R.sup.19 and R.sup.19′ or R.sup.20 and R.sup.20′ or R.sup.21 and R.sup.21′ or R.sup.22 and R.sup.22′ form together ═O, ##STR00328##  or ═CR.sup.23′R.sup.24′, wherein R.sup.23′ and R.sup.24′ represent independently of each other —H, —CH.sub.3, —C.sub.2H.sub.5, —CF.sub.3, —CH.sub.2CF.sub.3, —C.sub.2F.sub.5; R.sup.23-R.sup.25 represent independently of each other —H, —CH.sub.2—OCH.sub.3, —C.sub.2H.sub.4—OCH.sub.3, —C.sub.3H.sub.6—OCH.sub.3, —CH.sub.2—OC.sub.2H.sub.5, —C.sub.2H.sub.4—OC.sub.2H.sub.5, —C.sub.3H.sub.6—OC.sub.2H.sub.5, —CH.sub.2—OC.sub.3H.sub.7, —C.sub.2H.sub.4—OC.sub.3H.sub.7, —C.sub.3H.sub.6—OC.sub.3H.sub.7, —CH.sub.2—O-cyclo-C.sub.3H.sub.5, —C.sub.2H.sub.4—O-cyclo-C.sub.3H.sub.5, —C.sub.3H.sub.6—O-cyclo-C.sub.3H.sub.5, —CH.sub.2—OCH(CH.sub.3).sub.2, —C.sub.2H.sub.4—OCH(CH.sub.3).sub.2, —C.sub.3H.sub.6—OCH(CH.sub.3).sub.2, —CH.sub.2—OC(CH.sub.3).sub.3, —C.sub.2H.sub.4—OC(CH.sub.3).sub.3, —C.sub.3H.sub.6—OC(CH.sub.3).sub.3, —CH.sub.2—OC.sub.4H.sub.9, —C.sub.2H.sub.4—OC.sub.4H.sub.9, —C.sub.3H.sub.6—OC.sub.4H.sub.9, —CH.sub.2—OPh, —C.sub.2H.sub.4—OPh, —C.sub.3H.sub.6—OPh, —CH.sub.2—OCH.sub.2-Ph, —C.sub.2H.sub.4—OCH.sub.2-Ph, —C.sub.3H.sub.6—OCH.sub.2-Ph, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —CH.sub.2Cl, —CH.sub.2Br, —CH.sub.2I, —CH.sub.2—CH.sub.2F, —CH.sub.2—CHF.sub.2, —CH.sub.2—CF.sub.3, —CH.sub.2—CH.sub.2Cl, —CH.sub.2—CH.sub.2Br, —CH.sub.2—CH.sub.2I, -cyclo-C.sub.8H.sub.15, -Ph, —CH.sub.2-Ph, —CH.sub.2—CH.sub.2-Ph, —CH═CH-Ph, —CPh.sub.3, —CH.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3).sub.3, —C.sub.5H.sub.11, —CH(CH.sub.3)—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3).sub.3, —CH(C.sub.2H.sub.5).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3).sub.2, —C.sub.6H.sub.13, —C.sub.7H.sub.15, —C.sub.8H.sub.17, —C.sub.3H.sub.6—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3)—C.sub.3H.sub.7, —CH(CH.sub.3)—CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—CH(CH.sub.3)—C.sub.2H.sub.5, —CH.sub.2—CH(CH.sub.3)—CH(CH.sub.3).sub.2, —CH.sub.2—C(CH.sub.3).sub.2—C.sub.2H.sub.5, —C(CH.sub.3).sub.2—C.sub.3H.sub.7, —C(CH.sub.3).sub.2—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—C(CH.sub.3).sub.3, —CH(CH.sub.3)—C(CH.sub.3).sub.3, —CH═CH.sub.2, —CH.sub.2—CH═CH.sub.2, —C(CH.sub.3)═CH.sub.2, —CH═CH—CH.sub.3, —C.sub.2H.sub.4—CH═CH.sub.2, —CH.sub.2—CH═CH—CH.sub.3, —CH═CH—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—CH═CH, —CH═C(CH.sub.3).sub.2, —C(CH.sub.3)═CH—CH.sub.3, —CH═CH—CH═CH.sub.2, —C.sub.3H.sub.6—CH═CH.sub.2, —C.sub.2H.sub.4—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—C.sub.2H.sub.5, —CH═CH—C.sub.3H.sub.7, —CH.sub.2—CH═CH—CH═CH.sub.2, —CH═CH—CH═CH—CH.sub.3, —CH═CH—CH.sub.2—CH═CH.sub.2, —C(CH.sub.3)═CH—CH═CH.sub.2, —CH═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—C(CH.sub.3)═CH.sub.2, —C.sub.2H.sub.4—C(CH.sub.3)═CH.sub.2, —CH.sub.2—CH(CH.sub.3)—CH═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —CH.sub.2—CH═C(CH.sub.3).sub.2, —CH.sub.2—C(CH.sub.3)═CH—CH.sub.3, —CH(CH.sub.3)—CH═CH—CH.sub.3, —CH═CH—CH(CH.sub.3).sub.2, —CH═C(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3)═CH—C.sub.2H.sub.5, —C(CH.sub.3)═C(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—CH═CH.sub.2, —CH(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═CH—CH═CH.sub.2, —CH═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—C(CH.sub.3)═CH.sub.2, —C.sub.4H.sub.8—CH═CH.sub.2, —C.sub.3H.sub.6—CH═CH—CH.sub.3, —C.sub.2H.sub.4—CH═CH—C.sub.2H.sub.5, —CH.sub.2—CH═CH—C.sub.3H.sub.7, —CH═CH—C.sub.4H.sub.9, —C.sub.3H.sub.6—C(CH.sub.3)═CH.sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—CH═CH.sub.2, —CH.sub.2—CH(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —C.sub.2H.sub.4—CH═C(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.4—CH═CH.sub.2, —C.sub.2H.sub.4—C(CH.sub.3)═CH—CH.sub.3, —CH.sub.2—CH(CH.sub.3)—CH═CH—CH.sub.3, —CH(CH.sub.3)—CH.sub.2—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—CH(CH.sub.3).sub.2, —CH.sub.2—CH═C(CH.sub.3)—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3)═CH—C.sub.2H.sub.5, —CH(CH.sub.3)—CH═CH—C.sub.2H.sub.5, —CH═CH—CH.sub.2—CH(CH.sub.3).sub.2, —CH═CH—CH(CH.sub.3)—C.sub.2H.sub.5, —CH—C(CH.sub.3)—C.sub.3H.sub.7, —C(CH.sub.3)═CH—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C[C(CH.sub.3).sub.3]═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—CH(CH.sub.3)—CH═CH.sub.2, —CH═CH—C.sub.2H.sub.4—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3).sub.2—CH═CH.sub.2, —C(CH.sub.3).sub.2—CH.sub.2—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═C(CH.sub.3).sub.2, —CH(CH.sub.3)—CH═C(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—CH═CH—CH.sub.3, —CH═CH—CH.sub.2—CH═CH—CH.sub.3, —CH(CH.sub.3)—C(CH.sub.3)═CH—CH.sub.3, —CH═C(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3)═CH—CH(CH.sub.3).sub.2, —C(CH.sub.3)═C(CH.sub.3)—C.sub.2H.sub.5, —CH═CH—C(CH.sub.3).sub.3, —C(CH.sub.3).sub.2—C(CH.sub.3)═CH.sub.2, —CH(C.sub.2H.sub.5)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)(C.sub.2H.sub.5)—CH═CH.sub.2, —CH(CH.sub.3)—C(C.sub.2H.sub.5)═CH.sub.2, —CH.sub.2—C(C.sub.3H.sub.7)═CH.sub.2, —CH.sub.2—C(C.sub.2H.sub.5)═CH—CH.sub.3, —CH(C.sub.2H.sub.5)—CH═CH—CH.sub.3, —C(C.sub.4H.sub.9)═CH.sub.2, —C(C.sub.3H.sub.7)═CH—CH.sub.3, —C(C.sub.2H.sub.5)═CH—C.sub.2H.sub.5, —C(C.sub.2H.sub.5)═C(CH.sub.3).sub.2, —C[CH(CH.sub.3)(C.sub.2H.sub.5)]═CH.sub.2, —C[CH.sub.2—CH(CH.sub.3).sub.2]═CH.sub.2, —C.sub.2H.sub.4—CH═CH—CH═CH.sub.2, —CH.sub.2—CH═CH—CH.sub.2—CH═CH.sub.2, —C.sub.3H.sub.6—C≡C—CH.sub.3, —CH.sub.2—CH═CH—CH═CH—CH.sub.3, —CH═CH—CH═CH—C.sub.2H.sub.5, —CH.sub.2—CH═CH—C(CH.sub.3)═CH.sub.2, —CH.sub.2—CH═C(CH.sub.3)—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═CH—CH═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—C≡CH, —CH(CH.sub.3)—CH═CH—CH═CH.sub.2, —CH═CH—CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—C≡C—CH.sub.3, —CH═CH—CH(CH.sub.3)—CH═CH.sub.2, —CH═C(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—C≡CH, —C(CH.sub.3)═CH—CH.sub.2—CH═CH.sub.2, —CH═CH—CH═C(CH.sub.3).sub.2, —CH.sub.2—CH(CH.sub.3)—CH.sub.2—C≡CH, —CH═CH—C(CH.sub.3)═CH—CH.sub.3, —CH═C(CH.sub.3)—CH═CH—CH.sub.3, —CH.sub.2—CH(CH.sub.3)—C≡CH, —C(CH.sub.3)═CH—CH═CH—CH.sub.3, —CH═C(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═CH—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—CH═CH—CH═CH.sub.2, —C≡CH, —C≡C—CH.sub.3, —CH.sub.2—C≡CH, —C.sub.2H.sub.4—C≡CH, —CH.sub.2—C≡C—CH.sub.3, —C≡C—C.sub.2H.sub.5, —C.sub.3H.sub.6—C≡CH, —C.sub.2H.sub.4—C≡C—CH.sub.3, —CH.sub.2—C≡C—C.sub.2H.sub.5, —C≡C—C.sub.3H.sub.7, —CH(CH.sub.3)—C≡CH, —C.sub.4H.sub.8—C≡CH, —C.sub.2H.sub.4—C≡C—C.sub.2H.sub.5, —CH.sub.2—C≡C—C.sub.3H.sub.7, —C≡C—C.sub.4H.sub.9, —C≡C—C(CH.sub.3).sub.3, —CH(CH.sub.3)—C.sub.2H.sub.4—C≡CH, —CH.sub.2—CH(CH.sub.3)—C≡C—CH.sub.3, —CH(CH.sub.3)—CH.sub.2—C≡C—CH.sub.3, —CH(CH.sub.3)—C≡C—C.sub.2H.sub.5, —CH.sub.2—C≡C—CH(CH.sub.3).sub.2, —C≡C—CH(CH.sub.3)—C.sub.2H.sub.5, —C≡C—CH.sub.2—CH(CH.sub.3).sub.2, —CH(C.sub.2H.sub.5)—C≡C—CH.sub.3, —C(CH.sub.3).sub.2—C≡C—CH.sub.3, —CH(C.sub.2H.sub.5)—CH.sub.2—C≡CH, —CH.sub.2—CH(C.sub.2H.sub.5)—C≡CH, —C(CH.sub.3).sub.2—CH.sub.2—C≡CH, —CH.sub.2—C(CH.sub.3).sub.2—C≡CH, —CH(CH.sub.3)—CH(CH.sub.3)—C≡CH, —CH(C.sub.3H.sub.7)—C≡CH, —C(CH.sub.3)(C.sub.2H.sub.5)—C≡CH, —CH.sub.2—CH(C≡CH).sub.2, —C≡C—C≡CH, —CH.sub.2—C≡C—C≡CH, —C≡C—C≡C—CH.sub.3, —CH(C≡CH).sub.2, —C.sub.2H.sub.4—C≡C—C≡CH, —CH.sub.2—C≡C—CH.sub.2—C≡CH, —C≡C—C.sub.2H.sub.4—C≡CH, —CH.sub.2—C≡C—C≡C—CH.sub.3, —C≡C—CH.sub.2—C≡C—CH.sub.3, —C≡C—C≡C—C.sub.2H.sub.5, —C(C≡CH).sub.2—CH.sub.3, —C≡C—CH(CH.sub.3)—C≡CH, —CH(CH.sub.3)—C≡C—C≡CH, —CH(C≡CH)—CH.sub.2—C≡CH, —CH(C≡CH)—C≡C—CH.sub.3; R.sup.N represents —H, —CH.sub.2—OCH.sub.3, —C.sub.2H.sub.4—OCH.sub.3, —C.sub.3H.sub.6—OCH.sub.3, —CH.sub.2—OC.sub.2H.sub.5, —C.sub.2H.sub.4—OC.sub.2H.sub.5, —C.sub.3H.sub.6—OC.sub.2H.sub.5, —CH.sub.2—OC.sub.3H.sub.7, —C.sub.2H.sub.4—OC.sub.3H.sub.7, —C.sub.3H.sub.6—OC.sub.3H.sub.7, —CH.sub.2—O-cyclo-C.sub.3H.sub.5, —C.sub.2H.sub.4—O-cyclo-C.sub.3H.sub.5, —C.sub.3H.sub.6—O-cyclo-C.sub.3H.sub.5, —CH.sub.2—OCH(CH.sub.3).sub.2, —C.sub.2H.sub.4—OCH(CH.sub.3).sub.2, —C.sub.3H.sub.6—OCH(CH.sub.3).sub.2, —CH.sub.2—OC(CH.sub.3).sub.3, —C.sub.2H.sub.4—OC(CH.sub.3).sub.3, —C.sub.3H.sub.6—OC(CH.sub.3).sub.3, —CH.sub.2—OC.sub.4H.sub.9, —C.sub.2H.sub.4—OC.sub.4H.sub.9, —C.sub.3H.sub.6—OC.sub.4H.sub.9, —CH.sub.2—OPh, —C.sub.2H.sub.4—OPh, —C.sub.3H.sub.6—OPh, —CH.sub.2—OCH.sub.2-Ph, —C.sub.2H.sub.4—OCH.sub.2-Ph, —C.sub.3H.sub.6—OCH.sub.2-Ph, —CHO, —COCH.sub.3, —COC.sub.2H.sub.5, —COC.sub.3H.sub.7, —CO-cyclo-C.sub.3H.sub.5, —COCH(CH.sub.3).sub.2, —COC(CH.sub.3).sub.3, —COCN, —COOCH.sub.3, —COOC.sub.2H.sub.5, —COOC.sub.3H.sub.7, —COO-cyclo-C.sub.3H.sub.5, —COOCH(CH.sub.3).sub.2, —COOC(CH.sub.3).sub.3, —CONH.sub.2, —CONHCH.sub.3, —CONHC.sub.2H.sub.5, —CONHC.sub.3H.sub.7, —CONH-cyclo-C.sub.3H.sub.5, —CONH[CH(CH.sub.3).sub.2], —CONH[C(CH.sub.3).sub.3], —CON(CH.sub.3).sub.2, —CON(C.sub.2H.sub.5).sub.2, —CON(C.sub.3H.sub.7).sub.2, —CON(cyclo-C.sub.3H.sub.5).sub.2, —CON[CH(CH.sub.3).sub.2].sub.2, —CON[C(CH.sub.3).sub.3].sub.2, —SO.sub.2CH.sub.3, —SO.sub.2C.sub.2H.sub.5, —SO.sub.2C.sub.3H.sub.7, —SO.sub.2-cyclo-C.sub.3H.sub.5, —SO.sub.2CH(CH.sub.3).sub.2, —SO.sub.2C(CH.sub.3).sub.3, —CH.sub.2—OCF.sub.3, —C.sub.2H.sub.4—OCF.sub.3, —C.sub.3H.sub.6—OCF.sub.3, —OC.sub.2F.sub.5, —CH.sub.2—OC.sub.2F.sub.5, —C.sub.2H.sub.4—OC.sub.2F.sub.5, —C.sub.3H.sub.6—OC.sub.2F.sub.5, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —CH.sub.2Cl, —CH.sub.2Br, —CH.sub.2I, —CH.sub.2—CH.sub.2F, —CH.sub.2—CHF.sub.2, —CH.sub.2—CF.sub.3, —CH.sub.2—CH.sub.2Cl, —CH.sub.2—CH.sub.2Br, —CH.sub.2—CH.sub.2I, -cyclo-C.sub.8H.sub.15, -Ph, —CH.sub.2-Ph, —CH.sub.2—CH.sub.2-Ph, —CH═CH-Ph, —CPh.sub.3, —CH.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3).sub.3, —C.sub.5H.sub.11, —CH(CH.sub.3)—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3).sub.3, —CH(C.sub.2H.sub.5).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3).sub.2, —C.sub.6H.sub.13, —C.sub.7H.sub.15, —C.sub.8H.sub.17, —C.sub.3H.sub.6—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3)—C.sub.3H.sub.7, —CH(CH.sub.3)—CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—CH(CH.sub.3)—C.sub.2H.sub.5, —CH.sub.2—CH(CH.sub.3)—CH(CH.sub.3).sub.2, —CH.sub.2—C(CH.sub.3).sub.2—C.sub.2H.sub.5, —C(CH.sub.3).sub.2—C.sub.3H.sub.7, —C(CH.sub.3).sub.2—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—C(CH.sub.3).sub.3, —CH(CH.sub.3)—C(CH.sub.3).sub.3, —CH═CH.sub.2, —CH.sub.2—CH═CH.sub.2, —C(CH.sub.3)═CH.sub.2, —CH═CH—CH.sub.3, —C.sub.2H.sub.4—CH═CH.sub.2, —CH.sub.2—CH═CH—CH.sub.3, —CH═CH—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—CH═CH, —CH═C(CH.sub.3).sub.2, —C(CH.sub.3)═CH—CH.sub.3, —CH═CH—CH═CH.sub.2, —C.sub.3H.sub.6—CH═CH.sub.2, —C.sub.2H.sub.4—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—C.sub.2H.sub.5, —CH═CH—C.sub.3H.sub.7, —CH.sub.2—CH═CH—CH═CH.sub.2, —CH═CH—CH═CH—CH.sub.3, —CH═CH—CH.sub.2—CH═CH.sub.2, —C(CH.sub.3)═CH—CH═CH.sub.2, —CH═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—C(CH.sub.3)═CH.sub.2, —C.sub.2H.sub.4—C(CH.sub.3)═CH.sub.2, —CH.sub.2—CH(CH.sub.3)—CH═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —CH.sub.2—CH═C(CH.sub.3).sub.2, —CH.sub.2—C(CH.sub.3)═CH—CH.sub.3, —CH(CH.sub.3)—CH═CH—CH.sub.3, —CH═CH—CH(CH.sub.3).sub.2, —CH═C(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3)═CH—C.sub.2H.sub.5, —C(CH.sub.3)═C(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—CH═CH.sub.2, —CH(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═CH—CH═CH.sub.2, —CH═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—C(CH.sub.3)═CH.sub.2, —C.sub.4H.sub.8—CH═CH.sub.2, —C.sub.3H.sub.6—CH═CH—CH.sub.3, —C.sub.2H.sub.4—CH═CH—C.sub.2H.sub.5, —CH.sub.2—CH═CH—C.sub.3H.sub.7, —CH═CH—C.sub.4H.sub.9, —C.sub.3H.sub.6—C(CH.sub.3)═CH.sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—CH═CH.sub.2, —CH.sub.2—CH(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —C.sub.2H.sub.4—CH═C(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.4—CH═CH.sub.2, —C.sub.2H.sub.4—C(CH.sub.3)═CH—CH.sub.3, —CH.sub.2—CH(CH.sub.3)—CH═CH—CH.sub.3, —CH(CH.sub.3)—CH.sub.2—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—CH(CH.sub.3).sub.2, —CH.sub.2—CH═C(CH.sub.3)—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3)═CH—C.sub.2H.sub.5, —CH(CH.sub.3)—CH═CH—C.sub.2H.sub.5, —CH═CH—CH.sub.2—CH(CH.sub.3).sub.2, —CH═CH—CH(CH.sub.3)—C.sub.2H.sub.5, —CH—C(CH.sub.3)—C.sub.3H.sub.7, —C(CH.sub.3)═CH—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C[C(CH.sub.3).sub.3]═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—CH(CH.sub.3)—CH═CH.sub.2, —CH═CH—C.sub.2H.sub.4—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3).sub.2—CH═CH.sub.2, —C(CH.sub.3).sub.2—CH.sub.2—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═C(CH.sub.3).sub.2, —CH(CH.sub.3)—CH═C(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—CH═CH—CH.sub.3, —CH═CH—CH.sub.2—CH═CH—CH.sub.3, —CH(CH.sub.3)—C(CH.sub.3)═CH—CH.sub.3, —CH═C(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3)═CH—CH(CH.sub.3).sub.2, —C(CH.sub.3)═C(CH.sub.3)—C.sub.2H.sub.5, —CH═CH—C(CH.sub.3).sub.3, —C(CH.sub.3).sub.2—C(CH.sub.3)═CH.sub.2, —CH(C.sub.2H.sub.5)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)(C.sub.2H.sub.5)—CH═CH.sub.2, —CH(CH.sub.3)—C(C.sub.2H.sub.5)═CH.sub.2, —CH.sub.2—C(C.sub.3H.sub.7)═CH.sub.2, —CH.sub.2—C(C.sub.2H.sub.5)═CH—CH.sub.3, —CH(C.sub.2H.sub.5)—CH═CH—CH.sub.3, —C(C.sub.4H.sub.9)═CH.sub.2, —C(C.sub.3H.sub.7)═CH—CH.sub.3, —C(C.sub.2H.sub.5)═CH—C.sub.2H.sub.5, —C(C.sub.2H.sub.5)═C(CH.sub.3).sub.2, —C[CH(CH.sub.3)(C.sub.2H.sub.5)]═CH.sub.2, —C[CH.sub.2—CH(CH.sub.3).sub.2]═CH.sub.2, —C.sub.2H.sub.4—CH═CH—CH═CH.sub.2, —CH.sub.2—CH═CH—CH.sub.2—CH═CH.sub.2, —C.sub.3H.sub.6—C≡C—CH.sub.3, —CH.sub.2—CH═CH—CH═CH—CH.sub.3, —CH═CH—CH═CH—C.sub.2H.sub.5, —CH.sub.2—CH═CH—C(CH.sub.3)═CH.sub.2, —CH.sub.2—CH═C(CH.sub.3)—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═CH—CH═CH.sub.2, —CH(CH.sub.3)—CH.sub.2—C≡CH, —CH(CH.sub.3)—CH═CH—CH═CH.sub.2, —CH═CH—CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—C≡C—CH.sub.3, —CH═CH—CH(CH.sub.3)—CH═CH.sub.2, —CH═C(CH.sub.3)—CH.sub.2—CH═CH.sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—C≡CH, —C(CH.sub.3)═CH—CH.sub.2—CH═CH.sub.2, —CH═CH—CH═C(CH.sub.3).sub.2, —CH.sub.2—CH(CH.sub.3)—CH.sub.2—C≡CH, —CH═CH—C(CH.sub.3)═CH—CH.sub.3, —CH═C(CH.sub.3)—CH═CH—CH.sub.3, —CH.sub.2—CH(CH.sub.3)—C≡CH, —C(CH.sub.3)═CH—CH═CH—CH.sub.3, —CH═C(CH.sub.3)—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═CH—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—CH═CH—CH═CH.sub.2, —C≡CH, —C≡C—CH.sub.3, —CH.sub.2—C≡CH, —C.sub.2H.sub.4—C≡CH, —CH.sub.2—C≡C—CH.sub.3, —C≡C—C.sub.2H.sub.5, —C.sub.3H.sub.6—C≡CH, —C.sub.2H.sub.4—C≡C—CH.sub.3, —CH.sub.2—C≡C—C.sub.2H.sub.5, —C≡C—C.sub.3H.sub.7, —CH(CH.sub.3)—C≡CH, —C.sub.4H.sub.8—C≡CH, —C.sub.2H.sub.4—C≡C—C.sub.2H.sub.5, —CH.sub.2—C≡C—C.sub.3H.sub.7, —C≡C—C.sub.4H.sub.9, —C≡C—C(CH.sub.3).sub.3, —CH(CH.sub.3)—C.sub.2H.sub.4—C≡CH, —CH.sub.2—CH(CH.sub.3)—C≡C—CH.sub.3, —CH(CH.sub.3)—CH.sub.2—C≡C—CH.sub.3, —CH(CH.sub.3)—C≡C—C.sub.2H.sub.5, —CH.sub.2—C≡C—CH(CH.sub.3).sub.2, —C≡C—CH(CH.sub.3)—C.sub.2H.sub.5, —C≡C—CH.sub.2—CH(CH.sub.3).sub.2, —CH(C.sub.2H.sub.5)—C≡C—CH.sub.3, —C(CH.sub.3).sub.2—C≡C—CH.sub.3, —CH(C.sub.2H.sub.5)—CH.sub.2—C≡CH, —CH.sub.2—CH(C.sub.2H.sub.5)—C≡CH, —C(CH.sub.3).sub.2—CH.sub.2—C≡CH, —CH.sub.2—C(CH.sub.3).sub.2—C≡CH, —CH(CH.sub.3)—CH(CH.sub.3)—C≡CH, —CH(C.sub.3H.sub.7)—C≡CH, —C(CH.sub.3)(C.sub.2H.sub.5)—C≡CH, —CH.sub.2—CH(C≡CH).sub.2, —C≡C—C≡CH, —CH.sub.2—C≡C—C≡CH, —C≡C—C≡C—CH.sub.3, —CH(C≡CH).sub.2, —C.sub.2H.sub.4—C≡C—C≡CH, —CH.sub.2—C≡C—CH.sub.2—C≡CH, —C≡C—C.sub.2H.sub.4—C≡CH, —CH.sub.2—C≡C—C≡C—CH.sub.3, —C≡C—CH.sub.2—C≡C—CH.sub.3, —C≡C—C≡C—C.sub.2H.sub.5, —C(C≡CH).sub.2—CH.sub.3, —C≡C—CH(CH.sub.3)—C≡CH, —CH(CH.sub.3)—C≡C—C≡CH, —CH(C≡CH)—CH.sub.2—C≡CH, or —CH(C≡CH)—C≡C—CH.sub.3; L.sub.1, L.sub.2 and L.sub.3 represent independently of each other: a bond, —CH.sub.2—, —C.sub.2H.sub.4—, —C.sub.3H.sub.6—, —C.sub.4H.sub.8—, —C.sub.5H.sub.10—, —C.sub.6H.sub.12—, —C.sub.7H.sub.14—, —C.sub.8H.sub.16—, —C.sub.9H.sub.18—, —C.sub.10H.sub.20—, —CH.sub.2CH.sub.2O—, —CH(CH.sub.3)—, —C[(CH.sub.3).sub.2]—, —CH(C.sub.3H.sub.7)—, —CH.sub.2—CH(CH.sub.3)—, —CH(CH.sub.3)—CH.sub.2—, —CH(CH.sub.3)—C.sub.2H.sub.4—, —CH.sub.2—CH(CH.sub.3)—CH.sub.2—, —C.sub.2H.sub.4—CH(CH.sub.3)—, —CH.sub.2—C[(CH.sub.3).sub.2]—, —C[(CH.sub.3).sub.2]—CH.sub.2—, —CH(CH.sub.3)—CH(CH.sub.3)—, —C[(C.sub.2H.sub.5)(CH.sub.3)]—, —(CH.sub.2—CH.sub.2—O).sub.n—CH.sub.2—CH.sub.2—, —C(CH.sub.3)═CH—C(CH.sub.3)═CH—, —C.sub.2H.sub.4—CH═CH—CH═CH—, —CH.sub.2—CH═CH—CH.sub.2—CH═CH—, —C.sub.3H.sub.6—C≡C—CH.sub.2—, —CH.sub.2—CH═CH—CH═CH—CH.sub.2—, —CH(CH.sub.3)—C≡C—CH.sub.2—, —CH═CH—CH═CH—C.sub.2H.sub.4—, —CH.sub.2—CH═CH—C(CH.sub.3)═CH—, —CH.sub.2—CH═C(CH.sub.3)—CH═CH—, —CH.sub.2—C(CH.sub.3)═CH—CH═CH—, —CH(CH.sub.3)—CH═CH—CH═CH—, —CH═CH—CH.sub.2—C(CH.sub.3)═CH—, —CONH—, —NHCO—, —CH.sub.2—CONH—, —CONH—CH.sub.2—, —NHCO—CH.sub.2—, —CH.sub.2—NHCO—; wherein n is an integer from 1 to 10; or L.sub.1-R.sup.B and L.sub.2-R.sup.C or L.sub.1-R.sup.B and L.sub.3-R.sup.D or L.sub.2-R.sup.C and L.sub.3-R.sup.D form together a cyclic ring selected from the group consisting of: ##STR00329## or enantiomers, stereoisomeric forms, mixtures of enantiomers, anomers, deoxy-forms, diastereomers, mixtures of diastereomers, prodrugs, tautomers, hydrates, solvates and racemates of the above mentioned compounds and pharmaceutically acceptable salts thereof, with the proviso that the following compounds are excluded: the compounds having X=—CH.sub.2CH.sub.2CH.sub.2—, and Y=—O—, and Z=a bond, and R*=—CH.sub.3, —CH.sub.2CH.sub.3, —CH(CH.sub.3).sub.2, —CH(CH.sub.3)CH.sub.2CH.sub.3, -cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11, -Ph, or —CH.sub.2Ph, and R.sup.A=-Ph, L.sub.1-R.sup.B=—H, ##STR00330##  L.sub.3-R.sup.D=—CH.sub.3, or ##STR00331## the compounds having X=—CH.sub.2CH.sub.2CH.sub.2—, and Y=—O—, and Z=a bond, and R*=—CH.sub.2CH.sub.3, and ##STR00332##  L.sub.1-R.sup.B=—H, ##STR00333## the compounds having X=—CH.sub.2CH.sub.2CH.sub.2—, and Y=—O—, and Z=a bond, and R*=—CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2CH.sub.3, —CH.sub.2CH═CH.sub.2, —CH(CH.sub.3).sub.2, -cyclo-C.sub.3H.sub.5, and ##STR00334##  L.sub.1-R.sup.B=—H, ##STR00335## the compounds having X=—CH.sub.2CH.sub.2CH.sub.2—, and Y=—O—, and Z=a bond, and R*=—CH.sub.3, —CH.sub.2CH.sub.3, or —CH.sub.2CH.sub.2CH.sub.3, and R.sup.A=—CH.sub.3, —CH.sub.2CH.sub.3, or —CH.sub.2CH.sub.2CH.sub.3, and L.sub.1-R.sup.B=—H, and ##STR00336##  and the compound having X=—CH.sub.2CH.sub.2CH.sub.2—, and Y=—O—, and Z=a bond, and R*=—OPh, and R.sup.A=-cyclo-C.sub.5H.sub.9, and L.sub.1-R.sup.B=—H, and L.sub.2-R.sup.C=—CH.sub.2CH.sub.2Ph, and ##STR00337##

2. Compound according to claim 1 of the general formula (Ia): ##STR00338## wherein X, Y, Z, R*, R.sup.A and R.sup.B are defined according to claim 1; R.sup.C represents —R.sup.38; R.sup.D represents —H, —CH.sub.3, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —C.sub.2H.sub.5, —CH.sub.2OH, —CH.sub.2OMe, —CH.sub.2NH.sub.2, —CH.sub.2NHCH.sub.3, —CH.sub.2N(CH.sub.3).sub.2, —CH.sub.2NHCOH, or —CH.sub.2NHCOCH.sub.3; or R.sup.C and R.sup.D can form together a carbocyclic ring selected from the group consisting of: ##STR00339## R.sup.38 and R.sup.39 are defined according to claim 1; L.sub.1 represents a bond, —CH.sub.2—, —C.sub.2H.sub.4—, —C.sub.3H.sub.6—, —C.sub.4H.sub.8—, —C.sub.5H.sub.10—, —C.sub.6H.sub.12—, —C.sub.7H.sub.14—, —C.sub.8H.sub.16—, —C.sub.9H.sub.18—, —C.sub.10H.sub.20—, —CH(CH.sub.3)—, —C[(CH.sub.3).sub.2]—, —CH.sub.2—CH(CH.sub.3)—, —CH(CH.sub.3)—CH.sub.2—, —CH(CH.sub.3)—C.sub.2H.sub.4—, —CH.sub.2—CH(CH.sub.3)—CH.sub.2—, —C.sub.2H.sub.4—CH(CH.sub.3)—, —CH.sub.2—C[(CH.sub.3).sub.2]—, —C[(CH.sub.3).sub.2]—CH.sub.2—, —CH(CH.sub.3)—CH(CH.sub.3)—, —C[(C.sub.2H.sub.5)(CH.sub.3)]—, —CH(C.sub.3H.sub.7)—, —CH.sub.2CH.sub.2O—, —(CH.sub.2—CH.sub.2—O).sub.n—CH.sub.2—CH.sub.2—, —C(CH.sub.3)═CH—C(CH.sub.3)═CH—, —CH(CH.sub.3)—C≡C—CH.sub.2—, —C.sub.2H.sub.4—CH═CH—CH═CH—, —CH.sub.2—CH═CH—CH.sub.2—CH═CH—, —C.sub.3H.sub.6—C≡C—CH.sub.2—, —CH.sub.2—CH═CH—CH═CH—CH.sub.2—, —CH═CH—CH═CH—C.sub.2H.sub.4—, —CH.sub.2—CH═CH—C(CH.sub.3)═CH—, —CH.sub.2—CH═C(CH.sub.3)—CH═CH—, —CH.sub.2—C(CH.sub.3)═CH—CH═CH—, —CH(CH.sub.3)—CH═CH—CH═CH—, —CH═CH—CH.sub.2—C(CH.sub.3)═CH—, —(C═O)NH—, —NH(C═O)—, —CH.sub.2(C═O)NH—, —(C═O)NHCH.sub.2—, —NH(C═O)CH.sub.2—, —CH.sub.2NH(C═O)—, wherein n is an integer from 1 to 10.

3. Compound according to claim 1 of the general formula (VI): ##STR00340## wherein X.sub.A represents —CH.sub.2CH.sub.2—, —CH═CH—, —CH.sub.2—S—, —S—CH.sub.2—; p is an integer of 0 or 1; R.sup.11, R.sup.12, R.sup.13, R.sup.B, R.sup.C, R.sup.D, L.sub.1, L.sub.2 and L.sub.3 are defined according to claim 1, wherein at least one of R.sup.11, R.sup.12, R.sup.13 is not —H; “” represents a C═C bond or a C—C bond.

4. Compound according to claim 1 selected from the group consisting of: TABLE-US-00016 A02 2-(3-((R)-3-(3,4-Dimethoxyphenyl)-1-(((S)-1-((S)-2-(3,4,5- trimethoxyphenyl) pent-4-enoyl)piperidine-2-carbonyl)oxy)propyl) phenoxy)acetic acid, A04 (S)-1,7-di(pyridin-3-yl)heptan-4-yl 1-((S)-2-(3,4,5-trimethoxyphenyl)pent-4- enoyl)piperidine-2-carboxylate, A05 (S)-N-((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2- morpholinoethoxy)phenyl)propyl)-1-((S)-2-(3,4,5-trimethoxyphenyl)pent-4- enoyl)piperidine-2-carboxamide, A06 2-(3-((R)-3-(3,4-Dimethoxyphenyl)-1-(((S)-1-((S)-2-(3,4,5- trimethoxyphenyl)pent-4-enoyl)-1,2,3,6-tetrahydropyridine-2- carbonyl)oxy)propyl)phenoxy) acetic acid, A08 (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl- 1-((S)-3-cyclopropyl-2-(3,4,5-trimethoxyphenyl)propanoyl)piperidine-2- carboxylate, A10 2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-(((S)-1-((S)-3-phenyl-2-(3,4,5- trimethoxyphenyl)propanoyl)piperidine-2-carbonyl)oxy)propyl) phenoxy)acetic acid, A11 2-(3-((R)-1-(((S)-1-((S)-2-((S)-Cyclohex-2-en-1-yl)-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4- dimethoxyphenyl)propyl)phenoxy) acetic acid, A12 (S)-(R)-3-(3,4-Dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl- 1-((S)-2-((S)-cyclohex-2-en-1-yl)-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxylate, A13 (S)-1,7-Di(pyridin-3-yl)heptan-4-yl-1-((S)-2-((S)-cyclohex-2-en-1-yl)-2- (3,4,5-trimethoxy phenyl) acetyl)piperidine-2-carboxylate, A14 (S)-2-(3,4-Dimethoxyphenoxy)ethyl-1-((S)-2-((R)-cyclohex-2-en-1-yl)-2- (3,4,5-trimethoxy phenyl)acetyl)piperidine-2-carboxylate, A16 2-(3-((R)-1-((S)-1-((S)-2-((R)-Cyclohex-2-en-1-yl)-2-(3,4,5- trimethoxyphenyl)acetyl)piper-idine-2-carboxamido)-3-(3,4- dimethoxyphenyl)propyl)phenoxy) acetic acid, A17 2-(3-((R)-1-(((S)-1-((S)-2-Cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4- dimethoxyphenyl)propyl)phenoxy)acetic acid, A18 (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl- 1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2- carboxylate, A19 (2S)-1,7-di(pyridin-3-yl)heptan-4-yl 1-(2-cyclohexyl-2-(3,4,5-trimethoxy phenyl)acetyl)piperidine-2-carboxylate, A20 (S)-2-(3,4-dimethoxyphenoxy)ethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxy phenyl)acetyl)piperidine-2-carboxylate, A22 2-(3-((R)-1-((S)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamido)-3-(3,4- dimethoxyphenyl)propyl)phenoxy)acetic acid, A23 2-(3-(1-(((2S)-1-(2-benzamido-2-cyclohexylacetyl) piperidine-2- carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetic acid, A24 2-(3-(1-(((2S)-1-(2-cyclohexyl-2-(2-hydroxy benzamido)acetyl)piperidine- 2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl) propyl)phenoxy)acetic acid, A25 2-(3-(1-(((2S)-1-(2-cyclohexyl-2-(picolinamido) acetyl)piperidine-2- carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy) acetic acid, A26 2-(3-(1-(((2S)-1-(2-(cyclohexanecarboxamido)-2- cyclohexylacetyl)piperidine-2-carbonyl)oxy)-3-(3,4- dimethoxyphenyl)propyl)phenoxy)acetic acid, A27 2-(3-(1-(((2S)-1-(2-cyclohexyl-2-(3H-1,2,4-triazole-3- carboxamido)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl) propyl)phenoxy)acetic acid, A28 2-(3-(1-(((2S)-1-(2-cyclohexyl-2-(3,5-dichloro benzamido)acetyl)piperidine- 2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl) propyl)phenoxy)acetic acid, A29 (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R)-2-cyclohexyl-3-hydroxybutanoyl)piperidine-2-carboxylate, A30 (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R,E)-2-cyclohexyl-3-hydroxyhex-4-enoyl)piperidine-2-carboxylate, A31 (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R)-2-cyclohexyl-3-(methoxymethoxy)-5- methylhexanoyl)piperidine-2-carboxylate, A32 (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R)-2-cyclohexyl-3-hydroxy-5-methylhexanoyl)piperidine-2- carboxylate, A36 2-(3-((R)-1-(((S)-1-((S)-2-cyclohexyl-2-(3-fluorophenyl)acetyl)piperidine-2- carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl) phenoxy)acetic acid A37 2-(3-((R)-1-(((S)-1-((R)-2-cyclohexylpropanoyl)piperidine-2-carbonyl)oxy)- 3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetic acid A38 2-(3-((R)-1-(((S)-1-((R)-2-cyclohexylpent-4-enoyl)piperidine-2- carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy) acetic acid B03 (S)-N-((S)-1-amino-3-methyl-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B04 (S)-N-((R)-1-amino-3-methyl-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B05 (S)-N-((S)-1-amino-1-oxo-3-phenylpropan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B06 (S)-N-((R)-1-amino-1-oxo-3-phenylpropan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B07 (S)-N-((S)-1-amino-3-cyclohexyl-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B08 (S)-N-((S)-1-amino-1-oxo-4-phenylbutan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B09 (S)-N-((S)-1-amino-4-cyclohexyl-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B10 (S)-N-(2-amino-2-oxoethyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B11 (S)-N-(1-amino-2-methyl-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B12 (S)-N-((S)-1-amino-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B13 (S)-N-((R)-1-amino-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B14 (S)-N-((2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B15 (S)-N-((2R,3R)-1-amino-3-methyl-1-oxopentan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B16 (S)-N-((S)-2-amino-2-oxo-1-phenylethyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B17 (S)-N-((R)-2-amino-2-oxo-1-phenylethyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B18 (S)-N-((S)-2-amino-1-cyclohexyl-2-oxoethyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B19 (S)-N-((S)-1-amino-4-hydroxy-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B20 (S)-N-((R)-1-amino-4-hydroxy-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B21 (S)-N-((R)-1-amino-3-hydroxy-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B22 (S)-N-((S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B23 (S)-2-((S)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine- 2-carboxamido)pentanediamide, B24 (R)-2-((S)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine- 2-carboxamido)pentanediamide, B25 (S)-N-(4-amino-2-methyl-4-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B26 (S)-N-(1-carbamoylcyclopropyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B27 (S)-N-(1-carbamoylcyclobutyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B28 (S)-N-(1-carbamoylcyclopentyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B29 (S)-N-(3-amino-3-oxopropyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B30 (S)-N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)-1-((S)-2-cyclohexyl-2- (3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide, B31 (S)-N-(1-carbamoylcyclohexyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl) acetyl)piperidine-2-carboxamide B32 (S)-N-(1-carbamoylcyclohexyl)-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl) acetyl)piperidine-2-carboxamide B33 (S)-N-(1-((2-amino-2-oxoethyl)carbamoyl)cyclopentyl)-1-((S)-2-cyclohexyl- 2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B34 (S)-N-((R)-1-amino-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)-1-((S)-2- cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B35 (S)-N-((S)-1-amino-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)-1-((S)-2- cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide C01 (S)-methyl 1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxylate, C02 (S)-ethyl 1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine- 2-carboxylate, C03 (S)-propyl 1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine- 2-carboxylate, C04 (S)-isopropyl 1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxylate, C05 (S)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)-N- ethylpiperidine-2-carboxamide, C07 (S)-(S)-sec-butyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C08 (S)-(R)-sec-butyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C09 (S)-pentan-3-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C10 (S)-tert-butyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C11 (S)-1-methylcyclopentyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxylate C12 (S)-tetrahydro-2H-pyran-4-yl-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxylate C13 (S)-cyclopentyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C14 (S)-cyclopent-3-en-1-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxylate C15 (2S)-cyclohex-2-en-1-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxylate C16 (S)-cycloheptyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C17 (S)-allyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2- carboxylate C18 (S)-2-methoxyethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C19 (S)-2-(benzyloxy)ethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxylate C20 (S)-2-hydroxyethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C21 (S)-3-(benzyloxy)propyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxylate C22 (S)-2-hydroxyethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C23 (S)-4-methoxybutyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C24 (S)-(R)-1-(benzyloxy)propan-2-yl-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxylate C25 (R)-(R)-1-(benzyloxy)propan-2-yl-1-((S)-2-cyclohexyl-2-(3,4,5- trimethoxyphenyl)acetyl)piperidine-2-carboxylate.

5. A method or inhibiting a FK506-binding protein comprising contacting a cell with an effective amount of a compound according to claim 1.

6. Pharmaceutical composition comprising at least one compound according to claim 1 together with at least one pharmaceutically acceptable carrier, solvent or excipient.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1: Effects of FKBP51-selective ligands A17 (A) and A18 (D) on neurite outgrowth of N2a-cells. Both FKBP51-selective ligands promote neurite outgrowth in N2a cells more potently compared to FK506 (B). High concentrations do not lead to reduction of the neuronal differentiation (in contrast to unselective ligands like FK506. (C) FK506 decreases neurite outgrowth of N2a cells in a dose-dependent manner in the presence of 100 nM A17.

(2) FIG. 2: (A) A17 rescues reduced neurite length triggered by 1 μM Ru26988 of N2a-cells. The GR-agonist Ru26988 enhances neurite outgrowth of N2a-cells until an optimal concentration of 100 nM. Higher concentrations leads to a reduction of neurite outgrowth (U-shaped dose-dependency). Reduction of neuronal differentiation can be blocked by addition of 10 nM A17. (B) FK506 does not rescue reduced neurite length triggered by 1 μM Ru26988 in N2a-cells. Aldosterone enhances neurite outgrowth of N2a-cells until an optimal concentration of 100 nM. Higher concentrations lead to a reduction of neurite outgrowth (U-shaped dose-dependency). Reduction of neuronal differentiation cannot be blocked by addition of the unselective ligand FK506 (in contrast to selective FKBP51 ligands). (C) A17 rescues Ru26988 effect. A17 dose-dependently rescues the reduction of total neurite length triggered by high aldosterone concentrations. A17 reverts the reduction of neurite outgrowth triggered by aldosterone (1 μM) in a dose-dependent manner. (D) The analog A18 enhanced struggling time and reduced floating time in a forced swim test. (E) The selective FKBP51 inhibitor A18 enhances the regulation of stress hormone secretion in test.

(3) FIG. 3: The backbone of FKBP51 is shown as green cartoon. A12 is shown in orange sticks, the atoms of the FKBP51-BINDING SITE are shown as gray sticks, with the atom names shown in black.

(4) FIG. 4: Conformational reorganization of F67: (A) apo crystal structure of FKBP51FK1; (B) crystal structure FKBP51FK1 and A12. The dihedral angle N-Cα-Cβ-Cγ defining the conformational flip is indicated.

(5) FIG. 5: (A) Crystal structure of FKBP51 and inhibitor A12. (B) Chemical structure of the FKBP51-selective inhibitor A12. Conserved hydrogen bonds with I87 and Y113 are shown as dotted lines, hydrophobic interaction with W90 are indicated in grey. (C) FKBP51-unselective ligand IF63 is not able to induce the induced-fit structure which is characterized by the conformational change of phenylalanine 67 (Phe67), which flips out of the binding pocket as demonstrated by the FKBP51-unselective ligand as shown in FIG. 5a. (D) The three major interactions of the FKBP51-unselective ligand IF63 with the protein which are the two hydrogen bonds to Ile87 and Tyr113 through Tyr57 and Asp68 and the hydrophobic interaction with the amino acids Val86, Ile87 and Trp90 at the bottom of the binding pocket.

(6) FIG. 6: (A) Cocrystal Structure of A12 in complex with FKBP51 (Form I). Preferred residues of the INDUCED-FIT FKBP51 BINDING SITE are shown in green sticks and labelled in bold. Atoms constituting the INDUCED-FIT FKBP51 BINDING SURFACE are labelled with their atoms numbers. The INDUCED-FIT FKBP51 INHIBITOR A12 is shown in pink lines, atoms of A12 that induce the fit and occupy the CENTER OF A HOLE are labelled (CAI-CAT). (B) Crystal structure of FKBP51 a in complex with inhibitor A12 (not shown) showing the key residues G59, F67, I87, W90, Y113 and F130 and the distances that can be used to quantify the conformational change of F67.

(7) FIG. 7: Pharmacophore model for selective FKBP51 ligands (A) A12, (B) A01, (C) A09, (D) A02, and for non-selective ligands (E) from 4DRN.sup.2, (F) from 4DRK.sup.2, (G) 3O5R.sup.1, (H) 4DRQ.sup.3. .sup.1Bracher et al., Acta Crystallogr D, 2011, 549-559. .sup.2Gopalakrishnan et al, J Med Chem, 2012, 55, 4114-4122. .sup.3Gopalakrishnan et al, J Med Chem, 2012, 55, 4123-4131

(8) FIG. 8: (a) Component of a crystal. The asymmetric unit is that part of the crystal that shows no symmetry. A symmetry operator (for example, a C2 axis) generates the lattice motif. Repeating this motif by translation generates the corner of the unit cell, which is the basic repeating unit of the crystal lattice; (b) unit cell definition.

(9) FIG. 9: Coordinates for the complex of FKBP51.sup.A19T with A12 (Form I). Coordinates of the Ligand A12 are in bold.

EXAMPLES

Abbreviations

(10) DCM dichloromethane DIPEA N,N-Diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethylacetate Fmoc Fluorenylmethyloxycarbonyl HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOBt Hydroxybenzotriazole tBu tert-butyl TEA triethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TMSCl trimethylsilyl chloride
General Information

(11) Solvents were purchased from Roth or Sigma Aldrich with qualities, ROTOSOLV, ROTIPURAN; ROTIDRY or HPLC quality with ≧99% purity. Anhydrous solvents were used from Sigma Aldrich with sure seals. All reactions were carried out with magnetic stirring and, when air or moisture sensitive, in flame-dried glassware under argon (Westfalen, 99.999 Vol % Klasse 5.0). Syringes were used to transfer reagents. Reagents used in very moisture-sensitive reactions were dried overnight under high vacuum (<1×10.sup.−2 mbar). 1D .sup.1H, .sup.13C-NMR and 2D HSQC, HMBC and COSY were recorded at the department of chemistry and pharmacy of the LMU on a Bruker AC 300, a Bruker XL 400, or a Bruker AMX 600 at room temperature. Chemical shifts for .sup.1H or .sup.13C are given in ppm (δ) relative to tetramethylsilane (TMS) as internal standard. CDCl.sub.3 and d6-DMSO were used as solvents. .sup.1H and .sup.13C spectra were calibrated on the specific solvent. The coupling constants (J) are given in Hertz (Hz). The multiplicities are abbreviated as singlet (s), dublet (d), triplet (t), quartet (q) and multiplet (m). Mass spectra (m/z) were recorded on a Thermo Finnigan LCQ DECA XP Plus mass spectrometer at the Max Planck Institute of Psychiatry, while the high resolution mass spectrometry was carried out at MPI for Biochemistry (Microchemistry Core facility) on Varian Mat711 mass spectrometer. The purity of the compounds was verified by reversed phase HPLC. All gradients were started after 1 min of equilibration with starting percentage of solvent mixture. For manual column chromatography, Silicagel 60 (Roth) with a particle size of 0.04-0.063 mm was used. Automated flash chromatography was performed, using an Interchim Puriflash 430 with an UV detector at 254 nm. Preparative thin layer chromatography (TLC) was performed on glass plates coated with 2 mm SiO.sub.2 (Merck SIL-G-200, F-254). For TLC aluminum plates coated with SiO.sub.2 (Merck 60, F-254) were used. The spots were visualized by UV light and/or by staining of the TLC plate with one of the solutions below followed, if necessary, by heating with a heat gun.

(12) HPLC

(13) The purity of the compounds was verified by reversed phase HPLC. All gradients were started after 1 min of equilibration with starting percentage of solvent mixture.

(14) Analytical:

(15) Pump: Beckman System Gold 125S Solvent Module Detector: Beckman System Gold Diode Array Detector Module 168 Column: Phenomenex Jupiter 4μ Proteo 90 Å, 250×4.6 mm 4 micron Solvent A: 95% H.sub.2O 5% CH.sub.3CN 0.1% TFA Solvent B: 95% CH.sub.3CN 5% H.sub.2O 0.1% TFA Standard Gradient: 0-100% B in 20 min, 1 ml/min Detection wavelength: 220 nm/280 nm
Chiral: Pump: Waters 515 HPLC Pump Detector: LDC Analytical Spectromonitor 5000 Photodiode Array Detector Column: DAICEL Chemical Industries LTD. Chiralcel OD-H Solvent A: Hexane Solvent B: i-propanol Standard Gradient: 1:1 60 min, 0.5 ml/min Detection wavelength: 220 nm
Preparative: Pump: Beckman System Gold Programmable Solvent Module 126 NMP Detector: Beckman Programmable Detector Module 166 Column: Phenomenex Jupiter 10μ Proteo 90 Å, 250×21.2 mm 10 micron Methods: Described at the specific compound
Semi-Preparative: Pump: Beckman System Gold 125S Solvent Module Detector: Beckman System Gold Diode Array Detector Module 168 Column: Phenomenex Jupiter 10μ Proteo 90 Å, 250×10 mm 10 micron Methods: Described at the specific compound
LC-MS: Pump: Beckman System Gold 125S Solvent Module Detector: System Gold Diode Array Detector Module 168 Column: YMC Pack Pro C8, 100×4.6 mm, 3 μm Solvent A: 95% H.sub.2O 5% CH.sub.3CN 0.1% Formic acid Solvent B: 95% CH.sub.3CN 5% H.sub.2O 0.1% Formic acid Standard Gradient: 0-100% B in 11 min, 1 ml/min Detection wavelength: 220 nm, 280 nm
General Coupling Reaction Procedures

(16) All reactions were carried out with magnetic stirring and, when air or moisture sensitive, in flame-dried glassware under argon (Westfalen, 99.999 Vol % Klasse 5.0). Syringes were used to transfer reagents. Reagents used in very moisture-sensitive reactions were dried overnight under high vacuum (<1×10.sup.−2 mbar).

(17) Synthetic Procedures of Synthetic Building Blocks A

Example 1-1

Preparation of (E)-3-(3,4-Dimethoxyphenyl)-1-(3-hydroxyphenyl) prop-2-en-1-one (2)

(18) ##STR00097##

(19) 2 was synthesized according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-2

Preparation of 3-(3,4-Dimethoxyphenyl)-1-(3-hydroxyphenyl) propan-1-one (3)

(20) ##STR00098##

(21) 3 was synthesized according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-3

Preparation of tert-Butyl-2-[3-{3-(3,4-dimethoxyphenyl) propanoyl}phenoxy] acetate (4a)

(22) ##STR00099##

(23) 4a was synthesized according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-4

Preparation of (R)-tert-Butyl-2-[3-{3-(3,4-dimethoxyphenyl)-1-hydroxypropyl}phenoxy] acetate (5a)

(24) ##STR00100##

(25) 5a was synthesized according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-5

Preparation of (S)-1-(((9H-Fluoren-9-yl)methoxy) carbonyl)piperidine-2-carboxylic acid (6a)

(26) ##STR00101##

(27) 6a was synthesized according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-6

Preparation of (S)-1-[9H-Fluoren-9-yl]methyl-ester-2-[(R)-1-{3-(2-tert-butoxy-2-oxo-ethoxy)phenyl}-3-(3,4-dimethoxyphenyl)propyl]piperidin-2-carboxylate (7a)

(28) ##STR00102##

(29) 7a was synthesized according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-7

Preparation of (S)-[(R)-1-{3-(2-tert-Butoxy-2-oxoethoxy)phenyl}-3-(3,4-dimethoxyphenyl) propyl] piperidin-2-carboxylate (8a)

(30) ##STR00103##

(31) 8a was synthesized according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-8

Preparation of Oxycarbonyl-2-((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy) phenyl)propyl) (S)-1-(9H-Fluoren-9-yl)methylpiperidine-2-carboxylate (9a)

(32) ##STR00104##

(33) 9a was synthesized according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-9

Preparation of (S)-((R)-3-(3,4-Dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl) piperidine-2-carboxylate (10a)

(34) ##STR00105##

(35) 10a was synthesized oil according to Gopalakrishnan et al, Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52, JMC, 2012, 55, 4114-4122.

Example 1-10

Preparation of (R)-(R)-3-(3,4-Dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-thiomorpholine-3-carboxylate (10b)

(36) ##STR00106##

(37) A solution of alcohol 5b (0.10 g, 0.25 mmol), Fmoc-thiopipecolate 6b (92 mg, 0.37 mmol), and catalytic amount of DMAP (3 mg, 25 μmol) in 10 mL DCM was treated with EDC (53 mg, 0.28 mmol). The mixture was stirred for 14 h at RT. The crude product was concentrated, flash chromatographed (DCM/MeOH 97:3) and consequently dissolved in 1.8 mL DCM. Then 0.2 mL 4-methylpiperidine was added and the mixture was stirred for 14 h at RT. 4-Methylpiperidine and DCM were evaporated under reduced pressure. The raw product was purified by flash chromatography (DCM/MeOH 92:8). 10b was obtained as a slight yellow oil (32 mg, 0.13 mmol, 48%).

(38) TLC [MeOH/DCM 8:92]: R.sub.f=0.18.

(39) HPLC [0-100% Solvent B, 20 min]: R.sub.t=11.7 min, purity (220 nm)=92%

(40) .sup.1H NMR (300 MHz, d6-DMSO) δ 7.24-7.16 (m, 1H), 6.91-6.73 (m, 5H), 6.66 (td, J=8.2, 7.8, 2.0 Hz, 1H), 5.63 (dd, J=8.4, 4.7 Hz, 1H), 4.09-4.00 (m, 2H), 3.97 (t, J=3.6 Hz, 1H), 3.72-3.67 (m, 6H), 3.58-3.51 (m, 4H), 3.06-2.85 (m, 3H), 2.69-2.60 (m, 2H), 2.60-2.50 (m, 2H), 2.47-2.39 (m, 5H), 2.17-2.04 (m, 2H), 1.98 (d, J=14.7 Hz, 2H).

(41) .sup.13C NMR (75 MHz, d6-DMSO) δ 170.62, 158.91, 148.86, 147.47, 142.32, 133.89, 129.68, 120.20, 118.75, 114.35, 112.88, 111.96, 74.91, 66.47, 65.39, 59.53, 57.34, 55.87, 54.09, 46.21, 38.16, 31.03, 28.82, 27.36.

(42) Mass: (ESI.sup.+), calculated 531.25 [C.sub.28H.sub.38N.sub.2O.sub.6S+H].sup.+, found 531.21 [M+H].sup.+.

Example 1-11

Preparation of (S)-1-((9H-Fluoren-9-yl)methyl)ester-2-((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy) phenyl)propyl) pyrrolidine-2-carboxylate (9c)

(43) ##STR00107##

(44) 5b (200 mg, 0.50 mmol), Fmoc-proline 6c (185 mg, 0.55 mmol) and DMAP (12 mg, 0.10 mmol) were dissolved in DCM at 0° C. then EDC (143 mg, 0.75 mmol) was added and the reaction was allowed to warm to RT, followed by stirring for 14 hours. The raw product was subjected to column chromatography (gradient 0%-5% MeOH in DCM). 9c (276 mg, 0.383 mmol, 77%) was obtained as a slight yellow oil.

(45) TLC [MeOH/DCM 5:95]: R.sub.f=0.2.

(46) HPLC [0-100% Solvent B, 20 min]: R.sub.t=16.7 min, purity (220 nm)=98%

(47) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.78-7.67 (m, 2H), 7.65-7.53 (m, 1H), 7.53-7.45 (m, 1H), 7.42-7.26 (m, 3H), 7.25-7.18 (m, 1H), 6.94-6.53 (m, 7H), 5.73 (dt, J=8.0, 5.8 Hz, 1H), 4.49 (dt, J=8.9, 3.7 Hz, 1H), 4.41 (dd, J=10.1, 6.8 Hz, 2H), 4.34-4.13 (m, 1H), 4.14-4.07 (m, 2H), 3.85-3.82 (m, 6H), 3.77-3.66 (m, 4H), 3.31 (td, J=9.1, 3.2 Hz, 1H), 3.26-3.14 (m, 1H), 3.07 (dt, J=10.4, 6.8 Hz, 1H), 2.80 (dt, J=6.9, 5.7 Hz, 4H), 2.64-2.52 (m, 4H), 2.35-2.18 (m, 1H), 2.15-1.96 (m, 2H), 1.95-1.76 (m, 2H).

(48) .sup.13C NMR (125 MHz, CDCl.sub.3) δ 171.90, 159.63, 157.44, 150.39, 148.33, 144.14, 143.58, 139.48, 135.20, 129.28, 127.63, 126.29, 125.14, 121.85, 120.96, 119.20, 115.53, 114.12, 113.68, 113.06, 77.03, 67.50, 67.38, 66.80, 63.34, 56.83, 54.73, 52.94, 48.12, 47.31, 36.38, 34.08, 28.00, 24.98.

(49) Mass (ESI.sup.+): calculated [C.sub.43H.sub.48N.sub.2O.sub.8+H].sup.+ 721.35, found 721.25 [M+H].sup.+.

Example 1-12

Preparation of (S)-(R)-3-(3,4-Dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-pyrrolidine-2-carboxylate (10c)

(50) ##STR00108##

(51) 9c (234 mg, 0.32 mmol) was dissolved in 1.8 mL dry DCM, then 200 μL 4-methylpiperidine was added and stirred for 14 h. The product was purified using flash chromatography (gradient 0%-10% MeOH in DCM) to obtain 10c (140 mg, 0.28 mmol, 86%) as a yellow oil.

(52) TLC [MeOH/DCM 6:94]: R.sub.f=0.10.

(53) HPLC [0-100% Solvent B, 20 min]: R.sub.t=11.6 min, purity (220 nm)=92%.

(54) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.25-7.18 (m, 1H), 6.94-6.83 (m, 2H), 6.83-6.72 (m, 2H), 6.70-6.61 (m, 2H), 5.72 (dd, J=7.9, 5.9 Hz, 1H), 4.64 (dd, J=7.8, 5.3 Hz, 1H), 4.14-4.07 (m, 2H), 3.85-3.82 (m, 6H), 3.77-3.66 (m, 4H), 3.31 (td, J=9.1, 3.2 Hz, 1H), 3.26-3.14 (m, 1H), 3.07 (dt, J=10.4, 6.8 Hz, 1H), 2.80 (dt, J=6.9, 5.7 Hz, 4H), 2.64-2.52 (m, 4H), 2.35-2.18 (m, 1H), 2.15-1.96 (m, 2H), 1.95-1.76 (m, 2H).

(55) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 172.34, 158.73, 148.77, 147.17, 146.44, 141.28, 134.43, 133.35, 129.43, 119.09, 118.46, 113.45, 113.13, 111.75, 111.19, 73.61, 66.82, 65.70, 59.64, 57.63, 55.92, 54.05, 40.65, 31.64, 29.89, 24.75.

(56) Mass (ESI.sup.+): calculated [C.sub.28H.sub.38N.sub.2O.sub.6+H].sup.+ 499.28, found 499.22 [M+H].sup.+.

Example 1-13

Preparation of (S)-1-((9H-Fluoren-9-yl)methyl)ester-2-(1,7-di(pyridin-3-yl)heptan-4-yl) piperidine-2-dicar-boxylate (9d)

(57) ##STR00109##

(58) A solution of alcohol 5c (0.30 g, 1.1 mmol) and carboxylic acid 6a (0.39 g, 1.1 mmol) in 10 mL DCM was treated with EDC (0.23 g, 1.2 mmol). The reaction mixture was stirred for 14 h at RT. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography (gradient 0%-100% EtOAc in cyclohexane) to afford 9d as a yellow oil (0.49 g, 0.8 mmol, 73%).

(59) ##STR00110##

(60) TLC [EtOAc 99%+1% TEA]: R.sub.f=0.2.

(61) LCMS: [0-100% Solvent B, 10 min]: R.sub.t=7.1 min, purity (220 nm)=96%.

(62) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.47-8.34 (m, 4H), 7.77 (d, J=7.1 Hz, 2H), 7.63-7.56 (m, 2H), 7.53-7.45 (m, 2H), 7.45-7.27 (m, 4H), 7.24-7.06 (m, 2H), 4.93 (dd, J=29.0, 23.9 Hz, 2H), 4.50-4.23 (m, 3H), 4.23-4.01 (m, 1H), 2.67-2.47 (m, 4H), 2.23 (d, J=13.3 Hz, 1H), 1.82-1.38 (m, 10H), 1.35-1.16 (m, 4H).

(63) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 171.54, 156.48, 149.32, 147.14, 143.57, 141.28, 137.13, 135.83, 127.71, 127.04, 125.09, 123.28, 120.07, 74.16, 67.71, 60.38, 54.22, 47.09, 41.86, 33.45, 32.37, 29.69, 26.28, 24.46, 21.27, 20.55, 14.25.

(64) Mass: (ESI.sup.+), calculated 604.32 [C.sub.38H.sub.41N.sub.3O.sub.4+H].sup.+, found 604.30 [M+H].sup.+.

Example 1-14

Preparation of (S)-1,7-Di(pyridin-3-yl)heptan-4-yl piperidine-2-carboxylate (10d)

(65) ##STR00111##

(66) 9d (0.44 g, 0.73 mmol) was dissolved in 1.8 mL dry DCM, then 0.2 mL 4-Methylpiperidin was added and stirred for 14 h at RT. The crude mixture was concentrated and purified by flash chromatography (gradient 0%-15% MeOH in DCM). 10d (0.22 g, 0.58 mmol, 80%) was obtained as a slight yellow oil.

(67) TLC [MeOH/DCM 10:90]: R.sub.f=0.42.

(68) HPLC [0-50% Solvent B, 20 min]: Rt=9.0 min, purity (220 nm)=90%.

(69) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.46-8.38 (m, 4H), 7.42-7.38 (m, 2H), 7.18-7.14 (m, J=7.5 Hz, 2H), 4.83 (tt, J=6.3, 4.9 Hz, 1H), 3.16-3.03 (m, 2H), 2.73 (dt, J=12.2, 5.2 Hz, 1H), 2.62-2.56 (m, 4H), 2.12 (ddt, J=12.0, 7.5, 5.9 Hz, 1H), 2.00 (s, 1H), 1.78-1.69 (m, 1H), 1.69-1.63 (m, 4H), 1.62-1.56 (m, 3H), 1.55-1.51 (m, 1H), 1.51-1.46 (m, 4H).

(70) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 169.23, 149.61, 147.27, 137.42, 137.13, 136.99, 136.08, 135.90, 123.48, 75.55, 56.98, 45.31, 43.48, 36.56, 32.26, 27.26, 26.20, 22.20.

(71) Mass: (ESI.sup.+), calculated 382.25 [C.sub.23H.sub.31N.sub.3O.sub.2+H].sup.+, found 382.20 [M+H].sup.+.

Example 1-15

Preparation of (S)-1-((9H-Fluoren-9-yl)methyl)ester-2-((R)-1-(3-(2-(tert-butoxy)-2-oxoethoxy) phenyl)-3-(3,4-dimethoxyphenyl)propyl) piperidine-2-carboxylate (7b)

(72) ##STR00112##

(73) 6a (0.25 g, 0.71 mmol), DIPEA (0.37 g, 2.85 mmol) and HATU (410 mg, 1.07 mmol) were dissolved in 1.5 mL DMF and stirred for 30 min. Then (R)-tert-butyl-2-(3-(1-amino-3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetate 5e (0.29 g, 0.71 mmol) dissolved in 2 mL DCM was added to the reaction mixture and stirred at RT for 14 h. The solvent was removed in vacuo and the crude product was purified by flash chromatography (EtOAc/cyclohexane 3:7) to afford 7b (0.48 g, 0.65 mmol, 92%) as a slightly yellow solid.

(74) ##STR00113##

(75) TLC [EtOAc/cyclohexane 3:7]: R.sub.f=0.25.

(76) HPLC [0-100% Solvent B, 20 min]: R.sub.t=20.5 min, purity (220 nm)=98%

(77) .sup.1H NMR (400 MHz, DMSO) δ 7.83-7.80 (m, 2H), 7.63-7.58 (m, 2H), 7.46-7.39 (m, 4H), 7.32-7.20 (m, 2H), 7.04-7.02 (m, 2H), 6.88-6.84 (m, 3H), 6.80-6.74 (m, 2H), 5.20-5.17 (m, 1H), 5.00-4.93 (m, 4H), 4.83 (t, J=6.2 Hz, 1H), 4.17-4.11 (m, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.53-3.47 (m, 1H), 2.82 (t, J=4.3 Hz, 1H), 2.69 (t, J=7.9 Hz, 2H), 2.34-2.20 (m, 2H), 2.08-1.91 (m, 2H), 1.79-1.66 (m, 3H), 1.34 (s, 9H).

(78) .sup.13C NMR (101 MHz, DMSO) δ 170.45, 168.32, 162.49, 158.23, 155.70, 148.71, 147.54, 145.61, 144.45, 141.16, 134.01, 129.35, 128.18, 127.22, 125.45, 120.40, 119.48, 113.43, 112.65, 112.08, 81.47, 64.94, 59.93, 55.91, 54.51, 51.97, 46.97, 41.90, 38.41, 36.27, 32.22, 31.25, 28.31, 26.80, 24.78, 21.20.

(79) Mass: (ESI.sup.+), calculated 531.25 [C.sub.44H.sub.50N.sub.2O.sub.8+H].sup.+, found 531.21 [M+H].sup.+.

Example 1-16

Preparation of tert-Butyl-2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-piperidine-2-carboxamido)propyl)phenoxy) acetate (8b)

(80) ##STR00114##

(81) 7b (0.43 mg, 0.59 mmol) was dissolved in 4.5 mL dry DCM, then was added 0.5 mL 4-methylpiperidine and stirred for 14 h. The raw product was concentrated and subjected to flash chromatography (gradient 0-100% EtOAc in cyclohexane, then EtOAc/MeOH 99:1, 1% TEA). 8b (160 mg, 0.312, 53%) was obtained as a white solid.

(82) TLC [EtOAc/MeOH 99:1, 1% TEA]: R.sub.f=0.20.

(83) HPLC [0-100% Solvent B, 20 min]: R.sub.t=14.8 min, purity (220 nm)=95%

(84) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.26-7.20 (m, 1H), 7.18 (d, J=9.4 Hz, 1H), 6.94-6.88 (m, 1H), 6.86 (dd, J=2.6, 1.5 Hz, 1H), 6.78-6.72 (m, 2H), 6.69-6.64 (m, 2H), 4.96 (q, J=7.7 Hz, 1H), 4.49 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.23-3.15 (m, 1H), 3.02-2.91 (m, 1H), 2.68-2.58 (m, 1H), 2.59-2.50 (m, 2H), 2.21-2.00 (m, 4H), 1.98-1.87 (m, 1H), 1.80-1.70 (m, 1H), 1.59-1.49 (m, 1H), 1.47 (s, 9H).

(85) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 172.71, 167.65, 158.24, 148.73, 146.82, 144.02, 133.90, 129.60, 120.08, 119.82, 113.37, 112.87, 111.74, 111.20, 82.20, 65.69, 60.12, 55.90, 52.51, 45.68, 37.93, 32.24, 29.75, 28.02, 25.69, 23.88.

(86) Mass: (ESI+), calculated 530.30 [C.sub.29H.sub.40N.sub.2O.sub.6+H].sup.+, found 530.28 [M+H].sup.+.

(87) Synthetic Procedures of Synthetic Building Blocks B

Example 2-1

Preparation of Pentafluorophenyl 2-(3,4,5-trimethoxyphenyl) acetate (12)

(88) ##STR00115##

(89) 2-(3,4,5-Trimethoxyphenyl)acetic acid 11 (8.2 g, 36.2 mmol) was dissolved in 140 ml dry DCM (then EDC (10.4 g 54.3 mmol) was added and stirred for 15 min at RT

(90) 2,3,4,5,6-pentafluorophenol (10.0 g, 54.3 mmol) was dissolved in 60 ml dry DCM and added to the solution. The mixture was stirred for 6 h at RT and then concentrated and subjected to flash chromatography (EtOAc/cyclohexane, 2:8). 12 (13.4 g, 34.1 mmol, 94%) was obtained as a white solid.

(91) TLC [EtOAc/cyclohexane, 2:8]: R.sub.f=0.31.

(92) HPLC [0-100% Solvent B, 30 min]: R.sub.t=25.8 min, purity (220 nm)=95%.

(93) .sup.1H-NMR (300 MHz, CDCl3): δ=6.56 (s, 2H), 3.90 (s, 2H), 3.87 (s, 6H), 3.85 (s, 3H).

(94) .sup.13C-NMR (150 MHz, CDCl3): δ=167.39, 153.48, 137.59, 127.47, 106.19, 60.855, 56.12, 40.37.

(95) HRMS (ESI.sup.+): calculated [C.sub.17H.sub.13F.sub.5O.sub.5+H.sup.+] 393.0756, found 393.0711 [M]+H.sup.+.

Example 2-2

Preparation of (S)-4-isopropyl-3-[2-(3,4,5-trimethoxyphenyl)acetyl]oxazolidin-2-one (13)

(96) ##STR00116##

(97) n-Butyllithium (2.5 M in Cyclohexane, 1.4 mL, 3.6 mmol) was added to (S)-4-Isopropyl-oxazolidin-2-one (0.46 g, 3.6 mmol) dissolved in 17 mL dry THF at −78° C., then was stirred for 1 h −78° C. After that 12 (1.4 g, 3.6 mmol) dissolved in 17 mL dry THF was added to the above solution and stirred for 2 h at −78° C. and 14 h at 0° C. The reaction mixture was quenched by adding sat. NH.sub.4Cl solution. The aqueous solution was extracted with DCM. The org. phases were dried over MgSO.sub.4. The crude product was concentrated and purified by column chromatography (EtOAc/cyclohexane, 1:2). 13 was afforded as a yellow oil (0.67 mg, 1.98 mmol, 53%).

(98) TLC [EtOAc/cyclohexane, 2:8]: R.sub.f=0.31.

(99) HPLC [0-100% Solvent B, 30 min]: Rt=22.4 min, purity (220 nm)=98%.

(100) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=6.56 (s, 2H), 4.43-4.41 (m, 2H), 4.38-4.17 (m, 3H), 3.85 (d, 9H), 2.38-2.27 (m, 1H), 0.96 (d, J=6 Hz, 3H), 0.85 (d, J=6 Hz, 3H).

(101) .sup.13C-NMR (150 MHz, CDCl.sub.3): δ=167.39, 153.48, 137.59, 127.47, 106.19, 60.855, 56.12, 40.37.

(102) Mass (ESI.sup.+): calculated [C.sub.17H.sub.23NO.sub.6+H.sup.+] 338.16, found 338.20 [M]+H.sup.+.

Example 2-3

Preparation of (S)-4-Isopropyl-3-((S)-2-(3,4,5-trimethoxyphenyl)pent-4-enoyl)oxazolidin-2-one (14)

(103) ##STR00117##

(104) 13 (2.0 g, 5.9 mmol) was dissolved in 5 mL anhydrous THF, cooled to −78° C. and then NaHMDS (7.1 mL, 7.1 mmol, 1M in THF) was added to the solution. After stirring for 30 min at −78° C., the reaction was stirred for another 30 min at 0° C., then allylbromide (0.63 mL, 7.1 mmol) was added and stirred for 2 h at −78° C., and another 10 h at 0° C. The reaction was quenched by the addition of saturated NH.sub.4Cl solution. The biphasic aqueous solution was extracted with DCM. The organic phases were combined and dried over MgSO.sub.4. The crude mixture was concentrated and purified by column chromatography (EtOAc/cyclohexane, 2:8). 14 was obtained as yellow oil (1.0 g, 2.7 mmol, 45%, d.r. >95:5).

(105) TLC [EtOAc/cyclohexane 2:8]: R.sub.f=0.31.

(106) HPLC [0-100% Solvent B, 30 min]: R.sub.t=25.0 min, purity (220 nm)=98%.

(107) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 6.60 (s, 2H), 5.80-5.70 (m, 1H), 5.20-5.15 (dd, J=9.5, 5.8 Hz, 1H), 5.14-5.07 (dq, J=17.1, 1.6 Hz, 1H), 5.04-4.98 (dq, J=10.2, 1.1 Hz, 1H), 4.40-4.34 (m, 1H), 4.18-4.13 (m, 2H), 3.85-3.82 (s, 6H), 3.83-3.79 (s, 3H), 2.93-2.84 (m, 1H), 2.52-2.44 (m, 1H), 2.43-2.35 (m, 1H), 0.92-0.84 (m, 6H).

(108) .sup.13C NMR (150 MHz, CDCl.sub.3) δ 173.36, 153.67, 153.04, 137.10, 135.07, 133.80, 117.14, 105.43, 62.99, 60.82, 58.93, 56.12, 47.79, 38.67, 28.37, 17.88, 14.58.

(109) HRMS (EI.sup.+): calculated [C.sub.20H.sub.27NO.sub.6+H].sup.+ 378.19, found 378.13 [M+H].sup.+.

Example 2-4

Preparation of (S)-2-(3,4,5-Trimethoxyphenyl)pent-4-enoic acid (15)

(110) ##STR00118##

(111) 14 (0.70 g, 1.86 mmol) was dissolved in 10 mL THF/H.sub.2O (1:1) and cooled to 0° C. for 5 min. Then LiOH (89 mg, 3.71 mmol) was added followed by addition of H.sub.2O.sub.2 (0.60 mL, 7.42 mmol). The reaction mixture was stirred at 0° C. for 4 h. The reaction was quenched by the addition of 1.5 M Na.sub.2SO.sub.3. The aqueous solution was diluted with brine and extracted with DCM. Then, the aqueous phase was acidified to pH<2 and further extracted with DCM. The organic layers were combined and dried over MgSO.sub.4. The raw product was concentrated and purified using flash chromatography (gradient 0%-30% EtOAc in n-hexane, 0.1% AcOH). 15 (324 mg, 1.22 mmol, 66%) was obtained as a yellow oil.

(112) TLC [EtOAc/n-hexane 1:2]: R.sub.f=0.22.

(113) HPLC [0-100% Solvent B, 30 min]: R.sub.t=17.9 min, purity (220 nm)=98%.

(114) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.56 (d, J=1.1 Hz, 2H), 5.84-5.67 (m, 1H), 5.19-5.00 (m, 2H), 3.87-3.84 (m, J=0.7 Hz, 9H), 3.58 (dd, J=8.6, 6.9 Hz, 1H), 2.88-2.75 (m, 1H), 2.53 (dtt, J=14.5, 6.8, 1.4 Hz, 1H).

(115) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 178.95, 153.31, 137.47, 134.79, 133.38, 117.31, 105.08, 60.81, 56.14, 51.50, 37.18, 20.72.

(116) Mass: (ESI+), calculated 287.12 [C.sub.14H.sub.18O.sub.5+H].sup.+, found 287.13 [M+H].sup.+.

Example 2-5

Preparation of (S)-3-((S)-2-((S)-cyclohex-2-en-1-yl)-2-(3,4,5-trimethoxyphenyl)acetyl)-4-isopropyl-oxazolidin-2-one (16a)

(117) ##STR00119##

(118) dr=85:15

(119) 13 (3.0 g, 8.89 mmol) was dissolved in 1 mL anhydrous THF and cooled to −78° C. Then NaHMDS (14.23 mL, 14.23 mmol, 1 M in THF) was added dropwise and stirred for 1 h. The reaction mixture was briefly warmed to 0° C. and cooled again to −78° C. cyclohexene bromide (1.0 mL, 8.9 mmol) was added dropwise and stirred for 1 h at −78° C. finally it was slowly warmed to 0° C. and stirred for another 14 h. The reaction mixture was quenched with sat. NH.sub.4Cl solution and extracted with DCM. The organic phase was dried over MgSO.sub.4 and the solvent was removed in vacuo. The raw product was purified using column chromatography (EtOAc/cyclohexane 1:3) to obtain a mixture of 16a/b (2.03 g, 4.9 mmol, 55%) as yellow orange solid. A dr at C.sub.β of 85:15 was determined via .sup.13C NMR. The distribution shown above is based on the co-crystal structure with A12.

(120) TLC [EtOAc/n-hexane 1:2]: R.sub.f=0.5.

(121) HPLC 16a/b [55-65% Solvent B, 20 min]: Rt=20.3 min, purity (220 nm)≧99%.

(122) HPLC 16a/b [55-65% Solvent B, 20 min]: Rt=16.6 min, purity (220 nm)≧99%.

(123) .sup.1H NMR (300 MHz, d6-DMSO) major diastereomer δ 6.54-6.53 (s, 2H), 5.74-5.66 (m, 1H), 5.61-5.54 (dd, J=10.3, 2.3 Hz, 1H), 4.73-4.67 (d, J=11.2 Hz, 1H), 4.49-4.42 (m, 1H), 4.34-4.27 (m, 1H), 4.20-4.15 (dd, J=9.0, 3.1 Hz, 1H), 3.70-3.69 (s, 6H), 3.62-3.60 (s, J=1.9 Hz, 3H), 1.68-1.55 (m, 3H), 1.47-1.35 (m, 2H), 1.34-1.20 (dd, J=14.4, 7.5 Hz, 2H), 1.11-0.98 (m, 1H), 0.73-0.69 (d, J=7.0 Hz, 3H), 0.35-0.32 (d, J=6.8, 3H).

(124) .sup.13C NMR (75 MHz, d6-DMSO) major diastereomer δ 172.85, 172.83, 153.81, 153.09, 137.22, 133.09, 129.97, 128.88, 106.30, 63.53, 60.45, 57.97, 56.30, 54.06, 37.30, 28.12, 26.52, 25.25, 20.99, 17.56, 14.44.

(125) Mass: (ESI.sup.+), calculated 418.22 [C.sub.23H.sub.31NO.sub.6+H].sup.+, found 418.25 [M+H].sup.+.

Example 2-6

Preparation of (S)-2-((R)-Cyclohex-2-en-1-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid (17)

(126) ##STR00120##

(127) 16 (0.65 mg, 1.56 mmol) was dissolved in 13 mL THF/H.sub.2O 8:5 at RT. Then lithium hydroxide (75 mg, 3.12 mmol) and hydrogen peroxide (0.68 mL, 28.1 mmol) were added and stirred until complete dissolved. The reaction mixture was cooled to 0° C. and stirred for 4 h and another 2 h at RT. Finally the reaction was quenched with 5 mL 1.5 M Na.sub.2SO.sub.3 solution and was subsequently diluted with brine and extracted with DCM. The aqueous phase was acidified to pH<2 and extracted again with DCM. All organic phases were checked with TLC and LCMS, product containing phases were combined, dried over MgSO.sub.4 and concentrated. 17 (470 mg, 1.53 mmol, 96%) was obtained without further purification as a yellow oil with a dr 85:15 (determined via .sup.13C NMR).

(128) TLC [EtOAc/n-hexane 1:1.5, 1% AcOH]: R.sub.f=0.40.

(129) HPLC [55-65% Solvent B, 20 min]: Rt=19.0 min, purity (220 nm)=98%.

(130) .sup.1H NMR (300 MHz, d6-DMSO) major diastereomer δ 6.61 (s, 2H), 5.72 (dd, J=10.0, 2.3 Hz, 1H), 5.61 (d, J=10.3 Hz, 1H), 3.72 (s, 6H), 3.62 (s, 3H), 3.50 (dtd, J=8.6, 6.1, 1.1 Hz, 1H), 3.13 (dd, J=11.1, 4.6 Hz, 1H), 1.91 (s, 2H), 1.41-1.20 (m, 3H), 1.10-0.91 (m, 1H).

(131) .sup.13C NMR (75 MHz, d6-DMSO) major diastereomer δ 174.80, 159.27, 153.00, 136.89, 134.47, 129.95, 128.78, 105.95, 60.30, 57.67, 56.28, 38.26, 26.37, 25.16, 20.75,

(132) Mass: (ESI.sup.+), calculated 307.15 [C.sub.17H.sub.22O.sub.5+H].sup.+, found 307.18 [M+H].sup.+.

Example 2-7

Preparation of (S)-3-((S)-2-Cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)-4-isopropyl oxazolidin-2-one (18)

(133) ##STR00121##

(134) 16 (0.20 mg, 0.48 mmol) was dissolved in 10 mL of MeOH and placed in an autoclave (Roth, Lab autoclave model II). Palladium on activated charcoal (10% Pd basis, 20 mg, 18.8 μmol) was added and the autoclave was flushed with argon and hydrogen gas. Finally it was filled with 30 bar hydrogen gas and the reaction mixture stirred for 2 d. The reaction progress was monitored by LCMS. If educt was still present another amount of Palladium on activated charcoal (10% Pd basis, 10 mg, 9.40 μmol) was added and above described procedure repeated. The palladium containing crude product was filtered through celite and concentrated. 18 (188 mg, 0.45 mmol, 94%, dr 99:1) was obtained as slight yellow oil and used without further purification. No residual 16 could be observed in the NMR spectra. The diastereomeric rate was determined by HPLC.

(135) TLC [EtOAc/n-hexane 1:2]: R.sub.f=0.5.

(136) HPLC [60-70% Solvent B, 20 min]: R.sub.t=17.9 min, purity (220 nm)=98%, dr ≧99:1.

(137) .sup.1H NMR (300 MHz, d6-DMSO) δ 6.56 (s, 2H), 4.79 (d, J=10.6 Hz, 1H), 4.38 (dt, J=7.3, 3.5 Hz, 1H), 4.27-4.21 (m, 2H), 3.71 (s, 6H), 3.61 (s, 3H), 2.25 (td, J=7.0, 3.4 Hz, 1H), 2.04 (d, J=10.9 Hz, 1H), 1.65 (d, J=11.0 Hz, 2H), 1.56 (d, J=8.0 Hz, 2H), 1.25-0.99 (m, 6H), 0.84 (d, J=1.6 Hz, 3H), 0.80 (d, J=6.9 Hz, 3H).

(138) .sup.13C NMR (75 MHz, d6-DMSO) δ 173.58, 154.13, 153.06, 137.13, 133.36, 108.74, 106.47, 63.15, 60.37, 58.76, 56.19, 53.74, 31.49, 30.26, 28.33, 26.28, 25.80, 25.66, 17.88, 14.63.

(139) Mass: (ESI.sup.+), calculated 420.24 [C.sub.23H.sub.33NO.sub.6+H].sup.+, found 420.25 [M+H].sup.+.

Example 2-8

Preparation of (S)-2-Cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetic acid (19)

(140) ##STR00122##

(141) 18 (0.50 g, 1.19 mmol) was dissolved in 6 mL THF/H.sub.2O 8:5 and cooled to 0° C., then lithium hydroxide (57.1 mg, 2.38 mmol) and hydrogen peroxide (0.52 mL, 21.45 mmol) were added and stirred for 24 h. Subsequently the reaction mixture was quenched by adding 5 mL of a 1.5 M Na.sub.2SO.sub.3 solution. Finally the reaction was quenched with 5 mL 1.5 M Na.sub.2SO.sub.3 solution and was subsequently diluted with brine and extracted with DCM. The aqueous phase was acidified to pH<2 and extracted again with DCM. All organic phases were checked with TLC and LCMS, product containing phases were combined, dried over MgSO.sub.4 and concentrated. 19 (220 mg, 0.71 mmol, 60%) was obtained as a pale yellow oil without further purification.

(142) TLC [EtOAc/n-hexane 1:1.5, 1% AcOH]: R.sub.f=0.33.

(143) HPLC [60-70% Solvent B, 20 min]: R.sub.t=14.4 min, purity (220 nm)=95%

(144) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.54 (s, 2H), 3.84 (s, 6H), 3.82 (s, 3H), 3.12 (d, J=10.7 Hz, 1H), 2.01-1.83 (m, 3H), 1.81-1.59 (m, 3H), 1.42-1.21 (m, 2H), 1.20-0.99 (m, 3H).

(145) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 179.31, 153.13, 137.33, 132.79, 105.60, 60.80, 58.89, 56.12, 40.86, 31.91, 30.25, 26.23, 25.91.

Example 2-9

Preparation of N-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-N-methyl-2-(3,4,5-trimethoxy phenyl)acetamide (20)

(146) ##STR00123##

(147) Trimethoxyphenyl acetic acid 11 (5.0 g, 22.1 mmol), triethylamine (3.5 mL, 46.0 mmol), EDC-HCl (3.9 g, 20.26 mmol) and HOAt (2.76 g, 20.26 mmol) were dissolved in DCM at 0° C. Then (S,S)-pseudoephedrine (3.0 g, 18.4 mmol) was added and the reaction was stirred at RT for 14 h. The crude product was concentrated and purified using flash chromatography (gradient 0%-100% EtOAc in cyclohexane). 20 (6.37 g, 17.06 mmol, 92%) was obtained as a white solid.

(148) TLC [EtOAc, 1% TEA]: R.sub.f=0.33.

(149) HPLC [0-100% Solvent B, 20 min]: R.sub.t=14.4 min, purity (220 nm)≧99%.

(150) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.38-7.20 (m, 5H), 6.47 (s, 2H), 4.66-4.40 (m, 1H), 4.25-3.94 (m, 1H), 3.84 (s, 6H), 3.82 (s, 3H), 3.65 (s, 2H), 2.85 (s, 3H), 1.11-1.02 (m, 3H).

(151) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 173.11, 153.10, 142.00, 136.81, 130.26, 128.65, 128.40, 127.78, 126.77, 126.49, 105.74, 75.43, 60.81, 58.73, 56.13, 42.02, 32.76, 14.40.

(152) Mass: (ESI.sup.+), calculated 374.20 [C.sub.21H.sub.27NO.sub.5+H].sup.+, found 374.20 [M+H].sup.+.

Example 2-10

Preparation of (S)-3-Cyclopropyl-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-2-(3,4,5-trimethoxyphenyl)propanamide (21)

(153) ##STR00124##

(154) 20 (1.0 g, 2.7 mmol) and lithium chloride (0.68 mg, 16.07 mmol) were put each into a Schlenck flask and kept under high vacuum for 14 h. Additionally LiCl was heated to 150° C. using an oil bath. Then 20 was dissolved in 18 mL anhydrous THF and added to the dry LiCl. The mixture was cooled to −78° C. LDA (2.95 mL, 5.89 mmol, 2.0 M in THF/heptane/ethylbenzene) was added dropwise and then stirred for 1 h. The reaction mixture was warmed to 0° C., and stirred for 15 min, finally warmed briefly to RT, then cooled again to 0° C. and treated with cyclopropylmethylbromide (1.3 mL, 13.4 mmol). The reaction mixture was stirred for 2 h at 0° C. then slowly warmed to RT and stirred for another 14 h. The raw product was diluted with brine, acidified with 1 M HCl to pH˜2 and extracted with DCM. The organic phases were combined and dried over MgSO.sub.4. The crude product was concentrated and purified by flash chromatography (gradient 0%-50% EtOAc in cyclohexane). 21 (0.65 g, 1.51 mmol, 56%) was obtained as yellow crystals.

(155) TLC [MeOH/DCM, 5:95]: R.sub.f=0.40.

(156) HPLC [0-100% Solvent B, 20 min]: R.sub.t=14.4 min, purity (220 nm)=98%, dr 95:5.

(157) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.41 (s, 1H), 7.38-7.31 (m, 2H), 7.28 (d, J=1.0 Hz, 2H), 6.52 (s, 2H), 4.58 (d, J=6.3 Hz, 1H), 4.14 (d, J=7.1 Hz, 1H), 3.87-3.80 (m, 9H), 3.65 (t, J=7.2 Hz, 1H), 2.79 (s, 3H), 2.12-1.93 (m, 1H), 1.58-1.46 (m, 1H), 1.14 (d, J=6.8 Hz, 3H), 0.67 (s, 1H), 0.43 (dd, J=8.5, 4.6 Hz, 2H), 0.23-0.00 (m, 2H).

(158) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 175.54, 153.41, 142.33, 136.85, 135.47, 128.31, 127.60, 126.37, 104.71, 75.45, 60.83, 56.18, 50.68, 40.34, 27.33, 14.17, 9.42, 4.66, 4.63.

(159) Mass: (ESI.sup.+), calculated 428.24 [C.sub.25H.sub.33NO.sub.5+H].sup.+, found 428.52 [M+H].sup.+.

Example 2-11

Preparation of (S)-3-cyclopropyl-2-(3,4,5-trimethoxyphenyl)propanoic acid (22)

(160) ##STR00125##

(161) 21 (0.28 mg, 0.66 mmol) was dissolved in 4 mL dioxane at RT. 4 mL of a 4 M solution of H.sub.2SO.sub.4 in water were added dropwise. The mixture was refluxed for 4 h (150° C.). The reaction was quenched by addition of 50% (w/v) NaOH followed by extraction with DCM. The aqueous phase was acidified with 1 M HCl to pH<2 and extracted again. The organic layers of the acidic extraction were combined and dried over MgSO.sub.4. The raw product was concentrated and purified using preparative TLC (MeOH/DCM, 9:91, 1% AcOH). 22 (68 mg, 0.24 mmol, 37%) was obtained as a yellow oil.

(162) TLC [EtOAc/cyclohexane, 1:1, 1% AcOH]: R.sub.f=0.35.

(163) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.1 min, purity (220 nm)=95%.

(164) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.57 (s, 2H), 3.87 (s, 6H), 3.84 (s, 3H), 3.62 (dd, J=8.2, 7.0 Hz, 1H), 1.91 (dt, J=13.9, 7.8 Hz, 1H), 1.75 (dt, J=13.7, 6.8 Hz, 1H), 0.75-0.61 (m, 1H), 0.49-0.41 (m, 2H), 0.16-0.04 (m, 2H).

(165) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 179.79, 153.24, 137.35, 134.17, 105.09, 60.44, 56.14, 52.16, 38.39, 9.20, 4.46.

(166) Mass: (ESI.sup.+), calculated 281.14 [C.sub.15H.sub.20O.sub.5+H].sup.+, found 281.37 [M+H].sup.+.

Example 2-12

Preparation of (S)-3-phenyl-2-(3,4,5-trimethoxyphenyl)propanoic acid (24)

(167) ##STR00126##

(168) 20 (0.5 g, 1.34 mmol) and dry lithium chloride (0.34 g, 8.03 mmol, dried as described for 21) were dissolved in 5 mL anhydrous THF and cooled to −78° C. LDA (1.4 mL, 2.95 mmol) was added and stirred for 1 h. The reaction mixture was warmed to 0° C., and stirred for 15 min, finally warmed briefly to RT, then cooled again to 0° C. and treated with benzyl bromide (0.8 mL, 6.69 mmol). The reaction mixture was stirred at 0° C. for 14 h. The crude product was concentrated and purified by flash chromatography (gradient, 0%-40% EtOAc in cyclohexane). 23 (0.33 mg, 0.77 mmol, 58%) was obtained as a yellow oil which was directly further reacted.

(169) ##STR00127##

(170) TLC [EtOAc/cyclohexane, 2:1]: R.sub.f=0.33.

(171) HPLC [0-100% Solvent B, 20 min]: R.sub.t=23.5 min, purity (220 nm)=95%, dr=95:5.

(172) Mass (ESI.sup.+), calculated 464.24 [C.sub.28H.sub.33NO.sub.5+H].sup.+, found 464.27 [M+H].sup.+.

(173) 23 (0.28 mg, 0.60 mmol) was dissolved in 4 mL dioxane and then 3.5 mL of a 4 M aq solution of H.sub.2SO.sub.4 was added. The mixture was refluxed for 4 h. (150° C.). The reaction was quenched by addition of 50% (w/v) NaOH then was extracted with DCM. Now was acidified with 1 M HCl to pH<2 and again extracted. These organic layers were combined and dried over MgSO.sub.4. The raw product was purified using preparative TLC (EtOAc/cyclohexane, 3:7, 4% AcOH). 24 (113 mg, 0.36 mmol, 60%) was obtained as a yellow oil.

(174) TLC [EtOAc/cyclohexane, 3:7, 4% AcOH]: R.sub.f=0.42.

(175) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.9 min, purity (220 nm)≧99%.

(176) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.29-7.20 (m, 3H), 7.14 (dd, J=7.9, 1.7 Hz, 2H), 6.53 (s, 2H), 3.85 (s, 6H), 3.84 (s, 3H), 3.40 (dd, J=13.8, 8.5 Hz, 2H), 3.04 (dd, J=13.7, 6.8 Hz, 1H).

(177) .sup.13C NMR (75 MHz, cdcl.sub.3) δ 178.92, 153.27, 138.58, 137.50, 133.49, 130.37, 128.90, 128.41, 126.54, 105.19, 60.84, 56.16, 53.59, 39.38, 20.76, 1.03.

(178) Mass: (ESI.sup.+), calculated 317.14 [C.sub.18H.sub.20O.sub.5+H].sup.+, found 317.13 [M+H].sup.+.

(179) Synthetic Procedures of Synthetic Building Blocks E

Example 2-13

Preparation of (S)-Methyl 2-(2-nitrophenylsulfonamido)pent-4-enoate (25)

(180) ##STR00128##

(181) 25 was synthesized according to Varray et al ( ). L-allyl-glycine (1.0 g, 8.69 mmol) was dissolved in 10 mL MeOH, cooled to 0° C., and then 3 mL TMS-Cl was added. The mixture was allowed to warm to RT and stirred for 24 h. The solvent was removed in vacuo and the resulting white oil was dissolved in hot EtOAc and precipitated with hexane. L-allyl-glycine methylester (1.1 g, 8.51 mmol, 98%) was obtained as white crystals without further purification and reacted with o-nitrobenzenesulfonyl chloride (2.08 g, 9.37 mmol). For this it was dissolved in 15 mL anhydrous DCM, then TEA (1.40 mL, 17.03 mmol) was added and stirred for 5 h. The reaction mixture was diluted with DCM and washed with brine. The aqueous phases were reextracted with DCM. The organic phases were combined, dried over MgSO.sub.4, and the solvent was removed in vacuo. The product was purified using flash chromatography (gradient 0%-30% EtOAc in cyclo-hexene). 25 (1.22 g, 3.88 mmol, 46%) was obtained as a slightly yellow solid.

(182) TLC [EtOAc/cyclohexane, 1:1.5]: R.sub.f=0.40.

(183) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.3 min, purity (220 nm)=98%.

(184) HRMS (EI.sup.+): calculated [C.sub.12H.sub.14N.sub.2O.sub.6S+H].sup.+ 315.0651, found 315.0637 [M+H].sup.+.

Example 2-14

Preparation of (S)-Methyl 2-(N-allyl-2-nitrophenylsulfonamido) pent-4-enoate (26)

(185) ##STR00129##

(186) 26 was synthesized according to Varray et al. 25 (1.0 g, 3.18 mmol) was dissolved in 25 mL DMF. Then allylbromide (0.44 mL, 5.10 mmol) and potassium carbonate (2.40 g, 17.18 mmol) were added and stirred at RT for 10 h. The raw product mixture was diluted with H.sub.2O and then extracted with DCM. The organic solvent was removed in vacuo and the organic phase was dried over MgSO.sub.4. 26 (0.94 g, 2.64 mmol, 83%) was obtained without further purification as an orange oil.

(187) TLC [EtOAc/cyclohexane, 3:7]: R.sub.f=0.24.

(188) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.1 min, purity (220 nm)=95%.

(189) HRMS (EI.sup.+): calculated [C.sub.15H.sub.18N.sub.2O.sub.6S+H].sup.+ 355.0963, found 355.0936 [M+H].sup.+.

Example 2-15

Preparation of (S)-Methyl 1,2,3,6-tetrahydropyridine-2-carboxylate (27)

(190) ##STR00130##

(191) 27 was synthesized according to Varray et al. 26 (0.90 g, 2.54 mmol) was dissolved in 200 mL dry DCM, then Grubbs II catalyst (0.22 g, 0.25 mmol) was added. The reaction was stirred for 2.5 h, then 50 mL 15% H.sub.2O.sub.2 was added and stirred for 15 min. The aqueous phase was extracted with DCM and the organic phases were combined and dried over MgSO.sub.4. The raw product was subjected to flash chromatography (gradient 0%-40% EtOAc in cyclohexane) to give 26a (0.74 g, 2.27 mmol, 89%) as a dark brown oil.

(192) ##STR00131##

(193) 26a (0.64 g, 1.96 mmol) was dissolved in 1 mL dry CH.sub.3CN, then Cs.sub.2CO.sub.3 (1.0 g, 3.10 mmol) and Thiophenol (0.23 mL, 2.25 mmol) was added and stirred for 1.5 h. The suspension turned from light yellow into a strong yellow slurry. The reaction mixture was subsequently diluted with DCM and extracted with H.sub.2O. The aqueous Phase was reextracted with DCM. The organic phases were combined and dried over MgSO.sub.4. The crude product was concentrated and purified using flash chromatography (gradient 0%-10% MeOH in DCM) to give 27 (0.22 g, 1.59 mmol, 81%) as a dark brown oil.

(194) TLC [MeOH/DCM, 5:95]: R.sub.f=0.25, stained with KMnO.sub.4 stain

(195) HPLC: not UV active.

(196) HRMS (EI.sup.+): calculated [C.sub.7H.sub.11NO.sub.2+H].sup.+ 142.0868, found 142.0864 [M+H].sup.+.

Example 2-16

Preparation of (S)-Methyl-1-((S)-2-(3,4,5-trimethoxyphenyl)pent-4-enoyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (28)

(197) ##STR00132##

(198) 15 (0.14 g, 0.53 mmol), HATU (0.22 g, 0.58 mmol) and DIPEA (0.36 mL, 2.13 mmol) were dissolved in 2 mL dry DCM and stirred for 15 min. Then 27 (75 mg, 0.53 mmol) in 1 mL dry DCM was added and stirred for 14 h at RT. The crude product was diluted with DCM and washed with brine. The organic layer was dried over MgSO.sub.4, concentrated and the methyl ester was cleaved by dissolving in 1 mL 1:1 THF/H.sub.2O and addition of LiOH (10 mg, 0.42 mmol). The mixture was stirred for 14 h then was diluted with brine and extracted with DCM. The aqueous layer was acidified to pH=2 and again extracted with DCM. The organic phases were combined and dried over MgSO.sub.4. 28 (84 mg, 0.22 mmol, 79%) was obtained without further purification as a pale yellow oil. The diastereomeric rate was determined by HPLC.

(199) TLC [EtOAc/cyclohexane, 2:1]: R.sub.f=0.60.

(200) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.6 min, purity (220 nm)=95%, dr 95:5.

(201) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.45 (s, 2H), 5.81 (ddd, J=13.8, 6.9, 3.9 Hz, 1H), 5.76-5.66 (m, 1H), 5.62 (dd, J=6.7, 1.6 Hz, 1H), 5.56 (dd, J=10.2, 2.9 Hz, 1H), 5.09-4.97 (m, 2H), 4.12-4.03 (m, 1H), 3.83 (s, 6H), 3.81 (s, 3H), 3.79-3.72 (m, 2H), 3.63-3.51 (m, 1H), 2.85 (d, J=6.4 Hz, 1H), 2.70 (dd, J=17.4, 5.9 Hz, 1H), 2.43 (m, 2H).

(202) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 176.22, 172.77, 153.28, 136.85, 136.32, 133.90, 123.33, 122.98, 116.51, 105.05, 60.86, 56.11, 50.17, 49.37, 43.19, 39.33, 26.36.

(203) Mass: (ESI.sup.+), calculated 376.18 [C.sub.20H.sub.25NO.sub.6+H].sup.+, found 376.28 [M+H].sup.+.

(204) Coupling Reaction of Synthetic Building Blocks A and B or D and E

Example 3-A

General Synthesis Procedure A for (the Coupling of Morpholine Containing Top-Groups (Block B))

(205) The alkylated acid (20 mg, 75 μmol) was dissolved in 300 μL DCM or DMF, then DIPEA (41 μL, 0.24 mmol) and HATU (46 mg, 0.12 mmol) were added and stirred for 15 min. Subsequently, the different top groups (block B) with a free secondary amine (32 mg, 60 μmol) in 300 μL DCM were added and stirred for 14 h. The reaction mixture was concentrated and flash chromatographed or purified by preparative HPLC.

Example 3-B

General Synthesis Procedure B for the Coupling of Free Acid Top-Groups (Block B)

(206) The alkylated acid (57 mg, 0.21 mmol) and DIPEA (0.13 mL, 0.78 mmol) were dissolved in dry DCM (2 mL) at RT and stirred for 15 min. Then, HATU (110 mg, 0.29 mmol) was added and stirred for another 15 min. Subsequently, the different top groups (block B) with a free secondary amine (32 mg, 0.06 mmol) in 300 μL DCM was added and stirred for 14 h. The raw product was purified with flash chromatography and then the acid was liberated using 10% TFA in DCM at RT for 5 h. The reaction mixture was concentrated and flash chromatographed or purified by preparative HPLC.

Reference Example 3-1

Preparation of 2-(3-((R)-3-(3,4-Dimethoxyphenyl)-1-(((S)-1-((S)-2-(3,4,5-trimethoxyphenyl) pent-4-enoyl)piperidine-2-carbonyl)oxy)propyl) phenoxy)acetic acid (A01)

(207) ##STR00133##

(208) General synthesis procedure B for free acid ligands with 8a (0.10 g, 0.20 mmol) and 15 (57 mg, 0.21 mmol) was used. The crude product was purified using flash chromatography (gradient 0%-10% MeOH in DCM) to obtain A01 (38 mg, 54 μmol, 55%) as a colorless oil. The diastereomeric rate was determined by HPLC.

(209) TLC [EtOAc/cyclohexane, 1:1, 1% AcOH]: R.sub.f=0.28.

(210) HPLC [60-80% Solvent B, 20 min]: R.sub.t=8.1 min, purity (220 nm)=95%, dr 95:5.

(211) .sup.1H NMR (599 MHz, d6-DMSO) δ 7.20 (dd, J=7.8, 0.8 Hz, 1H), 6.85-6.71 (m, 4H), 6.67 (d, J=2.0 Hz, 1H), 6.59 (s, 2H), 6.56 (dd, J=8.2, 2.0 Hz, 1H), 5.76-5.64 (m, 1H), 5.48 (dd, J=8.7, 4.6 Hz, 1H), 5.22 (dd, J=5.9, 2.5 Hz, 1H), 5.03-4.92 (m, 2H), 4.65 (s, 2H), 3.71 (t, J=2.3 Hz, 3H), 3.69 (s, 3H), 3.68 (s, 4H), 3.64 (s, 3H), 3.61 (s, 1H), 3.51 (s, 3H), 2.75-2.64 (m, 2H), 2.44-2.37 (m, 2H), 2.34-2.25 (m, 2H), 2.15-2.06 (m, 2H), 1.84 (ddd, J=34.5, 8.0, 5.4 Hz, 2H), 1.63-1.52 (m, 2H), 1.05-0.95 (m, 2H).

(212) .sup.13C NMR (151 MHz, CDCl3) δ 176.94, 175.44, 175.30, 162.96, 157.84, 153.83, 152.17, 147.35, 141.80, 141.17, 140.09, 138.19, 134.63, 125.13, 123.41, 121.43, 117.28, 110.32, 80.06, 69.53, 64.83, 61.09, 60.78, 60.65, 60.51, 56.95, 52.14, 42.66, 35.80, 31.40, 29.98, 25.70.

(213) Mass: (ESI.sup.+), calculated 728.30 [C.sub.39H.sub.47NO.sub.11+Na].sup.+, found 728.40 [M+H].sup.+.

Example 3-2

Preparation of 2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-(((S)-1-((S)-2-(3,4,5-trimethoxyphenyl)pent-4-enoyl)pyrrolidine-2-carbonyl)oxy)propyl)phenoxy)acetic acid A02

(214) ##STR00134##

Example 3-3

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl1-((S)-2-(3,4,5-trimethoxyphenyl) pent-4-enoyl)piperidine-2-carboxylate A03

(215) ##STR00135##

(216) General synthesis procedure A for morpholine ligands with 8a (190 mg, 371 μmol) and 15 (99 mg, 371 μmol) was used. The crude product was purified using flash chromatography (gradient 0%-80% EtOAc in cylcohexane) to obtain A03 (163 mg, 4 μmol, 58%) as a white foam. The diastereomeric rate was determined by HPLC.

(217) TLC [98:1:1 EtOAc/MeOH/TEA]: R.sub.f=0.25.

(218) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.9 min, purity (220 nm)=99%, dr ≧99:1.

(219) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.17-7.13 (t, J=7.6, 1.0 Hz, 1H), 6.88-6.84 (m, 1H), 6.80-6.75 (m, 3H), 6.66-6.62 (m, 2H), 6.40-6.39 (s, 2H), 5.82-5.73 (m, 2H), 5.62-5.58 (dd, J=8.1, 5.5 Hz, 1H), 5.46-5.43 (m, 1H), 5.08-5.02 (dd, J=17.2, 1.7 Hz, 1H), 5.01-4.97 (m, 1H), 4.16-4.09 (s, 2H), 3.85-3.84 (d, J=1.4 Hz, 6H), 3.83-3.83 (s, 2H), 3.79-3.78 (s, 3H), 3.77-3.72 (m, 5H), 3.69-3.68 (s, 6H), 2.85-2.79 (m, 3H), 2.63-2.58 (m, 4H), 2.56-2.51 (m, 1H), 2.49-2.43 (m, 1H), 2.42-2.36 (m, 1H), 2.33-2.27 (d, J=13.3 Hz, 1H), 2.14-2.06 (m, 1H), 1.98-1.90 (m, 1H), 1.74-1.66 (m, 2H), 1.62-1.57 (d, J=12.7 Hz, 2H).

(220) .sup.13C NMR (150 MHz, CDCl.sub.3) δ 172.11, 170.67, 158.76, 153.37, 148.96, 147.47, 141.98, 136.86, 136.79, 134.78, 120.30, 118.71, 116.34, 114.30, 114.00, 111.85, 111.39, 105.08, 77.16, 76.09, 66.97, 65.76, 60.86, 57.78, 56.44, 56.12, 56.06, 55.97, 54.22, 52.21, 49.35, 43.54, 39.61, 38.36, 31.44.

(221) Mass: (ESI.sup.+), calculated 761.40 [C.sub.42H.sub.54N.sub.2O.sub.10S+H].sup.+, found 761.44 [M+H].sup.+.

Example 3-4

Preparation of (S)-1,7-di(pyridin-3-yl)heptan-4-yl 1-((S)-2-(3,4,5-trimethoxyphenyl)pent-4-enoyl)piperidine-2-carboxylate (A04)

(222) ##STR00136##

Example 3-5

Preparation of (S)-N-((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl)-1-((S)-2-(3,4,5-trimethoxyphenyl)pent-4-enoyl)piperidine-2-carboxamide (A05)

(223) ##STR00137##

Example 3-6

Preparation of 2-(3-((R)-3-(3,4-Dimethoxyphenyl)-1-(((S)-1-((S)-2-(3,4,5-trimethoxyphenyl) pent-4-enoyl)-1,2,3,6-tetrahydropyridine-2-carbonyl)oxy)propyl)phenoxy) acetic acid (A06)

(224) ##STR00138##

(225) 28 (20 mg, 53 μmol), DMAP (1.0 mg, 5.3 μmol) and DCC (7.0 mg, 59 μmol) were dissolved in 1 mL DCM at 0° C. and stirred for 15 min. Then 10a (23 mg, 59 μmol) in 500 μL DCM was added, and the mixture was allowed to warm to RT and stirred for 14 h. The crude product was concentrated and purified using flash chromatography (gradient 0%-8% MeOH in DCM). A06 (17 mg, 22.4 μmol, 42%) was obtained as a colorless oil. The diastereomeric rate was determined by HPLC.

(226) TLC [MeOH/DCM, 6:94]: R.sub.f=0.42.

(227) HPLC [0-100% Solvent B, 20 min]: R.sub.t=16.6 min, purity (220 nm)=98%, dr 95:5.

(228) .sup.1H NMR (400 MHz, d6-DMSO) δ 7.23 (ddd, J=10.0, 7.7, 3.1 Hz, 1H), 7.14-7.08 (m, 1H), 6.88-6.77 (m, 2H), 6.72-6.56 (m, 3H), 6.55 (s, 1H), 6.44 (d, J=7.7 Hz, 1H), 5.71-5.63 (m, 1H), 5.57 (d, J=2.8 Hz, 1H), 5.49-5.45 (m, 1H), 5.38 (dd, J=8.5, 5.1 Hz, 1H), 5.29 (dt, J=5.7, 2.6 Hz, 1H), 4.98 (dd, J=17.2, 2.1 Hz, 1H), 4.91 (dd, J=10.2, 2.2 Hz, 1H), 4.08-4.03 (m, 3H), 3.72-3.69 (m, 3H), 3.67-3.63 (m, 6H), 3.60 (s, 3H), 3.57 (s, 3H), 3.55 (s, 2H), 3.54 (s, 2H), 3.50-3.47 (m, 2H), 2.69 (dd, J=12.8, 6.1 Hz, 2H), 2.67-2.61 (m, 3H), 2.43 (t, J=5.0 Hz, 3H), 2.30 (dd, J=8.8, 7.0 Hz, 2H), 2.24 (t, J=7.4 Hz, 2H), 1.95 (d, J=6.5 Hz, 2H).

(229) .sup.13C NMR (101 MHz, d6-DMSO) δ 173.73, 172.42, 158.74, 153.18, 149.05, 147.40, 142.24, 136.62, 134.74, 133.73, 133.41, 130.14, 124.03, 122.95, 120.36, 118.25, 116.77, 114.02, 112.69, 112.22, 105.67, 75.54, 66.62, 65.79, 60.30, 57.54, 56.39, 56.30, 56.02, 55.92, 55.75, 54.07, 51.56, 49.97, 49.38, 48.03, 42.98, 33.65, 31.71, 27.03, 26.55, 24.84.

(230) Mass: (ESI.sup.+), calculated 759.39 [C.sub.43H.sub.54N.sub.2O.sub.10+H].sup.+, found 759.42 [M+H].sup.+.

Reference Example 3-7

Preparation of 2-(3-((R)-1-(((S)-1-((S)-3-cyclopropyl-2-(3,4,5-trimethoxyphenyl)propanoyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetic acid (A07)

(231) ##STR00139##

(232) General synthesis procedure B for free acid ligands with 8a (100 mg, 0.20 mmol) and 22 (55 mg, 0.20 mmol) 57.0 mg, 0.21 mmol) was used. The crude product was concentrated and purified using flash chromatography (gradient 0%-10% MeOH in DCM) to obtain A07 (38 mg, 54 μmol, 55%) as a colorless oil. The diastereomeric rate was determined by HPLC.

(233) TLC [MeOH/DCM, 6:94]: R.sub.f=0.27.

(234) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.3 min, purity (220 nm)=95%, dr=95:5.

(235) .sup.1H NMR (400 MHz, d6-DMSO) δ 7.22 (s, 1H), 7.12 (dd, J=15.6, 7.9 Hz, 1H), 6.85-6.69 (m, 3H), 6.63-6.55 (m, 2H), 6.51 (s, 1H), 5.50 (dd, J=8.2, 5.2 Hz, 1H), 5.25 (s, 1H), 4.64 (s, 2H), 3.71 (d, J=2.0 Hz, 2H), 3.68 (s, 3H), 3.67 (s, 3H), 3.60 (d, J=2.5 Hz, 1H), 3.56 (s, 6H), 3.53 (s, 3H), 2.68-2.60 (m, 1H), 2.52 (t, J=5.3 Hz, 2H), 2.45-2.40 (s, 2H), 2.38-2.33 (m, 2H), 2.14 (d, J=12.0 Hz, 1H), 1.94-1.84 (m, 2H), 1.64-1.57 (m, 4H), 0.63-0.56 (m, 1H), 0.36-0.28 (m, 2H), 0.07-−0.03 (m, 2H).

(236) .sup.13C NMR (101 MHz, d6-DMSO) δ 172.66, 170.73, 170.52, 158.01, 153.09, 149.14, 147.59, 142.39, 136.43, 135.93, 133.44, 129.79, 120.34, 113.88, 112.82, 112.64, 112.34, 109.94, 105.52, 75.34, 64.87, 60.20, 57.45, 56.30, 55.95, 55.88, 52.05, 47.92, 43.37, 30.92, 26.67, 21.10, 14.38, 9.71, 4.73.

(237) Mass: (ESI.sup.+), calculated 720.34 [C.sub.40H.sub.49NO.sub.11+H].sup.+, found 720.32 [M+H].sup.+.

Example 3-8

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-1-((S)-3-cyclopropyl-2-(3,4,5-trimethoxyphenyl)propanoyl)piperidine-2-carboxylate (A08)

(238) ##STR00140##

(239) General synthesis procedure A for morpholine ligands with 22 (8 mg, 29 μmol) and 10a (14 mg, 27 μmol) was used. Then was purified using flash chromatography (gradient 0%-10% MeOH in DCM) to obtain A08 (6 mg, 7.74 μmol, 29%) as a colorless oil. The diastereomeric rate was determined by HPLC.

(240) TLC [MeOH/DCM, 8:92]: R.sub.f=0.52.

(241) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.1 min, purity (220 nm)=95%, dr 95:5

(242) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.26-7.24 (m, 1H), 7.02-6.97 (m, 1H), 6.90-6.71 (m, 5H), 6.60 (s, 2H), 5.45-5.43 (m, 1H), 4.88-4.86 (m, 1H), 4.08-4.05 (m, 2H), 3.84-3.74 (m, 6H), 3.72-3.70 (m, 8H), 3.70-3.59 (m, 2H), 3.55-3.53 (m, J=4.7 Hz, 4H), 3.49-3.45 (m, 1H), 2.76-2.64 (m, 4H), 2.53-2.41 (m, 5H), 2.16-2.06 (m, 3H), 1.99-1.97 (m, J=7.2 Hz, 1H), 1.92-1.82 (m, 3H), 1.74-1.60 (m, 3H), 0.88-0.75 (m, 1H), 0.31-0.20 (m, 2H), 0.05-−0.06 (m, 2H).

(243) .sup.13C NMR (125 MHz, CDCl.sub.3) δ 175.62, 170.15, 159.63, 156.01, 150.39, 148.33, 143.58, 137.88, 135.20, 132.08, 129.28, 121.85, 119.20, 115.53, 114.12, 113.68, 113.06, 107.04, 77.03, 67.38, 66.80, 60.70, 58.74, 56.83, 54.73, 52.94, 48.18, 43.29, 36.38, 34.08, 33.96, 25.91, 25.47, 22.24, 9.61, 7.11.

(244) Mass: (ESI.sup.+), calculated 775.42 [C.sub.44H.sub.58N.sub.2O.sub.10+H].sup.+, found 775.48 [M+H].sup.+.

Example 3-9

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-1-((S)-3-cyclopropyl-2-(3,4,5-trimethoxyphenyl)propanoyl)pyrrolidine-2-carboxylate (A09)

(245) ##STR00141##

(246) General synthesis procedure A for morpholine ligands with 10c (40 mg, 80 μmol) and 22 (22 mg, 80 μmol) was used. Then was purified using preparative HPLC (gradient 55%-70% Solvent B in Solvent A, 20 min) to obtain A09 (17 mg, 7.7 μmol, 28%) as a colorless oil. The diastereomeric rate was determined by HPLC.

(247) TLC [MeOH/DCM, 8:92]: R.sub.f=0.44.

(248) HPLC [0-100% Solvent B, 20 min]: R.sub.t=16.3 min, purity (220 nm)=95%, dr 95:5

(249) .sup.1H NMR (400 MHz, d6-DMSO) δ 7.52 (d, J=7.7 Hz, 1H), 7.33-7.20 (m, 1H), 6.97-6.85 (m, 2H), 6.84-6.78 (m, 2H), 6.64-6.56 (m, 2H), 6.50 (s, 1H), 5.54 (ddd, J=37.2, 8.3, 4.8 Hz, 2H), 4.46 (dd, J=8.6, 3.4 Hz, 1H), 4.41-4.29 (m, 3H), 3.84-3.74 (m, 3H), 3.73-3.69 (m, 5H), 3.69-3.67 (m, 5H), 3.61-3.58 (m, 3H), 3.56-3.49 (m, 6H), 2.59 (s, 4H), 2.47 (p, J=1.8 Hz, 1H), 2.38-2.28 (m, 1H), 2.23-2.05 (m, 2H), 1.93-1.76 (m, 2H), 1.75-1.65 (m, 1H), 1.37-1.26 (m, 1H), 1.22 (dt, J=12.1, 6.8 Hz, 2H), 0.60 (s, 1H), 0.36-0.22 (m, 2H), 0.02 (qd, J=10.2, 4.6 Hz, 2H).

(250) .sup.13C NMR (101 MHz, d6-DMSO) δ 171.83, 171.50, 158.19, 153.15, 152.99, 149.04, 147.39, 142.69, 136.39, 135.86, 133.76, 133.68, 123.98, 120.49, 114.37, 112.75, 112.42, 105.67, 75.17, 63.75, 62.51, 60.23, 56.30, 55.99, 55.78, 52.16, 49.87, 46.13, 30.78, 29.12, 24.88, 21.14, 14.40, 9.61, 8.81, 4.85.

(251) Mass: (ESI.sup.+), calculated 761.40 [C.sub.43H.sub.56N.sub.2O.sub.10+H].sup.+, found 761.41 [M+H].sup.+.

Example 3-10

Preparation of 2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-(((S)-1-((S)-3-phenyl-2-(3,4,5-trimethoxyphenyl)propanoyl)piperidine-2-carbonyl)oxy)propyl) phenoxy)acetic acid (A10)

(252) ##STR00142##

(253) General synthesis procedure B for free acid ligands with 24 (68 mg, 0.21 mmol) and 8a (100 mg, 0.20 mmol) was used. Then was purified using reversed phase flash (Gradient 40%-70% MeOH in H.sub.2O+1% AcOH) to obtain A10 (49 mg, 0.13 mmol, 49%) as a slight yellow oil. The diastereomeric rate was determined by HPLC.

(254) TLC [MeOH/DCM, 8:92]: R.sub.f=0.20.

(255) HPLC [isochratic 60% B, 20 min]: R.sub.t=10.4 min, purity (220 nm)=98%, dr 95:5.

(256) .sup.1H NMR (599 MHz, d6-DMSO) δ 7.27-7.03 (m, 6H), 6.86-6.65 (m, 5H), 6.59 (s, 2H), 5.50 (dd, J=8.2, 5.1 Hz, 1H), 5.19 (dd, J=6.0, 2.5 Hz, 1H), 4.61 (s, 2H), 4.35 (dd, J=8.9, 6.0 Hz, 1H), 3.99 (d, J=13.2 Hz, 1H), 3.70 (s, 3H), 3.69 (s, 3H), 3.66 (s, 1H), 3.62 (s, 6H), 3.53 (d, J=0.7 Hz, 3H), 3.31-3.26 (m, 2H), 2.85 (dd, J=13.5, 5.9 Hz, 1H), 2.70 (td, J=13.4, 2.9 Hz, 1H), 2.43 (ddd, J=14.0, 9.0, 5.7 Hz, 1H), 2.33 (dt, J=14.0, 8.1 Hz, 1H), 2.08 (d, J=13.4 Hz, 1H), 1.88 (qd, J=8.5, 8.0, 5.4 Hz, 2H), 1.54-1.44 (m, 2H), 1.44-1.35 (m, 1H), 1.12-1.03 (m, 1H), 1.01-0.93 (m, 1H).

(257) .sup.13C NMR (151 MHz, d6-DMSO) δ 172.30, 170.60, 158.34, 153.05, 149.12, 147.61, 142.67, 140.25, 136.47, 135.16, 133.44, 130.00, 129.79, 129.59, 129.38, 129.37, 128.49, 128.26, 126.26, 120.50, 118.49, 113.89, 112.61, 112.53, 112.42, 105.76, 75.42, 65.12, 60.25, 56.09, 55.98, 55.86, 55.72, 52.13, 49.02, 43.34, 41.21, 38.10, 31.04, 26.52, 20.78.

(258) Mass: (ESI.sup.−), calculated 756.34 [C.sub.43H.sub.49NO.sub.11+H].sup.−, found 756.33 [M+H].sup.+.

Example 3-11

Preparation of 2-(3-((R)-1-(((S)-1-((S)-2-((S)-Cyclohex-2-en-1-yl)-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy) acetic acid (A11)

(259) ##STR00143##

(260) General synthesis procedure B for free acid ligands with 8a (50 mg, 0.20 mmol) and 17 (29.8 mg, 0.20 mmol) was used. Then was purified using flash chromatography (gradient 0%-4% MeOH in DCM) to obtain A11 (25 mg, 33.5 μmol, 67%, dr 85:15) as a slight yellow oil. The dr was determined by NMR.

(261) TLC [MeOH/DCM, 6:94]: R.sub.f=0.12.

(262) HPLC [0-100% Solvent B, 20 min]: R.sub.t=20.0 min, purity (220 nm)=98%.

(263) .sup.1H NMR (600 MHz, d6-DMSO) major diastereomer δ 7.08 (td, J=8.1, 1.7 Hz, 1H), 6.80 (dd, J=8.3, 1.1 Hz, 1H), 6.75 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 6.69-6.66 (m, 2H), 6.64 (d, J=11.4 Hz, 2H), 6.60-6.58 (m, 1H), 6.38-6.34 (m, 1H), 5.69-5.65 (m, 1H), 5.59 (dq, J=9.8, 3.6 Hz, 1H), 5.52 (dd, J=10.0, 2.4 Hz, 1H), 5.47-5.40 (m, 1H), 5.30-5.25 (m, 1H), 4.62 (d, J=1.3 Hz, 1H), 4.13 (d, J=13.4 Hz, 1H), 3.71 (d, J=0.8 Hz, 1H), 3.69 (s, 3H), 3.68 (s, 3H), 3.62-3.61 (m, 3H), 3.59 (s, 3H), 3.57 (s, 3H), 3.53 (d, J=0.7 Hz, 3H), 2.82-2.71 (m, 2H), 2.67-2.53 (m, 1H), 2.42-2.32 (m, 1H), 2.25 (ddt, J=24.0, 13.8, 8.2 Hz, 2H), 2.11 (d, J=12.9 Hz, 1H), 1.90 (s, 2H), 1.84-1.73 (m, 2H), 1.62-1.51 (m, 2H), 1.24-1.12 (m, 1H), 1.06 (dtd, J=22.1, 12.1, 3.1 Hz, 1H)

(264) .sup.13C NMR (151 MHz, d6-DMSO) major diastereomer δ 171.70, 170.42, 158.01, 152.87, 149.01, 147.50, 142.19, 136.44, 133.42, 129.78, 128.05, 120.17, 118.44, 113.74, 112.91, 112.46, 112.01, 106.25, 105.80, 75.23, 64.94, 60.03, 56.06, 56.05, 55.92, 55.76, 52.41, 51.92, 43.29, 38.91, 38.02, 30.80, 26.69, 25.42, 21.21.

(265) Mass: (ESI.sup.+), calculated 746.35 [C.sub.42H.sub.51NO.sub.11+H].sup.+, found 746.38 [M+H].sup.+.

Example 3-12

Preparation of (S)-(R)-3-(3,4-Dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-1-((S)-2-((S)-cyclohex-2-en-1-yl)-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate (A12)

(266) ##STR00144##

(267) General synthesis procedure A for morpholine ligands with 17 (10 mg, 33 μmol) and 10a (17 mg, 33 μmol) was used. The product was purified using flash chromatography (gradient 0%-6% MeOH in DCM). A12 (16 mg, 20 μmol, 75%, dr 85:15) was obtained as a colorless oil. The dr was determined by NMR.

(268) TLC [MeOH/DCM, 6:94]: R.sub.f=0.22.

(269) HPLC [50-60% Solvent B, 20 min]: R.sub.t=10.5 min, purity (220 nm)=98%.

(270) .sup.1H NMR (400 MHz, d6-DMSO) major diastereomer δ 7.08 (t, J=7.9 Hz, 1H), 6.93-6.87 (m, 1H), 6.83-6.76 (m, 2H), 6.72 (q, J=2.5, 2.0 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 6.62 (d, J=11.1 Hz, 2H), 6.36 (t, J=7.1 Hz, 1H), 5.69-5.63 (m, 1H), 5.55-5.49 (m, 1H), 5.47-5.38 (m, 1H), 5.26 (s, 1H), 4.06 (dd, J=14.6, 6.1 Hz, 2H), 3.72-3.70 (m, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 3.61 (t, J=1.5 Hz, 1H), 3.58 (s, 1H), 3.55 (s, 2H), 3.53 (s, 2H), 3.29-3.27 (m, 10H), 2.82-2.70 (m, 2H), 2.65-2.56 (m, 1H), 2.32-2.22 (m, 2H), 2.11 (d, J=13.2 Hz, 2H), 1.90 (s, 2H), 1.80 (dt, J=14.9, 6.8 Hz, 3H), 1.59 (d, J=13.8 Hz, 3H), 1.49-1.36 (m, 1H), 1.21 (d, J=3.6 Hz, 3H), 0.88-0.77 (m, 2H).

(271) .sup.13C NMR (101 MHz, d6-DMSO) major diastereomer δ 172.07, 170.39, 158.51, 153.10, 148.83, 147.53, 142.35, 136.56, 133.51, 130.70, 129.85, 128.16, 120.38, 118.26, 114.15, 112.85, 112.65, 112.33, 106.17, 75.31, 66.60, 65.63, 60.20, 60.11, 57.40, 56.45, 56.04, 55.93, 55.77, 54.00, 52.60, 52.01, 51.96, 43.13, 37.92, 30.92, 28.64, 28.01, 26.71, 25.32, 22.42, 21.21, 20.82.

(272) Mass: (ESI.sup.+), calculated 801.43 [C.sub.46H.sub.60N.sub.2O.sub.10+H].sup.+, found 801.42 [M+H].sup.+.

Example 3-13

Preparation of (S)-1,7-Di(pyridin-3-yl)heptan-4-yl-1-((S)-2-((S)-cyclohex-2-en-1-yl)-2-(3,4,5-trimethoxy phenyl) acetyl)piperidine-2-carboxylate (A13)

(273) ##STR00145##

(274) 17 (42 mg, 0.14 mmol) was dissolved in 500 μL DMF, then HATU (91 mg, 0.25 mmol) and DIPEA (86 μL, 0.50 mmol) were added and stirred for 30 min. Then 10d (48 mg, 0.14 mmol) in 500 μL DMF was added and stirred for 14 h. Subsequently, 3 mL H.sub.2O/MeOH 1:1 with 0.1% TFA was added and subjected to reversed phase flash chromatography (gradient 0%-45% MeOH in H.sub.2O+0.1% TFA). A13 (53 mg, 79 μmol, 63%, 85:15) was obtained as a yellow oil. The dr was determined by NMR.

(275) TLC [MeOH/DCM, 15:85]: R.sub.f=0.25.

(276) HPLC [0-100% Solvent B, 20 min]: R.sub.t=13.2 min, purity (220 nm)=95%.

(277) .sup.1H NMR (300 MHz, CDCl.sub.3) major diastereomer δ 8.69 (d, J=15.8 Hz, 4H), 8.23 (dd, J=24.2, 7.7 Hz, 2H), 7.81 (s, 2H), 6.51 (d, J=12.9 Hz, 2H), 5.83-5.68 (m, 1H), 5.65-5.48 (m, 1H), 5.30 (s, 1H), 4.84 (s, 1H), 3.85-3.82 (m, 1H), 3.81 (s, 3H), 3.78 (s, 6H), 3.63-3.43 (m, 1H), 2.95-2.84 (m, 2H), 2.80-2.67 (m, 4H), 2.21 (d, J=12.9 Hz, 2H), 1.99 (s, 3H), 1.76-1.34 (m, 14H), 1.12 (d, J=11.3 Hz, 1H).

(278) .sup.13C NMR (75 MHz, CDCl.sub.3) major diastereomer δ 172.71, 172.51, 171.03, 170.84, 152.77, 145.17, 144.97, 141.86, 141.49, 139.45, 136.89, 133.18, 130.02, 128.94, 126.52, 105.84, 72.97, 60.90, 56.13, 53.91, 52.42.

(279) Mass: (ESI.sup.+), calculated 670.39 [C.sub.40H.sub.51N.sub.3O.sub.6+H].sup.+, found 670.39 [M+H].sup.+.

Example 3-14

Preparation of (S)-2-(3,4-Dimethoxyphenoxy)ethyl-1-((S)-2-((R)-cyclohex-2-en-1-yl)-2-(3,4,5-trimethoxy phenyl)acetyl)piperidine-2-carboxylate (A14)

(280) ##STR00146##

(281) 17 (45 mg, 0.15 mmol) was dissolved in 700 μL dry DMF then N-ethyl-N-isopropylpropan-2-amine (102 μL, 0.60 mmol) and HATU (83 mg, 0.22 mmol) was added and stirred for 15 min. Then 10e (45 mg, 0.15 mmol) was dissolved in 600 μL DCM/DMF 1:1 and added to the reaction mixture. Then was stirred for 14 h at RT. The product was purified using flash chromatography (Gradient 0%-50% EtOAc in cyclohexane). A14 (12 mg, 20 μmol, 13%, dr 85:15) was obtained as a slight yellow oil. The dr was determined by NMR.

(282) ##STR00147##

(283) TLC [EtOAc/cyclohexane, 1:1]: R.sub.f=0.29.

(284) HPLC [60-80% Solvent B, 20 min]: R.sub.t=12.0 min, purity (220 nm)=95%.

(285) .sup.1H NMR (400 MHz, d6-DMSO) major diastereomer δ 6.81-6.77 (m, 1H), 6.67 (d, J=6.9 Hz, 1H), 6.59 (s, 2H), 6.46 (d, J=2.7 Hz, 1H), 5.68-5.63 (m, 1H), 5.55-5.52 (m, 1H), 5.15-5.12 (m, 1H), 4.44-4.39 (m, 1H), 4.16-4.10 (m, 2H), 4.02-3.95 (m, 2H), 3.82-3.76 (m, 1H), 3.69 (s, 3H), 3.67 (s, 6H), 3.66 (s, 3H), 3.62-3.60 (m, 3H), 3.59-3.52 (m, 1H), 2.73-2.66 (m, 2H), 2.09-2.01 (m, 1H), 1.98-1.86 (m, 3H), 1.84-1.73 (m, 2H), 1.70-1.52 (m, 3H), 1.32 (d, J=7.5 Hz, 2H).

(286) .sup.13C NMR (101 MHz, d6-DMSO) major diastereomer δ 172.25, 171.15, 153.21, 152.92, 150.00, 143.62, 136.44, 134.87, 133.53, 131.40, 128.24, 113.13, 106.42, 104.61, 101.36, 66.53, 63.39, 60.70, 56.48, 56.37, 56.19, 55.83, 52.76, 52.36, 43.22, 38.91, 26.91, 26.74, 26.58, 25.39, 21.13, 20.93.

(287) Mass: (ESI+), calculated 598.30 [C.sub.33H.sub.43NO.sub.9+H].sup.+, found 598.28 [M+H].sup.+.

Example 3-15

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-1-((S)-2-((R)-cyclohex-2-en-1-yl)-2-(3,4,5-trimethoxyphenyl)acetyl)pyrrolidine-2-carboxylate (A15)

(288) ##STR00148##

(289) General synthesis procedure A for morpholine ligands with 17 (30 mg, 98 μmol) and 10c (40 mg, 80 μmol). The product was purified using flash chromatography. A15 (44 mg, 20 μmol, 70%, dr 85:15) was obtained as colorless oil. The dr was determined by NMR.

(290) TLC [MeOH/DCM, 8:92]: R.sub.f=0.29.

(291) HPLC [0-100% Solvent B, 20 min]: R.sub.t=16.6 min, purity (220 nm)=98%.

(292) .sup.1H NMR (400 MHz, d6-DMSO) major diastereomer δ 7.24-7.14 (m, 1H), 6.94 (d, J=29.5 Hz, 1H), 6.88-6.78 (m, 2H), 6.70 (dd, J=6.1, 2.0 Hz, 1H), 6.68-6.63 (m, 1H), 6.63-6.59 (m, 1H), 6.57 (d, J=5.9 Hz, 2H), 5.72-5.64 (m, 1H), 5.58 (ddd, J=14.8, 10.1, 2.2 Hz, 1H), 5.41 (ddd, J=12.6, 8.2, 5.0 Hz, 1H), 5.09 (dd, J=10.2, 2.5 Hz, 1H), 4.47 (ddd, J=14.3, 8.6, 3.1 Hz, 1H), 4.22-4.13 (m, 1H), 3.73-3.71 (m, 1H), 3.70 (s, 2H), 3.68 (s, 3H), 3.64-3.61 (m, 3H), 3.55 (s, 3H), 3.54 (d, J=1.5 Hz, 4H), 3.32 (s, 9H), 3.23-3.19 (m, 1H), 2.89-2.74 (m, 2H), 2.75-2.61 (m, 2H), 2.46-2.24 (m, 2H), 2.25-2.13 (m, 2H), 1.97-1.86 (m, 2H), 1.80-1.67 (m, 3H), 1.67-1.54 (m, 1H), 1.53-1.29 (m, 3H), 1.27-1.14 (m, 1H).

(293) .sup.13C NMR (101 MHz, d6-DMSO) major diastereomer δ 171.90, 171.05, 159.55, 153.08, 149.26, 147.35, 142.64, 136.73, 133.54, 130.79, 129.87, 129.38, 128.68, 120.50, 114.23, 112.82, 112.32, 106.54, 106.04, 75.16, 67.84, 66.99, 60.86, 59.81, 58.96, 57.75, 56.19, 54.80, 53.88, 47.26, 32.66, 30.54, 29.34, 28.63, 25.48, 24.79, 21.81, 21.31.

(294) Mass: (ESI.sup.−), calculated 787.42 [C.sub.45H.sub.58N.sub.2O.sub.10+H].sup.−, found 787.35 [M+H].sup.+.

Example 3-16

Preparation of 2-(3-((R)-1-((S)-1-((S)-2-((R)-Cyclohex-2-en-1-yl)-2-(3,4,5-trimethoxyphenyl)acetyl)piper-idine-2-carboxamido)-3-(3,4-dimethoxyphenyl)propyl)phenoxy) acetic acid (A16)

(295) ##STR00149##

(296) General synthesis procedure B for free acid ligands with 8b (50 mg, 0.20 mmol) and 17 (30 mg, 0.20 mmol) was used. The product was purified using preparative TLC (MeOH/DCM 8:92) to obtain A16 (25 mg, 33.5 μmol, 67%, dr 85:15) as a slight yellow oil. The diastereomeric rate was determined by NMR.

(297) TLC [MeOH/DCM, 8:92]: R.sub.f=0.29.

(298) HPLC [0-100% Solvent B, 20 min]: R.sub.t=11.7 min, purity (220 nm)=98%.

(299) .sup.1H NMR (400 MHz, dmso) major diastereomer δ 7.10-7.05 (m, 1H), 6.92-6.86 (m, 1H), 6.81 (t, J=8.4 Hz, 1H), 6.72 (dq, J=11.8, 2.0 Hz, 2H), 6.69-6.64 (m, 1H), 6.63-6.57 (m, 1H), 6.56-6.51 (m, 2H), 5.70-5.61 (m, 1H), 5.53 (d, J=10.2 Hz, 1H), 5.12-5.04 (m, 1H), 4.79-4.66 (m, 2H), 4.66-4.53 (m, 3H), 3.73-3.69 (m, 2H), 3.69-3.66 (m, 6H), 3.62-3.60 (m, 1H), 3.55-3.51 (m, 9H), 2.93-2.81 (m, 2H), 2.79-2.67 (m, 2H), 2.40-2.27 (m, 2H), 2.16-2.02 (m, 2H), 1.96-1.84 (m, 2H), 1.84-1.73 (m, 3H), 1.56 (d, J=8.2 Hz, 2H), 1.31 (d, J=9.6 Hz, 1H).

(300) .sup.13C NMR (101 MHz, dmso) δ 172.44, 170.72, 170.56, 158.10, 152.97, 149.05, 147.45, 145.74, 136.42, 134.04, 133.70, 131.15, 129.51, 128.15, 120.46, 113.07, 112.76, 112.70, 112.19, 106.01, 64.77, 63.52, 60.15, 56.41, 55.97, 55.92, 55.78, 52.86, 52.23, 51.90, 43.24, 38.97, 38.62, 32.03, 27.78, 27.48, 26.54, 25.31, 21.12, 20.41.

(301) Mass: (ESI.sup.−), calculated 745.37 [C.sub.42H.sub.52N.sub.2O.sub.10+H].sup.+, found 745.40 [M−H].sup.+.

Example 3-17

Preparation of 2-(3-((R)-1-(((S)-1-((S)-2-Cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetic acid (A17)

(302) ##STR00150##

(303) General synthesis procedure B for free acid ligands with 8a (96 mg, 0.20 mmol) and 19 (58 mg, 0.20 mmol) was used. The crude product was purified using preparative TLC (EtOAc/cyclohexane 1:1.5+1% AcOH) to obtain 56 (17 mg, 33.5 μmol, 23%) as a colorless oil.

(304) TLC [EtOAc/cyclohexane 1:1]: R.sub.f=0.20.

(305) HPLC [0-100% Solvent B, 20 min]: R.sub.t=20.6 min, purity (220 nm)≧99%.

(306) .sup.1H NMR (599 MHz, d6-DMSO) δ 7.03 (t, J=7.9 Hz, 1H), 6.90-6.84 (m, 1H), 6.83-6.73 (m, 2H), 6.70-6.65 (m, 2H), 6.62 (s, 1H), 6.57 (dd, J=8.1, 2.0 Hz, 1H), 6.28 (d, J=7.6 Hz, 1H), 5.40 (dd, J=7.6, 6.0 Hz, 1H), 5.27 (dd, J=5.8, 2.4 Hz, 1H), 4.36 (s, 2H), 4.19 (d, J=13.4 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.60 (s, 1H), 3.58 (s, 6H), 3.51 (s, 3H), 3.48-3.43 (m, 1H), 2.67-2.60 (m, 1H), 2.37-2.29 (m, 2H), 2.22 (dt, J=13.9, 8.1 Hz, 1H), 2.14-2.06 (m, 2H), 1.99-1.91 (m, 2H), 1.78-1.69 (m, 2H), 1.63 (d, J=12.4 Hz, 1H), 1.54-1.41 (m, 2H), 1.35-1.28 (m, 1H), 1.19 (d, J=17.2 Hz, 2H), 1.15-1.02 (m, 2H), 0.96-0.85 (m, 2H), 0.80 (ddt, J=20.6, 12.1, 7.3 Hz, 2H).

(307) .sup.13C NMR (151 MHz, d6-DMSO) δ 172.48, 172.08, 170.61, 158.61, 152.66, 149.15, 147.47, 142.13, 136.20, 134.32, 133.43, 120.48, 118.07, 113.80, 113.07, 112.53, 112.13, 106.25, 75.16, 66.46, 60.33, 56.62, 55.90, 55.74, 53.12, 52.03, 43.53, 41.10, 37.94, 32.41, 31.32, 30.58, 29.98, 26.87, 26.32, 25.93, 25.38, 20.93.

(308) Mass: (ESI.sup.−), calculated 748.37 [C.sub.42H.sub.53NO.sub.11+H].sup.+, found 768.41[M+H].sup.+.

Example 3-18

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate (A18)

(309) ##STR00151##

(310) General synthesis procedure A for morpholine ligands with 19 (30 mg, 97 μmol) and 10a (50 mg, 97 μmol). The product was purified using flash chromatography (gradient 0%-15% MeOH in DCM). A18 (11 mg, 13.6 μmol, 14%) was obtained as a colorless oil.

(311) TLC [MeOH/DCM 6:94]: R.sub.f=0.44.

(312) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.7 min, purity (220 nm)=98%.

(313) .sup.1H NMR (400 MHz, d6-DMSO) δ 7.08 (t, J=7.9 Hz, 1H), 6.93-6.87 (m, 1H), 6.83-6.76 (m. 2H). 6.72 (a. J=2.5. 2.0 Hz. 1H). 6.68 (d. J=2.0 Hz. 1H). 6.62 (d. J=11.1 Hz, 2H), 6.36 (t, J=7.1 Hz, 1H), 5.47-5.38 (m, 1H), 5.26 (s, 1H), 4.06 (dd, J=14.6, 6.1 Hz, 2H), 3.72-3.70 (m, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 3.61 (t, J=1.5 Hz, 1H), 3.58 (s, 1H), 3.55 (s, 3H), 3.53 (s, 3H), 3.29-3.27 (m, 10H), 2.82-2.70 (m, 2H), 2.65-2.56 (m, 1H), 2.32-2.22 (m, 2H), 2.11 (d, J=13.2 Hz, 2H), 1.90 (s, 2H), 1.80 (dt, J=14.9, 6.8 Hz, 4H), 1.59 (d, J=13.8 Hz, 4H), 1.49-1.36 (m, 1H), 1.21 (d, J=3.6 Hz, 3H), 0.88-0.77 (m, 2H).

(314) .sup.13C NMR (151 MHz, d6-DMSO) δ 172.55, 170.94, 162.94, 153.03, 149.33, 147.72, 137.03, 133.56, 129.26, 120.19, 112.20, 75.37, 60.37, 56.68, 55.84, 55.30, 53.99, 51.62, 46.53, 43.54, 36.39, 32.08, 30.77, 27.00, 25.93, 25.39, 21.16, 17.17, 9.63.

(315) Mass: (ESI.sup.−), calculated 803.34 [C.sub.46H.sub.62N.sub.2O.sub.10+H].sup.+, found 803.38[M+H].sup.+.

Example 3-19

Preparation of (2S)-1,7-di(pyridin-3-yl)heptan-4-yl 1-(2-cyclohexyl-2-(3,4,5-trimethoxy phenyl)acetyl)piperidine-2-carboxylate A19

(316) ##STR00152##

(317) 19 (39 mg, 0.13 mmol) was dissolved in 500 μL DMF, then HATU (48 mg, 0.13 mmol) and DIPEA (86 μL, 0.50 mmol) were added and stirred for 30 min. Then 10d (48 mg, 0.125 mmol) in 500 μL DMF was added and stirred for 16 h. The raw product was purified by flash chromatography MeOH/EE 1:9. A19 (62 mg, 92 μmol, 73%, 85:15) was obtained as a white solid.

(318) TLC [MeOH/EE, 10:90+0.1% TEA]: R.sub.f=0.45.

(319) LCMS [0-100% Solvent B, 20 min]: R.sub.t=13.2 min, purity (220 nm)=95%.

(320) .sup.1H NMR (400 MHz, DMSO) δ 8.40-8.34 (m, 4H), 7.58-7.52 (m, 2H), 7.32-7.25 (m, 2H), 6.61-6.57 (s, 2H), 5.18-5.12 (d, J=5.3 Hz, 1H), 4.81-4.73 (m, 1H), 4.25-4.15 (d, J=14.1 Hz, 1H), 3.73-3.70 (s, 2H), 3.66-3.63 (s, 6H), 3.63-3.62 (s, 1H), 3.62-3.60 (s, 3H), 2.73-2.64 (m, 2H), 2.64-2.53 (m, 3H), 2.48-2.41 (m, 4H), 2.09-2.02 (m, 2H), 1.77-1.66 (m, 2H), 1.68-1.46 (m, 6H), 1.42-1.27 (m, 5H), 1.25-1.05 (m, 4H).

(321) .sup.13C NMR (100 MHz, DMSO) δ 172.06, 170.67, 152.47, 149.48, 147.13, 137.18, 135.64, 133.82, 123.40, 105.78, 73.21, 59.85, 55.63, 52.78, 51.64, 43.04, 40.70, 39.52, 32.81, 31.62, 31.51, 29.81, 26.34, 26.16, 25.62, 25.09, 20.61.

(322) Mass: (ESI.sup.+), calculated 672.40 [C.sub.40H.sub.53N.sub.3O.sub.6+H].sup.+, found 672.44 [M+H].sup.+.

Example 3-20

Preparation of (S)-2-(3,4-dimethoxyphenoxy)ethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxy phenyl)acetyl)piperidine-2-carboxylate A20

(323) ##STR00153##

(324) 19 (37 mg, 0.12 mmol) was dissolved in 500 μL dry DMF then N-ethyl-N-isopropylpropan-2-amine (82 μL, 0.48 mmol) and HATU (46 mg, 0.12 mmol) was added and stirred for 15 min. Then 10e (37 mg, 0.12 mmol) was dissolved in 500 μL DCM/DMF 1:1 and added to the reaction mixture. Then was stirred for 14 h at RT. The product was purified using flash chromatography (Gradient 0%-50% EtOAc in cyclohexane). A20 (9 mg, 15 μmol, 17%) was obtained as a slight yellow oil.

(325) TLC [EtOAc/cyclohexane, 1:1.5]: R.sub.f=0.26.

(326) HPLC [0-100% Solvent B, 20 min]: R.sub.t=21.0 min, purity (220 nm)=95%.

(327) .sup.1H NMR (400 MHz, d6-DMSO) δ 6.83-6.79 (d, J=8.8 Hz, 1H), 6.59-6.57 (s, 2H), 6.50-6.48 (d, J=2.8 Hz, 1H), 6.34-6.30 (dd, J=8.7, 2.8 Hz, 1H), 5.17-5.14 (m, 1H), 4.19-4.12 (m, 2H), 4.04-3.96 (m, 2H), 3.87-3.79 (m, 1H), 3.71-3.71 (s, 3H), 3.69-3.69 (s, 6H), 3.68-3.68 (s, 3H), 3.63-3.63 (s, 3H), 3.55-3.47 (m, 1H), 2.85-2.76 (m, 2H), 2.09-1.99 (m, 2H), 1.98-1.87 (q, J=10.9 Hz, 2H), 1.77-1.69 (d, J=10.2 Hz, 1H), 1.64-1.53 (m, 4H), 1.25-1.04 (m, 5H), 0.97-0.86 (m, 1H), 0.84-0.74 (m, 1H).

(328) .sup.13C NMR (101 MHz, d6-DMSO) δ 172.17, 170.74, 152.55, 152.42, 149.66, 143.35, 136.02, 133.60, 112.72, 105.88, 104.33, 100.94, 65.96, 62.75, 59.89, 56.07, 55.73, 55.40, 53.04, 51.84, 39.52, 31.89, 29.81, 26.54, 26.34, 26.12, 25.65, 25.04, 24.21, 20.53.

(329) Mass: (ESI+), calculated 600.32 [C.sub.33H.sub.46NO.sub.9+H].sup.+, found 600.25 [M+H].sup.+.

Example 3-21

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)pyrrol-idine-2-carboxylate A21

(330) ##STR00154##

(331) General synthesis procedure A was used with 19 (100 mg, 100 μmol) and 10c (50 mg, 100 μmol). The crude product was purified using flash chromatography. A21 (50 mg, 20 μmol, 63%) was obtained as colorless oil.

(332) TLC [MeOH/DCM, 8:92]: R.sub.f=0.35.

(333) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.0 min, purity (220 nm)=97%.

(334) .sup.1H NMR (600 MHz, CDCl.sub.3) Rotamers are present. Major rotamer: δ 7.17-7.13 (m, 1H), 7.04 (dd, J=7.7, 0.9 Hz, 0H), 7.00 (t, J=2.0 Hz, 1H), 6.87 (dd, J=8.4, 2.6 Hz, 0H), 6.79 (d, J=8.3 Hz, 0H), 6.77 (s, 1H), 6.70-6.67 (m, 0H), 6.47 (s, 1H), 5.52 (dd, J=7.8, 5.6 Hz, 1H), 4.63 (dd, J=8.6, 2.6 Hz, 1H), 4.19-4.05 (m, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.82 (d, J=0.9 Hz, 1H), 3.77 (s, 3H), 3.76-3.74 (m, 2H), 3.72-3.69 (m, 2H), 3.66 (s, 6H), 3.63-3.58 (m, 1H), 3.56-3.52 (m, 1H), 2.89 (bs, 1H), 2.67 (bs, 2H), 2.57 (bs, 2H), 2.48-2.29 (m, 3H), 2.19-2.10 (m, 2H), 2.09-1.97 (m, 2H), 1.96-1.86 (m, 2H), 1.74-1.60 (m, 2H), 1.53-1.48 (m, 1H), 1.46-1.41 (m, 1H), 1.40-1.36 (m, 3H), 1.33-1.28 (m, 3H), 1.16-1.10 (m, 2H), 0.95-0.86 (m, 2H), 0.80-0.72 (m, 1H).

(335) .sup.13C NMR (151 MHz, CDCl.sub.3) Rotamers are present. Major rotamer: δ 171.74, 171.59, 159.16, 153.09, 148.94, 147.36, 141.74, 136.98, 133.73, 133.43, 129.55, 120.47, 119.51, 114.14, 113.81, 112.07, 111.83, 111.50, 111.40, 106.09, 77.16, 75.88, 66.92, 65.74, 60.98, 59.12, 57.84, 57.42, 56.34, 56.14, 56.10, 56.06, 56.02, 54.20, 47.68, 47.01, 41.37, 38.76, 38.23, 37.53, 32.83, 32.39, 31.68, 31.62, 31.08, 30.77, 29.97, 29.32, 26.67, 26.34, 24.81, 22.59, 21.19.

(336) Mass: (ESI.sup.−), calculated 789.43 [C.sub.45H.sub.58N.sub.2O.sub.10+H].sup.−, found 789.40 [M+H].sup.+.

Example 3-22

Preparation of 2-(3-((R)-1-((S)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamido)-3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetic acid A22

(337) ##STR00155##

(338) General synthesis procedure B for free acid ligands with 8b (50 mg, 0.20 mmol) and 19 (30 mg, 0.20 mmol) was used. The product was purified using preparative HPLC (Gradient: 65-75% B in 20 min) to obtain A22 (15 mg, 20 μmol, 24%) as an colourless oil.

(339) TLC [MeOH/DCM, 8:92]: R.sub.f=0.29.

(340) HPLC [0-100% Solvent B, 20 min]: R.sub.t=11.7 min, purity (220 nm)=99%.

(341) .sup.1H NMR (400 MHz, dmso, major rotamer) δ 7.13-7.08 (m, 1H), 6.95-6.90 (m, 1H), 6.84 (t, J=8.4 Hz, 1H), 6.75 (dq, J=11.8, 2.0 Hz, 2H), 6.72-6.67 (m, 1H), 6.66-6.60 (m, 1H), 6.59-6.54 (m, 2H), 5.15-5.07 (m, 1H), 4.82-4.69 (m, 1H), 4.69-4.56 (m, 3H), 3.76-3.72 (m, 1H), 3.72-3.69 (m, 6H), 3.65-3.64 (m, 1H), 3.58-3.54 (m, 9H), 2.96-2.84 (m, 2H), 2.82-2.70 (m, 2H), 2.43-2.30 (m, 2H), 2.19-2.05 (m, 2H), 1.99-1.87 (m, 2H), 1.88-1.76 (m, 3H), 1.59 (d, J=8.2 Hz, 2H), 1.34 (d, J=9.6 Hz, 1H), 1.16-1.10 (m, 2H), 0.95-0.86 (m, 2H).

(342) .sup.13C NMR (101 MHz, dmso) δ 171.99, 170.28, 170.12, 157.65, 152.52, 148.61, 147.00, 145.30, 135.97, 133.59, 130.71, 127.70, 120.01, 112.62, 112.31, 112.26, 111.74, 105.56, 64.33, 63.08, 59.70, 55.96, 55.52, 55.48, 55.34, 52.42, 51.79, 51.45, 42.79, 39.52, 38.52, 38.17, 31.59, 27.34, 27.03, 26.09, 24.87, 20.68, 19.97.

(343) Mass: (ESI.sup.−), calculated 745.37 [C.sub.42H.sub.52N.sub.2O.sub.10+H].sup.+, found 745.40 [M−H].sup.+.

Ligand Synthesis by Solid Phase Coupling Reaction

Example 3-C

General Synthetic Procedure C for Solid Phase Coupling Reaction

(344) ##STR00156##

(345) The resin was prepared according to Gopalakrishnan et al, (Exploration of Pipecolate Sulfonamides as Binders of the FK506-Binding Proteins 51 and 52, 2012, 55, 4123-4131). To the resin was added a solution of Fmoc-Chg-OH (760 μmol, 3 eq.), HATU (290 mg, 760 μmol, 3 eq.), HOAt (104 mg, 760 μmol, 4.8 eq.) and DIEA (260 μL, 1.5 mmol, 6 eq.) in 1 mL DMF/NMP. The reaction mixture was stirred for 3 h. The resin was washed with DMF (3×7 mL), THF (3×7 mL), DCM (3×7 mL), Et.sub.2O (3×7 mL). A solution of benzoic acid derivative (760 μmol, 3 eq.), HATU (290 mg, 760 μmol, 3 eq.), HOAt (104 mg, 760 μmol, 4.8 eq.) and DIEA (260 μL, 1.5 mmol, 6 eq.) in 1 mL DMF/NMP was added to the resin. The reaction mixture was stirred for 2 h followed by washing with NMP, DMF, THF, DCM and Et.sub.2O each 3×1 mL. The resin was dried overnight in vacuo. The final compounds were cleaved from the resin using 1.5 mL TFA/DCM 1:99. Purification was performed by preparative HPLC.

Example 3-23

Preparation of 2-(3-(1-(((2S)-1-(2-benzamido-2-cyclohexylacetyl) piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetic acid A23

(346) ##STR00157##

(347) General procedure C for solid phase organic synthesis was used. A23 (2.9 mg, 4.2 μmol).

(348) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.7 min.

(349) Mass: (ESI.sup.−), calculated 701.34 [C40H48N2O9+H].sup.−, found 701.38 [M+H].sup.+.

Example 3-24

Preparation of 2-(3-(1-(((2S)-1-(2-cyclohexyl-2-(2-hydroxy benzamido)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl) propyl)phenoxy)acetic acid A24

(350) ##STR00158##

(351) General procedure C for solid phase organic synthesis was used. A24 (1.7 mg, 2.3 μmol).

(352) HPLC [0-100% Solvent B, 20 min]: R.sub.t=20.6 min.

(353) Mass: (ESI.sup.−), calculated 717.34 [C40H48N2O10+H].sup.−, found 717.50 [M+H].sup.+.

Example 3-25

Preparation of 2-(3-(1-(((2S)-1-(2-cyclohexyl-2-(picolinamido) acetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy) acetic acid A25

(354) ##STR00159##

(355) General procedure C for solid phase organic synthesis was used. A25 (3.2 mg, 4.6 μmol).

(356) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.7 min.

(357) Mass: (ESI.sup.−), calculated 702.34 [C39H47N3O9+H].sup.−, found 702.50 [M+H].sup.+.

Example 3-26

Preparation of 2-(3-(1-(((2S)-1-(2-(cyclohexanecarboxamido)-2-cyclohexylacetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetic acid A26

(358) ##STR00160##

(359) General procedure C for solid phase organic synthesis was used. A26 (2.8 mg, 3.9 μmol).

(360) HPLC [0-100% Solvent B, 20 min]: R.sub.t=20.6 min.

(361) Mass: (ESI.sup.−), calculated 707.39 [C40H54N2O9+H].sup.−, found 707.46 [M+H].sup.+.

Example 3-27

Preparation of 2-(3-(1-(((2S)-1-(2-cyclohexyl-2-(3H-1,2,4-triazole-3-carboxamido)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl) propyl)phenoxy)acetic acid A27

(362) ##STR00161##

(363) General procedure C for solid phase organic synthesis was used. A27 (2.7 mg, 3.8 μmol).

(364) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.2 min.

(365) Mass: (ESI.sup.−), calculated 692.33 [C40H54N2O9+H].sup.−, found 692.35 [M+H].sup.+.

Example 3-28

Preparation of 2-(3-(1-(((2S)-1-(2-cyclohexyl-2-(3,5-dichloro benzamido)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl) propyl)phenoxy)acetic acid A28

(366) ##STR00162##

(367) General procedure C for solid phase organic synthesis was used. A28 (0.6 mg, 0.7 μmol).

(368) HPLC [0-100% Solvent B, 20 min]: R.sub.t=21.5 min.

(369) Mass: (ESI.sup.−), calculated 769.26 [C40H54N2O9+H].sup.−, found 769.21 [M+H].sup.+.

Example 3-D

General Synthetic Procedure for Aldol Products

(370) ##STR00163##

(371) ##STR00164##

(372) ##STR00165##

(373) ##STR00166##

Example 3-29

Preparation of (S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)-2-cyclohexylethanone 29

(374) To a solution of (S)-4-benzylthiazolidine-2-thione (1 g, 4.78 mmol) in THF (dry, 50 mL) was added n-BuLi (2.87 mL, 7.17 mmol, 2.5 M) at −78° C. The resulting mixture was stirred at that temperature for 1.5 h, then 2-cyclohexylacetyl chloride (1.10 ml, 7.17 mmol) was added. The temperature was maintained at −78° C. for 2.5 h. Then the reaction mixture was allowed to warm to RT and stirred for 16 h. After an aqueous work up with saturated NH4Cl solution the crude product was purified by flash chromatography (cyclohexane) to afford 29 as a yellow crystalline solid (1.48 g, 4.45 mmol, 93%).

(375) TLC [cyclohexane/EE, 8:2]: Rf=0.6

(376) Mass (ESI+), calculated 333.12 [C18H23NOS2+H].sup.+, found=334.04 [M+H].sup.+.

Example 3-30

Preparation of (2S,3R)-1-((S)-4-benzyl-2-thioxothiazolidin-3-yl)-2-cyclohexyl-3-hydroxybutan-1-one 30a

(377) 29 (200 mg, 0,600 mmol) in DCM (dry, 2 mL) was cooled to 0° C. Then TiCl4 (660 μl, 0.660 mmol, 1 M) was added drop wise. After 5 min TMEDA (226 μl, 1.50 mmol) was added and the resulting dark red enolate was stirred for 20 min at 0° C. the. Acetaldehyde (0.10 mL, 1.80 mmol) was then added drop wise and it was stirred for 4 h at 0° C.

(378) After an aqueous work up with half-saturated NH4Cl solution the crude product was purified by flash chromatography (0-100% DCM in cyclohexane) to afford 30a as yellow oil (116.6 mg, 0.31 mmol, 52%).

(379) TLC [DCM]: Rf=0.19

(380) Mass (ESI+), calculated 378.57 [C20H27NO2S2+H].sup.+, found=377.88 [M+H].sup.+.

Example 3-31

Preparation of (2S,3R,E)-1-((S)-4-benzyl-2-thioxothiazolidin-3-yl)-2-cyclohexyl-3-hydroxyhex-4-en-1-one 30b

(381) 30b was synthesized according to 30a with (E)-but-2-enal (0.15 mL, 1.80 mmol) to afford 30b as yellow solid (171.3 mg, 0.43 mmol, 71%).

(382) TLC [DCM]: Rf=0.39

(383) Mass (ESI+), calculated 404.17 [C22H29NO2S2+H].sup.+, found=404.01 [M+H].sup.+.

Example 3-32

Preparation of (2S,3R)-1-((S)-4-benzyl-2-thioxothiazolidin-3-yl)-2-cyclohexyl-3-hydroxy-5-methylhexan-1-one 30c

(384) 30c was synthesized according to 30a with 3-methylbutanal (0.19 mL, 1.80 mmol) to afford 30c as yellow solid (172 mg, 0.41 mmol, 68.3%).

(385) TLC [DCM]: Rf=0.52

(386) Mass (ESI+), calculated 420.20 [C23H33NO2S2+H].sup.+, found=420.04 [M+H].sup.+.

Example 3-33

Preparation of (2S,3R)-2-cyclohexyl-3-hydroxybutanoic acid 31a

(387) 30a (115 mg, 0.305 mmol) was dissolved in THF/H2O (8:5, 6.5 mL). Then LiOH (32.8 mg, 1.37 mmol) and H2O2 (0.15 mL, 1.47 mmol, 30% Wt) were added and it was stirred at RT for 2 h. The reaction mixture was quenched with NaaSO3 solution (1.5 M) and it was extracted with DCM, whereby the organic layer was discarded. The aqueous layer was acidified and the product was extracted several times with DCM. The combined organics were dried over anhydrous MgSO4 filtrated and concentrated to afford 31a (23.5 mg, 0.15 mmol. 50%) as colourless oil.

Example 3-34

Preparation of (2S,3R,E)-2-cyclohexyl-3-hydroxyhex-4-enoic acid 31b

(388) 31b was synthesized according to 31a with 30b (120 mg, 0.297 mmol), LiOH (32.0 mg, 1.34 mmol) and H2O2 (76 μL, 0.74 mmol, 30% Wt) to afford 31b as colourless oil (50 mg, 0.23 mmol, 79%).

(389) TLC [cyclohexane/EE, 1:1]: Rf=0.26

Example 3-35

Preparation of (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-cyclohexylbutanoic acid 32a

(390) 31a (23 mg, 0.123 mmol) was dissolved in DCM (dry, 1 mL) and 2,6-Lutidine (71.9 μl, 0.617 mmol) was added. It was cooled to −78° C. and TBSOTf (85 μl, 0.370 mmol) was added dropwise. The reaction mixture was stirred for 2 h and then quenched with sat. NaHCO3 solution. The layers were separated and it was extracted with Et2O. The solvent was removed, after drying over MgSO4 and filtration. Then the residue was dissolved in MeOH/THF (1 mL, 1:1). A solution of K2CO3 (37.5 mg, 0.272 mmol) in H2O (0.5 mL) was added and it was stirred at RT for 1 h.

(391) The organic layer was evaporated and the aqueous layer, when pH >7, was extracted with DCM, whereby the organic layer was discarded. Then the aqueous layer was acidified and the product was extracted several times with DCM. The combined organics were dried over anhydrous MgSO4 filtrated and concentrated to afford 32a (14 mg, 0.05 mmol, 38%) as colourless oil.

(392) TLC [cyclohexane/EE, 4:6]: Rf=0.20

Example 3-36

Preparation of (2S,3R,E)-3-((tert-butyldimethylsilyl)oxy)-2-cyclohexylhex-4-enoic acid 32b

(393) 32b was synthesized according to 32a with 31b (50 mg, 0.236 mmol), TBSOTf (162 μl, 0.707 mmol) and 2,6-Lutidine (137 μl, 1.178 mmol) in DCM (dry, 2 mL) and K2CO3 (71.6 mg, 0.518 mmol) in H2O (0.4 mL) to afford 32b as colourless oil (22 mg, 0.068 mmol, 29%).

(394) TLC [cyclohexane/EE, 1:1]: Rf=0.65

Example 3-37

Preparation of (2S,3R)-2-cyclohexyl-3-(methoxymethoxy)-5-methylhexanoic acid 33c

(395) 30b (170 mg, 0.407 mmol) and DIPEA (213 μl, 1.221 mmol) were dissolved in DCM (dry, 0.5 mL) and cooled to 0° C. Then MOM-Cl (155 μl, 2.035 mmol) was added and it was stirred at RT for 2.5 h. The reaction mixture was diluted with DCM and washed with half-saturated NH4Cl solution and half-saturated NaHCO3 solution I. The organic layer was dried over MgSO4, filtrated and the solvent was removed under vacuum. Then the residue was dissolved in THF/H2O (8:5, 1.3 mL) followed by the addition of LiOH (43.9 mg, 1.832 mmol) and H2O2 (104 μl, 1.018 mmol, 30% Wt). The reaction mixture was stirred at RT for 2 h and then quenched with Na2SO3 solution (1.5 M) and it was extracted with DCM, whereby the organic layer was discarded. The aqueous layer was acidified and the product was extracted several times with DCM. The combined organics were dried over anhydrous MgSO4 filtrated and concentrated to afford 33c (46 mg, 0.167 mmol. 41%) as colourless oil.

(396) TLC [cyclohexane/EE, 1:1]: Rf=0.45

Example 3-38

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-cyclohexylbutanoyl)piperidine-2-carboxylate 34a

(397) 10a (39.2 mg, 0.077 mmol), 32a (23 mg, 0.077 mmol), PyBrop (53.5 mg, 0.115 mmol) and DIPEA (40.1 μl, 0.23 mmol) were stirred in DCM (dry, 1 mL) at RT for 16 h. The crude product was directly loaded on silica and purified by flash chromatography (0-100% EE+2% MeOH+0.1% TEA in cyclohexane) to afford 34a as a light yellow oil (28.9 mg, 0.037 mmol, 47.5%).

(398) TLC [EE+2% MeOH+1% TEA]: Rf=0.42

(399) Mass (ESI+), calculated 795.50 [C45H70N2O8Si+H].sup.+, found 795.68=[M+H].sup.+.

Example 3-39

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R,E)-3-((tert-butyldimethylsilyl)oxy)-2-cyclohexylhex-4-enoyl)piperidine-2-carboxylate 34b

(400) 34b was synthesized according to 34a with 32b (20 mg, 0.061 mmol), 10a (34.5 mg, 0.067 mmol), PyBrop (42.8 mg, 0.092 mmol) and DIPEA (32.1 μl, 0.184 mmol) in DCM (dry, 1 mL) to afford 34b as colourless oil (33.6 mg, 0.041 mmol, 66.8%).

(401) TLC [EE+2% MeOH+1% TEA]: Rf=0.59

(402) Mass: (ESI+), calculated 821.51 [C47H72N2O8Si+H].sup.+, found 821.59=[M+H].sup.+.

Example 3-40

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R)-2-cyclohexyl-3-hydroxybutanoyl)piperidine-2-carboxylate A29

(403) ##STR00167##

(404) 34a (28 mg, 0.035 mmol) was stirred in EtOH (0.94 mL) and concentrated HCl (60 μL) at RT for 20 h. The crude product was directly loaded on silica and purified by flash chromatography (EE+2% MeOH+0.1% TEA) to afford A29 as a colourless oil (28.9 mg, 0.037 mmol, 47.5%).

(405) TLC [EE+5% MeOH+1% TEA]: Rf=0.27

(406) Mass: (ESI+), calculated 681.41 [C39H56N2O8+H].sup.+, found=681.87 [M+H].sup.+.

Example 3-41

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R,E)-2-cyclohexyl-3-hydroxyhex-4-enoyl)piperidine-2-carboxylate A30

(407) ##STR00168##

(408) A30 was synthesized according to A29 with 34b (33 mg, 0.040 mmol) to afford A30 as colourless oil (3.88 mg, 5.36 μmol, 13.4%).

(409) LCMS (0-100% Solvent B, 20 min): Rt=9.5 min

(410) Mass: (ESI+), calculated 723.46 [C41H58N2O8+H].sup.+, found=707.42 [M+H].sup.+.

Example 3-42

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R)-2-cyclohexyl-3-(methoxymethoxy)-5-methylhexanoyl)piperidine-2-carboxylate A31

(411) ##STR00169##

(412) A31 was synthesized according to 34a with 33c (30 mg, 0.110 mmol), 10a (62.1 mg, 0.121 mmol), PyBrop (77 mg, 0.165 mmol) and DIPEA (57.7 μl, 0.330 mmol) in DCM (dry, 3 mL) to afford A31 as colourless oil (19 mg, 0.025 mmol, 22.6%).

(413) TLC [EE+2% MeOH+1% TEA]: Rf=0.37

(414) Mass: (ESI.sup.+), calculated 767.48 [C44H66N2O9+H].sup.+, found 767.58=[M+H].sup.+.

Example 3-43

Preparation of (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((2S,3R)-2-cyclohexyl-3-hydroxy-5-methylhexanoyl)piperidine-2-carboxylate A32

(415) ##STR00170##

(416) A32 was synthesized according to A29 with A31 (19 mg, 0.025 mmol) in 44 h to afford A32 as light yellow oil (11.2 mg, 0.016 mmol, 62.6%).

(417) TLC [EE+5% MeOH+1% TEA]: Rf=0.59

(418) Mass: (ESI.sup.+), calculated 707.43 [C42H62N2O8+H]*, found=723.50 [M+H].sup.+.

Reference Example 3-44

Preparation of (S)-(R)-3-(3,4-Dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-1-((S)-2-(3,4,5-trimethoxyphenyl)pent-4-enoyl)pyrrolidine-2-carboxylate (A33)

(419) ##STR00171##

(420) General synthesis procedure A for morpholine ligands with 10c (31 mg, 62 μmol) and 15 (17 mg, 62 μmol) was used. Then the crude product was purified using flash chromatography (gradient 0%-10% MeOH in DCM) to obtain A33 (31 mg, 44 μmol, 67%) as a light yellow oil. The diastereomeric rate was determined by HPLC.

(421) TLC [MeOH/DCM, 3:97, 1% TEA]: R.sub.f=0.24.

(422) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.8 min, purity (220 nm)=95%, dr 95:5.

(423) .sup.1H NMR (400 MHz, d6-DMSO) δ 7.17 (t, J=7.9 Hz, 1H), 6.86 (t, J=1.9 Hz, 1H), 6.82-6.77 (m, 2H), 6.73-6.68 (m, 2H), 6.64-6.57 (m, 1H), 6.49 (s, 2H), 5.77-5.62 (m, 1H), 5.48 (dd, J=8.3, 5.0 Hz, 1H), 5.05-4.87 (m, 3H), 4.45 (dd, J=8.7, 3.4 Hz, 1H), 4.17-4.02 (m, 3H), 3.77 (dd, J=8.5, 6.0 Hz, 1H), 3.74-3.62 (m, 6H), 3.59-3.46 (m, 9H), 3.28-3.18 (m, 4H), 2.68-2.57 (m, 4H), 2.52-2.37 (m, 5H), 2.31-2.11 (m, 5H), 1.83-1.73 (m, 2H).

(424) .sup.13C NMR (100 MHz, d6-DMSO) δ 171.88, 170.71, 158.80, 153.15, 149.10, 147.33, 142.50, 137.04, 136.45, 135.00, 133.82, 129.55, 120.44, 118.37, 116.77, 114.28, 112.73, 112.34, 112.06, 105.68, 75.33, 66.60, 65.65, 60.08, 59.00, 57.39, 55.95, 54.07, 49.32, 46.83, 38.96, 38.10, 30.91, 29.17, 24.83.

(425) Mass: (ESI+), calculated 747.39 [C.sub.42H.sub.54N.sub.2O.sub.10+H].sup.+, found 747.51 [M+H].sup.+.

Reference Example 3-45

Preparation of (R)-(R)-3-(3,4-Dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl-4-((S)-2-(3,4,5-trimethoxyphenyl)pent-4-enoyl)thiomorpholine-3-carboxylate (A34)

(426) ##STR00172##

(427) General synthesis procedure A for morpholine ligands with 10b (32 mg, 60 μmol) and 15 (20 mg, 75 μmol) was used. The crude product was purified using flash chromatography (gradient 0%-80% EtOAc in cylcohexane) to obtain A34 (31 mg, 4 μmol, 67%) as a light yellow oil. The diastereomeric rate was determined by HPLC.

(428) TLC [EtOAc/cyclohexane, 3:7, 4% AcOH]: R.sub.f=0.42.

(429) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.88 min, purity (220 nm)=92%, dr ≧99:1.

(430) .sup.1H NMR (400 MHz, d6-DMSO) δ 7.29-7.23 (m, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.95-6.57 (m, 5H), 6.52 (s, 2H), 5.71-5.65 (m, 1H), 5.62-5.54 (m, 1H), 5.03-4.87 (m, 2H), 4.10-4.04 (m, 3H), 3.73 (d, J=2.2 Hz, 3H), 3.69 (s, 3H), 3.69-3.67 (m, 6H), 3.62 (d, J=2.3 Hz, 3H), 3.60 (s, 3H), 3.57 (s, 2H), 3.55 (s, 2H), 3.48 (d, J=1.9 Hz, 1H), 3.32 (s, 1H), 3.14-3.08 (m, 1H), 2.91 (dd, J=13.9, 4.0 Hz, 1H), 2.75-2.62 (m, 5H), 2.53-2.44 (m, 6H), 2.38-2.29 (m, 1H).

(431) .sup.13C NMR (101 MHz, d6-DMSO) δ 172.40, 168.83, 158.77, 153.39, 153.14, 149.03, 149.01, 147.44, 142.29, 142.22, 136.93, 136.73, 135.78, 135.03, 133.78, 129.93, 120.46, 116.81, 114.19, 112.68, 112.28, 105.51, 75.80, 66.52, 65.46, 60.19, 56.36, 56.00, 55.90, 55.79, 55.75, 55.35, 54.01, 52.52, 52.20, 51.58, 47.42, 44.49, 33.69, 31.73, 31.00, 26.99, 24.85, 22.54.

(432) Mass: (ESI.sup.+), calculated 779.36 [C.sub.42H.sub.54N.sub.2O.sub.10S+H].sup.+, found 779.37 [M+H].sup.+.

Reference Example 3-46

Preparation of 2-(3-((1R)-1-(((2S)-1-(2-cyclohexyl-2-phenylacetyl)piperidine-2-carbonyl)oxy)-3-(3,4 dimethoxyphenyl)propyl)phenoxy)acetic acid

(433) ##STR00173##

(434) 2-cyclohexyl-2-phenylacetic acid (87.8 mg, 0.4 mmol), 8a (50 mg, 0.1 mmol), COMU (94.6 mg, 0.22 mmol) and 2,2,6,6-tetramethylpiperidine (67.8 μL, 0.40 mmol) were stirred in DMF (1.5 mL) for 25 h at RT. The reaction mixture was directly loaded on silica and purified by flash chromatography (gradient 0-10% EtOAc in cyclohexane). The tert-butyl ester was stirred in DCM/TFA (2 mL, 1:1) for 6 h at RT and then poured into saturated NaHCO.sub.3. The free carboxylic acid was extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered and purified by preparative chromatography (gradient 0-30% EtOAc+1% HCOOH in cyclohexane) to obtain A35 (58.4 mg, 88.8 μmol, 88.3%) as a colourless oil.

(435) TLC [EtOAc/cyclohexane, 1:1+1% HCOOH]: R.sub.f=0.33

(436) .sup.1H NMR (599 MHz, CDCl.sub.3) major diastereomer δ 7.28-7.25 (m, 2H), 7.23-7.17 (m, 2H), 7.17-7.12 (m, 1H), 7.11-7.06 (m, 1H), 6.93-6.81 (m, 2H), 6.81-6.72 (m, 2H), 6.69-6.61 (m, 2H), 5.56 (dd, J=8.6, 5.3 Hz, 1H), 5.52-5.45 (m, 1H), 4.66-4.53 (m, 2H), 4.02-3.92 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.46 (d, J=9.9 Hz, 1H), 3.24-3.15 (m, 1H), 2.74 (td, J=13.6, 3.0 Hz, 1H), 2.62-2.46 (m, 2H), 2.42-2.36 (m, 1H), 2.18-2.09 (m, 1H), 1.95-1.82 (m, 2H), 1.82-1.75 (m, 1H), 1.64-1.51 (m, 4H), 1.50-1.39 (m, 2H), 1.34-1.22 (m, 3H), 1.15-1.06 (m, 2H), 0.93-0.84 (m, 1H), 0.74-0.66 (m, 1H).

(437) .sup.13C NMR major diastereomer δ 172.64, 171.25, 170.32, 157.64, 148.77, 147.22, 141.97, 138.50, 137.70, 133.58, 129.57, 128.75, 128.46, 128.19, 126.89, 120.20, 119.75, 114.52, 111.99, 111.77, 111.66, 111.27, 111.13, 75.77, 65.16, 55.90, 55.83, 54.94, 52.18, 43.73, 41.11, 37.81, 36.76, 32.72, 31.68, 31.12, 30.61, 29.67, 26.78, 26.50, 26.11, 25.46, 24.86, 20.96.

(438) HPLC [70-80% Solvent B, 20 min]: Rt=13.4 min, purity (220 nm)=100%.

(439) Mass: (ESI.sup.+), calculated 658.34 [C.sub.39H.sub.47NO.sub.8+H].sup.+, found 658.17 [M+H].sup.+.

Example 3-47

Preparation of 2-(3-((R)-1-(((S)-1-((S)-2-cyclohexyl-2-(3-fluorophenyl)acetyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl) phenoxy)acetic acid

(440) ##STR00174##

(441) (S)-2-cyclohexyl-2-(3-fluorophenyl)acetic acid (13 mg, 0.06 mmol), 8a (28 mg, 0.06 mmol), COMU (25.9 mg, 0.06 mmol) and 2,2,6,6-tetramethylpiperidine (18.6 μL, 0.11 mmol) were stirred in DMF (1.0 mL) for 1 h at RT. The resulting orange reaction mixture was directly loaded on silica and purified by flash chromatography (gradient 0-10% EtOAc in cyclohexane).

(442) The tert-butyl ester was stirred in DCM/TFA (2.0 mL, 1:1) for 1 h at RT and then poured into sat. NaHCO.sub.3. The free carboxylic acid was extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered and purified by preparative chromatography (gradient 0-30% EtOAc+1% HCOOH in hexane) to obtain A36 (18.2 mg, 26.9 μmol, 47.8%) as a colourless oil.

(443) TLC [EtOAc/cyclohexane, 1:1+1% HCOOH]: R.sub.f=0.26.

(444) HPLC [50-100% Solvent B, 20 min]: Rt=17.2 min, purity (220 nm)=99%.

(445) .sup.1H NMR (599 MHz, CDCl.sub.3) δ 7.22-7.10 (m, 2H), 7.04-6.98 (m, 2H), 6.93-6.83 (m, 2H), 6.82-6.74 (m, 2H), 6.66-6.63 (m, 2H), 6.57 (d, J=7.6 Hz, 1H), 5.57 (dd, J=8.6, 5.3 Hz, 1H), 5.47-5.43 (m, 1H), 4.65-4.50 (m, 3H), 3.97-3.90 (m, 1H), 3.85-3.82 (m, 6H), 3.50-3.43 (m, 1H), 2.89-2.80 (m, 1H), 2.60-2.50 (m, 2H), 2.47-2.39 (m, 1H), 2.34-2.21 (m, 2H), 2.14-2.07 (m, 1H), 2.03-1.98 (m, 1H), 1.94-1.81 (m, 2H), 1.72-1.65 (m, 2H), 1.63-1.58 (m, 2H), 1.50-1.43 (m, 1H), 1.29-1.22 (m, 3H), 1.11 (qd, J=9.3, 2.8 Hz, 2H), 0.92-0.86 (m, 1H), 0.72 (qd, J=12.0. 4.2 Hz. 1H).

(446) .sup.13C NMR (151 MHz, CDCl.sub.3) δ 172.34, 171.52, 170.09, 157.63, 148.80, 147.28, 142.02, 133.43, 129.86, 129.80, 129.61, 124.48, 120.20, 119.65, 115.65, 115.51, 114.85, 113.98, 113.84, 111.74, 111.43, 111.33, 111.28, 77.20, 76.98, 76.77, 75.86, 65.25, 55.90, 55.83, 54.60, 52.36, 43.71, 41.22, 37.78, 32.59, 31.17, 30.55, 26.91, 26.41, 26.04, 25.44, 20.95.

(447) Mass: (ESI.sup.+), calculated 676.33 [C.sub.39H.sub.46FNO.sub.8+H].sup.+, found 676.26 [M+H].sup.+.

Example 3-48

Preparation of (R)-4-benzyl-3-(2-cyclohexylacetyl)oxazolidin-2-one

(448) ##STR00175##

(449) To a solution of (R)-4-benzyloxazolidin-2-one (500 mg, 2.82 mmol) in THF (25.0 mL) was added BuLi (1.7 mL, 4.23 mmol) at −78° C. and the resulting mixture was stirred at that temperature for 1.5 h, whereby it turned into a orange solution. To the resulting mixture was added 2-cyclohexylacetyl chloride (0.65 mL, 4.23 mmol) at −78° C. The reaction was stirred at that temperature for 2.5 h and was then slowly warmed to RT.

(450) After stirring at 16 h the colourless reaction mixture was quenched with saturated NH.sub.4Cl solution. The aqueous layer was extracted with Et.sub.2O. The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient 0-10% EtOAc in cyclohexane) to yield (R)-4-benzyl-3-(2-cyclohexylacetyl)oxazolidin-2-one (850 mg, 2.82 mmol, quant.) as a colourless solid.

(451) TLC [EtOAc/cyclohexane, 2:8]: R.sub.f=0.3.

(452) .sup.1H NMR (599 MHz, CDCl.sub.3) δ 7.35-7.31 (m, 2H), 7.29-7.26 (m, 1H), 7.23-7.20 (m, 2H), 4.70-4.65 (m, 1H), 4.21-4.14 (m, 2H), 3.31 (dd, J=13.4, 3.4 Hz, 1H), 2.90-2.86 (m, 1H), 2.81-2.73 (m, 2H), 1.94-1.87 (m, 1H), 1.81-1.64 (m, 5H), 1.35-1.24 (m, 2H), 1.17 (qt, J=12.7, 3.5 Hz, 1H), 1.09-0.99 (m, 2H).

(453) .sup.13C NMR (151 MHz, CDCl.sub.3) δ 172.59, 153.40, 135.33, 129.39, 128.92, 128.90, 127.30, 66.05, 55.19, 42.65, 37.99, 34.29, 33.11, 33.06, 26.19, 26.12, 26.10.

(454) Mass: (ESI.sup.+), calculated 302.18 [C.sub.18H.sub.23NO.sub.3+H].sup.+, found 302.14 [M+H].sup.+.

Example 3-49

Preparation of (R)-4-benzyl-3-((R)-2-cyclohexylpent-4-enoyl)oxazolidin-2-one

(455) ##STR00176##

(456) NaHMDS (1.5 mL, 1.5 mmol, 1.0 M in THF) was added to a solution of (R)-4-benzyl-3-(2-cyclohexylacetyl)oxazolidin-2-one (300 mg, 1.0 mmol) in THF (2.0 mL) at −78° C. and stirred for 1 h, whereby it turned into a light yellow solution. Allyl bromide (129 μL, 1.5 mmol) was then added dropwise. The reaction was stirred for 1 h at −78° C. and then for 16 h at 4° C.

(457) The reaction mixture was quenched with saturated NH.sub.4Cl solution and the aqueous layer was extracted with Et.sub.2O. The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient 0-5% EtOAc in cyclohexane) to yield the title compound (249 mg, 0.72 mmol, 73.2%) as a colourless solid.

(458) TLC [EtOAc/cyclohexane, 2:8]: R.sub.f=0.43.

(459) .sup.1H NMR (599 MHz, CDCl.sub.3) δ 7.47-6.99 (m, 5H), 5.90-5.71 (m, 1H), 5.07 (dq, J=17.0, 1.5 Hz, 1H), 5.02-4.98 (m, 1H), 4.67 (ddt, J=10.3, 6.7, 3.2 Hz, 1H), 4.17-4.05 (m, 2H), 3.90 (ddd, J=9.6, 7.6, 4.4 Hz, 1H), 3.30 (dd, J=13.4, 3.3 Hz, 1H), 2.62 (dd, J=13.4, 10.1 Hz, 1H), 2.51-2.32 (m, 2H), 1.87-1.79 (m, 1H), 1.77-1.58 (m, 4H), 1.30-1.15 (m, 3H), 1.17-1.04 (m, 2H), 1.00 (qd, J=12.4, 3.6 Hz, 1H).

(460) .sup.13C NMR (151 MHz, CDCl.sub.3) δ 175.83, 153.22, 135.64, 135.55, 129.38, 128.88, 127.22, 116.88, 65.69, 55.64, 47.40, 40.05, 38.06, 33.78, 31.17, 29.66, 26.28.

(461) Mass: (ESI.sup.+), calculated 342.21 [C.sub.21H.sub.27NO.sub.3+H].sup.+, found 342.27 [M+H].sup.+.

Example 3-50

Preparation of (R)-4-benzyl-3-((R)-2-cyclohexylpropanoyl) oxazolidin-2-one

(462) ##STR00177##

(463) NaHMDS (1.0 mL, 1.0 mmol, 1.0 M in THF) was added to a solution of (R)-4-benzyl-3-(2-cyclohexylacetyl)oxazolidin-2-one (200 mg, 0.66 mmol) in THF (2.0 mL) at −78° C. and stirred for 1 h, whereby it turned into a light yellow solution. Iodomethane (415 μL, 6.64 mmol) was then added dropwise. The reaction was stirred for 2.5 h at −78° C. and then for 16 h at 4° C.

(464) The reaction mixture was quenched with saturated NH.sub.4Cl solution and the aqueous layer was extracted with Et.sub.2O. The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient 0-5% EtOAc in cyclohexane) to yield the title compound (163 mg, 0.52 mmol, 78.0%) as a colourless solid.

(465) TLC [EtOAc/cyclohexane, 2:8]: R.sub.f=0.43.

(466) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.48-7.10 (m, 5H), 4.66 (ddt, J=10.0, 6.6, 3.3 Hz, 1H), 4.22-4.11 (m, 2H), 3.64 (p, J=7.0 Hz, 1H), 3.28 (dd, J=13.2, 3.2 Hz, 1H), 2.75 (dd, J=13.3, 9.6 Hz, 1H), 1.79-1.53 (m, 6H), 1.29-0.89 (m, 8H).

(467) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 177.16, 153.12, 135.38, 129.40, 128.89, 127.27, 65.88, 55.44, 42.62, 40.47, 37.89, 31.47, 29.03, 26.30, 26.25, 14.16.

(468) Mass: (ESI.sup.+), calculated 316.19 [C.sub.19H.sub.25NO.sub.3+H].sup.+, found 316.03 [M+H].sup.+.

Example 3-51

Preparation of (R)-2-cyclohexylpropanoic acid

(469) ##STR00178##

(470) LiOH (51.3 mg, 2.14 mmol) and H.sub.2O.sub.2 (243 μl, 2.38 mmol) were added to a solution of (R)-4-benzyl-3-((R)-2-cyclohexylpropanoyl)oxazolidin-2-one (150 mg, 0.48 mmol) in THF/H.sub.2O (6.5 mL, 8:5) at 0° C. The resulting turbid solution was stirred at that temperature for 1.5 h and at RT for 1.5 h.

(471) Then reaction mixture was quenched with saturated Na.sub.2SO.sub.3 solution at 0° C. and it was extracted with DCM. Then the aqueous layer was acidified with concentrated HCl to pH=1 and extracted with DCM. These layers were combined, dried over MgSO.sub.4 and the solvent was removed. The title compound (74.3 mg, 0.48 mmol, quant.) was obtained without further purification as a colourless oil.

(472) TLC [EtOAc/cyclohexane, 4:6]: R.sub.f=0.44.

(473) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.27 (p, J=7.1 Hz, 1H), 1.84-1.42 (m, 6H), 1.38-0.76 (m, 8H).

(474) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 182.63, 45.25, 40.44, 31.12, 29.37, 26.26, 26.25, 26.21, 13.64.

(475) Mass: (ESI.sup.+), calculated 157.12 [C.sub.9H.sub.16O.sub.2+H].sup.+, found 157.08 [M+H].sup.+.

Example 3-52

Preparation of 2-(3-((R)-1-(((S)-1-((R)-2-cyclohexylpropanoyl) piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy)acetic acid

(476) ##STR00179##

(477) 8a (49.3 mg, 0.10 mmol), (R)-2-cyclohexylpropanoic acid (15 mg, 0.10 mmol), COMU (61.7 mg, 0.14 mmol) and DIPEA (33.5 μL, 0.19 mmol) were stirred in DMF (1.0 mL) for 20 h at RT. The orange reaction mixture was diluted with Et.sub.2O and washed with brine. The combined organic layers were dried over MgSO.sub.4, filtrated and the solvent was removed under reduced pressure.

(478) The crude tert-butyl ester was stirred in DCM/TFA (2.0 mL, 1:1) for 1 h at RT and then poured into saturated NaHCO.sub.3. The free carboxylic acid was extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered and purified by flash chromatography (gradient 0-40% EtOAc+0.5% HCOOH in cyclohexane) to obtain A37 (44.6 mg, 74.9 μmol, 78.0%) as a light yellow oil.

(479) TLC [EtOAc/cyclohexane, 1:1+1% HCOOH]: R.sub.f=0.16.

(480) HPLC [50-100% Solvent B, 20 min]: Rt=15.0 min, purity (220 nm)=94%.

(481) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.24-7.18 (m, 1H), 6.89-6.82 (m, 2H), 6.81-6.74 (m, 2H), 6.72-6.61 (m, 2H), 5.66 (dd, J=8.7, 4.9 Hz, 1H), 5.53-5.46 (m, 1H), 4.70-4.56 (m, 2H), 3.93-3.87 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.37-3.21 (m, 1H), 2.71-2.47 (m, 3H), 2.42-2.31 (m, 1H), 2.26-2.13 (m, 1H), 2.15-2.04 (m, 1H), 1.89-1.46 (m, 10H), 1.44-1.37 (m, 2H), 1.22-1.10 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.95-0.78 (m, 2H).

(482) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 177.32, 171.32, 170.34, 163.23, 158.01, 148.91, 147.38, 142.08, 133.43, 129.65, 120.18, 119.41, 115.65, 111.71, 111.37, 110.14, 76.35, 65.46, 60.42, 55.91, 55.86, 52.28, 43.51, 41.19, 40.53, 38.03, 31.90, 31.44, 29.51, 27.21, 26.88, 26.38, 26.27, 26.22, 25.50, 21.07, 14.32.

(483) Mass: (ESI.sup.+), calculated 596.32 [C.sub.34H.sub.45NO.sub.8+H].sup.+, found 595.96 [M+H].sup.+.

Example 3-53

Preparation of 2-(3-((R)-1-(((S)-1-((R)-2-cyclohexylpent-4-enoyl)piperidine-2-carbonyl)oxy)-3-(3,4-dimethoxyphenyl)propyl)phenoxy) acetic acid

(484) ##STR00180##

(485) 8a (141 mg, 0.27 mmol), (R)-2-cyclohexylpent-4-enoic acid (50 mg, 0.27 mmol), COMU (176 mg, 0.41 mmol) and DIPEA (96 μl, 0.55 mmol) were stirred in DMF (3.0 mL) for 20 h at RT. The resulting dark red reaction mixture was directly loaded on silica and purified by flash chromatography (gradient 0-20% EtOAc in cyclohexane). The tert-butyl ester was stirred in DCM/TFA (2.0 mL, 1:1) for 1 h at RT and then poured into sat. NaHCO.sub.3. The free carboxylic acid was extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered and purified by preparative chromatography (gradient 0-10% EtOAc+1% HCOOH in hexane) to obtain A38 (13.4 mg, 21.6 μmol, 7.8%) as a yellow colourless oil.

(486) TLC [EtOAc/cyclohexane, 1:1+1% HCOOH]: R.sub.f=0.19.

(487) HPLC [50-100% Solvent B, 20 min]: Rt=16.0 min, purity (220 nm)=98%.

(488) .sup.1H NMR (599 MHz, DMSO-d6) δ 7.31-7.19 (m, 1H), 6.91-6.87 (m, 1H), 6.86-6.77 (m, 3H), 6.75-6.70 (m, 1H), 6.67-6.60 (m, 1H), 5.78-5.68 (m, 1H), 5.67-5.63 (m, 1H), 5.37-5.30 (m, 1H), 5.07-4.90 (m, 2H), 4.85 (d, J=10.2 Hz, 1H), 4.63-4.56 (m, 2H), 4.00 (d, J=13.4 Hz, 1H), 3.69 (s, 3H), 3.68 (s, 3H), 2.95 (t, J=13.1 Hz, 1H), 2.70-2.62 (m, 1H), 2.46-2.38 (m, 1H), 2.27-2.13 (m, 3H), 2.13-1.94 (m, 2H), 1.84-1.73 (m, 1H), 1.68-1.48 (m, 5H), 1.45-1.38 (m, 2H), 1.37-1.24 (m, 2H), 1.20-1.02 (m, 4H), 0.92 (p, J=12.7, 11.1 Hz, 2H).

(489) .sup.13C NMR (599 MHz, DMSO-d6) δ 174.30, 170.79, 170.58, 158.36, 149.06, 147.47, 142.26, 137.00, 133.67, 129.98, 120.35, 119.12, 116.34, 114.28, 112.73, 112.53, 112.33, 75.77, 66.32, 65.16, 55.92, 55.76, 51.90, 47.41, 45.65, 43.66, 38.15, 34.22, 31.07, 29.91, 27.01, 26.41, 26.35, 25.52, 21.17.

(490) Mass: (ESI.sup.+), calculated 622.34 [C.sub.36H.sub.47NO.sub.8+H].sup.+, found 622.17 [M+H].sup.+.

Example 4-A

General Synthetic Procedure D for Solid Phase Coupling Reaction

(491) ##STR00181##

(492) All steps were performed at rt. Sieber amide resin (108 mg, 80 μmol) was treated with 20% 4-methylpiperidine in DMF (2 mL) for 20 min. The resin was filtered and washed with DMF (2 mL×4). To the resin was added a solution of the top-group fmoc protected amino acid (400 μmol, 5 eq.), HBTU (145 mg, 386 μmol, 4.8 eq.), HOBt (52 mg, 386 μmol, 4.8 eq.) and DIEA (140 μL, 800 μmol, 10 eq.) in 2 mL DMF. The mixture was mixed on a shaker for 2 hours. The resin was filtered and washed with DMF (2 mL×4). The fmoc deprotection and washing was performed as before. (S)-N-Fmoc-piperidine-2-carboxylic acid (112 mg, 320 μmol, 4 eq.), HBTU (115 mg, 304 μmol, 3.8 eq.), HOBt (41 mg, 304 μmol, 4.8 eq.) and DIEA (120 μL, 640 μmol, 8 eq.) in 2 mL DMF was added to the resin and mixed for 2 hours. Washing and deprotecting as before was repeated followed by the addition of A (48 mg, 160 μmol, 2 eq.), HATU (61 mg, 160 μmol, 2 eq.) and DIEA (60 μl, 320 μmol, 4 eq.). The suspension was mixed for 16 hours. The resin was washed with DMF (2 mL×4), methanol (2 mL×2), dichloromethane (2 mL×4) and ether (2 mL×4) then dried in vacuo. The compounds were cleaved from the resin using 2 mL of 1% TFA/1% TIS/98% DCM for 2 minutes. This was repeated 5 times and after every step was neutralized using 20 ml sat. NaHCO.sub.3 solution. The aqueous solution was extracted three times with dichloromethane.

Example 4-1

Preparation of (S)-N-((S)-1-amino-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B01

(493) ##STR00182##

(494) General procedure D was used and B01 was obtained as colourless oil (15 mg, 31 μmol).

(495) HPLC [0-100% Solvent B, 20 min]: R.sub.t=16.4 min, purity (220 nm)=96%.

(496) Mass: (ESI.sup.−), calculated 490.29 [C26H40N3O6+H].sup.−, found 490.20 [M+H].sup.+.

Example 4-2

Preparation of (S)-N-((R)-1-amino-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B02

(497) ##STR00183##

(498) General procedure D was used and B02 was obtained as colourless oil (8 mg, 17 μmol).

(499) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.1 min, purity (220 nm)=96%.

(500) Mass: (ESI.sup.−), calculated 490.29 [C26H40N3O6+H].sup.−, found 490.19 [M+H].sup.+.

Example 4-3

Preparation of (S)-N-((S)-1-amino-3-methyl-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B03

(501) ##STR00184##

(502) General procedure D was used and B01 was obtained as white crystals (24 mg, 46 μmol).

(503) LCMS [0-100% Solvent B, 20 min]: R.sub.t=9.2 min, purity (220 nm)=96%.

(504) Mass: (ESI.sup.−), calculated 518.32 [C28H44N3O6+H].sup.−, found 518.20 [M+H].sup.+.

Example 4-4

Preparation of (S)-N-((R)-1-amino-3-methyl-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B04

(505) ##STR00185##

(506) General procedure D was used and B01 was obtained as white solid (31 mg, 63 μmol).

(507) LCMS [0-100% Solvent B, 20 min]: R.sub.t=9.1 min, purity (220 nm)=96%.

(508) Mass: (ESI.sup.−), calculated 518.32 [C28H44N3O6+H].sup.−, found 518.30 [M+H].sup.+.

Example 4-5

Preparation of (S)-N-((S)-1-amino-1-oxo-3-phenylpropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B05

(509) ##STR00186##

(510) General procedure D was used and B05 was obtained as white solid (15 mg, 23 μmol).

(511) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.1 min, purity (220 nm)=97%.

(512) Mass: (ESI.sup.−), calculated 566.32 [C32H43N3O6+H].sup.−, found 566.25 [M+H].sup.+.

Example 4-6

Preparation of (S)-N-((R)-1-amino-1-oxo-3-phenylpropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B06

(513) ##STR00187##

(514) General procedure D was used and B06 was obtained as white solid (19 mg, 34 μmol).

(515) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.4 min, purity (220 nm)=99%.

(516) Mass: (ESI.sup.−), calculated 566.32 [C32H43N3O6+H].sup.−, found 566.10 [M+H].sup.+.

Example 4-7

Preparation of (S)-N-((S)-1-amino-3-cyclohexyl-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B07

(517) ##STR00188##

(518) General procedure D was used and B07 was obtained as white solid (19 mg, 34 μmol).

(519) LCMS [30-100% Solvent B, 10 min]: R.sub.t=10.8 min, purity (220 nm)=99%.

(520) Mass: (ESI.sup.−), calculated 572.37 [C32H49N3O6+H].sup.−, found 572.27 [M+H].sup.+.

Example 4-8

Preparation of (S)-N-((S)-1-amino-1-oxo-4-phenylbutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide (S)-N-((S)-1-amino-1-oxo-4-phenylbutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B08

(521) ##STR00189##

(522) General procedure D was used and B08 was obtained as white solid (34 mg, 58 μmol).

(523) HPLC [0-100% Solvent B, 10 min]: R.sub.t=19.2 min, purity (220 nm)=96%.

(524) Mass: (ESI.sup.−), calculated 580.34 [C33H45N3O6+H].sup.−, found 580.30 [M+H].sup.+.

Example 4-9

Preparation of (S)-N-((S)-1-amino-4-cyclohexyl-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B09

(525) ##STR00190##

(526) General procedure D was used and B09 was obtained as pale white oil (13 mg, 20 μmol).

(527) HPLC [0-100% Solvent B, 10 min]: R.sub.t=19.2 min, purity (220 nm)=96%.

(528) Mass: (ESI.sup.−), calculated 586.39 [C33H51N3O6+H].sup.−, found 586.15 [M+H].sup.+.

Example 4-10

Preparation of (S)-N-(2-amino-2-oxoethyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B10

(529) ##STR00191##

(530) General procedure D was used and B10 was obtained as colourless oil (34 mg, 58 μmol).

(531) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.2 min, purity (220 nm)=96%.

(532) Mass: (ESI.sup.−), calculated 580.34 [C25H37N3O6+H].sup.−, found 580.30 [M+H].sup.+.

Example 4-11

(S)-N-(1-amino-2-methyl-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B11

(533) ##STR00192##

(534) General procedure D was used and B11 was obtained as pale white oil (29 mg, 58 μmol).

(535) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.1 min, purity (220 nm)=96%.

(536) Mass: (ESI.sup.−), calculated 504.31 [C27H41N3O6+H].sup.−, found 504.10 [M+H].sup.+.

Example 4-12

Preparation of (S)-N-((S)-1-amino-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B12

(537) ##STR00193##

(538) General procedure D was used and B12 was obtained as pale yellow oil (29 mg, 58 μmol).

(539) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.8 min, purity (220 nm)=96%.

(540) Mass: (ESI.sup.−), calculated 504.31 [C27H41N3O6+H].sup.−, found 504.13 [M+H].sup.+.

Example 4-13

Preparation of (S)-N-((R)-1-amino-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B13

(541) ##STR00194##

(542) General procedure D was used and B13 was obtained as pale yellow oil (29 mg, 53 μmol).

(543) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.3 min, purity (220 nm)=95%.

(544) Mass: (ESI.sup.−), calculated 504.31 [C27H41N3O6+H].sup.−, found 504.17 [M+H].sup.+.

Example 4-14

Preparation of (S)-N-((2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B14

(545) ##STR00195##

(546) General procedure D was used and B14 was obtained as yellow oil (25 mg, 47 μmol).

(547) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.3 min, purity (220 nm)=97%.

(548) Mass: (ESI.sup.−), calculated 532.34 [C29H45N3O6+H].sup.−, found 532.30 [M+H].sup.+.

Example 4-15

Preparation of (S)-N-((2R,3R)-1-amino-3-methyl-1-oxopentan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B15

(549) ##STR00196##

(550) General procedure D was used and B15 was obtained as yellow oil (39 mg, 73 μmol).

(551) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.0 min, purity (220 nm)=95%.

(552) Mass: (ESI.sup.−), calculated 532.34 [C29H45N3O6+H].sup.−, found 532.10 [M+H].sup.+.

Example 4-16

Preparation of (S)-N-((S)-2-amino-2-oxo-1-phenylethyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B16

(553) ##STR00197##

(554) General procedure D was used and B16 was obtained as pale yellow oil (38 mg, 69 μmol).

(555) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.6 min, purity (220 nm)=97%.

(556) Mass: (ESI.sup.−), calculated 552.31 [C31H41N3O6+H].sup.−, found 552.30 [M+H].sup.+.

Example 4-17

Preparation of (S)-N-((R)-2-amino-2-oxo-1-phenylethyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B17

(557) ##STR00198##

(558) General procedure D was used and B17 was obtained as pale yellow oil (29 mg, 53 μmol).

(559) HPLC [0-100% Solvent B, 20 min]: R.sub.t=17.8 min, purity (220 nm)=98%.

(560) Mass: (ESI.sup.−), calculated 552.31 [C31H41N3O6+H].sup.−, found 552.10 [M+H].sup.+.

Example 4-18

(S)-N-((S)-2-amino-1-cyclohexyl-2-oxoethyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B18

(561) ##STR00199##

(562) General procedure D was used and B18 was obtained as colourless oil (22 mg, 39 μmol).

(563) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.7 min, purity (220 nm)=98%.

(564) Mass: (ESI.sup.−), calculated 558.36 [C31H47N3O6+H].sup.−, found 558.20 [M+H].sup.+.

Example 4-19

Preparation of (S)-N-((S)-1-amino-4-hydroxy-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B19

(565) ##STR00200##

(566) General procedure D was used and B19 was obtained as colourless oil (25 mg, 39 μmol).

(567) LCMS [0-100% Solvent B, 20 min]: R.sub.t=9.3 min, purity (220 nm)=97%.

(568) Mass: (ESI.sup.−), calculated 520.30 [C27H41N3O7+H].sup.−, found 520.20 [M+H].sup.+.

Example 4-20

Preparation of (S)-N-((R)-1-amino-4-hydroxy-1-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B20

(569) ##STR00201##

(570) General procedure D was used and B20 was obtained as colourless oil (4 mg, 8 μmol).

(571) LCMS [0-100% Solvent B, 20 min]: R.sub.t=9.4 min, purity (220 nm)=93%.

(572) Mass: (ESI.sup.−), calculated 520.30 [C27H41N3O7+H].sup.−, found 520.20 [M+H].sup.+.

Example 4-21

Preparation of (S)-N-((R)-1-amino-3-hydroxy-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B21

(573) ##STR00202##

(574) General procedure D was used and B21 was obtained as pale yellow oil (28 mg, 55 μmol).

(575) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.4 min, purity (220 nm)=90%.

(576) Mass: (ESI.sup.−), calculated 506.29 [C26H39N3O7+H].sup.−, found 506.30 [M+H].sup.+.

Example 4-22

Preparation of (S)-N-((S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B22

(577) ##STR00203##

(578) General procedure D was used and B22 was obtained as pale yellow oil (32 mg, 63 μmol).

(579) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.8 min, purity (220 nm)=93%.

(580) Mass: (ESI.sup.−), calculated 506.29 [C26H39N3O7+H].sup.−, found 506.14 [M+H].sup.+.

Example 4-23

Preparation of (S)-2-((S)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamido)pentanediamide B23

(581) ##STR00204##

(582) General procedure D was used and B23 was obtained as colorless oil (25 mg, 46 μmol).

(583) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.1 min, purity (220 nm)=97%.

(584) Mass: (ESI.sup.−), calculated 547.31 [C28H42N4O7+H].sup.−, found 547.14 [M+H].sup.+.

Example 4-24

Preparation of (R)-2-((S)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamido)pentanediamide B24

(585) ##STR00205##

(586) General procedure D was used and B24 was obtained as colorless oil (28 mg, 51 μmol).

(587) HPLC [0-100% Solvent B, 20 min]: R.sub.t=14.8 min, purity (220 nm)=97%.

(588) Mass: (ESI.sup.−), calculated 547.31 [C28H42N4O7+H].sup.−, found 547.20 [M+H].sup.+.

Example 4-25

Preparation of (S)-N-(4-amino-2-methyl-4-oxobutan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B25

(589) ##STR00206##

(590) General procedure D was used and B25 was obtained as colorless oil (34 mg, 66 μmol).

(591) HPLC [0-100% Solvent B, 15 min]: R.sub.t=14.6 min, purity (220 nm)=98%.

(592) Mass: (ESI.sup.−), calculated 518.32 [C28H43N3O6+H].sup.−, found 518.12 [M+H].sup.+.

Example 4-26

Preparation of (S)-N-(1-carbamoylcyclopropyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B26

(593) ##STR00207##

(594) General procedure D was used and B26 was obtained as colorless oil (31 mg, 62 μmol).

(595) HPLC [0-100% Solvent B, 20 min]: R.sub.t=16.8 min, purity (220 nm)=98%.

(596) Mass: (ESI.sup.−), calculated 502.29 [C27H39N3O6+H]—, found 502.27 [M+H].sup.+.

Example 4-27

Preparation of (S)-N-(1-carbamoylcyclobutyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B27

(597) ##STR00208##

(598) General procedure D was used and B27 was obtained as colourless oil (34 mg, 66 μmol).

(599) LCMS [0-100% Solvent B, 20 min]: R.sub.t=8.9 min, purity (220 nm)=98%.

(600) Mass: (ESI.sup.−), calculated 516.31 [C28H41N3O6+H].sup.−, found 516.14 [M+H].sup.+.

Example 4-28

Preparation of (S)-N-(1-carbamoylcyclopentyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B28

(601) ##STR00209##

(602) General procedure D was used and B28 was obtained as colourless oil (32 mg, 60 μmol).

(603) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.1 min, purity (220 nm)=99%.

(604) Mass: (ESI.sup.−), calculated 530.32 [C29H43N3O6+H].sup.−, found 530.30 [M+H].sup.+.

Example 4-29

Preparation of (S)-N-(3-amino-3-oxopropyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B29

(605) ##STR00210##

(606) General procedure D was used and B29 was obtained as colourless oil (29 mg, 59 μmol).

(607) HPLC [0-100% Solvent B, 20 min]: R.sub.t=15.9 min, purity (220 nm)=98%.

(608) Mass: (ESI.sup.−), calculated 490.29 [C26H39N3O6+H].sup.−, found 490.20 [M+H].sup.+.

Example 4-30

Preparation of (S)-N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B30

(609) ##STR00211##

(610) General procedure D was used and B30 was obtained as colourless oil (31 mg, 58 μmol).

(611) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.8 min, purity (220 nm)=97%.

(612) Mass: (ESI.sup.−), calculated 532.34 [C29H45N3O6+H].sup.−, found 532.24 [M+H].sup.+.

Example 4-31

(S)-N-(1-carbamoylcyclohexyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxamide B31

(613) ##STR00212##

(614) General procedure D was used and B31 was obtained as colourless oil (34 mg, 63 μmol).

(615) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.9 min, purity (220 nm)=98%.

(616) Mass: (ESI.sup.−), calculated 544.34 [C.sub.30H.sub.45N.sub.3O.sub.6+H].sup.+, found 544.17 [M+H].sup.+.

Example 4-32

(S)-N-(1-carbamoylcyclohexyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxamide B32

(617) ##STR00213##

(618) General procedure D was used and B32 was obtained as colourless oil (33 mg, 60 μmol).

(619) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.9 min, purity (220 nm)=98%.

(620) Mass: (ESI.sup.−), calculated 546.32 [C.sub.29H.sub.44N.sub.3O.sub.7+H].sup.+, found 546.03 [M+H].sup.+.

Example 4-33

(S)-N-(1-((2-amino-2-oxoethyl)carbamoyl)cyclopentyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B33

(621) ##STR00214##

(622) General procedure D was used and B33 was obtained as colourless oil (29 mg, 49 μmol).

(623) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.1 min, purity (220 nm)=91%.

(624) Mass: (ESI.sup.−), calculated 587.34 [C.sub.31H.sub.47N.sub.4O.sub.7+H].sup.+, found 587.24 [M+H].sup.+.

Example 4-34

(S)-N-((R)-1-amino-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B34

(625) ##STR00215##

(626) HPLC [0-100% Solvent B, 20 min]: R.sub.t=13.2 min, purity (220 nm)=99%.

(627) Mass: (ESI.sup.−), calculated 556.31 [C.sub.29H.sub.42N.sub.5O.sub.6+H].sup.+, found 556.30 [M+H].sup.+.

Example 4-35

(S)-N-((S)-1-amino-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide B35

(628) ##STR00216##

(629) General procedure D was used and B35 was obtained as colourless oil (3 mg, 23 μmol).

(630) HPLC [0-100% Solvent B, 20 min]: R.sub.t=13.7 min, purity (220 nm)=99%.

(631) Mass: (ESI.sup.−), calculated 556.31 [C.sub.29H.sub.42N.sub.5O.sub.6+H].sup.+, found 556.29 [M+H].sup.+.

Example 5-A

General Synthetic Procedures for Coupling of Synthetic Building Blocks A and B (Coupled with Alcohol and Amine)

(632) ##STR00217##

(633) (S)-pipecolinic acid was dissolved in 3 mL of alcohol followed by the addition of 2 eq Thionylchloride at rt. The reaction mixture was refluxed for 5 h and quenched with NaHCO.sub.3. The raw product was extracted, dried over MgSO.sub.4 and used without further purification.

Example 5-1

Preparation of (S)-methyl 1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C01

(634) ##STR00218##

(635) 19 (107 mg, 349 μmol), HATU (133 mg, 349 μmol) and DIEA (238 μL, 1.4 mmol) were dissolved in 2 mL DCM and stirred for 15 min at rt followed by the addition of (S)-methyl piperidine-2-carboxylate (50 mg, 349 μmol). The crude product was purified using flash chromatography (EtOAc/Hexane 2:1). C01 (76 mg, 175 μmol, 50%) was obtained as colorless oil.

(636) TLC [EtOAc/Cyclohexane, 1:2]: R.sub.f=0.42.

(637) HPLC [0-100% Solvent B, 20 min]: R.sub.t=20.4 min, purity (220 nm)=99%.

(638) Mass: (ESI.sup.−), calculated 434.25 [C.sub.42H.sub.52N.sub.2O.sub.10+H].sup.+, found 434.17 [M−H].sup.+.

Example 5-2

Preparation of (S)-ethyl 1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C02

(639) ##STR00219##

(640) 19 (107 mg, 349 μmol), HATU (30 mg, 97 μmol) and DIEA (66 μL, 389 μmol) were dissolved in 500 μL DCM and stirred for 15 min at rt followed by the addition of (S)-ethyl piperidine-2-carboxylate (15 mg, 97 μmol). The reaction mixture was stirred for 16 h The crude product was purified using flash chromatography (EtOAc/Hexane 1:2). C02 (11 mg, 24 μmol, 25%) was obtained as colorless oil.

(641) TLC [EtOAc/Cyclohexane, 1:2]: R.sub.f=0.34.

(642) HPLC [0-100% Solvent B, 20 min]: R.sub.t=21.2 min, purity (220 nm)=99%.

(643) Mass: (ESI.sup.−), calculated 448.27 [C.sub.42H.sub.52N.sub.2O.sub.10+H].sup.+, found 448.20 [M−H].sup.+.

Example 5-3

Preparation of (S)-propyl 1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C03

(644) ##STR00220##

(645) 19 (138 mg, 449 μmol), HATU (171 mg, 449 μmol) and DIEA (305 μL, 1.8 mmol) were dissolved in 2 mL DMF and stirred for 15 min at it followed by the addition of (S)-ethyl piperidine-2-carboxylate (15 mg, 97 μmol). The crude product was purified using flash chromatography (EtOAc/Hexane 1:2). C03 (127 mg, 275 μmol, 61%) was obtained as colorless oil.

(646) TLC [EtOAc/Cyclohexane, 1:2]: R.sub.f=0.39.

(647) HPLC [0-100% Solvent B, 20 min]: R.sub.t=22.0 min, purity (220 nm)=96%.

(648) Mass: (ESI.sup.−), calculated 462.29 [C.sub.42H.sub.52N.sub.2O.sub.10+H].sup.+, found 462.23 [M−H].sup.+.

Example 5-4

Preparation of (S)-isopropyl 1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C04

(649) ##STR00221##

(650) 19 (63 mg, 204 μmol), HATU (78 mg, 204 μmol) and DIEA (139 μL, 816 μmol) were dissolved in 2 mL DCM and stirred for 15 min at rt followed by the addition of (S)-ethyl piperidine-2-carboxylate (15 mg, 97 μmol). The crude product was purified using flash chromatography (EtOAc/Hexane 1:2). C04 (37 mg, 80 μmol, 40%) was obtained as colorless oil.

(651) TLC [EtOAc/Cyclohexane, 1:2]: R.sub.f=0.43.

(652) HPLC [0-100% Solvent B, 20 min]: R.sub.t=21.9 min, purity (220 nm)=96%.

(653) Mass: (ESI.sup.−), calculated 462.29 [C.sub.42H.sub.52N.sub.2O.sub.10+H].sup.+, found 462.20 [M−H].sup.+.

Example 5-5

Preparation of (S)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)-N-ethylpiperidine-2-carboxamide C05

(654) ##STR00222##

(655) 19 (79 mg, 256 μmol), HATU (97 mg, 256 μmol) and DIEA (174 μL, 1024 μmol) were dissolved in 2 mL DCM and stirred for 15 min at rt followed by the addition of (S)-ethyl (S)-N-ethylpiperidine-2-carboxamide (40 mg, 97 μmol). The crude product was purified using flash chromatography (EtOAc/Hexane 1:2). C05 (68 mg, 152 μmol, 60%) was obtained as colorless oil.

(656) TLC [EtOAc/Cyclohexane, 1:2]: R.sub.f=0.37.

(657) HPLC [0-100% Solvent B, 20 min]: R.sub.t=18.8 min, purity (220 nm)=96%.

(658) Mass: (ESI.sup.−), calculated 447.28 [C.sub.42H.sub.52N.sub.2O.sub.10+H].sup.+, found 447.20 [M−H].sup.+.

Example 5-6

Preparation of (S)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylic acid C06

(659) ##STR00223##

(660) C02 (148 mg, 329 μmol) was dissolved in THF/H.sub.2O followed by the addition of 493 μl 1M LiOH (aq). The reaction mixture was stirred at rt for 16 h. Brine was added and the aqueous solution extracted with DCM. The organic phase was discarded and the aqueous phase acidified to pH=2 followed by extraction with DCM. The solution was dried over MgSO4 and the solvent reduced in vacuo. C06 was obtained as a white foam (130 mg, 310 μmol, 94%)

(661) TLC [EtOAc/Cyclohexane, 1:2+0.1% AcOH]: R.sub.f=0.15.

(662) HPLC [0-100% Solvent B, 20 min]: R.sub.t=13.4 min, purity (220 nm)=95%.

(663) Mass: (ESI.sup.−), calculated 419.23 [C.sub.42H.sub.52N.sub.2O.sub.10+H].sup.+, found 419.17 [M−H].sup.+.

Example 5-7

(S)-(S)-sec-butyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C07

(664) ##STR00224##

(665) 19 (20.81 mg, 0.067 mmol), HATU (25.7 mg, 0.067 mmol) and N-ethyl-N-isopropylpropan-2-amine (45.0 μl, 0.270 mmol) were dissolved in 500 μl DMF and stirred for 1 min. (S)-(S)-sec-butyl piperidine-2-carboxylate (12.5 mg, 0.067 mmol) dissolved in 500 μl DCM was added and stirred for 16 h. The crude product was concentrated and purified using flash chromatography (gradient 0-20% EtOAc in cyclohexane) C07 was obtained as a pale yellow oil (30 mg, 63 μmol, 93%).

(666) TLC [EtOAc/cyclohexane, 4:6]: R.sub.f=0.39.

(667) HPLC [0-100% Solvent B, 20 min]: R.sub.t=22.9 min, purity (220 nm)=98%.

(668) Mass: (ESI.sup.−), calculated 476.30 [C.sub.27H.sub.42NO.sub.6+H].sup.+, found 476.36 [M+H].sup.+.

(669) .sup.1H NMR (300 MHz, CDCl.sub.3) major rotamer δ 6.49 (s, 2H), 5.33 (d, J=5.4 Hz, 1H), 4.71 (q, J=6.4 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 3.83 (s, 9H), 3.36 (d, J=9.8 Hz, 1H), 3.00-2.86 (m, 1H), 2.29-2.20 (m, 1H), 2.18-2.06 (m, 2H), 1.88 (d, J=13.3 Hz, 1H), 1.75-1.51 (m, 6H), 1.37-1.20 (m, 4H), 1.19-1.06 (m, 3H), 1.01 (d, J=6.2 Hz, 3H), 0.89-0.73 (m, 2H), 0.69 (t, J=7.4 Hz, 3H).

(670) .sup.13C NMR (75 MHz, CDCl.sub.3) major rotamer δ 172.50, 171.03, 153.08, 136.93, 133.79, 106.00, 77.16, 73.03, 52.36, 32.91, 30.83, 28.72, 26.74, 26.36, 26.31, 25.78.

Example 5-8

(S)-(R)-sec-butyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C08

(671) ##STR00225##

(672) 19 (24.97 mg, 0.081 mmol), HATU (30.8 mg, 0.081 mmol) and N-ethyl-N-isopropylpropan-2-amine (54.0 μl, 0.324 mmol) were dissolved in 500 μl DMF and stirred for 1 min. (S)-(R)-sec-butyl piperidine-2-carboxylate (12.5 mg, 0.067 mmol) dissolved in 500 μl DCM was added and stirred for 16 h. The crude product was concentrated and purified using flash chromatography (gradient 0-20% EtOAc in cyclohexane) C08 was obtained as a pale yellow oil (35 mg, 74 μmol, 91%).

(673) TLC [EtOAc/cyclohexane, 2:8]: R.sub.f=0.22.

(674) HPLC [0-100% Solvent B, 20 min]: R.sub.t=22.9 min, purity (220 nm)=98%.

(675) Mass: (ESI.sup.−), calculated 476.30 [C.sub.27H.sub.42NO.sub.6+H].sup.+, found 476.23 [M+H].sup.+.

(676) .sup.1H NMR (300 MHz, CDCl.sub.3) major rotamer δ 6.49 (s, 2H), 5.33 (d, J=5.4 Hz, 1H), 4.71 (q, J=6.4 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 3.83 (s, 9H), 3.36 (d, J=9.8 Hz, 1H), 3.00-2.86 (m, 1H), 2.29-2.20 (m, 1H), 2.18-2.06 (m, 2H), 1.88 (d, J=13.3 Hz, 1H), 1.75-1.51 (m, 6H), 1.37-1.20 (m, 4H), 1.19-1.06 (m, 3H), 1.01 (d, J=6.2 Hz, 3H), 0.89-0.73 (m, 2H), 0.69 (t, J=7.4 Hz, 3H).

(677) .sup.13C NMR (75 MHz, CDCl.sub.3) major rotamer δ 172.50, 171.03, 153.08, 136.93, 133.79, 106.00, 77.16, 73.03, 52.36, 32.91, 30.83, 28.72, 26.74, 26.36, 26.31, 25.78.

Example 5-9

(S)-pentan-3-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C09

(678) ##STR00226##

(679) 19 (38.7 mg, 0.125 mmol), N-ethyl-N-isopropylpropan-2-amine (16.21 mg, 0.125 mmol) and HATU (47.7 mg, 0.125 mmol) were dissolved in 600 μL DMF followed by the addition of (S)-pentan-3-yl piperidine-2-carboxylate (25.0 mg, 0.125 mmol) dissolved in 600 μL DCM. The reaction mixture was stirred at rt for 16 h. The crude product was concentrated and purified using flash chromatography (gradient 0-20% EtOAc in cyclohexane). C09 was obtained as a colorless oil (48 mg, 98 μmol, 78%).

(680) TLC [EtOAc/cyclohexane, 3:7]: R.sub.f=0.47.

(681) HPLC [0-100% Solvent B, 20 min]: R.sub.t=23.5 min, purity (220 nm)=90%.

(682) Mass: (ESI.sup.−), calculated 490.32 [C.sub.28H.sub.44NO.sub.6+H].sup.+, found 490.19 [M+H].sup.+.

(683) .sup.1H NMR (300 MHz, CDCl.sub.3) major rotamer δ 6.49 (s, 2H), 5.36 (d, J=5.3 Hz, 1H), 4.85 (q, J=6.0 Hz, 1H), 3.99 (d, J=13.8 Hz, 1H), 3.84-3.80 (m, 9H), 3.37 (d, J=9.9 Hz, 1H), 2.94 (td, J=13.0, 2.8 Hz, 1H), 2.27 (d, J=14.1 Hz, 1H), 2.09 (dt, J=17.1, 9.4 Hz, 2H), 1.88 (d, J=13.2 Hz, 1H), 1.73-1.53 (m, 6H), 1.39-1.21 (m, 4H), 1.20-1.05 (m, 2H), 0.98-0.86 (m, 3H), 0.72 (dt, J=9.2, 7.4 Hz, 8H).

(684) .sup.13C NMR (75 MHz, CDCl.sub.3) major rotamer δ 172.51, 171.22, 153.07, 136.93, 133.79, 105.99, 78.45, 77.16, 60.89, 56.45, 56.27, 55.11, 52.28, 43.77, 41.40, 32.87, 30.83, 27.05, 26.90, 26.75, 26.55, 26.47, 26.37, 26.30, 21.18, 9.72, 9.60.

Example 5-10

(S)-tert-butyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C10

(685) ##STR00227##

(686) 19 (33.3 mg, 0.108 mmol), DIEA (0.074 ml, 0.432 mmol) and HATU (41.0 mg, 0.108 mmol) were dissolved in 500 μL DMF and stirred for 5 min at RT. (S)-tert-butyl piperidine-2-carboxylate (20 mg, 0.108 mmol) dissolved in 500 μL DCM was added and stirred for 16 h at rt. The crude product was concentrated and purified using flash chromatography (gradient 0-20% EtOAc in cyclohexane) C10 was obtained as a colorless oil (15 mg, 32 μmol, 30%).

(687) HPLC [0-100% Solvent B, 20 min]: R.sub.t=22.8 min, purity (220 nm)=91%.

(688) Mass: (ESI.sup.−), calculated 476.30 [C.sub.27H.sub.42NO.sub.6+H].sup.+, found 476.02 [M+H].sup.+.

(689) .sup.1H NMR (400 MHz, d6-DMSO) major rotamer δ 6.17 (s, 2H), 4.54-4.49 (m, 1H), 3.69 (d, J=13.5 Hz, 1H), 2.86 (s, 9H), 2.42-2.32 (m, 1H), 1.64-1.40 (m, 2H), 1.34-1.09 (m, 6H), 1.07-0.87 (m, 5H), 0.83-0.58 (m, 12H), 0.55-0.24 (m, 2H).

(690) .sup.13C NMR (101 MHz, d6-DMSO) major rotamer δ 171.99, 170.13, 152.44, 136.04, 133.78, 105.82, 80.37, 59.80, 55.73, 52.84, 52.19, 42.73, 40.80, 39.52, 31.73, 29.72, 27.65, 27.34, 27.11, 26.60, 26.11, 25.58, 25.10, 20.47.

Example 5-11

(S)-1-methylcyclopentyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C11

(691) ##STR00228##

(692) 19 (46.7 mg, 0.151 mmol), HATU (57.6 mg, 0.151 mmol) and DIEA (60 μl, 0.344 mmol) were dissolved in 500 μL DMF and stirred for 1 min at rt. (S)-1-methylcyclopentyl piperidine-2-carboxylate (32 mg, 0.151 mmol) dissolved in 500 μL DCM was added and stirred at rt for 3 h. The crude product was concentrated and purified using flash chromatography (gradient 0-20% EtOAc in cyclohexane) C11 was obtained as a colorless oil (56 mg, 112 μmol, 74%).

(693) TLC [EtOAc/cyclohexane, 3:7]: R.sub.f=0.49.

(694) HPLC [0-100% Solvent B, 20 min]: R.sub.t=23.7 min, purity (220 nm)=98%.

(695) Mass: (ESI.sup.−), calculated 502.32 [C.sub.29H.sub.44NO.sub.6+H].sup.+, found 502.12 [M+H].sup.+.

(696) .sup.1H NMR (400 MHz, dmso) δ 6.63 (s, 2H), 5.04-4.98 (m, 1H), 4.18 (d, J=13.2 Hz, 1H), 3.72 (s, 6H), 3.61 (s, 3H), 3.17 (d, J=5.2 Hz, 1H), 2.78 (t, J=12.4 Hz, 1H), 2.01 (dd, J=22.6, 10.2 Hz, 3H), 1.85-1.53 (m, 9H), 1.55-1.28 (m, 6H), 1.29-1.02 (m, 8H), 0.85 (dq, J=41.6, 13.6, 12.4 Hz, 2H).

(697) .sup.13C NMR (100 MHz, dmso) δ 172.02, 170.11, 152.59, 136.38, 133.82, 105.83, 89.93, 59.97, 55.57, 52.08, 42.84, 40.85, 39.52, 38.30, 37.92, 31.74, 29.77, 26.53, 26.11, 25.56, 25.16, 23.76, 23.38, 23.06, 22.94, 20.60.

Example 5-12

(S)-tetrahydro-2H-pyran-4-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxylate C12

(698) ##STR00229##

(699) C06 (20 mg, 0.048 mmol), tetrahydro-2H-pyran-4-ol (9.74 mg, 0.095 mmol) and N,N-dimethylpyridin-4-amine (1.747 mg, 0.014 mmol) were dissolved in dry DCM and cooled to 0° C. EDC (18.28 mg, 0.095 mmol) was added and the reaction was allowed to warm to it over night. The crude product was concentrated and purified using flash chromatography (gradient 0-30% EtOAc in cyclohexane) C12 was obtained as a colorless oil (14 mg, 28 μmol, 58%).

(700) TLC [EtOAc/cyclohexane, 3:7]: R.sub.f=0.19.

(701) HPLC [0-100% Solvent B, 20 min]: R.sub.t=21.0 min, purity (220 nm)=90%.

(702) Mass: (ESI.sup.−), calculated 504.30 [C.sub.28H.sub.42NO.sub.7+H].sup.+, found 504.20 [M+H].sup.+.

Example 5-13

(S)-cyclopentyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C13

(703) ##STR00230##

(704) C06 (20 mg, 0.048 mmol) and DBU (8.5 μL, 0.057) were dissolved in 1 mL MeCN followed by the addition of bromo-cyclopentane (7.8 mg, 0.052 mmol). The reaction was stirred at it for 16 h. The crude product was concentrated and purified using flash chromatography (EtOAc/cyclohexane, 1:2). C13 was obtained as a pale yellow oil (10 mg, 20.5 μmol, 44%).

(705) TLC [EtOAc/cyclohexane, 1:2]: R.sub.f=0.58.

(706) HPLC [0-100% Solvent B, 20 min]: R.sub.t=23.0 min, purity (220 nm)=98%.

(707) Mass: (ESI.sup.−), calculated 488.30 [C.sub.28H.sub.42NO.sub.6+H].sup.+, found 488.30 [M+H].sup.+.

Example 5-14

(S)-cyclopent-3-en-1-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C14

(708) ##STR00231##

(709) C06 (110 mg, 0.36 mmol), HATU (130 mg, 0.36 mmol) and DIEA (243 μl, 0.36 mmol) were dissolved in 500 μL DMF and stirred for 1 min at rt. (S)-cyclopent-3-en-1-yl piperidine-2-carboxylate (70 mg, 0.36 mmol) dissolved in 500 μL DCM was added and stirred at rt for 3 h. The crude product was concentrated and purified using flash chromatography (EtOAc/cyclohexane, 1:2). C14 was obtained as a white solid (120 mg, 112 μmol, 69%).

(710) TLC [EtOAc/cyclohexane, 1:2]: R.sub.f=0.52.

(711) HPLC [0-100% Solvent B, 20 min]: R.sub.t=22.6 min, purity (220 nm)=98%.

(712) Mass: (ESI.sup.−), calculated 426.29 [C.sub.28H.sub.39NO.sub.6+H].sup.+, found 486.16 [M+H].sup.+.

(713) .sup.1H NMR (400 MHz, CDCl.sub.3) major rotamer δ 6.46 (s, 1H), 5.59-5.53 (m, 2H), 5.27 (d, J=5.5 Hz, 1H), 5.25-5.20 (m, 1H), 3.94 (d, J=13.7 Hz, 1H), 3.85-3.78 (m, 9H), 3.35 (d, J=9.8 Hz, 1H), 2.92 (td, J=13.2, 2.9 Hz, 2H), 2.85-2.75 (m, 3H), 2.65-2.53 (m, 3H), 2.45-2.36 (m, 1H), 2.22 (d, J=13.5 Hz, 1H), 2.17-1.98 (m, 2H), 1.92-1.82 (m, 1H), 1.71-1.54 (m, 3H), 1.35-1.23 (m, 2H), 1.19-1.05 (m, 1H), 0.94-0.82 (m, 2H), 0.79-0.66 (m, 2H).

(714) .sup.13C NMR (101 MHz, CDCl.sub.3) major rotamer δ 172.50, 171.16, 152.89, 136.67, 133.58, 128.00, 127.89, 105.68, 74.73, 60.76, 56.09, 54.97, 52.19, 43.60, 41.19, 39.55, 39.40, 32.71, 30.67, 26.89, 26.56, 26.19, 26.15, 25.51, 20.99.

Example 5-15

(2S)-cyclohex-2-en-1-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C15

(715) ##STR00232##

(716) C06 (20 mg, 0.048 mmol) and DBU (8.5 μL, 0.057) were dissolved in 1.0 mL MeCN followed by the addition of bromo-cyclohexane (6.0 μL, 0.052 mmol). The reaction was stirred at it for 16 h. The crude product was concentrated and purified using flash chromatography (EtOAc/cyclohexane, 1:2) C15 was obtained as a yellow oil (6 mg, diastereomeric mixture, 13 μmol, 30%).

(717) TLC [EtOAc/cyclohexane, 1:2]: R.sub.f=0.60.

(718) HPLC [0-100% Solvent B, 20 min]: R.sub.t=23.2 min, purity (220 nm)=90%.

(719) Mass: (ESI.sup.−), calculated 500.30 [C.sub.29H.sub.42NO.sub.6+H].sup.+, found 500.17 [M+H].sup.+.

(720) .sup.1H NMR (300 MHz, CDCl.sub.3) mixture of diastereomers δ 6.49 (s, 2H), 5.88-5.81 (m, 1H), 5.61-5.47 (m, 1H), 5.35-5.31 (m, 1H), 5.21-5.10 (m, 1H), 4.01-3.91 (m, 2H), 3.83 (s, 6H), 3.82 (s, 3H), 3.14 (d, J=9.5 Hz, 1H), 2.14-2.01 (m, 5H), 1.97-1.82 (m, 3H), 1.66 (t, J=13.6 Hz, 7H), 1.50-1.01 (m, 6H), 0.84 (ddd, J=38.8, 22.8, 10.6 Hz, 2H).

(721) .sup.13C NMR (75 MHz, CDCl.sub.3) mixture of diastereomers δ 172.42, 170.59, 152.87, 133.90, 133.28, 132.67, 125.08, 105.50, 68.49, 60.51, 56.28, 52.27, 43.39, 41.00, 32.70, 29.66, 27.81, 27.20, 26.28, 25.05, 20.82, 18.37.

Example 5-16

(S)-cycloheptyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C16

(722) ##STR00233##

(723) C06 (10 mg, 0.024 mmol) and DBU (5.0 μL, 0.029) were dissolved in 1.0 mL MeCN followed by the addition of bromo-cycloheptane (8.0 μL, 0.056 mmol). The reaction was stirred at rt for 16 h. The crude product was concentrated and purified using flash chromatography (EtOAc/cyclohexane, 1:2) C16 was obtained as a yellow oil (6.3 mg, 12 μmol, 50%):

(724) TLC [EtOAc/cyclohexane, 1:2]: R.sub.f=0.70.

(725) HPLC [0-100% Solvent B, 20 min]: R.sub.t=24.4 min, purity (220 nm)=90%.

(726) Mass: (ESI.sup.−), calculated 516.33 [C.sub.30H.sub.46NO.sub.6+H].sup.+, found 516.40 [M+H].sup.+.

Example 5-17

(S)-allyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C17

(727) ##STR00234##

(728) C06 (20 mg, 0.048 mmol) and DBU (8.5 μL, 0.057) were dissolved in 1.0 mL MeCN followed by the addition of bromo-cyclohexane (4.5 μL, 0.052 mmol). The reaction was stirred at rt for 16 h. The crude product was concentrated and purified using flash chromatography (EtOAc/cyclohexane, 1:2). C17 was obtained as a yellow oil (12.0 mg, 26 μmol, 54%).

(729) TLC [EtOAc/cyclohexane, 1:2]: R.sub.f=0.49.

(730) HPLC [0-100% Solvent B, 20 min]: R.sub.t=22.2 min, purity (220 nm)=98%.

(731) Mass: (ESI.sup.−), calculated 460.27 [C.sub.26H.sub.38NO.sub.6+H].sup.+, found 460.27 [M+H].sup.+.

(732) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.47 (s, 2H), 5.77-5.59 (m, 1H), 5.41-5.33 (m, 1H), 5.19-5.03 (m, 2H), 4.47 (tt, J=5.5, 1.6 Hz, 1H), 3.98-3.88 (m, 1H), 3.84-3.81 (m, 9H), 3.37 (d, J=9.8 Hz, 1H), 3.01-2.84 (m, 1H), 2.26 (d, J=13.9 Hz, 1H), 2.16-2.00 (m, 2H), 1.88 (d, J=12.5 Hz, 2H), 1.73-1.55 (m, 4H), 1.40-1.04 (m, 6H), 0.97-0.68 (m, 3H).

(733) .sup.13C NMR (75 MHz, cdcl3) δ 172.51, 170.86, 152.91, 136.76, 134.31, 133.38, 131.69, 117.86, 105.83, 65.29, 60.78, 56.28, 56.14, 55.13, 52.26, 43.63, 41.15, 32.81, 30.70, 29.66, 26.76, 26.57, 26.22, 26.18, 26.09, 25.49, 20.99.

Example 5-18

(S)-2-methoxyethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C18

(734) ##STR00235##

(735) C06 (30 mg, 0.072 mmol) and DBU (13 μL, 0.086) were dissolved in 1.0 mL MeCN followed by the addition of bromo-2-methoxyethane (7.4 μL, 0.079 mmol). The reaction was stirred at rt for 16 h. The crude product was concentrated and purified using flash chromatography (gradient 0-50% EtOAc in cyclohexane). C18 was obtained as a yellow oil (15.5 mg, 32 μmol, 45%).

(736) TLC [EtOAc/cyclohexane, 1:2]: R.sub.f=0.19.

(737) HPLC [0-100% Solvent B, 20 min]: R.sub.t=21.01 min, purity (220 nm)=97%.

(738) Mass: (ESI.sup.−), calculated 478.28 [C.sub.26H.sub.39NO.sub.7+H].sup.+, found 478.19 [M+H].sup.+.

(739) .sup.1H NMR (400 MHz, d6-DMSO) δ 6.60 (s, 2H), 5.18-5.10 (m, 1H), 4.27-4.23 (m, 1H), 3.72-3.72 (m, 7H), 3.63 (s, 3H), 3.57-3.53 (m, 1H), 3.11 (s, 3H), 2.86-2.75 (m, 1H), 2.10-2.03 (m, OH), 2.01-1.87 (m, 1H), 1.75 (t, J=13.9 Hz, 1H), 1.68-1.46 (m, 6H), 1.41-1.26 (m, 3H), 1.25-1.04 (m, 5H), 1.00-0.72 (m, 4H).

(740) .sup.13C NMR (101 MHz, d6-DMSO) δ 171.99, 170.71, 136.02, 134.75, 105.85, 69.40, 63.29, 59.87, 57.84, 55.75, 52.92, 51.74, 42.83, 40.82, 39.52, 31.85, 29.80, 26.52, 26.10, 25.08, 20.53.

Example 5-19

(S)-2-(benzyloxy)ethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C19

(741) ##STR00236##

(742) C06 (50.0 mg, 0.119 mmol), potassium iodide (2.0 mg, 0,012 mmol) and Benzyl 2-bromoethyl ether (19.0 μl, 0.119 mmol) were dissolved in 1 ml dry DCM followed by the addition of DBU (20.0 μl, 0.133 mmol). The reaction mixture was stirred at rt for 16 h. The crude product was concentrated and purified using flash chromatography (gradient 0-30% EtOAc in cyclohexane) C19 was obtained as a yellow oil (15.5 mg, 32 μmol, 45%).

(743) TLC [EtOAc/cyclohexane, 2:8]: R.sub.f=0.22.

(744) HPLC [0-100% Solvent B, 20 min]: R.sub.t=22.7 min, purity (220 nm)=91%.

(745) Mass: (ESI.sup.−), calculated 554.31 [C.sub.32H.sub.44NO.sub.7+H].sup.+, found 554.27 [M+H].sup.+.

Example 5-20

(S)-2-hydroxyethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C20

(746) ##STR00237##

(747) C19 (37.0 mg, 0.067 mmol) was dissolved in 1 mL MeOH (degassed with Argon). Pd/C 10% (21.3 mg, 0.020 mmol) was added and the reaction was put under hydrogen atmosphere. The reaction was stirred for 16 h at rt. The crude product was concentrated and purified using flash chromatography (gradient 0-100% EtOAc in cyclohexane). 19 was obtained as colourless oil (10.0 mg, 0.022 mmol, 33%).

(748) TLC [EtOAc/cyclohexane, 2:8]: R.sub.f=0.26.

(749) HPLC [0-100% Solvent B, 20 min]: R.sub.t=23.7 min, purity (220 nm)=98%.

(750) Mass: (ESI.sup.−), calculated 464.26 [C.sub.25H.sub.38NO.sub.7+H].sup.+, found 464.30 [M+H].sup.+.

(751) .sup.1H NMR (400 MHz, d6-DMSO) major rotamer δ 6.58 (s, 2H), 5.15-5.08 (m, 1H), 4.41 (d, J=13.0 Hz, 1H), 3.72 (s, 6H), 3.63 (s, 3H), 2.88-2.78 (m, 1H), 2.13-2.05 (m, 1H), 2.03-1.89 (m, 2H), 1.81-1.69 (m, 1H), 1.69-1.53 (m, 6H), 1.52-1.44 (m, 1H), 1.29-1.13 (m, 4H), 1.14-1.03 (m, 4H), 0.98-0.88 (m, 2H), 0.87-0.74 (m, 2H).

(752) .sup.13C NMR (101 MHz, d6-DMSO) major rotamer δ 172.55, 171.22, 152.84, 136.45, 134.10, 106.32, 66.88, 66.34, 60.34, 59.16, 56.37, 56.20, 53.42, 52.28, 43.28, 41.25, 32.31, 30.26, 27.03, 26.55, 26.10, 26.07, 26.00, 25.53, 21.19, 21.04.

Example 5-21

(S)-3-(benzyloxy)propyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C21

(753) ##STR00238##

(754) C06 (50.0 mg, 0.119 mmol), sodium iodide (10.0 mg, 0.067 mmol) and ((3-bromopropoxy)methyl)benzene (137 mg, 0.596 mmol) were dissolved in 1 ml dry DMF followed by the addition of DBU (90.0 μL, 0.596 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was stirred at rt for 16 h. The crude product was concentrated and purified using flash chromatography (gradient 0-30% EtOAc in cyclohexane) C21 was obtained as an colourless oil (35.0 mg, 0.061 mmol, 50%).

(755) TLC [EtOAc/cyclohexane, 4:6]: R.sub.f=0.52.

(756) HPLC [0-100% Solvent B, 20 min]: R.sub.t=23.2 min, purity (220 nm)=92%.

(757) Mass: (ESI.sup.−), calculated 568.33 [C.sub.33H.sub.46NO.sub.7+H].sup.+, found 568.23 [M+H].sup.+.

(758) .sup.1H NMR (300 MHz, CDCl.sub.3) major rotamer δ 6.47 (s, 2H), 5.33 (d, J=5.0 Hz, 1H), 4.40 (d, J=7.1 Hz, 2H), 4.18-4.02 (m, 2H), 3.90 (d, J=13.7 Hz, 1H), 3.84-3.79 (m, 9H), 3.55 (t, J=5.9 Hz, 2H), 3.47 (s, 1H), 3.40-3.23 (m, 2H), 3.11 (d, J=9.7 Hz, 1H), 2.93-2.81 (m, 1H), 2.21 (d, J=14.0 Hz, 1H), 2.14-2.04 (m, 1H), 2.02-1.80 (m, 2H), 1.77-1.49 (m, 6H), 1.46-1.37 (m, 1H), 1.36-1.17 (m, 4H), 1.16-1.00 (m, 2H), 0.97-0.82 (m, 2H), 0.82-0.66 (m, 2H).

(759) .sup.13C NMR (75 MHz, CDCl.sub.3) major rotamer δ 172.44, 171.12, 152.91, 138.29, 136.76, 133.52, 128.31, 127.51, 105.81, 72.88, 66.28, 62.02, 60.77, 56.14, 52.19, 43.57, 41.25, 32.78, 30.70, 28.83, 26.80, 26.56, 26.21, 26.18, 25.52, 20.99.

Example 5-22

(S)-2-hydroxyethyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylate C22

(760) ##STR00239##

(761) C21 (30.0 mg, 0.053 mmol) was dissolved in 1 mL EtOH (degassed with Argon). Pd/C 10% (16.9 mg, 0.016 mmol) was added and the reaction was put under hydrogen atmosphere. Argon was exchanged by H.sub.2 gas and the reaction was stirred for 16 h. The crude product was concentrated and purified using flash chromatography (gradient 0-100% EtOAc in cyclohexane). C22 was obtained as pale yellow oil (15.0 mg, 0.016 mmol, 58%).

(762) TLC [EtOAc/cyclohexane, 1:1]: R.sub.f=0.20.

(763) HPLC [0-100% Solvent B, 20 min]: R.sub.t=19.1 min, purity (220 nm)=90%.

(764) Mass: (ESI.sup.−), calculated 478.28 [C.sub.26H.sub.40NO.sub.7+H].sup.+, found 478.14 [M+H].sup.+.

(765) .sup.1H NMR (400 MHz, d6-DMSO) δ 6.61 (s, 2H), 4.99-4.94 (m, 1H), 4.13 (d, J=13.5 Hz, 1H), 3.71 (s, 6H), 3.65-3.61 (m, 3H), 3.60 (s, 3H), 3.54-3.49 (m, 2H), 2.82 (td, J=13.2, 2.7 Hz, 1H), 2.06-1.87 (m, 2H), 1.79-1.47 (m, 4H), 1.45-1.28 (m, 2H), 1.29-1.02 (m, 9H), 0.99-0.71 (m, 2H).

(766) .sup.13C NMR (100 MHz, d6-DMSO) δ 172.41, 171.27, 152.86, 136.46, 135.24, 134.10, 106.34, 62.07, 60.20, 57.67, 57.30, 56.36, 56.21, 52.19, 43.34, 41.25, 32.27, 31.98, 31.74, 30.24, 26.95, 26.56, 26.07, 25.55, 21.07.

Example 5-23

(S)-4-methoxybutyl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylate C23

(767) ##STR00240##

(768) C06 (50.0 mg, 0.119 mmol), sodium iodide (10.0 mg, 0.067 mmol) and 1-bromo-4-methoxybutane (77.0 μL, 0.596 mmol) were dissolved in 1 ml dry DMF followed by the addition of DBU (90.0 μl, 0.596 mmol). The reaction mixture was stirred at it for 16 h. The crude product was concentrated and purified using flash chromatography (gradient 0-30% EtOAc in cyclohexane). C23 was obtained as an yellow oil (37.0 mg, 0.073 mmol, 61%).

(769) TLC [EtOAc/cyclohexane, 1:2]: R.sub.f=0.12.

(770) HPLC [0-100% Solvent B, 20 min]: R.sub.t=21.6 min, purity (220 nm)=90%.

(771) Mass: (ESI.sup.−), calculated 506.31 [C.sub.28H.sub.44NO.sub.7+H].sup.+, found 506.20 [M+H].sup.+.

(772) .sup.1H NMR (400 MHz, d6-DMSO) δ 6.56 (s, 2H), 5.13-5.01 (m, 1H), 4.16-4.00 (m, 2H), 3.97-3.88 (m, 1H), 3.89-3.80 (m, 1H), 3.69 (d, J=2.5 Hz, 6H), 3.60 (s, 3H), 3.14 (s, 3H), 2.79-2.70 (m, 1H), 2.07-1.84 (m, 3H), 1.78-1.65 (m, 2H), 1.66-1.39 (m, 6H), 1.38-1.24 (m, 4H), 1.22-1.00 (m, 4H), 0.97-0.68 (m, 4H).

(773) .sup.13C NMR (100 MHz, d6-DMSO) δ 172.00, 170.73, 152.41, 136.12, 133.56, 105.82, 71.07, 64.09, 59.88, 57.64, 55.68, 52.87, 51.75, 42.91, 40.84, 39.52, 31.82, 29.79, 26.48, 26.10, 25.57, 25.26, 24.85, 20.61.

Example 5-24

(S)-(R)-1-(benzyloxy)propan-2-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxylate C24

(774) ##STR00241##

(775) 19 (33.4 mg, 0.108 mmol), HATU (41.1 mg, 0.108 mmol) and N-ethyl-N-isopropylpropan-2-amine (74.6 μL, 0.433 mmol) were dissolved in 0.5 mL DMF and stirred for 5 min followed by the addition of (S)-(R)-1-(benzyloxy)propan-2-yl piperidine-2-carboxylate (30.0 mg, 0.108 mmol) dissolved in 0.5 mL DCM. The reaction mixture was stirred for 3 h. The crude product was concentrated and purified using flash chromatography (gradient 0-50% EtOAc in cyclohexane). C24 was obtained as a colorless oil (43 mg, 0.076 mmol, 70%).

(776) TLC [EtOAc/cyclohexane, 3:7]: R.sub.f=0.34.

(777) HPLC [0-100% Solvent B, 20 min]: R.sub.t=23.7 min, purity (220 nm)=90%.

(778) Mass: (ESI.sup.−), calculated 568.33 [C.sub.33H.sub.46NO.sub.7+H].sup.+, found 568.22 [M+H].sup.+.

Example 5-25

(R)-(R)-1-(benzyloxy)propan-2-yl-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl) acetyl)piperidine-2-carboxylate C25

(779) ##STR00242##

(780) C24 (38.0 mg, 0.067 mmol) was dissolved in EtOH and degassed with Argon. Pd/C 10% (14.25 mg, 9.51 μmol) was added and the reaction was put under hydrogen atmosphere. The reaction mixture was stirred for 16 h. The Pd was filtered and the crude product was concentrated followed by purification using flash chromatography (gradient 0-50% EtOAc in cyclohexane).flash chromatography. C25 (12.0 mg, 25.0 μmol, 37%) was obtained as colorless oil.

(781) TLC [EtOAc/cyclohexane, 3:7]: R.sub.f=0.22.

(782) LCMS [30-100% Solvent B, 15 min]: R.sub.t=10.1 min, purity (220 nm)=99%.

(783) Mass: (ESI.sup.−), calculated 478.28 [C.sub.26H.sub.39NO.sub.7+H].sup.+, found 478.25 [M+H].sup.+.

Example 6-A

Expression and Purification of FKBPs (FKBP51, FKBP51 (K58T/K60W/F129V), FKBP52, FKBP52 (T58K/W60K/V129F)

(784) The protein expressions were performed according to Kozany, C.; Marz, A.; Kress, C.; Hausch, F., Fluorescent probes to characterise FK506-binding proteins. Chembiochem 2009, 10, (8), 1402-10.

(785) Plasmids harbouring the cDNA of FKBP12 and expression plasmids for full-length FKBP51 and FKBP52 with additional carboxy terminal FLAG-tag were kindly provided by Dr. Theo Rein (Max Planck Institute for Psychiatry, Munich, Germany). Plasmids containing the cDNA sequences of FKBP12.6, −13 and −25 were kindly provided by Dr. Gunter Fischer (Max Planck Institute for Enzymology, Halle, Germany). FKBP12 was amplified with the sense primer: 5′-AAA GAA TTC ATG GGA GTG CAG GTG GAA ACC-3′, and the antisense primer: 5′-CCC GTC GAC TCA TTC CAG TTT TAG AAG CTC C-3′. Cloning into plasmid pProExHta (Invitrogen, Carlsbad, USA) was performed with the restriction enzymes EcoRI (NEB, Ipswich, USA) and SalI (NEB). For the amplification of the coding sequence of FKBP51FK1 the sense primer: 5′-CAT GCC ATG GCA ATG ACT GAT G-3′, and the antisense primer: 5′-GCA GTC GAC TCA CTC TCC TTT GAA ATC AAG GAG C-3′, were used. For FKBP52FK1 the sense primer: 5′-GCG CCA TGG GGA TGA CAG CCG AGG AG-3′, and the antisense primer: 5′-GTC GAC TCA TTC TCC CTT AAA CTC AAA CAA CTC-3′ were utilized. FKBP51FK1 was cloned into pProExHta by using the restriction enzymes NcoI (NEB) and XbaI (NEB), FKBP52FK1 was cloned with NcoI and SalI. FKBP12.6 was amplified by using the sense primer: 5′-CCG GAA TTC ATG GGC GTG GAG ATC GAG-3′, and the antisense primer: 5′-CTC GAG TCA CTC TAA GTT GAG CAG CTC-3′. For FKBP13, the sense primer: 5′-CCG GAA TTC AAA AGG AAG CTG CAG ATC GG-3′, and the antisense primer: 5′-CTC GAG TTA CAG CTC AGT TCG CTC-3′, were used to amplify a truncated fragment of FKBP13 (amino acids 27-142) without a leader peptide. Full-length FKBP25 was amplified by using the sense primer: 5′-CCG GAA TTC ATG GCG GCC GTT CC-3′, and the antisense primer: 5′-CTC GAG TCA ATC AAT ATC CAC TAA TTC-3′. The PCR products of FKBP12.6, −13 and −25 were cloned into pProExHta by using the restriction enzymes EcoRI and XhoI (NEB).

(786) Induction of protein expression in E. coli BL21(DE3)pLysS was performed by addition of IPTG (0.6 mM; Eppendorf, Hamburg, Germany). FKBP12, FKBP12.6, FKBP13, FKBP25, FKBP52, FKBP51FK1 and FKBP52FK1 were purified by a single Ni-NTA (Qiagen, Hilden, Germany) affinity column. The standard protocol was modified by using HEPES (50 mM, pH 8), NaCl (20 mM), glycerol (10%) and imidazol (30 mM) as washing buffer. The elution buffer was HEPES (50 mM, pH 8), NaCl (20 mM), glycerol (10%) and imidazol (300 mM). For full-length FKBP51 a tandem purification strategy was employed by using Ni-NTA chromatography as the first step and an additional FLAG affinity chromatography as the second step. The eluate from the Ni-NTA column was passed over FLAG M2 affinity gel (Sigma-Aldrich, St. Louis, USA) and eluted with FLAG-peptide (100 μg mL-1; Sigma-Aldrich). Proteins were analysed by SDS-PAGE and stained with Coomassie brilliant blue (Carl Roth GmbH, Karlsruhe, Germany). The protein yield was quantified by UV quantification or Bradford assay (BioRad, Hercules, USA).

Example 6-B

Fluorescence Polarization (FP) Assays

(787) In-vitro fluorescence polarization assays were performed to determine the binding affinities for FKBP51 and 52 according to a literature procedure (Kozany, C.; Marz, A.; Kress, C.; Hausch, F., Fluorescent probes to characterise FK506-binding proteins. Chembiochem 2009, 10, (8), 1402-10).

(788) For fluorescence polarization assays the fluorescent ligand F2 or F4 was dissolved in HEPES (20 mm, pH 8), Triton-X100 (0.01%), at double the concentration required for the final sample. The target protein was also diluted in this assay buffer at double the highest concentration required for the final sample. This protein stock was used for a 1:1 serial dilution.

(789) The fluorescent ligand F2 or F4 was diluted in assay buffer to a concentration double the final concentration (20 nM F2, 3 nM F4). The inventive compound was dissolved in DMSO to reach a 100-times concentrated stock solution. This was used for a 1:1 serial dilution in DMSO. Every sample of this serial dilution was diluted by a factor of 50 in assay buffer supplemented with ligand F2 or F4 to achieve a 2× concentrated mixture of ligand F2/F4 and the inventive compound. To each of these competitive ligand double the protein concentration for F2 assay: FKBP51.sup.WT 560 nM (2×280 nM), FKBP52.sup.WT 800 nM (2×400 nM), FKBP12.sup.WT 20 nM (2×10 nM), for F4 assay: FKBP51.sup.WT 10 nM diluted in assay buffer was added.

(790) The samples were transferred to black 384-well assay plates (No.: 3575; Corning Life Sciences). After incubation at room temperature for 30 min the fluorescence anisotropy was measured (GENios Pro, Tecan, M_nnedorf, Switzerland) by using an excitation filters of 485/20 nm and emission filters of 535/25 nm. For FKBP12, −51, and −52 the binding assays were performed in duplicates in the plate format.

(791) The competition curves were analyzed by using SigmaPlot9. Data were fitted to a four parameter logistic curve to deduce the IC.sub.50 values. For the analysis of K.sub.i values, data were fitted to the following equation (Z. X. Wang, FEBS Lett. 1995, 360, 111-114).
A=(A.sub.max−A.sub.min)/[L].sub.t×(([L].sub.t×((2×((K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)^2−3×(K.sub.comp×([L].sub.t−[R].sub.t)+K.sub.lig×([I].sub.t−[R].sub.t)+K.sub.lig×K.sub.comp))^0.5×COS(ARCCOS((−2×(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)^3+9×(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)×(K.sub.comp×([L].sub.t−[R].sub.t)+K.sub.lig×([I].sub.t−[R].sub.t)+K.sub.lig×K.sub.comp)−27×(−1×K.sub.lig×K.sub.comp×[R].sub.t))/(2×((((K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)^2−3×(K.sub.comp×([L].sub.t−[R].sub.t)+K.sub.lig×([I].sub.t−[R].sub.t)+K.sub.lig×K.sub.comp))^3)^0.5)))/3))−(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)))/((3×K.sub.lig)+((2×((K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)^2−3×(K.sub.comp×([L].sub.t−[R].sub.t)+K.sub.lig×([I].sub.t−[R].sub.t)+K.sub.lig×K.sub.comp))^0.5×COS(ARCCOS((−2×(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)^3+9×(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)×(K.sub.comp×([L].sub.t−[R].sub.t)+K.sub.lig×([I].sub.t−[R].sub.t)+K.sub.lig×K.sub.comp)−27×(−1×K.sub.lig×K.sub.comp×[R].sub.t))/(2×((((K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t)^2−3×(K.sub.comp×([L].sub.t−[R].sub.t)+K.sub.lig×([I].sub.t−[R].sub.t)+K.sub.lig×K.sub.comp))^3)^0.5)))/3))−(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t−[R].sub.t))))+A.sub.min

(792) In this equation K.sub.lig and K.sub.comp stand for the K.sub.d values of the used tracer or competing inhibitor, [I].sub.t is referring to the total concentration of the titrated inhibitor.

(793) ##STR00243##

(794) These assays revealed that Cα-substitutents (R*) consistently induced a selectivity for FKBP51 vs. FKBP52. Furthermore, selected R*-substituents substantially increased the affinity for FKBP51 compared to all known FKBP51 ligands so far. Tables 4 and 5 summarize the binding data of exemplary compounds.

(795) Table 4: Summary of Selectivity Factors FKBP51 vs. FKBP52

(796) The Selectivity of the Compounds was Classified by Ki(FKBP51)/Ki(FKBP52)

(797) Inhibition constants were measured in a fluorescence polarization binding assay by titrating the compounds. Purified FK1-domains of FKBP51WT (4.5 nM) with F4 (3 nM), FKBP52WT (400 nM) with F2 (20 nM).

(798) The compounds A02-A06, A08-A32, A36-A38 are selective FKBP51 inhibitors of which Ki values are: K.sub.i≦0.1 μM ++++ 0.1 μM<K.sub.i≦1 μM +++ 1 μM<K.sub.i≦10 μM ++ 10 μM<K.sub.i≦50 μM +

(799) Selectivity over FKBP52 with a factor of: <5 not selective >5 + >50 ++ >500 +++ >5000 ++++

(800) TABLE-US-00007 TABLE 5 Summary of Binding Assay (Ki values) of the compounds B01-B35 and C01-C25 Compound Ki(FKBP51)/Ki(FKBP52) Affinity(Ki) for FKBP51 Reference A01 not selective + A02 + + A03 + + A04 + + A05 + ++ A06 + + Reference A07 not selective + A08 + ++ A09 + + A10 + + A11 +++ ++++ A12 +++ ++++ A13 +++ ++++ A14 ++ +++ A15 +++ ++++ A16 ++ +++ A17 ++++ ++++ A18 ++++ ++++ A19 +++ ++++ A20 ++ +++ A21 ++ ++++ A22 ++ +++ A23 + + A24 + + A25 + + A26 + + A27 + + A28 + + A29 +++ + A30 ++ + A31 + + A32 + + Reference A33 not selective Reference A34 not selective A36 +++ ++ A37 ++ + A38 ++ ++

(801) ##STR00244##

(802) The compounds B01-C25 are selective FKBP51 inhibitors of which Ki values are: K.sub.i≦0.1 μM ++++ 0.1 μM<K.sub.i≦1 μM +++ 1 μM<K.sub.i≦10 μM ++ 10 μM<K.sub.i≦50 μM +

(803) Selectivity over FKBP52 with a factor of: >5 + >50 ++ >500 +++ >5000 ++++

(804) TABLE-US-00008 Affinity(Ki) for Compound R Ki(FKBP51)/Ki(FKBP52 FKBP51 B01 ++ ++ B02 ++ ++ B03 + + B04 + ++ B05 ++ ++ B06 0 ++ ++ B07 + + B08 ++ ++ B09 ++ + B10 + + B11 +++ ++ B12 ++ ++ B13 ++ ++ B14 ++ ++ B15 ++ ++ B16 0 ++ ++ B17 +++ ++ B18 ++ ++ B19 ++ + B20 ++ ++ B21 ++ ++ B22 ++ ++ B23 + + B24 ++ ++ B25 +++ ++ B26 0 ++ + B27 ++ ++ B28 ++++ +++ B29 ++ ++ B30 ++ ++ B31 ++ ++ B32 ++ + B33 +++ ++ B34 ++ + B35 + + C01 0 ++ ++ C02 ++ ++ C03 +++ ++ C04 +++ +++ C05 ++ + C06 + + C07 ++ + C08 ++ ++ C09 ++ + C10 +++ ++ C11 0 +++ ++ C12 +++ ++ C13 +++ ++ C14 +++ ++ C15 ++ ++ C16 ++ + C17 ++ + C18 ++ ++ C19 ++ ++ C20 +++ ++ C21 00 ++ ++ C22 01 +++ ++ C23 02 +++ ++ C24 03 +++ ++ C25 04 ++ ++

Example 6-C

Fluorescence Polarization (FP) Assays with FKBP Mutants

(805) In-vitro fluorescence polarization assays were performed to determine the binding affinities for FKBP51, FKBP51 (K58T/K60W/F129V), FKBP52, FKBP52 (T58K/W60K/V129F).

(806) For this fluorescence polarization assay the fluorescent tracer F2 and F4 were used.

(807) ##STR00305##

Example 7

N2a Cellular Assay

(808) At day one N2a cells were plated into 24-well plates with cover slips (pretreated with polylysine) at a density of 35,000 cells/well and cultured with DMEM (incl. FCS 10% and Pen/Strep 1%) for 24 h. Next, cells were transfected with 80 ng expression plasmids encoding Venus as well as 720 ng pRK5 (mock transfection) in a total volume of 500 μl starvation media containing different concentrations of compounds or DMSO for 36 h (media without FCS; induction of neurite outgrowth). Therefore media was removed and replaced by 400 μl DMEM (empty). Next an equivalent volume of plasmids were given to 50 μl OPTIMEM and incubated for 5 min at RT. Additionally 1.5 μl Lipofectamine 2000 was separately dissolved in 50 μl OPTIMEM. After 5 min both solutions (plasmids and Lipofactamine 2000 containing media) were combined and incubated again for another 20 min. After that 100 μl of this mixture was given to 400 μl media per well. (See also protocol of the provider—Life Technologies).

(809) On the next day cells were washed with PBS and incubated for 30 min with 300 μl PFA (4%) and sucrose (5%) to fix cells. After fixation cells were washed three times, mounted onto microscope slides using 4 μl Vectashield (mounting media) and analyzed by fluorescence microscopy. Each bar represents the mean of the neurite length of 30-50 cells after the indicated treatment (FIGS. 1-2).

Example 8

Crystallization Method of FKBP 51 and Measurement of FKBP 51 Crystal

(810) The protein-ligand complex was prepared by mixing a 1.75 mM solution of a construct of FKBP51 comprising residues 16-140 and carrying mutation A19T in 20 mM Tris-HCl pH 8.0 and 50 mM NaCl with ligand dissolved in DMSO, so that the final ligand concentration was 2 mM and the DMSO concentration smaller than 10%. For crystallization by the hanging-drop isothermal vapor diffusion method, 1 μl of the protein-ligand complex solution was mixed with 1 μl of a precipitant solution containing 25-35% PEG-3350, 0.2 M ammonium acetate and 0.1 M HEPES-NaOH pH 7.5, and equilibrated at 20° C. against 500 μl of the precipitant solution. Crystal formation took several days to weeks.

(811) Single crystals were harvested and cryo-mounted for X-ray diffraction data collection at synchrotron light sources at 100 K. The oscillation data images were integrated and processed using the programs XDS, Pointless, Scala and Truncate. The structures were solved by molecular replacement using the program Molrep and the apo structure as a search template. The programs Coot and Refmac were used for model building and refinement.

(812) Instructions for Superpositions

(813) For superposition of FKBP51 structures, the program Isqkab, as implemented in the program suite CCP4 6.1 (10/04/08), was used. The following program commands were executed: Isqkab xyzinm $name_r xyzinr $name_m\ RMSTAB $filename.tab <<EOF FIT RESIDUE ALL 20 TO 137 CHAIN $ch_m MATCH RESIDUE ALL 20 TO 137 CHAIN $ch_r OUTPUT RMS END EOF $name_m and $name_r are the filenames of the pdb-type coordinate files of new structure and reference structure, respectively. $ch_m and $ch_r specify the respective chain identifier of the respective FKBP51 protein chains in the coordinate files. $filename.tab is the name of the output file containing the list of residue rmsds.

Example 12

Behavioral Analysis

(814) For the forced swim test (FST), male C57Bl/6N mice at the age of 12 weeks were single housed and acclimated to the room for 2 weeks before the experiment. Initially, mice were split into two groups (n=11 vehicle, n=11 A18) and received a single injection of either of 20.0 mg/kg bodyweight of compound A18 (solubilized in 4% EtOH, 5% Tween80, 5% PEG400 in 0.9% saline) or vehicle solution in the afternoon, 16 hours prior to testing. The next morning, mice were subjected to a FST to assess stress-coping behavior. Each mouse was put into a 2 l glass beaker for 6 min and analyzed using an automated video-tracking system (Anymaze 4.20, Stoelting, Ill., USA). Time spent immobile (floating) and time spent struggling was scored by an experienced observer, blind to treatment or condition of the animals.

(815) TABLE-US-00009 TABLE 6 Coordinates of the atoms of the FKBP51 BINDING SURFACE in the Complex of A12 (Crystal From I) A12I Res number x y z CE1 TYR(Y57) 57 −17.534 −17.442 −8.462 CE2 TYR(Y57) 57 −16.800 −19.672 −9.000 CZ TYR(Y57) 57 −17.248 −18.414 −9.398 OH TYR(Y57) 57 −17.398 −18.103 −10.742 CB ASP(D68) 68 −20.240 −14.289 −10.552 CG ASP(D68) 68 −19.636 −15.496 −11.261 OD2 ASP(D68) 68 −18.475 −15.829 −10.963 CE2 PHE(F77) 77 −12.257 −21.051 −10.429 CZ PHE(F77) 77 −12.637 −20.473 −11.654 CA VAL(V86) 86 −7.362 −16.910 −11.307 C VAL(V86) 86 −6.692 −15.646 −10.757 CB VAL(V86) 86 −8.099 −17.687 −10.170 CG1 VAL(V86) 86 −8.954 −18.816 −10.755 N ILE(I87) 87 −7.491 −14.666 −10.347 CA ILE(I87) 87 −6.929 −13.428 −9.779 CB ILE(I87) 87 −8.025 −12.396 −9.410 CG1 ILE(I87) 87 −9.007 −12.992 −8.385 CG2 ILE(I87) 87 −8.734 −11.881 −10.695 CG TRP(W90) 90 −10.052 −16.555 −6.068 CD1 TRP(W90) 90 −10.757 −15.445 −5.626 CD2 TRP(W90) 90 −11.016 −17.584 −6.279 CE2 TRP(W90) 90 −12.289 −17.045 −5.954 CE3 TRP(W90) 90 −10.931 −18.921 −6.715 NE1 TRP(W90) 90 −12.101 −15.739 −5.554 CZ2 TRP(W90) 90 −13.473 −17.796 −6.063 CZ3 TRP(W90) 90 −12.117 −19.674 −6.822 CH2 TRP(W90) 90 −13.367 −19.107 −6.485 CE2 TYR(Y13) 113 −11.637 −9.899 −11.543 CZ TYR(Y13) 113 −11.354 −10.731 −12.606 OH TYR(Y13) 113 −11.822 −12.041 −12.595 CD1 ILE(122) 122 −15.618 −8.456 −12.157 CE1 PHE(F130) 130 −15.015 −14.048 −6.814 CZ PHE(F130) 130 −14.033 −13.070 −6.945 CAH DRG(A12) 1 −17.624 −11.138 −9.034 CAI DRG(A12) 1 −16.507 −11.773 −9.572 CAS DRG(A12) 1 −18.758 −10.764 −9.764 CAT DRG(A12) 1 −18.554 −10.734 −11.278

(816) TABLE-US-00010 TABLE 7 Coordinates of the atoms of the FKBP51 BINDING SURFACE in the Complex of A12 (Crystal From II) CE1 TYR(Y57) 57 −17.494 −17.472 −8.444 CE2 TYR(Y57) 57 −16.813 −19.687 −9.026 CZ TYR(Y57) 57 −17.255 −18.425 −9.391 OH TYR(Y57) 57 −17.419 −18.144 −10.730 CB ASP(D68) 68 −20.142 −14.330 −10.466 CG ASP(D68) 68 −19.563 −15.473 −11.255 OD2 ASP(D68) 68 −18.396 −15.823 −10.984 CE2 PHE(F77) 77 −12.413 −21.045 −10.410 CZ PHE(F77) 77 −12.751 −20.518 −11.656 CA VAL(V86) 86 −7.464 −16.858 −11.315 C VAL(V86) 86 −6.765 −15.608 −10.773 CB VAL(V86) 86 −8.163 −17.615 −10.141 CG1 VAL(V86) 86 −9.006 −18.727 −10.691 N ILE(I87) 87 −7.551 −14.653 −10.277 CA ILE(I87) 87 −6.982 −13.428 −9.732 CB ILE(I87) 87 −8.080 −12.418 −9.367 CG1 ILE(I87) 87 −9.086 −13.028 −8.358 CG2 ILE(I87) 87 −8.766 −11.905 −10.658 CG TRP(W90) 90 −10.031 −16.560 −6.074 CD1 TRP(W90) 90 −10.749 −15.438 −5.682 CD2 TRP(W90) 90 −10.995 −17.596 −6.282 CE2 TRP(W90) 90 −12.274 −17.047 −6.015 CE3 TRP(W90) 90 −10.898 −18.943 −6.662 NE1 TRP(W90) 90 −12.095 −15.736 −5.635 CZ2 TRP(W90) 90 −13.445 −17.792 −6.137 CZ3 TRP(W90) 90 −12.055 −19.667 −6.796 CH2 TRP(W90) 90 −13.317 −19.097 −6.518 CE2 TYR(Y13) 113 −11.693 −9.863 −11.520 CZ TYR(Y13) 113 −11.380 −10.712 −12.557 OH TYR(Y13) 113 −11.844 −12.016 −12.563 CD1 ILE(122) 122 −15.550 −8.503 −12.219 CE1 PHE(F130) 130 −14.919 −14.038 −6.827 CZ PHE(F130) 130 −13.983 −13.032 −6.979 CAH DRG(A12) 1 −17.583 −11.165 −9.069 CAI DRG(A12) 1 −16.495 −11.873 −9.610 CAS DRG(A12) 1 −18.698 −10.717 −9.797 CAT DRG(A12) 1 −18.511 −10.730 −11.322

(817) TABLE-US-00011 TABLE 8 Coordinates of the atoms of the FKBP51 BINDING SURFACE in the Complex of A22 A22 Res number x y z CE1 TYR(Y57) 57 −17.435 −17.393 −8.425 CE2 TYR(Y57) 57 −16.849 −19.655 −9.078 CZ TYR(Y57) 57 −17.186 −18.355 −9.429 OH TYR(Y57) 57 −17.266 −17.986 −10.735 CB ASP(D68) 68 −20.255 −14.402 −10.452 OD2 ASP(D68) 68 −18.432 −15.671 −10.907 CZ PHE(F77) 77 −13.024 −20.103 −11.356 CA VAL(V86) 86 −7.370 −16.959 −11.336 C VAL(V86) 86 −6.642 −15.696 −10.798 CB VAL(V86) 86 −8.045 −17.714 −10.131 CG1 VAL(V86) 86 −8.909 −18.912 −10.684 N ILE(I87) 87 −7.466 −14.747 −10.383 CA ILE(I87) 87 −6.890 −13.536 −9.825 CB ILE(I87) 87 −8.019 −12.493 −9.454 CG1 ILE(I87) 87 −9.036 −13.096 −8.463 CG2 ILE(I87) 87 −8.639 −11.914 −10.764 CG TRP(W90) 90 −10.012 −16.672 −6.020 CD1 TRP(W90) 90 −10.640 −15.510 −5.587 CD2 TRP(W90) 90 −11.017 −17.620 −6.226 CE2 TRP(W90) 90 −12.274 −17.007 −5.955 CE3 TRP(W90) 90 −10.956 −18.968 −6.675 NE1 TRP(W90) 90 −11.994 −15.700 −5.559 CZ2 TRP(W90) 90 −13.454 −17.720 −6.077 CZ3 TRP(W90) 90 −12.110 −19.632 −6.796 CH2 TRP(W90) 90 −13.378 −19.030 −6.512 CE2 TYR(Y13) 113 −11.705 −9.616 −11.441 CZ TYR(Y13) 113 −11.436 −10.403 −12.580 OH TYR(Y13) 113 −11.907 −11.692 −12.607 CE1 PHE(F130) 130 −14.935 −13.999 −6.763 CZ PHE(F130) 130 −13.966 −12.990 −6.872 CAU DRG(A22) 1 −17.304 −10.566 −9.106 CAZ DRG(A22) 1 −16.608 −11.888 −9.535 CAS DRG(A22) 1 −18.670 −10.506 −9.816

(818) TABLE-US-00012 TABLE 9 Coordinates of the atoms of the FKBP51 BINDING SURFACE in the Complex of A09 A09 Res number x y z CE1 TYR(Y57) 57 −17.562 −17.376 −8.501 TYR(Y57) CZ TYR(Y57) 57 −17.361 −18.391 −9.440 OH TYR(Y57) 57 −17.596 −18.144 −10.775 CB ASP(D68) 68 −20.411 −14.383 −10.579 CG ASP(D68) 68 −19.798 −15.577 −11.272 OD2 ASP(D68) 68 −18.629 −15.887 −10.940 PHE(F77) CZ PHE(F77) 77 −12.697 −20.488 −11.661 CA VAL(V86) 86 −7.389 −16.925 −11.247 C VAL(V86) 86 −6.719 −15.637 −10.731 CB VAL(V86) 86 −8.081 −17.656 −10.081 CG1 VAL(V86) 86 −8.917 −18.800 −10.595 N ILE(I87) 87 −7.492 −14.663 −10.252 CA ILE(I87) 87 −6.920 −13.441 −9.685 CB ILE(I87) 87 −7.999 −12.411 −9.298 CG1 ILE(I87) 87 −8.975 −13.000 −8.271 CG2 ILE(I87) 87 −8.719 −11.909 −10.548 TRP(W90) TRP(W90) CD2 TRP(W90) 90 −10.931 −17.586 −6.347 CE2 TRP(W90) 90 −12.197 −17.009 −6.071 CE3 TRP(W90) 90 −10.869 −18.916 −6.753 NE1 TRP(W90) 90 −11.987 −15.711 −5.674 CZ2 TRP(W90) 90 −13.397 −17.719 −6.211 CZ3 TRP(W90) 90 −12.069 −19.625 −6.910 CH2 TRP(W90) 90 −13.308 −19.028 −6.636 CE2 TYR(Y13) 113 −11.687 −9.984 −11.502 CZ TYR(Y13) 113 −11.427 −10.807 −12.590 OH TYR(Y13) 113 −11.906 −12.110 −12.614 CD1 ILE(122) 122 −15.663 −8.581 −11.760 CE1 PHE(F130) 130 −14.917 −13.982 −6.817 CZ PHE(F130) 130 −14.001 −12.952 −6.974 CAY DRG(A09) 1 −16.925 −11.302 −8.697 CBX DRG(A09) 1 −17.264 −12.300 −9.797 CAX DRG(A09) 1 −18.070 −11.014 −9.643

(819) TABLE-US-00013 TABLE 10 Coordinates of the atoms of the FKBP51 BINDING SURFACE in the Complex of A01 A01 Res number x y z CE1 TYR(Y57) 57 −17.399 −17.498 −8.429 CE2 TYR(Y57) 57 −16.783 −19.726 −9.105 CZ TYR(Y57) 57 −17.104 −18.425 −9.435 OH TYR(Y57) 57 −17.188 −18.051 −10.772 OD2 ASP(D68) 68 −18.327 −15.866 −10.901 CE2 PHE(F77) 77 −12.182 −20.911 −10.291 CZ PHE(F77) 77 −12.696 −20.137 −11.290 CA VAL(V86) 86 −7.311 −16.898 −11.357 C VAL(V86) 86 −6.641 −15.637 −10.834 CB VAL(V86) 86 −7.960 −17.651 −10.150 CG1 VAL(V86) 86 −8.819 −18.862 −10.631 N ILE(I87) 87 −7.455 −14.696 −10.370 CA ILE(I87) 87 −6.906 −13.454 −9.817 CB ILE(I87) 87 −8.003 −12.473 −9.420 CG1 ILE(I87) 87 −9.048 −13.091 −8.467 CG2 ILE(I87) 87 −8.656 −11.899 −10.679 CG TRP(W90) 90 −10.034 −16.690 −6.082 CD1 TRP(W90) 90 −10.680 −15.542 −5.683 CD2 TRP(W90) 90 −11.041 −17.675 −6.297 CE2 TRP(W90) 90 −12.295 −17.072 −5.997 CE3 TRP(W90) 90 −11.013 −19.023 −6.707 NE1 TRP(W90) 90 −12.047 −15.763 −5.629 CZ2 TRP(W90) 90 −13.513 −17.785 −6.116 CZ3 TRP(W90) 90 −12.215 −19.716 −6.817 CH2 TRP(W90) 90 −13.447 −19.106 −6.506 CE2 TYR(Y13) 113 −11.791 −9.790 −11.568 CZ TYR(Y13) 113 −11.416 −10.642 −12.595 OH TYR(Y13) 113 −11.878 −11.936 −12.632 CE1 PHE(F130) 130 −15.132 −14.049 −6.934 CZ PHE(F130) 130 −14.120 −13.066 −6.947 CAA DRG(A01) 1 −16.487 −11.284 −8.958 CAK DRG(A01) 1 −16.973 −12.118 −9.926

(820) TABLE-US-00014 TABLE 11 Data collection and Refinement Statistics Dataset AB3007 AA9426 AA9429 puck4-1 Ligand A09 A12 (Form I) A12 (Form II) A22 beamline SLS, PX-II ESRF, ID23-1 ESRF, ID23-1 SLS, PX-II wavelength (Å) 1.000 0.97780 0.97931 1.03679 space group P2.sub.12.sub.12 C222.sub.1 P2.sub.12.sub.12 P2.sub.12.sub.12.sub.1 cell dimensions, a, b, c (Å); 48.439, 48.745, 49.262, 45.029, 60.233, 84.709, 60.934, 48.414, α, β, γ (°) 38.071; 61.390; 38.059; 56.852; 90, 90, 90 90, 90, 90 90, 90, 90 90, 90, 90 resolution limits (Å)* 37.75-1.4  42.35-1.75  38.32-1.25  48.41-1.3  (1.48-1.4) (1.85-1.75) (1.32-1.25) (1.37-1.3) Rmerge**.sup.,* 0.057 (0.421) 0.087 (0.463) 0.046 (0.406) 0.053 (1.043) I/sigma**.sup.,* 11.9 (2.3)  16.5 (3.7)  15.8 (2.3)  15.7 (1.7)  multiplicity* 3.0 (2.3) 7.0 (7.0) 3.5 (2.5) 8.3 (7.4) completeness (%)* 95.0 (89.2) 99.4 (96.0) 92.4 (63.7) 99.5 (97.0) Wilson B-factor (Å.sup.2) 16.05 15.82 8.39 Refinement resolution range   20-1.4   20-1.75   20-1.25   20-1.3 reflections (test set) 19956 (1106)  12428 (640)  28325 (1523)  29475 (1550)  Rcryst 0.20587 0.19399 0.16999 0.19288 Rfree 0.24668 0.23176 0.20428 0.21853 number of atoms 1166 1143 1245 1169 r.m.s.d. bonds (Å) 0.012 0.012 0.012 0.028 r.m.s.d. angles (°) 1.560 1.451 1.640 2.503 Ramachandran plot % most favored region*** ? ? ? ? % additionally allowed*** ? ? ? ? *Values in parenthesis for outer shell. **As defined in Scala. ***As defined in Coot.

(821) TABLE-US-00015 Human FKBP51(13-139).sup.A19T SEQ ID NO: 1 GLY ALA PRO ALA THR VAL THR GLU.sup.20 GLN GLY GLU ASP ILE THR SER LYS LYS ASP.sup.30 ARG GLY VAL LEU LYS ILE VAL LYS ARG VAL.sup.40 GLY ASN GLY GLU GLU THR PRO MET ILE GLY.sup.50 ASP LYS VAL TYR VAL HIS TYR LYS GLY LYS.sup.60 LEU SER ASN GLY LYS LYS PHE ASP SER SER.sup.70 HIS ASP ARG ASN GLU PRO PHE VAL PHE SER.sup.80 LEU GLY LYS GLY GLN VAL ILE LYS ALA TRP.sup.90 ASP ILE GLY VAL ALA THR MET LYS LYS GLY.sup.100 GLU ILE CYS HIS LEU LEU CYS LYS PRO GLU.sup.110 TYR ALA TYR GLY SER ALA GLY SER LEU  PRO.sup.120 LYS ILE PRO SER ASN ALA THR LEU PHE PHE.sup.130  GLU ILE GLU LEU LEU ASP PHE LYS GLY

(822) Residues of the FKBP51 BINDING SITE are highlighted in bold.

Example 13

Neuroendocrine Analysis

(823) The combined Dex/CRH test was performed as described previously (Touma et al., Biol. Psych. 2011, 70, 928-36). Briefly, a reference blood sample was collected by an incision in the ventral tail vessel at 1500, three days prior to the actual test (‘untreated’ value). On the experimental day, at 0900, the mice (10 week old male C57BL/6 mice, n=10 per group) were injected intraperitoneally (i.p.) with either vehicle or compound A18 (20 mg/kg) immediately followed by an i.p. injection of dexamethasone (Dex, 0.05 mg/kg, ratiopharm GmbH, Ulm, Germany). The injected volume was 0.3 ml for each injection. At 1500, a second blood sample was drawn from the tail vessel (‘after Dex’ value), immediately followed by an i.p. injection of CRH (0.15 mg/kg). Thirty minutes later, the mice were sacrificed and trunk blood was collected (‘after CRH’ value). All blood samples were stored frozen at −20° C. until plasma CORT concentrations were analysed as described previously (Touma et al., Psychoneuroendocrinol. 2008, 33, 839-62).