CN1823040A - Diaryl methylene piperidine derivatives and their preparation and use - Google Patents

Abstract

Preparing a compound of the formula wherein R¹、R²、R³、R⁴And R⁷As defined in the specification, and salts, enantiomers thereof, and pharmaceutical compositions containing the compounds. They are useful in therapy, in particular in the management of pain.

Description

Diaryl methylene piperidine derivatives and their preparation and use

field of invention

The present invention relates to novel compounds, processes for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The new compounds are useful in therapy, in particular for the treatment of pain, anxiety and functional gastrointestinal disorders.

Background of the invention

Delta receptors have been established to have roles in many bodily functions such as the circulatory and pain systems. Accordingly, ligands for the delta receptors have found potential use as analgesics and/or as antihypertensive agents. In addition, ligands for the delta receptor have also been shown to possess immunomodulatory activity.

The recognition of at least three distinct populations (μ, δ, and κ) of opioid receptors has now been established, and all three distinct populations are evident in the central and peripheral nervous systems of many species, including humans . Analgesia has been observed in different animal models when one or more of these receptors is activated.

With rare exceptions, current selective opioid delta ligands are peptidic in nature and are not suitable for administration by systemic routes. An example of a non-peptidic delta-agonist is SNC80 (Bilsky E.J. et al., Journal of Pharmacology and Experimental Therapeutics, 273(1), pp.359-366 (1995)).

Many of the delta agonist compounds identified in the prior art have a number of disadvantages in that they have poor pharmacokinetics and are not analgesic when administered by systemic routes. Furthermore, it has been demonstrated that many of these delta agonist compounds exhibit pronounced convulsive effects when administered systemically.

Certain delta-agonists are described by Delorme et al. in US Patent No. 6,187,792.

However, there is still a need for improved delta-agonists.

Contents of the invention

Unless otherwise stated in this specification, the terms used in this specification generally follow the examples described in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F and H, Pergamon Press, Oxford, 1979 and Rules, Exemplary Chemical Structure Names and Nomenclature of Chemical Structures therein are incorporated herein by reference.

The term " _Cmn " or " _Cmn group" used alone or as a prefix refers to any group having m to n carbon atoms.

The term "hydrocarbon" used alone or as a suffix or prefix refers to any structure up to 14 carbon atoms containing only carbon and hydrogen atoms.

The terms "hydrocarbyl" or "hydrocarbyl" used alone or as suffix or prefix, refer to any structure resulting from the removal of one or more hydrogens from a hydrocarbon.

The term "alkyl" used alone or as a suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical containing 1 to about 12 carbon atoms.

The term "alkylene" used alone or as a suffix or prefix, refers to a divalent straight or branched chain hydrocarbon radical containing 1 to about 12 carbon atoms, which is used to link two structures.

The term "alkenyl" used alone or as suffix or prefix refers to a monovalent straight or branched chain hydrocarbon group having at least one carbon-carbon double bond and containing at least 2 and up to about 12 carbon atoms.

The term "alkynyl" used alone or as suffix or prefix refers to a monovalent straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond and containing at least 2 and up to about 12 carbon atoms.

The term "cycloalkyl" used alone or as a suffix or prefix, refers to a monovalent ring-containing hydrocarbon group containing at least 3 and up to about 12 carbon atoms.

The term "cycloalkenyl" used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon group having at least one carbon-carbon double bond and containing at least 3 and up to about 12 carbon atoms.

The term "cycloalkynyl" used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and containing from about 7 up to about 12 carbon atoms.

The term "aryl" used alone or as a suffix or prefix, refers to having one or more polyunsaturated carbocyclic rings of aromatic character (eg, 4n+2 delocalized electrons) and containing 5 up to about 14 A monovalent hydrocarbon group of carbon atoms.

The term "arylene" used alone or as a suffix or prefix, refers to having one or more polyunsaturated carbocyclic rings with aromaticity (for example, 4n+2 delocalized electrons) and containing 5 up to about A divalent hydrocarbon group of 14 carbon atoms used to link two structures.

The term "heterocycle" used alone or as a suffix or prefix means having one or more multivalent heteroatoms independently selected from N, O, P and S as part of a ring structure and comprising at least 3 Ring-containing structures or molecules up to about 20 atoms. A heterocycle may be saturated or unsaturated, contain one or more double bonds, and the heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally mean that at least two rings share two atoms with each other. A heterocyclic ring may or may not be aromatic.

The term "heteroaryl", used alone or as a suffix or prefix, means having one or more multivalent heteroatoms independently selected from N, O, P and S as part of a ring structure and comprising at least Ring-containing structures or molecules of 3 up to about 20 atoms, wherein said ring-containing structures or molecules are aromatic (eg, 4n+2 delocalized electrons).

The terms "heterocyclyl", "heterocyclic moiety", "heterocyclic" or "heterocyclo" when used alone or as a suffix or prefix, refer to a radical obtained by removing one or more hydrogens from a heterocyclic ring. group.

The term "heterocyclyl" used alone or as a suffix or prefix, refers to a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.

The term "heterocyclylene" used alone or as a suffix or prefix refers to a divalent group obtained by removing two hydrogens from a heterocyclic ring, which is used to link two structures.

The term "heteroaryl" used alone or as a suffix or prefix refers to an aromatic heterocyclic group.

The term "heterocycloalkyl" used alone or as a suffix or prefix, refers to a heterocyclic group which is non-aromatic.

The term "heteroarylene" used alone or as a suffix or prefix refers to an aromatic heterocyclic group.

The term "heterocycloalkylene" used alone or as a suffix or prefix refers to a heterocyclylene group which has no aromaticity.

The term "6-membered" when used as a prefix refers to a group having a ring containing 6 ring atoms.

The term "5-membered" when used as a prefix refers to a group having a ring containing 5 ring atoms.

A 5 membered ring heteroaryl is a heteroaryl having a ring of 5 ring atoms, wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.

Exemplary 5-membered ring heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazole Base, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1 , 2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A 6 membered ring heteroaryl is a heteroaryl having a ring of 6 ring atoms, wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.

Exemplary 6-membered ring heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term "substituted" when used as a prefix refers to a structure, molecule or group in which one or more hydrogens are replaced by one or more C 1-6 hydrocarbon groups or by one or more C _1-6 containing one or more heteroatoms Chemical group substitution, the heteroatom is selected from N, O, S, F, Cl, Br, I and P. Exemplary chemical groups containing one or more heteroatoms include _-NO2 , -OR, -Cl, -Br, -I, -F, _-CF3 , -C(=O)R, -C(= O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O )OR, -C(=O)NR ₂ , -NRC(=O)R, oxo (=O), imino (=NR), thio (=S) and oximo (=N-OR), wherein each "R" is a C _1-6 hydrocarbon group. For example, substituted phenyl can refer to nitrophenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, methoxy, chlorine and amino can replace any suitable of hydrogen.

The term "substituted" when used as a suffix to a first structure, molecule or group followed by the name of one or more chemical groups means to replace the first structure, molecule or group with one or more specified chemical groups A second structure, molecule or group derived from one or more hydrogens in a group. For example, "phenyl substituted by nitro" refers to nitrophenyl.

Heterocycles include, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane ), pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane, 2,3-hydrofuran, 2,5-dihydrofuran, tetrahydrofuran, tetrahydrothiophene (thiophane), piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran , 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4 , 7-tetrahydro-1H-azepine, homopiperazine, 1,3-dioxepane (dioxepane), 4,7-dihydro-1,3-dioxepin (dioxepin) and Cyclohexamethylene oxide.

In addition, heterocycles include aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2 , 3-triazole, tetrazole, 1,2,3-thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1, 2,4-oxadiazole, 1,3,4-triazole, 1,3,4-thiadiazole and 1,3,4-oxadiazole.

In addition, heterocycles include polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzo Dioxane, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzopyran, chroman, isobenzene Dihydropyran, xanthene, phenoxathiin, thianthrene, indazine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, Cinnoline, pteridine, phenanthridine, perylene, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole , benzothiazole, benzimidazole, benzotriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine and quinolizidine.

In addition to the polycyclic heterocycles described above, heterocycles also include polycyclic heterocycles in which ring fusion between two or more rings involves two rings sharing more than one bond and two rings sharing more than two atoms. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.

Heterocyclic groups include, for example, monocyclic heterocyclic groups, such as aziridyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, Thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolane, 2,3-dihydrofuranyl, 2,5 -dihydrofuryl, tetrahydrofuryl, tetrahydrothiophenyl, piperidinyl, 1,2,3,6-tetrahydro-pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, Thianyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridyl, 1,4-dioxanyl, 1,3-dioxanyl Alkyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepinyl (dioxepanyl), 4,7-dihydro-1,3-dioxepinyl (dioxepinyl) and hexamethylene oxidyl.

In addition, heterocyclic groups include aromatic heterocyclic groups or heteroaryl groups, for example, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thienyl, furyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, Oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadio Azolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4 -thiadiazolyl and 1,3,4-oxadiazolyl.

In addition, heterocyclic groups include polycyclic heterocyclic groups (including aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolyl, Isoquinolyl, tetrahydroisoquinolyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl , isobenzofuryl, benzopyranyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthryl , indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, naphthyl Diazaphenyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothienyl, benzoxazolyl, benzothiazole group, benzimidazole group, benzotriazolyl group, thioxanthinyl group (thioxanthinyl), carbazolyl group, carboline group, acridinyl group, pyrrolidinyl group (pyrolizidinyl) and quinolizidinyl group (quinolizidinyl).

In addition to the polycyclic heterocyclyl groups described above, heterocyclyl groups also include polycyclic heterocyclyl groups in which ring fusion between two or more rings includes two rings sharing more than one bond and two rings sharing more than two atom. Examples of the bridged heterocycle include quinuclidinyl, diazabicyclo[2.2.1]heptyl and 7-oxabicyclo[2.2.1]heptyl.

The term "alkoxy" used alone or as a suffix or prefix refers to a group of formula -O-R, wherein R is selected from hydrocarbyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy and propargyloxy.

The term "amine" or "amino" used alone or as a suffix or prefix, refers to a group of general formula -NRR', wherein R and R' are independently selected from hydrogen or hydrocarbyl.

Halogen includes fluorine, chlorine, bromine and iodine.

"Halo" as used as a prefix to a group means that one or more hydrogens on the group are replaced by one or more halogens.

"RT" or "rt" means room temperature.

In one aspect, the present invention provides compounds of formula I, pharmaceutically acceptable salts thereof, diastereomers thereof, enantiomers thereof, and mixtures thereof:

in

R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _{6- 10} aryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C _6-10 aryl-C _1-3 alkyl and optionally substituted C _2-9 heterocyclyl-C _1-3 alkyl;

n is 0, 1 or 2; m is 0, 1 or 2;

R ² , R ³ and R ⁴ are independently selected from hydrogen, optionally substituted C _1-6 alkyl and optionally substituted C _3-6 cycloalkyl;

R ⁵ and R ⁶ are independently selected from -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH , -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR, wherein R is independently hydrogen or C _1-6 alkyl; and

R ⁷ is selected from -H, -OH, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 -9} heterocyclyl, optionally substituted C _6-10 aryl-C _1-6 alkyl, optionally substituted C _2-9 heterocyclyl-C _1-6 alkyl, -C(=O)- NR ⁸ R ⁹ , -C(=O)-OR ⁸ , -S(=O)-R ⁸ , -S(=O) ₂ -R ⁸ , -C(=O)-R ⁸ and -SO ₃ H , wherein R ⁸ and R ⁹ are independently selected from -H, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally Substituted C _2-9 heterocyclyl, optionally substituted C _6-10 aryl-C _1-6 alkyl and optionally substituted C _2-9 heterocyclyl-C _1-6 alkyl.

In particular, the compounds of the invention are those of formula I, wherein R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl and optionally substituted C _3-6 cycloalkyl;

^R2 and ^R3 are ethyl;

R ⁴ is selected from hydrogen and C _1-3 alkyl;

R ⁹ is selected from -H, -OH, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _{3- 5} heterocyclyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkyl-C _{1- 3} alkyl, -C(=O)-NR ⁸ R ⁹ , -C(=O)-OR ⁸ , -S(=O)-R ⁸ , -S(=O) ₂ -R ⁸ , -C( =O)-R ⁸ and -SO ₃ H, wherein R ⁸ and R ⁹ are independently selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl -C _1-3 alkyl, optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, Optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl; and

n and m are 0.

More particularly, the compounds of the invention are those of formula I, wherein

R ¹ is selected from hydrogen and C _1-6 alkyl-OC(=O)-;

^R2 and ^R3 are ethyl;

^R is selected from hydrogen and methyl;

R ⁷ is selected from -H, phenyl-C _1-3 alkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _3-6 cycloalkyl, phenyl, optionally substituted C _{1- 6} alkyl, -C(=O)-NR ⁸ R ⁹ , -S(=O) ₂ -R ⁸ and -C(=O)-R ⁸ , wherein R ⁸ and R ⁹ are independently selected from -H, Phenyl-C _1-3 alkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _3-6 cycloalkyl, phenyl and optionally substituted C _1-6 alkyl; and

n and m are 0.

Most particularly, the compounds of the invention are those of formula I, wherein

^R1 is hydrogen;

^R2 and ^R3 are ethyl;

^R is selected from hydrogen and methyl;

R ⁷ is selected from -H, phenyl, benzyl or phenethyl, cyclohexyl, cyclohexylmethyl, -C(=O)-NH-R ⁸ , -S(=O) ₂ -R ⁸ and -C (=O)-R ⁸ , wherein R ⁸ is selected from 2,2,2-trifluoroethyl, phenyl, benzyl or phenethyl, cyclohexyl and cyclohexylmethyl; and

n and m are 0.

In another aspect, the present invention provides compounds of formula IA, pharmaceutically acceptable salts thereof, diastereomers thereof, enantiomers thereof, and mixtures thereof:

in

R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-3 alkyl and C _2-9 heterocyclyl-C _1-3 alkyl; wherein said C _1-6 alkyl, C _3-6 cycloalkyl, C _{6 -10} aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-3 alkyl and C _2-9 heterocyclyl-C _1-3 alkyl are optionally selected from one or more -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, - NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR are substituted, wherein R is independently hydrogen or C _1-6 alkyl;

R ² , R ³ and R ⁴ are independently selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein said C _1-6 alkyl and C _3-6 cycloalkyl are optionally One or more selected from -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C( =O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR, wherein R is independently hydrogen or C _1-6 alkyl; and

R ⁷ is selected from -H, -OH, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _{1- 6} alkyl, C _2-9 heterocyclyl-C _1-6 alkyl, -C(=O)-NR ⁸ R ⁹ , -C(=O)-OR ⁸ , -S(=O)-R ⁸ , -S(=O) ₂ -R ⁸ , -C(=O)-R ⁸ and -SO ₃ H, wherein R ⁸ and R ⁹ are independently selected from -H, C _1-6 alkyl, C _{3- 8} cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl, wherein The C _1-6 alkyl, C _{3-8 cycloalkyl, C 6-10} aryl, C _2-9 heterocyclyl, C _6-10 used in _the definition of R ⁷ , R ⁸ or R ⁹ Aryl-C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl are optionally selected from one or more of -R, -NO ₂ , -OR, -Cl, -Br, - I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ of R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O) _NR2 , -NRC(=O)R, and -NRC(=O)-OR The group is substituted, wherein R is independently hydrogen or C _1-6 alkyl.

In one embodiment, the compound of the present invention is represented by formula IA, wherein ^R is selected from hydrogen, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl, C _3-6 cycloalkane radical, benzyl and C _2-5 heteroarylmethyl, wherein said C _1-6 alkyl, C _3-6 cycloalkyl, benzyl and C _2-5 heteroarylmethyl are optionally replaced by one Or replaced by groups selected from C _1-6 alkyl, halogenated C _1-6 alkyl, -CF ₃ , C _1-6 alkoxy, chlorine, fluorine, bromine and iodine;

^R2 and ^R3 are ethyl;

R ⁴ is selected from hydrogen and C _1-3 alkyl;

R ⁷ is selected from -H, -OH, phenyl, C _3-5 heterocyclyl, phenyl-C _1-3 alkyl, C _3-5 heterocyclyl-C _1-3 alkyl, C _1-6 Alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl, -C(=O)-NR ⁸ R ⁹ , -C(=O)-OR ⁸ , -S (=O)-R ⁸ , -S(=O) ₂ -R ⁸ , -C(=O)-R ⁸ and -SO ₃ H, wherein R ⁸ and R ⁹ are independently selected from -H, phenyl, C _3-5 heterocyclyl, phenyl-C _1-3 alkyl, C _3-5 heterocyclyl-C _1-3 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _{3 -7} cycloalkyl-C _1-3 alkyl, wherein the phenyl, C _3-5 heterocyclyl, phenyl-C _1-3 alkyl used in the definition of R ⁷ , R ⁸ and R ⁹ , C _3-5 heterocyclyl-C _1-3 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl- _{C 1-3} alkyl is optionally replaced by one or Substituted by multiple groups selected from C _1-6 alkyl, halogenated C _1-6 alkyl, -CF ₃ , C _1-6 alkoxy, chlorine, fluorine, bromine and iodine.

In another embodiment, the compound of the present invention is represented by formula IA, wherein R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl, C _3-6 ring Alkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and N -Oxygen (oxido)-pyridylmethyl, wherein said C _1-6 alkyl, C _3-6 cycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, Furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and N-oxo-pyridylmethyl are optionally selected from C _1-6 alkyl, Substituted by halogenated C _1-6 alkyl, -CF ₃ , C _1-6 alkoxy, chlorine, fluorine, bromine and iodine;

^R2 and ^R3 are ethyl;

^R is selected from hydrogen and methyl;

R ⁷ is selected from -H, C _1-6 alkyl, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _3-7 cycloalkyl, phenyl, C _1-6 alkyl, -C(=O)-NR ⁸ R ⁹ , -S(=O) ₂ -R ⁸ , -C(=O)-OR ⁸ and -C(=O)-R ⁸ , Wherein R ⁸ and R ⁹ are independently selected from -H, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _3-7 cycloalkyl, phenyl and C _1-6 alkyl, wherein the phenyl-C _{1-3 alkyl, C 3-7 cycloalkyl} -C _1-3 alkyl, C ₃ used in the definition of R ⁷ , R ⁸ and R ⁹ _-7 cycloalkyl, phenyl, C _1-6 alkyl is optionally replaced by one or more selected from C _1-6 alkyl, halogenated C _1-6 alkyl, -CF ₃ , C _1-6 alkoxy radical, chlorine, fluorine, bromine and iodine radicals.

In another embodiment, the compound of the present invention is represented by formula IA, wherein ^R is selected from hydrogen, propyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl Base, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and N-oxy-pyridylmethyl;

^R2 and ^R3 are ethyl;

^R is selected from hydrogen and methyl;

^R is selected from -H, ethyl, phenyl, benzyl or phenethyl, naphthyl, fluorophenyl, chlorophenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexyl Methyl, -C(=O)-NH-R ⁸ , -S(=O) ₂ -R ⁸ , -C(=O)-OR ⁸ and -C(=O)-R ⁸ , wherein R ⁸ is selected from from methyl, 2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, methylphenyl, fluorophenyl, butyl, cyclohexyl and cyclohexylmethyl.

It is understood that when the compounds of the invention contain one or more chiral centers, the compounds of the invention may exist in enantiomeric or diastereomeric forms or racemic mixtures, or may be isolated as Forms of enantiomers, diastereoisomers or racemic mixtures. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of formula I or IA. Optically active forms of the compounds of the present invention can be prepared, for example, by chiral chromatographic separation of racemates, synthesis from optically active starting materials or asymmetric synthesis based on the methods described hereinafter.

It is also understood that certain compounds of the present invention may exist as geometric isomers, such as the E and Z isomers of alkenes. The present invention includes any geometric isomer of a compound of formula I or IA. Furthermore, it is also understood that the present invention includes tautomers of the compounds of formula I or IA.

It will also be appreciated that certain compounds of the present invention may exist in solvated, eg hydrated, as well as unsolvated forms. Furthermore, it is also understood that the present invention includes all such solvated forms of the compounds of formula I or IA.

Salts of compounds of formula I or IA are also within the scope of the invention. In general, pharmaceutically acceptable salts of compounds of the invention can be obtained using standard methods well known in the art, for example by reacting a sufficiently basic compound, such as an alkylamine, with a suitable acid, such as HCl or acetic acid, to obtain a physiologically acceptable anion. By treating with an equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as ethanolate or methoxide), or with a suitable basic organic amine (such as choline or meglumine) in an aqueous medium with a suitable acid Compounds of the invention with protons such as carboxylic acids or phenols, followed by conventional purification techniques, can likewise be prepared from the corresponding alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts.

In one embodiment, the above compound of formula I or IA can be converted into a pharmaceutically acceptable salt or solvate thereof, especially an acid addition salt such as hydrochloride, hydrobromide, phosphate, acetic acid salt, fumarate, maleate, tartrate, citrate, methanesulfonate or p-toluenesulfonate.

The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral Pain etc. However, this list should not be considered exhaustive.

The compounds of the present invention are useful as immunomodulators, especially for autoimmune diseases such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases and various allergies, and as Antineoplastic and antiviral agents.

The compounds of the invention are useful in disease states where opioid receptor degeneration or dysfunction is present or, in the exemplary case, opioid receptor degeneration or dysfunction is involved. This may include the use of isotopically labeled variants of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

The compound of the present invention can be used for treating diarrhea, depression, anxiety and stress-related disorders (stress-related disorders) such as post-traumatic stress disease, panic disorder (panic disorder), generalized anxiety disorder (generalized anxiety disorder) ), social phobia (social phobia) and obsessive compulsive disorder (obsessive compulsive disorder), urinary incontinence, premature ejaculation, various mental illnesses, cough, pulmonary edema (lung oedema), various gastrointestinal diseases such as constipation, functional gastrointestinal Functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia (Functional Dyspepsia), Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection after myocardial infarction, spinal cord Spinal injury and drug addiction, including alcohol, nicotine, opioid, and other drug abuse, and sympathetic nervous system disorders such as hypertension.

The compounds of the invention are used as analgesics during general anesthesia and monitored anesthesia care. Combinations of drugs of different nature are often used to achieve the balance of effects required to maintain the anesthesia state (eg, amnesia, analgesia, muscle relaxation, and sedation). This combination includes inhaled anesthetics, sleeping pills, anxiolytics, neuromuscular blocking agents, and opioids.

The present invention also includes the use of any compound of formula I or IA above for the manufacture of a medicament for the treatment of any of the above conditions.

Another aspect of the invention is a method of treating a patient suffering from any of the above disorders, wherein an effective amount of a compound of formula I or IA above is administered to the patient in need of such treatment.

Accordingly, the present invention provides a compound of formula I or IA as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

In another aspect, the present invention provides the use of a compound of formula I or IA as defined above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for use in therapy.

In the context of the present description, the term "treatment" also includes "prevention", unless it is specifically indicated to the contrary. The terms "therapeutic" and "therapeutically" should also be interpreted as above. In the context of the present invention, the term "treating" also includes the administration of an effective amount of a compound of the present invention in order to alleviate a pre-existing disease state, an acute or chronic condition or a recurrent condition. This definition also includes prophylactic treatment to prevent recurrence of the condition and continued treatment of chronic diseases.

The compounds of the invention are useful in therapy, especially in the treatment of various pain conditions including, but not limited to: chronic pain, neuropathic pain, acute pain, back pain, cancer pain and visceral pain.

In the therapeutic use of warm-blooded animals such as humans, the compounds of the present invention may be administered in the form of conventional pharmaceutical compositions by any route including oral, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous Intradural, epidural, intrathecal, intraventricular, and joint injections.

In one embodiment of the present invention, the route of administration may be oral, intravenous or intramuscular.

Dosage will depend on the route of administration, severity of the disease, patient age and weight and other factors normally considered by the attending physician in determining the individual treatment regimen and dosage level most suitable for a particular patient.

For preparing pharmaceutical compositions from the compounds of this invention, inert pharmaceutically acceptable carriers can be both solid and liquid. Solid preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.

A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be encapsulated substances.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted, and the active ingredient is dispersed therein, for example, by stirring. The molten homogeneous mixture is then injected into appropriately sized molds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, etc. .

The term composition also includes the preparation of the active ingredient with an encapsulating material which provides a capsule as a carrier, wherein the active ingredient (with or without other carriers) is enclosed by a carrier which is in association therewith. Similarly, the term composition also includes cachets.

Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, fragrances, stabilizing and thickening agents, as desired. It can be prepared for oral administration by dispersing the finely divided active ingredient in water with viscous material such as natural synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspending agents known in the pharmaceutical formulation art. Aqueous suspension used.

Depending on the mode of administration, the pharmaceutical composition preferably contains 0.05-99%w (weight percent), more preferably 0.10-50%w of the compound of the invention, all weight percents being based on the total weight of the composition.

The actual therapeutically effective amount of this invention can be determined by those skilled in the art using known criteria, including the age, weight and response of the individual patient, and will be interpreted in the context of the disease to be treated or prevented.

The invention also includes the use of any compound of formula I or IA as defined above for the manufacture of a medicament.

The invention also includes the use of any compound of formula I or IA for the manufacture of a medicament for the treatment of pain.

The present invention also provides the use of any compound of formula I or IA for the preparation of a medicament for the treatment of various pain conditions including, but not limited to: chronic pain, neuropathic pain, acute pain, back pain , cancer pain and visceral pain.

Another aspect of the invention is a method of treatment of a patient suffering from any of the conditions described above, wherein an effective amount of a compound according to formula I or IA above is administered to the patient in need of such treatment.

In addition, the present invention provides a pharmaceutical composition comprising a compound of formula I or IA or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In particular, the present invention provides a pharmaceutical composition for use in therapy, more particularly in the treatment of pain, comprising a compound of formula I or IA or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition, the present invention also provides a pharmaceutical composition for use in any of the above diseases, which comprises a compound of formula I or IA or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides methods of preparing compounds of formula I or IA.

In one embodiment, the present invention provides a method of preparing a compound of formula II, the method comprising:

Reaction of a compound of formula III with X ¹ -C(=O)-R ¹⁰ :

in

R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl and optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl;

X ¹ is selected from -OH, -OR ¹¹ , -OC(=O)-R ¹¹ , -Cl, -Br and -I, wherein R ¹¹ is C _1-6 alkyl;

R ² , R ³ and R ⁴ are independently selected from hydrogen, optionally substituted C _1-6 alkyl, and optionally substituted C _3-6 cycloalkyl; and

R ¹⁰ is selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclic Base-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl .

In particular, the present invention provides a method for preparing the above-mentioned compound of formula II, wherein

R ¹ is C _1-6 alkyl-OC(=O)-;

X ^is selected from -OH, -Cl, -Br and -I;

^R2 and ^R3 are ethyl;

^R4 is hydrogen; and

R ¹⁰ is selected from phenyl, phenyl-C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl-C _1-3 alkyl.

In a second embodiment, the present invention provides a process for preparing a compound of formula IV, said process comprising:

Reaction of a compound of formula V with R ¹² -C(=O)-R ¹³ :

in

R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl and optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl;

R and ^R are independently selected from hydrogen, optionally substituted C _1-6 alkyl ^, and optionally substituted C _3-6 cycloalkyl; and

R ¹² and R ¹³ are independently selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl; or R ¹² and R ¹³ together form part of a C _3-6 cycloalkyl ring or a C _3-5 heterocycle.

In particular, the present invention provides a method for preparing the above-mentioned compound of formula IV, wherein

R ¹ is C _1-6 alkyl-OC(=O)-;

^R2 and ^R3 are ethyl; and

R ¹² and R ¹³ are independently selected from -H, phenyl, phenyl-C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl-C _{1 -3} alkyl; or R ¹² and R ¹³ together form part of a C _3-6 cycloalkyl ring.

In a third embodiment, the present invention provides a method of preparing a compound of formula VI, said method comprising:

Reaction of a compound of formula V with R ¹⁴ -NCO:

in

R ¹ is C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl or optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl;

R and ^R are independently selected from hydrogen, optionally substituted C _1-6 alkyl ^, and optionally substituted C _3-6 cycloalkyl; and

R ¹⁴ is selected from optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl.

In particular, the present invention provides a method for preparing the above-mentioned compound of formula VI, wherein

R ¹ is C _1-6 alkyl-OC(=O)-;

^R2 and ^R3 are ethyl; and

R ¹⁴ is selected from phenyl, phenyl-C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl-C _1-3 alkyl.

In a fourth embodiment, the present invention provides a method of preparing a compound of formula VII, said method comprising:

Reaction of a compound of formula VIII with R ¹⁶ -X ² :

in

R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl and optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl;

R ² and R ³ are independently selected from hydrogen, optionally substituted C _1-6 alkyl and optionally substituted C _3-6 cycloalkyl;

X ^is selected from I, Br and Cl;

R ^is selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclic Base-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl ;and

R ¹⁶ is selected from optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclyl, optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl, any substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl.

In particular, the present invention provides a method for preparing the above-mentioned compound of formula VII, wherein

R ¹ is C _1-6 alkyl-OC(=O)-;

X ^is selected from -Cl, -Br and -I;

^R2 and ^R3 are ethyl;

^R is selected from hydrogen and methyl; and

R ¹⁶ is selected from phenyl, phenyl-C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl-C _1-3 alkyl.

In a fifth embodiment, the present invention provides a method of preparing a compound of formula IX, said method comprising:

The compound of formula III is reacted with ^X3 -S(=O) ₂ - ^R17 :

in

R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl and optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl;

X ³ is selected from -OH, -OR ¹¹ , -Cl, -Br and -I, wherein R ¹¹ is C _1-6 alkyl;

R ² , R ³ and R ⁴ are independently selected from hydrogen, optionally substituted C _1-6 alkyl, and optionally substituted C _3-6 cycloalkyl; and

R ^is selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclic Base-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl .

In particular, the present invention provides a method for preparing the compound of formula IX above, wherein

R ¹ is C _1-6 alkyl-OC(=O)-;

X ^is selected from -Cl, -Br and -I;

^R2 and ^R3 are ethyl;

^R4 is hydrogen;

R ¹⁷ is selected from phenyl, phenyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl-C _1-3 alkyl .

In another embodiment, the present invention provides a method of preparing a compound of formula IIA, said method comprising:

Reaction of a compound of formula IIIA with ^R5 - _CH2 -X or ^R5 -CHO:

wherein X is a halogen;

R ⁷ is selected from -C(=O)-OR ⁸ , -S(=O)-R ⁸ , -S(=O) ₂ -R ⁸ and -C(=O)-R ⁸ , wherein R ⁸ is selected from C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclic, C _6-10 aryl-C _1-6 alkyl and C _2-9 heterocyclic Base-C _1-6 alkyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl- C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl are optionally selected from one or more of -R, -NO ₂ , -OR, -Cl, -Br, -I, - F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, - The groups of S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR Substituted, wherein R is independently hydrogen or C _1-6 alkyl; and

R ⁵ is selected from C _6-10 aryl and C _2-5 heteroaryl, wherein said C _6-10 aryl and C _2-5 heteroaryl are optionally selected from one or more of -R, - NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(= O)R and -NRC(=O)-OR are substituted by a group, wherein R is independently hydrogen or C _1-6 alkyl.

In another embodiment, the present invention provides a method of preparing a compound of formula IIA, said method comprising:

Reaction of a compound of formula IVA with ^R7 -X or R7 ^{- OR7} :

wherein X is a halogen;

R ⁷ is selected from -C(=O)-OR ⁸ and -C(=O)-R ⁸ , wherein R ⁸ is selected from C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl , C _2-9 heterocyclyl, C _6-10 aryl-C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl Optionally selected from one or more of -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH , -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR are substituted, wherein R is independently hydrogen or C _1-6 alkyl; and

R ⁵ is selected from C _6-10 aryl and C _2-5 heteroaryl, wherein said C _6-10 aryl and C _2-5 heteroaryl are optionally selected from one or more of -R, - NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(= O)R and -NRC(=O)-OR are substituted by a group, wherein R is independently hydrogen or C _1-6 alkyl.

In another embodiment, the present invention provides a process for the preparation of a compound of formula VA,

Including compounds of the reduced formula VIA,

in

R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-3 alkyl and C _2-9 heterocyclyl-C _1-3 alkyl; wherein said C _1-6 alkyl, C _3-6 cycloalkyl, C _{6 -10} aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-3 alkyl and C _2-9 heterocyclyl-C _1-3 alkyl are optionally selected from one or more -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, - NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR are substituted, wherein R is independently hydrogen or C _1-6 alkyl; and

R ² and R ³ are independently selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein said C _1-6 alkyl and C _3-6 cycloalkyl are optionally replaced by one or more one selected from -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , - SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O) Substituted with groups of NR ₂ , -NRC(=O)R and -NRC(=O)-OR, wherein R is independently hydrogen or C _1-6 alkyl.

In particular, compounds of the present invention and intermediates used for their preparation can be prepared according to the synthetic routes shown in Schemes 1-18.

plan 1

Scenario 2

Intermediate 6 Compound 1: R ⁸ =Ph

Compound 2: R ⁸ =CH ₂ Ph

Compound 3: R ⁸ =C ₆ H ₁₁

Compound 4: R ⁸ =CH ₂ CH ₂ Ph

Compound 5: R ⁸ =CH ₂ C ₆ H ₁₁

Compound 16: R ⁸ =CH ₂ C ₅ H ₉

Compound 17: R ⁸ =C ₅ H ₉

Option 3

Intermediate 6 Compound 6: R ⁸ ═CH ₂ Ph

Compound 7: R ⁸ =C ₆ H ₁₁

Compound 8: R ⁸ =Ph

Compound 18: R ⁸ =CH ₂ CH ₂ Ph

Compound 19: R ⁸ =CH ₂ C ₆ H ₁₁

Option 4

Intermediate 6 Compound 9: R ⁷ =C ₆ H ₁₁

Compound 20: R ⁷ =C ₅ H ₉

Compound 21: R ⁷ =C ₇ H ₁₃

Option 5

Intermediate 6 Compound 10: R ⁸ =Ph

Compound 22: R ⁸ =CH ₂ Ph

Option 6

Intermediate 6 Compound 11: R ⁷ =Ph

Compound 23: R ⁷ =1-naptyl

Compound 24: R ⁷ =3-F-Ph

Compound 25: R ⁷ =4-Cl-Ph

Option 7

Intermediate 6 Compound 12: R＝Ph

Compound 26: R ⁷ =C ₆ H ₁₁

Option 8

Intermediate 6 Compound 13: R ⁸ =Ph

Compound 14: R ⁸ =CH ₂ Ph

Compound 15: R ⁸ =CH ₂ CF ₃

Compound 27: R ⁸ =4-Me-Ph

Compound 28: R ⁸ =2-F-Ph

Compound 29: R ⁸ =n-Bu

Option 9

Option 10

Compound 31: R ⁸ =Me

Compound 32: R ⁸ =OMe Compound 33: R ⁸ =Me

Compound 34: R ⁸ =OMe

Option 11

Compound 35: R ¹⁰ =4-thiazolyl

Compound 36: R ¹⁰ =5-thiazolyl

Option 12

Compound 35 Compound 37: R ⁸ =Me

Compound 38: R ⁸ =OMe

Option 13

Compound 31: R ⁸ =Me compound = Me, R ¹⁰ =5-thiazolyl

Compound 32: R ⁸ =OMe Compound 40: R ⁸ =OMe, R ¹⁰ =5-thiazolyl

Option 14

Intermediate 11: R ¹⁰ = n-propyl

Intermediate 12: R ¹⁰ =4-pyridyl

Intermediate 13: R ¹⁰ =3-pyridyl

Intermediate 14: R ¹⁰ =2-pyridyl

Compound 41: R ¹⁰ = n-propyl

Compound 42: R ¹⁰ =4-pyridyl

Compound 43: R ¹⁰ =3-pyridyl

Compound 44: R ¹⁰ =2-pyridyl

Option 15

Intermediate 12: R ¹⁰ =4-pyridyl Compound 45: R ¹⁰ =4-pyridyl

Intermediate 13: R ¹⁰ =3-pyridyl Compound 46: R ¹⁰ =3-pyridyl

Option 16

Compound 41: R ¹⁰ = n-propyl Compound 47: R ¹⁰ = n-propyl

Compound 44: R ¹⁰ =2-pyridyl Compound 48: R ¹⁰ =2-pyridyl

Option 17

Compound 41 R ¹⁰ = n-propyl Compound 49 R ¹⁰ = n-propyl

Compound 42 R ¹⁰ =4-pyridyl Compound 50 R ¹⁰ =4-pyridyl

Compound 43 R ¹⁰ =3-pyridyl Compound 51 R ¹⁰ =3-pyridyl

Compound 44 R ¹⁰ =2-pyridyl Compound 52 R ¹⁰ =2-pyridyl

Scheme 18

Compound 41 R ¹⁰ = n-propyl Compound 53 R ¹⁰ = n-propyl

Compound 42 R ¹⁰ = 4-pyridyl Compound 54 R ¹⁰ = 4-pyridyl

Compound 43 R ¹⁰ =3-pyridyl Compound 55 R ¹⁰ =3-pyridyl

Compound 44 R ¹⁰ =2-pyridyl Compound 56 R ¹⁰ =2-pyridyl

biological evaluation

It has now been found that compounds of the present invention are active at delta receptors in warm-blooded animals such as humans. In particular, it was found that the compounds of the present invention are potent delta receptor ligands. These surprising activities are demonstrated by the in vitro tests described below, especially the agonist potency and effects demonstrated in rat brain function tests and/or human delta receptor function tests. This feature may be related to in vivo activity and may not be linearly related to binding affinity. In these in vitro assays, the activity of compounds at delta receptors is determined and _IC50 obtained, thereby determining the selective activity of a particular compound at delta receptors. Herein, _IC50 generally refers to the concentration of compound at which 50% displacement of the standard radioactive delta receptor ligand is observed.

Using similar assays, the activity of compounds at kappa and mu receptors can also be determined.

in vitro model

cell culture

Human 293S cells were grown in suspension in shake flasks containing calcium-free DMEM 10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600 μg/ml Geneticin at 37°C and 5% _CO . Cells express cloned human kappa, delta and mu receptors and neomycin resistance.

Rat brains were weighed and washed in ice-cold PBS (containing 2.5 mM EDTA, pH 7.4). Homogenize the brain with a polytron in ice-cold lysis buffer (containing 50 mM Tris, pH 7.0, 2.5 mM EDTA, phenylmethanesulfonyl chloride (0.5 M stock solution in DMSO:ethanol) to 0.5 MmM just before use). 30 seconds (rat).

Membrane preparation

Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF (0.1 M stock solution in ethanol) to 0.1 mM just before use) and incubated on ice 15 minutes, then homogenize with a polytron for 30 seconds. The suspension was spun at 1000 g (maximum) for 10 minutes at 4°C. The supernatant was kept on ice, and the pellets were resuspended and spun as before. The supernatants from the two spins were combined and spun at 46,000g (maximum) for 30 minutes. The resulting pellet was resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again. Resuspend the final pellet in membrane buffer (50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene test tubes were frozen in dry ice/ethanol and stored at -70°C until use. Protein concentration was determined by a modified Lowry's test using sodium dodecyl sulfate.

binding assay

Membranes were thawed at 37°C, cooled on ice, passed 3 times through a 25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mM MgCl ₂ , 1 mg/ml BSA (Sigma A-7888), pH 7.4, via Store at 4°C after filtering through a 0.22 m filter, to which 5 μg/ml aprotinin, 10 μM bestatin and 10 μM diprotin A (without DTT) were freshly added. Aliquots of 100 μl were added to ice-cold 12 x 75 mm polypropylene test tubes containing 100 μl of the appropriate radioligand and 100 μl of test compound at various concentrations. Total (TB) binding and non-specific (NS) binding were determined with and without 10 [mu]M naloxone, respectively. The tubes were vortexed and incubated at 25°C for 60-75 minutes, then the contents were quickly vacuum filtered and washed with approximately 12 ml/tube of ice-cold wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl ₂ ) in 0.1% poly Wash GF/B filters (whatman) pre-soaked in ethyleneimine for at least 2 hours. The filters were soaked in vials containing 6-7 ml of scintillation fluid for at least 12 hours, and the radioactivity (dpm) retained on the filters was measured with a beta counter. If the assay is performed in a 96-position deep well plate, filtration is performed on a 96-position PEI soaked unifilter, which is washed with 3 x 1 ml wash buffer and oven-dried at 55°C. Dry for 2 hours. After addition of 50 [mu]l MS-20 scintillation fluid/well, filter plates were counted in a TopCount (Packard).

functional assay

Agonist activity of the compounds is detected by measuring the extent to which the compound-receptor complex activates GTP binding to the receptor-coupled G-protein. In the GTP binding assay, GTP[γ] ^35S is mixed with test compounds and membranes from HEK-293S cells expressing cloned human opioids or from homogenized rat or mouse brains receptor. In these membranes, agonists stimulate GTP[γ] ^35S binding. _EC50 and _Emax values of compounds were determined from dose-response curves. The delta agonist naltrindole shifted the dose-response curve to the right, confirming that the agonist activity is mediated by delta receptors. _Emax values are determined relative to the standard delta agonist SNC80, ie, above 100% indicates that the compound is more potent than SNC80.

Method for rat brain GTP

Rat meninges were thawed at 37°C, passed through a 25-gauge blunt needle 3 times, and added fresh: 1 mM _DTT , 0.1% BSA). Finally 120 μM GDP was added to the membrane dilution. EC50 and Emax of compounds were evaluated using 300 μl containing appropriate amount of membrane protein (20 μg/well) and 100000-130000 dpm of ^GTPγ35S /well (0.11-0.14 nM) to obtain a 10-point dose-response curve. Basal and maximal stimulus binding were determined with and without 3 μM SNC-80.

data analysis

Specific binding (SB) was calculated as TB-NS and expressed as a percentage of control SB in the presence of different test compounds. _IC50 values and Hill coefficients ( _nH ) for ligands that displace specifically bound radioligands are calculated from logarithmic plots or curve fitting programs, eg, Ligand, GraphPadPrism, SigmaPlot, or ReceptorFit. _Ki values were calculated using the Cheng-Prussoff formula. Mean ± SEM of _IC50 , _K1 and _nH of ligands tested in at least 3 displacement curves are reported.

Based on the above assay profile, we have found that the compounds of the present invention are active at the human delta receptor. In general, most of the compounds of the present invention have _IC50 values for human delta receptors in the range of 0.48nM-17.9nM. The _EC50 and %Emax of these compounds for the human delta receptor are generally in the range of 18.6 nM-1724 nM and 65-108, respectively. The _IC50 values of the compounds of the present invention for human kappa and mu receptors are generally in the range of 1317nM-9739nM and 261nM-9774nM, respectively.

receptor saturation test

Radioligand K _δ values are determined by performing binding assays on cell membranes using the appropriate radioligand at a concentration of 0.2 to 5 times the estimated K _δ (if the amount of radioligand required is appropriate, up to 10 times). Specific radioligand binding is expressed in μmol/mg membrane protein. _Kδ and _Bmax values for each assay were obtained by nonlinear fitting of specific binding (B) to nM free (F) radioligand in individuals according to the one-site model.

Mechano-allodynia using the Von Frey test

Testing was performed between 08:00-16:00h using the method described by Chaplan et al. (1994). The rats were placed in a plexiglass cage, and the bottom of the plexiglass cage was a wire mesh, which allowed the rats to touch their paws, and allowed the rats to adapt to the environment for 10-15 minutes. The test site was the mid-plantar of the left hind paw, avoiding the less sensitive foot pad. The mouse paw was touched with eight Von Frey hairs of increasing logarithmic hardness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51 and 15.14 grams; Stoelting, III, USA). Under the bottom of the wire mesh, Von Frey filaments were touched vertically to the plantar surface with sufficient force to slightly flex the paw and held for about 6-8 seconds. If the paw is withdrawn sharply, it is a positive reaction. Immediate retraction of the filament upon removal is also considered a positive response. Walking away was considered an ambiguous response, in which case the stimulus was repeated.

test record

For the FCA-treated group, animals were tested 1 day after surgery. The 50% withdrawal threshold was determined using the Dixon up-down method (1980). Trials were started with an intermediate durometer of 2.04g in the filament series. Regardless of increasing or decreasing, stimulation is always performed in a continuous manner. If there is no paw withdrawal response to the initially selected filament, a stronger stimulus is given; when there is a paw withdrawal response, a weaker stimulus is selected next time. Calculating the optimal threshold with this method requires 6 responses immediately around the 50% threshold, and these 6 responses are counted when the response first changes, eg, when the threshold is crossed for the first time. When the threshold falls outside the stimulus range, a value of 15.14 (normal sensitivity) or 0.41 (maximal allodynia) is assigned, respectively. The resulting positive and negative response patterns were tabulated using the convention, X = no withdrawal; O = withdrawal, and the 50% withdrawal threshold was interpolated using the following formula: 50% g threshold = 10 ^{(Xf + kδ )} /10,000

where Xf = value of the last Von Frey filament used (log units); k = tabulated value of positive/negative response pattern (from Chaplan et al. (1994)); and δ = mean difference between stimuli (log units) unit). Here δ=0.224.

The Von Frey threshold was converted to percent maximum possible efficacy (%MPE) according to Chaplan et al. 1994. Calculate %MPE using the following formula:

Administration of test substance

Before the von Frey test, rats are injected (subcutaneously, intraperitoneally, intravenously or orally) with the test substance, and the time between test compound administration and the von Frey test varies according to the nature of the test compound.

writhing test

When administered intraperitoneally to mice, acetic acid causes abdominal contractions. This makes the mice stretch their bodies in typical fashion. When an analgesic was administered, the above-mentioned actions were rarely observed, so this drug was selected as a likely good candidate.

A complete and typical writhing reflex is considered only when the following elements are present: the animal is not in motion; the lower back is slightly concave; the plantar surfaces of both paws can be observed. In this test, the compounds of the invention showed a significant inhibitory effect on the writhing response after an oral dose of 1-100 [mu]mol/kg.

(i) Solution preparation

Acetic acid (AcOH): 120 μL of acetic acid was added to 19.88 ml of distilled water to obtain a final volume of 20 ml with a final concentration of 0.6% AcOH. The solution was then mixed (vortexed) and ready for injection.

Compounds (drugs): Each compound is prepared and dissolved in the most suitable vehicle according to standard methods.

(ii) Solution Administration

20, 30 or 40 minutes before the test (depending on the type of compound and its properties), the compound (drug) was administered orally, intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously at a dose of 10 ml/kg (considering the average body weight of the mice) Intravenous (i.v.) administration. When compounds were delivered centrally: a volume of 5 μL was administered intraventricularly (i.c.v.) or intrathecally (i.t.).

AcOH was administered intraperitoneally (i.p.) at two sites at a dose of 10 ml/kg (considering the average body weight of the mice) just before the test.

(iii) test

The animals (mouses) were observed for 20 minutes, the number of reactions (writhing reflex) was recorded, and the data were collated at the end of the test. Mice were kept in individual "shoebox" cages with contact pads. Usually 4 mice were observed at the same time: 1 control mouse and 3 treated mice.

For anxiety and anxiety-like indications, efficacy has been demonstrated in the Geller-Semer conflict test in rats.

For functional gastrointestinal disorder indications, the potency of compounds can be demonstrated with rats in the assay described by Coutinho SV et al. in American Journal of Physiology-Gastrointestinal & Liver Physiology. 282(2):G307-16, 2002 Feb.

Other in vivo test methods

Test subjects and living environment (housing)

雄性Sprague-Dawley大鼠(175-200g)按每组5只置于温控室(22℃，40-70％湿度，12-小时明/暗循环)中。试验在循环明亮期进行。动物随意摄食和饮水，并在获得数据后立即处死。Will

Male Sprague-Dawley rats (175-200 g) were placed in a temperature-controlled room (22°C, 40-70% humidity, 12-hour light/dark cycle) in groups of 5. The test was carried out during the bright phase of the cycle. Animals were fed and watered ad libitum and sacrificed immediately after data acquisition.

sample

组不接受化合物(药物)或赋形剂；其它4组用带有或不带有药物的赋形剂处理。进行上述试验，以确定能降低USV的药物的抗焦虑或镇静效力。Compound (drug) tests included groups of rats without any treatment and other groups of rats treated with E. coli lipopolysaccharide (LPS). For the experiments with LPS treatment, 4 groups of rats were injected with LPS, then one of these four groups was treated with vehicle, while the other 3 groups were injected with drug and its vehicle. A second batch of experiments was performed involving 5 groups of rats; none of them received LPS treatment.

One group received no compound (drug) or vehicle; the other 4 groups were treated with vehicle with or without drug. The tests described above are performed to determine the anxiolytic or sedative efficacy of drugs that lower USV.

Administration of LPS

Rats were allowed to acclimatize to the laboratory environment for 15-20 minutes prior to treatment. Inflammation was induced by administration of LPS (Gram-negative E. coli serotype 0111:B4 endotoxin, Sigma). Under isoflurane anesthesia, LPS (2.4 μg) was injected intracerebroventricularly (i.c.v.) in a volume of 10 μl using standard stereotaxic surgical techniques. The interauricular skin is pulled toward the rostral side, and an approximately 1 cm longitudinal incision is made to expose the surface of the skull. The puncture location was determined according to the following coordinates: 0.8 mm posterior to bregma, 1.5 mm lateral (left) to the lambda (sagittal suture), and 5 mm below (vertical) the skull surface in the lateral ventricle. LPS was injected through a 5 mm long sterile stainless steel needle (26-G 3/8) connected to a 100-μl Hamilton syringe through polyethylene tubing (PE20; 10-15 cm). A 4mm plug made from a cut needle (20-G) was placed and secured to a 26-G needle with silicone glue to create the desired 5mm depth.

After LPS injection, the needle is held in place for an additional 10 seconds to allow the compound to diffuse, and then the needle is removed. The incision is closed and the rat is returned to its original cage and allowed to rest for a minimum of 3.5 hours prior to testing.

Air-spray (air-puff) irritation test protocol

After injecting LPS and administering the compound (drug) to the rat, the rat was placed in the test chamber. During the test, all the rats were taken out and placed outside the test room. One rat is brought into the test room each time, and it is placed in a clean (clear) box (9×9×18cm), and then the box is placed in a 62(w)×35(d)×46 ( h) cm sound attenuating ventilated cubicle (BRS/LVE, Div. Tech-Serv Inc). Air-spray delivery was controlled via a 0.32 cm air discharge nozzle by a system (AirStim, San Diego Intruments) capable of delivering air sprays of fixed duration (0.2 s) and fixed intensity with a frequency of 1 spray every 10 s. Give up to 10 sprays, or until the sound starts, which is always the first time it happens. The first air spray marks the beginning of the recording.

Ultrasound Recording Protocol

Vocalizations were recorded for 10 min with a loudspeaker (G.R.A.S. sound and vibrations, Vedbaek, Denmark) placed in each cubicle and controlled by LMS (LMS CADA-X 3.5B, DataAcquisition Monitor, Troy, Michigan) software. The frequency between 0-32000 Hz was recorded, saved and analyzed with the same software (LMS CADA-X3.5B, Time Data Processing Monitor and UPA (User Programming and Analysis)).

compound (drug)

All compounds (drugs) were adjusted to pH 6.5-7.5 and administered in a volume of 4 ml/kg. Following compound (drug) administration, animals are returned to their original cages until the time of the test.

analyze

Recordings were performed through a series of statistical and Fourier analyzes to filter (between 20-24kHz) and calculate parameters of interest. Data are presented as mean ± SEM. T-test (for comparison between naive and LPS-treated rats) and one-way ANOVA followed by Dunnett's multiple comparison test (post-hoc) (for drug efficacy) , to assess statistical significance. Differences between groups were considered significant when the minimum p-value was ≤0.05. Tests were repeated at least twice.

Example

The present invention will be illustrated in more detail by the following examples. The compounds of the present invention can be prepared, purified, analyzed and biologically tested by the described methods, which should not be construed as limiting the present invention.

Intermediate 1

A mixture of methyl 4-(bromomethyl)benzoate (11.2 g, 49 mmol) and trimethylphosphite (25 mL) was refluxed for 5 h under N2. Excess trimethylphosphite was removed by co-distillation with toluene to give intermediate 1 in quantitative yield. ¹ H NMR (CDCl ₃ ) δ 3.20 (d, 2H, J=22Hz, CH ₂ ), 3.68 (d, 3H 10.8 Hz, OCH ₃ ), 3.78 (d, 3H, 11.2 Hz, OCH ₃ ), 3.91 ( s, 3H, OCH ₃ ), 7.38 (m, 2H, Ar-H), 8.00 (d, 2H, J=8Hz, Ar-H).

Intermediate 2: tert-butyl 4-(4-methoxycarbonyl-benzylidene)-piperidine-1-carboxylate

To a solution of Intermediate 1 in dry THF (200 mL) was added lithium diisopropylamide (32.7 mL of a 1.5 M solution in hexane, 49 mmol) dropwise at -78 °C. The reaction mixture was then warmed to room temperature followed by the addition of N-tert-butoxycarbonyl-4-piperidone (9.76 g, 49 mmol in 100 mL dry THF). After 12 hours, the reaction mixture was quenched with water (300 mL), followed by extraction with ethyl acetate (3 x 300 mL). The combined organic phases were dried over MgSO ₄ and evaporated to give a crude product which was purified by flash chromatography to afford Intermediate 2 as a white solid (5.64 g, 35%). IR(NaCl) 3424, 2974, 2855, 1718, 1688, 1606, 1427, 1362, 1276cm ^-1 ; ¹ H NMR(CDCl ₃ ) δ1.44(s, 9H), 2.31(t, J=5.5Hz, 2H ), 2.42(t, J=5.5Hz, 2H), 3.37(t, J=5.5Hz, 2H), 3.48(t, J=5.5Hz, 2H), 3.87(s, 3H, OCH ₃ ), 6.33( s, 1H, CH), 7.20 (d J = 6.7Hz, 2H, Ar-H), 7.94 (d, J, = 6.7Hz, 2H, Ar-H); ¹³ C NMR (CDCl ₃ ) δ28.3, 29.2, 36.19, 51.9, 123.7, 127.8, 128.7, 129.4, 140.5, 142.1, 154.6, 166.8.

Intermediate 3: tert-butyl 4-bromo-4-[bromo-(4-methoxycarbonyl-phenyl)-methyl]-piperidine-1-carboxylate

To a mixture of intermediate 2 (5.2 g, 16 mmol) and _K2CO3 (1.0 g) in dry _{dichloromethane} (200 mL) was added bromine (2.9 g, 18 mmol) in 30 mL of _CH2Cl2 at ₀ °C solution. After 1.5 h at room temperature, the solution _{of K2CO3} was concentrated after filtration. Then, the residue was dissolved in ethyl acetate (200 mL), washed with water (200 mL), 0.5M HCl (200 mL) and brine (200 mL), then dried over MgSO ₄ . Removal of the solvent gave the crude product, which was recrystallized from methanol to give intermediate 3 (6.07 g, 78%) as a white solid. IR (NaCl) 3425, 2969, 1725, 1669, 1426, 1365, 1279, 1243 ^{cm -1} ; ¹ H NMR (CDCl ₃ ) δ1.28 (s, 9H), 1.75 (m, 1H), 1.90 (m, 1H ), 2.1 (m, 2H), 3.08 (br, 2H), 3.90 (s, 3H, OCH ₃ ), 4.08 (br, 3H), 7.57 (d, J=8.4Hz, 2H, Ar-H) 7.98 ( d, J=8.4Hz, 2H, Ar-H); ¹³ C NMR (CDCl ₃ ) δ 28.3, 36.6, 38.3, 40.3, 52.1, 63.2, 72.9, 129.0, 130.3, 130.4, 141.9, 154.4, 166.3.

Intermediate 4: tert-butyl 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine-1-carboxylate

A solution of Intermediate 3 (5.4 g, 11 mmol) in methanol (300 mL) and 2.0 M NaOH (100 mL) was heated at 40 °C for 3 hours. The solid was collected by filtration and dried overnight in vacuo. The dry salt was dissolved in 40% acetonitrile/water and the pH was adjusted to 2 with concentrated HCl. Intermediate 4 (3.8 g, 87%) was isolated by filtration as a white powder. ¹ H NMR (CDCl ₃ ) δ1.45 (s, 9H, ^tBu ), 2.22 (dd, J=5.5Hz, 6.1Hz, 2H), 2.64 (dd, J=5.5Hz, 6.1Hz, 2H), 3.34 (dd, J=5.5Hz, 6.1Hz, 2H), 3.54(dd, J=5.5Hz, 6.1Hz, 2H), 7.35(d, J=6.7Hz, 2H, Ar-H), 8.08(d, J =6.7Hz, 2H, Ar-H); ¹³ C NMR (CDCl ₃ ) δ 28.3, 31.5, 34.2, 44.0, 115.3, 128.7, 129.4, 130.2, 137.7, 145.2, 154.6, 170.3.

Intermediate 5: tert-butyl 4-[bromo-(4-diethylcarbamoyl-phenyl)-methylene]-piperidine-1-carboxylate

To a solution of Intermediate 4 (1.0 g, 2.5 mmol) in dry dichloromethane (10 mL) was added isobutyl chloroformate (450 mg, 3.3 mmol) at -20 °C. After 20 minutes at -20°C, diethylamine (4 mL) was added and the reaction was allowed to warm to room temperature. After 1.5 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO ₄ . Removal of the solvent gave a crude product which was purified by flash chromatography to afford intermediate 5 (800 mg, 73%) as white needles. IR (NaCl) 3051, 2975, 1694, 1633, 1416, 1281, 1168, 1115 ^{cm -1} ; ¹ H NMR (CDCl ₃ ) δ1.13 (br, 3H, CH ₃ ), 1.22 (br, 3H, CH ₃ ) , 1.44(s, 9H, ^tBu ), 2.22(t, J=5.5Hz, 2H), 2.62(t, J=5.5Hz, 2H), 3.33(m, 4H), 3.55(m, 4H), 7.31 (d, J=8.0Hz, 2H, Ar-H), 7.36 (d, J=8.0Hz, 2H, Ar-H); ¹³ C NMR (CDCl ₃ ) δ12.71, 14.13, 28.3, 31.5, 34.2, 39.1, 43.2, 79.7, 115.9, 126.3, 129.3, 136.8, 137.1, 140.6, 154.6, 170.5.

Intermediate 6: 1,1-Dimethylethyl 4-[(2-aminophenyl)[4-[(diethylamino)carbonyl]phenyl]methylene]-1-piperidinecarboxylate

To a mixture of Intermediate 5 (3.0 g, 6.65 mmol) and 2-aminophenylboronic acid (1.37 g, 9.97 mmol) in toluene (85 mL) and ethanol (17 mL) was added _2.0 M _Na2CO3 (13 mL). Tetrakis(triphenylphosphine)palladium (774 mg, 0.1 mmol) was added and the resulting mixture was heated at 90 °C under _N2 overnight. Then, the reaction was concentrated in vacuo, and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (3x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The crude product was purified by silica gel column chromatography eluting with 7:3 EtOAc:hexanes to afford Intermediate 6 (3.14 g, quantitative yield) as a beige solid. ¹ H NMR (400MHz, CDCl ₃ ) δ1.12(br s, 3H), 1.26(br s, 3H), 1.46(s, 9H), 2.22(m, 2H), 2.45(m, 2H), 3.28( br s, 1H), 3.37(m, 3H), 3.54(m, 4H), 3.66(s, 2H), 6.69(dd, J=7.91, 0.88Hz, 1H), 6.73(td, J=7.42, 1.17 Hz, 1H), 6.95(dd, J=7.71, 1.46Hz, 1H), 7.09(td, J=7.62, 1.56Hz, 1H), 7.21(d, J=8.40Hz, 2H), 7.31(d, J = 8.40Hz, 2H).

Compound 1: 4-[[2-(benzoylamino)phenyl]-4-piperidinylidene (piperidinylidene)methyl]-N,N-diethylbenzamide

To a solution of Intermediate 6 (400 mg, 0.86 mmol) in _CH2Cl2 (15 _mL ) was added triethylamine (0.36 mL, 2.59 mmol) followed by benzoyl chloride (133 mg, 0.95 mmol). The reaction was stirred at room temperature under _{N2 overnight} , diluted with _CH2Cl2 , and washed with saturated aqueous sodium bicarbonate (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was dissolved in _CH2Cl2 (15 _mL ), then trifluoroacetic acid (2.5 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 10-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 1 as TFA salt (275 mg, 46% yield). This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ HNMR (400MHz, CD ₃ OD) δ1.06(t, J=6.64Hz, 3H), 1.20(t, J=6.74Hz, 3H), 2.49-2.72(m, 4H), 3.10-3.15(m, 1H), 3.20-3.31(m, 4H), 3.31-3.40(m, 1H), 3.43-3.55(m, 2H), 7.05(d, J=8.40Hz, 2H) , 7.18(d, J=8.40Hz, 2H), 7.27-7.31(m, 1H), 7.37-7.43(m, 3H), 7.45(d, J=8.01Hz, 2H), 7.55(tt, J=7.42 , 1.37Hz, 1H), 7.66 (d, J=7.23Hz, 2H). Found: _{C ,} 62.61 _{; H} , 5.92; N, 6.71. Theoretical (has) _C , _62.52 ; _H , 5.86 ; N, 6.75%.

Compound 2: N-[2-[[4-[(diethylamino)carbonyl]phenyl]-4-piperidinylidenemethyl]phenyl]phenylacetamide

Using the same method of compound 1 and using intermediate 6 (400 mg, 0.86 mmol) and phenylacetyl chloride (133 mg, 0.95 mmol), compound 2 (381 mg, 62% yield) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.09(t, J=6.74Hz, 3H), 1.22(t, J=6.93Hz, 3H), 2.34-2.49(m , 3H), 2.49-2.59(m, 1H), 2.95-3.04(m, 1H), 3.09-3.30(m, 5H), 3.47-3.58 (overlapped d and m, J=5.66Hz, 4H), 6.89 (d, J=8.20Hz, 2H), 7.22(d, J=8.20Hz, 2H), 7.26-7.42(m, 9H). Found: C, 63.88; H, 6.13; N, 6.66. C ₃₀ H C _, 63.79; _{H , 6.14 ;} N, _6.72 %.

Compound 3: 4-[[2-[(cyclohexylcarbonyl)amino]phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide

Using the same method of compound 1 and using intermediate 6 (150 mg, 0.32 mmol) and cyclohexanecarbonyl chloride (52 mg, 0.35 mmol), compound 3 (159 mg, 83% yield) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.04-1.24 (m, 6H), 1.324-1.39 (m, 4H), 1.46 (dq, J=12.33, 3.03Hz, 1H), 1.58-1.91(m, 5H), 2.22(tt, J=11.28, 3.47Hz, 1H), 2.43-2.56(m, 2H), 2.61(dt, J=14.84, 5.86Hz, 1H), 2.72 (dt, J=15.04, 6.05Hz, 1H), 3.15-3.33(m, 6H), 3.47-3.55(m, J=6.83Hz, 2H), 7.19(d, J=8.40Hz, 2H), 7.26- 7.34 ₍ m _, 6H). Found _{value :} C, 60.51; H _{, 6.33} ; N _, 6.27. 6.26; N, 6.37%.

Compound 4: N-[2-[[4-[(diethylamino)carbonyl]phenyl]-4-piperidinylidenemethyl]phenyl]phenylpropanamide

Using the same method of compound 1 and using intermediate 6 (150 mg, 0.32 mmol) and phenylpropionyl chloride (60 mg, 0.35 mmol), compound 4 (157 mg, 79% yield) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.07(t, J=6.44Hz, 3H), 1.21(t, J=6.64Hz, 3H), 2.38-2.59(m , 5H), 2.69(dt, J=15.04, 5.66Hz, 1H), 2.79-2.94(m, 2H), 3.18-3.31(m, 6H), 3.50(br q, J=6.51Hz, 2H), 7.07 (d, J=8.20Hz, 2H), 7.15-7.35 (m, 11H). Found: C, 63.05; H, 5.89; N, 6.50. C ₃₂ H ₃₇ N ₃ O ₂ x1.4CF ₃ CO ₂ Hx0 _.4H2O Theoretical C, 63.09; H, 5.96; N, 6.34%.

Compound 5: 4-[[2-[(cyclohexylacetyl)amino]phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide

To a solution of cyclohexylacetic acid (74 mg, 0.52 mmol) and HATU (172 mg, 0.45 mmol) in DMF (7 mL) was added diisopropylethylamine (0.14 mL, 0.81 mmol), followed by intermediate 6 (150 mg, 0.32 mmol). The reaction was stirred at room temperature under _N2 overnight, then concentrated in vacuo. The residue was dissolved _{in CH2Cl2} and washed with 1N NaOH (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The product was purified by column chromatography on silica gel, eluting with 1:1 EtOAc:hexanes, and then redissolved in _CH2Cl2 ( ₁₀ mL). Trifluoroacetic acid (1 mL) was added and the reaction was stirred overnight at room temperature. The reaction was concentrated in vacuo and the residue was purified by reverse phase HPLC (gradient 10-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to give compound 5 as the TFA salt (130 mg, 67 % yield). This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ 0.90-1.06 (m, 2H), 1.05-1.33 (m, 9H), 1.61-1.80 (m, 6H), 1.97 ( dd, J=13.86, 7.23Hz, 1H), 2.13(dd, J=13.86, 6.64Hz, 1H), 2.51(t, J=5.96Hz, 2H), 2.61(ddd, J=14.84, 6.64, 5.27Hz , 1H), 2.71(ddd, J=14.84, 6.83, 5.47Hz, 1H), 3.17-3.33(m, 6H), 3.51(q, J=6.64Hz, 2H), 7.17(d, J=8.40Hz, 2H), 7.24-7.37(m, 6H). Found: C, 61.10; H, 6.47; N, 6.27. Theoretical value C of C ₃₁ H ₄₁ N ₃ O ₂ x1.6CF ₃ CO ₂ Hx0.1H ₂ O , 61.13; H, 6.42; N, 6.25%.

Compound 6: N,N-diethyl-4-[[2-[(2-phenylethyl)amino]phenyl]-4-piperidinylidenemethyl]benzamide

To a solution of intermediate 6 (300 mg, 0.65 mmol) in 1,2-dichloroethane (20 ml) was added phenylacetaldehyde (156 mg, 1.30 mmol), followed by glacial acetic acid (0.07 mL, 1.30 mmol) and NaBH (OAc) ₃ (344 mg, 1.63 mmol). The reaction was stirred overnight at room temperature under _N2 . Trifluoroacetic acid (2 mL) was added and the reaction was stirred for an additional 4 hours. The reaction was diluted with _CH2Cl2 , then _washed with saturated aqueous sodium bicarbonate (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by reverse phase HPLC (gradient 20-45% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to afford compound 6 as TFA salt (181 mg, 40% yield). This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.08(t, J=6.74Hz, 3H), 1.21(t, J=6.83Hz, 3H), 2.19-2.36(m , 2H), 2.56(t, J=6.05Hz, 2H), 2.84(t, J=6.64Hz, 2H), 2.96-3.05(m, 1H), 3.06-3.14(m, 1H), 3.13-3.21( m, 2H), 3.20-3.30(m, 2H), 3.29-3.46(m, 2H), 3.46-3.56(m, 2H), 6.63(td, J=7.42, 0.98Hz, 1H), 6.73(d, J=8.20Hz, 1H), 6.89(dd, J=7.42, 1.56Hz, 1H), 7.07(d, J=8.40Hz, 2H), 7.10-7.17(m, 1H), 7.18-7.27(m, 5H ), 7.27-7.33 (m, 2H). Measured value: C, 65.55; H, 6.48; N, 6.69. Theoretical value C of C ₃₁ H ₃₇ N ₃ Ox1.2CF ₃ CO ₂ Hx0.4H ₂ O, 65.58; H, 6.43; N, 6.87%.

Compound 7: 4-[[2-[(cyclohexylmethyl)amino]phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide

To a solution of Intermediate 6 (300 mg, 0.65 mmol) in 1,2-dichloroethane (20 mL) was added cyclohexanecarbaldehyde (146 mg, 1.30 mmol), followed by glacial acetic acid (0.07 mL, 1.30 mmol) and NaBH(OAc) ₃ (344 mg, 1.63 mmol). The reaction was stirred overnight at room temperature under _N2 . Trifluoroacetic acid (2 mL) was added and the reaction was stirred for an additional 4 hours. The reaction was diluted with _CH2Cl2 , then _washed with saturated aqueous sodium bicarbonate (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by reverse phase HPLC (gradient 20-50% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to afford compound 7 as TFA salt (190 mg, 43% yield). This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ.0.78-0.90 (m, 2H), 1.05-1.25 (m, 10H), 1.41-1.52 (m, 1H), 1.52- 1.72(m, 5H), 2.36-2.50(m, 2H), 2.64-2.77(m, 2H), 2.88(d, J=6.64Hz, 2H), 3.12-3.38(m, 5H), 3.46-3.55( m, 2H), 6.59-6.66(m, 2H), 6.96(dd, J=7.42, 1.37Hz, 1H), 7.12(ddd, J=8.70, 7.42, 1.56Hz, 1H), 7.31(s, 4H) . Found: C, 63.61; H, 6.86; N, 6.92. Theoretical value of C ₃₀ H ₄₁ N ₃ Ox1.4CF ₃ CO ₂ H C, 63.61; H, 6.90; N, 6.78%.

Compound 8: N,N-Diethyl-4-[[2-[(phenylmethyl)amino]phenyl]-4-piperidinylidenemethyl]-benzamide

To a solution of Intermediate 6 (309 mg, 0.67 mmol) in 1,2-dichloroethane (20 ml) was added benzaldehyde (140 μL, 1.38 mmol), followed by glacial acetic acid (38 μL, 0.66 mmol) and NaBH(OAc ) ₃ (283 mg, 1.34 mmol). The reaction was stirred overnight at room temperature under _N2 . Trifluoroacetic acid (2 mL) was added and the reaction was stirred for an additional 4 hours. The reaction was diluted with _CH2Cl2 , then _washed with saturated aqueous sodium bicarbonate (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by reverse phase HPLC (gradient 20-50% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 8 as TFA salt (203 mg, 45% yield). This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.11 (br t, J=7.62Hz, 3H), 1.24 (br t, J=7.62Hz, 3H), 2.46-2.52 (m, 2H), 2.64-2.79(m, 2H), 3.17-3.37(m, 6H), 3.49-3.58(m, 2H), 4.34(s, 2H), 6.54-6.57(m, 1H), 6.61 -6.66(m, 1H), 6.96(dd, J=7.62, 1.56Hz, 1H), 7.01-7.08(m, 1H), 7.11-7.27(m, 5H), 7.32-7.37(m, 4H). Measured Values: C, 62.71; _H , 5.89 _; N, 6.74 _. Theoretical C, 62.73 _; H, _5.95 ; N _, 6.65% for C30H35N3Ox1.5CF3CO2Hx0.4H2O.

Compound 9: 4-[[2-(cyclohexylamino)phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide

To a suspension of Intermediate 6 (200 mg, 0.43 mmol) and cyclohexanone (47 mg, 0.47 mmol) in MeOH (6 mL) was added decaborane (16 mg, 0.3 mmol). The reaction was stirred at room temperature under _N2 overnight, then concentrated in vacuo. The residue was filtered through a silica gel plug eluting with 1:1 EtOAc:hexanes, then concentrated in vacuo. The residue was dissolved in _CH2Cl2 (10 _mL ), then trifluoroacetic acid (1.5 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 10-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 9 (207 mg, 71% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ HNMR (400MHz, CD ₃ OD) δ0.69-0.82 (m, 1H), 1.05-1.38 (m, 11H), 1.47-1.61 (m, 2H), 1.69 (d , J=12.89Hz, 2H), 1.93(d, J=11.72Hz, 1H), 2.37-2.51(m, 2H), 2.66-2.81(m, 2H), 3.08-3.17(m, 1H), 3.17- 3.38(m, 5H), 3.51(br q, J=6.45Hz, 2H), 6.73-6.79(m, 2H), 7.06(dd, J=7.62, 1.56Hz, 1H), 7.18(ddd, J=8.25 , 7.37, 1.56Hz, 1H), 7.28-7.36(m, 4H). Found: C, 58.94; H, 6.47; N, 6.31. C ₂₉ H ₃₉ N ₃ Ox1.8CF ₃ CO ₂ Hx0.7H ₂ O Theoretical values for C, 59.01; H, 6.41; N, 6.33%.

Compound 10: N,N-Diethyl-4-[[2-[[(phenylamino)carbonyl]amino]phenyl]-4-piperidinylidenemethyl]benzamide

A solution of intermediate 6 (200 mg, 0.43 mmol) and phenylisocyanate (56 mg, 0.47 mmol) in 1,2-dichloroethane (10 mL) was stirred overnight at 70 °C under _N2 . The reaction was then _diluted with _CH2Cl2 , followed by washing with saturated aqueous sodium bicarbonate (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was dissolved in _CH2Cl2 (10 _mL ), then trifluoroacetic acid (1.5 mL) was added. The reaction was stirred at room temperature for 6 hours, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 10-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 10 as TFA salt (235 mg, 92% yield). This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ0.97(t, J=6.74Hz, 3H), 1.17(t, J=7.03Hz, 3H), 2.48(t, J =6.05Hz, 2H), 2.68(q, J=5.60Hz, 2H), 3.04-3.15(m, 2H), 3.15-3.27(m, 4H), 3.39-3.53(m, 2H), 6.98(tt, J=7.22, 1.17Hz, 1H), 7.16(td, J=7.42, 1.37Hz, 1H), 7.20-7.28(m, 6H), 7.28-7.30(m, 1H), 7.30(dd, J=1.76, 0.98Hz, 1H), 7.33-7.34(m, 1H), 7.34-7.37(m, 1H), 7.60(dd, J=8.10, 0.88Hz, 1H). Measured values: C, 57.39; H, 5.32; N C _, 57.32; H, _{5.25 ; N} , _{7.91 % .}

Compound 11: N,N-Diethyl-4-[[2-(phenylamino)phenyl]-4-piperidinylidenemethyl]benzamide

Intermediate 6 (300mg, 0.65mmol), bromobenzene (133mg, 0.85mmol), Pd ₂ (dba) ₃ (24mg, 0.026mmol), NaO ^t Bu (87mg, 0.91mmol), (±)-BINAP (32mg , 0.052 mmol) in toluene (3.7 mL) was charged to a microwave treatment vial. The vial was flushed with _N2 , capped, and then heated to 110 °C for 5 min with microwave irradiation. The resulting mixture was cooled, concentrated in vacuo, and purified by column chromatography on silica gel, eluting with 2:3 EtOAc:hexanes. The product was dissolved in _CH2Cl2 (20 _mL ), then trifluoroacetic acid (2 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 15-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 11 as TFA salt (193 mg, 44% yield). This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.01(t, J=6.83Hz, 3H), 1.19(t, J=7.03Hz, 3H), 2.48-2.58(m , 2H), 2.58-2.76(m, 2H), 3.03(q, J=6.83Hz, 2H), 3.11-3.26(m, 4H), 3.46(q, J=7.03Hz, 2H), 6.71-6.79( m, 3H), 6.98 (ddd, J=7.62, 6.25, 2.34Hz, 1H), 7.05-7.11 (m, 2H), 7.16-7.24 (m, 7H). Measured values: C, 65.08; H, 6.11; N, _7.20 . C, 65.08; H, _{6.18 ;} N _{, 730 %} .

Compound 12: N,N-Diethyl-4-[[2-(methylphenylamino)phenyl]-4-piperidinylidenemethyl]benzamide

Intermediate 6 (225 mg, 0.49 mmol), bromobenzene (99 mg, 0.63 mmol), Pd ₂ (dba) ₃ (18 mg, 0.019 mmol), NaO ^t Bu (65 mg, 0.68 mmol), (±)-BINAP (24 mg , 0.039 mmol) in toluene (2.8 mL) was charged to a microwave treatment vial. The vial was flushed with _N2 , capped, and then heated to 110 °C for 5 min with microwave irradiation. The resulting mixture was cooled, concentrated in vacuo, and purified by column chromatography on silica gel, eluting with 2:3 EtOAc:hexanes. The product (260 mg, 0.48 mmol) was dissolved in DMF (11 mL), followed by the addition of sodium hydride (46 mg, 1.16 mmol). The reaction was stirred at room temperature for 1 hour. Methyl iodide (171 mg, 1.21 mmol) was then added and the reaction was stirred at room temperature overnight. _After 18 hours, the reaction was quenched with saturated ammonium chloride, then extracted with _CH2Cl2 . The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was dissolved in _CH2Cl2 (10 _mL ), then trifluoroacetic acid (1.5 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 20-50% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 12 as a TFA salt (126 mg, 34% yield over two steps). This material was lyophilized from _CH3CN / _H2O to yield a light yellow solid. Purity (HPLC): 91% (215nm), 93% (254nm), 86% (280nm); ¹ H NMR (400MHz, CD ₃ OD) δ1.04 (br s, 3H), 1.19 (br s, 3H) , 2.38-2.57(m, 3H), 2.57-2.72(m, 4H), 2.93-3.18(m, 5H), 3.20-3.33(m, 1H), 3.48(br s, 2H), 6.27(d, J =8.20Hz, 2H), 6.60(t, J=7.32Hz, 1H), 6.92(d, J=8.01Hz, 2H), 7.01(t, J=7.81Hz, 2H), 7.13(d, J=7.62 Hz, 1H), 7.16-7.23 (m, 2H), 7.34 (t, J=7.03Hz, 1H), 7.43 (dd, J=14.65, 7.42Hz, 2H).

Compound 13: N,N-Diethyl-4-[[2-[(benzenesulfonyl)amino]phenyl]-4-piperidinylidenemethyl]benzamide

To a solution of Intermediate 6 (300 mg, 0.65 mmol) in pyridine (10 mL) was added benzenesulfonyl chloride (230 mg, 1.30 mmol). The reaction was stirred at room temperature under _N2 overnight, then concentrated in vacuo. The residue was dissolved in _CH2Cl2 , _then washed with saturated aqueous sodium bicarbonate (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was dissolved in _CH2Cl2 (15 _mL ), then trifluoroacetic acid (2.0 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo.

The residue was purified by reverse phase HPLC (gradient 10-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 13 (298 mg, 63% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a yellow solid. Purity (HPLC): >99%; ¹ HNMR (400MHz, CD ₃ OD) δ1.11(t, J=6.64Hz, 3H), 1.22(t, J=7.03Hz, 3H), 2.43-2.52(m, 1H), 2.52-2.61(m, 2H), 2.72-2.83(m, 1H), 3.22-3.36(m, 5H), 3.38-3.48(m, 1H), 3.47-3.60(m, 2H), 6.64( dd, J=8.01, 0.78Hz, 1H), 7.11 (ddd, J=8.01, 7.03, 1.95Hz, 1H), 7.1-7.34(m, 6H), 7.48-7.53(m, 2H), 7.60(tt, J=7.42, 1.37Hz, 1H), 7.64-7.69 (m, 2H). Found: C, 58.37; H, 5.58; N, 6.46. C ₂₉ H ₃₃ N ₃ O ₃ Sx1.1CF ₃ CO ₂ Hx0. Calcd for _7H2O C, 58.40; H, 5.58; N, 6.55%.

Compound 14: N,N-Diethyl-4-[[2-[[(phenylmethyl)sulfonyl]amino]phenyl]-4-piperidinylidenemethyl]benzamide

Using the same method of compound 13 and using intermediate 6 (250 mg, 0.54 mmol) and benzylsulfonyl chloride (206 mg, 1.08 mmol), compound 14 (253 mg, 63% yield) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.02(t, J=6.83Hz, 3H), 1.20(t, J=6.64Hz, 3H), 2.36-2.52(m , 2H), 2.52-2.62(m, 1H), 2.74(dt, J=15.38, 5.40Hz, 1H), 3.13-3.27(m, 5H), 3.30-3.39(m, 1H), 3.42-3.55(m , 2H), 4.13(d, J=13.86Hz, 1H), 4.25(d, J=13.67Hz, 1H), 7.17(dt, J=7.22, 1.17Hz, 1H), 7.22-7.36(m, 12H) . Found: C, 58.87; H, 5.76; N, 6.31. Theoretical value of C ₃₀ H ₃₅ N ₃ O ₃ Sx1.1CF ₃ CO ₂ Hx0.8H ₂ O C, 58.82; H, 5.78; N, 6.39% .

Compound 15: N,N-diethyl-4-[4-piperidinylidene[2-[[(2,2,2-trifluoroethyl)sulfonyl]amino]phenyl]methyl]benzyl Amide

Using the same method of compound 13 and using intermediate 6 (203 mg, 0.44 mmol) and 2,2,2-trifluoroethanesulfonyl chloride (0.097 mL, 0.88 mmol), compound 15 was obtained as TFA salt (244 mg, 89% yield Rate). This material was lyophilized from _CH3CN / _H2O to yield a yellowish solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.11 (br t, J=6.6Hz, 3H), 1.23 (br t, J=7.0Hz, 3H), 2.42-2.59 (m, 3H), 2.73-2.82(m, 1H), 3.19-3.40(m, 6H), 3.53(q, J=6.8Hz, 2H), 3.95-4.15(m, 2H), 7.26-7.44(m , 8H).

Compound 16: 4-[{2-[(cyclopentylacetyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

Using the same method of compound 1 and using intermediate 6 (175 mg, 0.377 mmol) and cyclopentylacetyl chloride (61 mg, 0.415 mmol), compound 16 (180 mg, 81%) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.06-1.26 (m, 8H), 1.49-1.70 (m, 4H), 1.72-1.87 (m, 2H), 2.08- 2.31(m, 3H), 2.52(t, J=5.96Hz, 2H), 2.56-2.66(m, 1H), 2.67-2.78(m, 1H), 3.16-3.34(m, 6H), 3.46-3.56( br q, J=6.83Hz, 2H), 7.17(d, J=8.40Hz, 2H), 7.26-7.37(m, 6H). Found: C, 63.19; H, 6.90; N, 6.59.C ₃₀ H _C , _{63.23 ;} H _{, 6.84 ;} N, 6.87%.

Compound 17: 4-[{2-[(cyclopentylcarbonyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

Using the same method of compound 1 and using intermediate 6 (145 mg, 0.313 mmol) and cyclopentanecarbonyl chloride (46 mg, 0.344 mmol), compound 17 (141 mg, 79%) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ 1.10 (br t, J=6.35Hz, 3H), 1.21 (br t, J=6.35Hz, 3H), 1.44-1.86 (m, 7H), 1.87-1.99(m, 1H), 2.47-2.54(m, 2H), 2.55-2.79(m, 3H), 3.16-3.34(m, 6H), 3.51(br q, J=7.16 Hz, 2H), 7.18 (d, J=8.40Hz, 2H), 7.27-7.35 (m, 6H). Found: C, 60.05; H, 6.05; N, 6.71. C ₂₉ H ₃₇ N ₃ O ₂ x1 .C, _60.07 ; H, 6.07; N, 6.53% _{for 6CF3CO2Hx0.1H2O} .

Compound 18: N,N-Diethyl-4-[{2-[(3-phenylpropyl)amino]phenyl}(piperidin-4-ylidene)methyl]benzamide

To a solution of Intermediate 6 (200 mg, 0.43 mmol) in 1,2-dichloroethane (13 ml) was added 3-phenylpropanal (93 mg, 0.69 mmol) followed by glacial acetic acid (39 μL, 0.69 mmol) and NaBH(OAc) ₃ (183 mg, 0.86 mmol). The reaction was stirred overnight at room temperature under _N2 . Trifluoroacetic acid (1.5 mL) was added, followed by reaction at room temperature overnight. The reaction was diluted with _CH2Cl2 , then _washed with saturated aqueous sodium bicarbonate (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 20-50% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 18 as TFA salt (112 mg, 37% yield). This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ0.99 (br t, J=6.69Hz, 3H), 1.18 (br t, J=6.64Hz, 3H), 1.71-1.81 (m, 2H), 2.37-2.56(m, 4H), 2.64-2.79(m, 2H), 3.00-3.27(m, 7H), 3.30-3.37(m, 1H), 3.48(br q, J=6.58 Hz, 2H), 6.60(d, J=7.71Hz, 1H), 6.66(dt, J=7.42, 0.98Hz, 1H), 6.98(dd, J=7.47, 1.61Hz, 1H), 7.04-7.08(m , 2H), 7.10-7.15(m, 2H), 7.18-7.24(m, 2H), 7.29-7.35(m, 4H). Found values: C, 62.11; H, 5.88; N, 5.69. C ₃₂ H _{39 N3Ox1.8CF3CO2Hx0.1H2O} Theoretical C, 62.08 _; H, 6.00; _N , 6.10% _.

Compound 19: 4-[{2-[(2-cyclohexylethyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

To a solution of Intermediate 6 (175 mg, 0.377 mmol) in 1,2-dichloroethane (12 ml) was added cyclohexylacetaldehyde (57 mg, 0.453 mmol) followed by glacial acetic acid (26 μL, 0.453 mmol) and NaBH (OAc) ₃ (160 mg, 0.755 mmol). The reaction was stirred overnight at room temperature under _N2 . Trifluoroacetic acid (1.5 mL) was added, followed by reaction at room temperature overnight. The reaction was diluted with _CH2Cl2 , then _washed with saturated aqueous sodium bicarbonate (1x). The two layers _were separated and the aqueous layer was extracted with additional _CH2Cl2 (2x). The combined organic phases were dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 20-50% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 19 (89 mg, 34% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ0.85-0.98 (m, 2H), 1.10 (br t, J=6.25Hz, 3H), 1.04-1.32 (m, 4H) ), 1.21(br t, J=7.08Hz, 3H), 1.32-1.44(m, 2H), 1.59-1.75(m, 5H), 2.35-2.48(m, 2H), 2.63-2.76(m, 2H) , 3.01-3.36(m, 8H), 3.48-3.56(m, 2H), 6.62-6.68(m, 2H), 6.94(dd, J=7.37, 1.32Hz, 1H), 7.14(ddd, J=8.30, 7.42, 1.66Hz, 1H), 7.29-7.35(m, 4H). Found: C, 64.57; H, 7.10; N, 6.95. C ₃₁ H ₄₃ N ₃ Ox1.3CF ₃ CO ₂ Hx0.2H ₂ O Theoretical C, 64.52; H, 7.20; N, 6.72%.

Compound 20: 4-[[2-(cyclopentylamino)phenyl](piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

Using the same method of compound 9 and using intermediate 6 (200 mg, 0.43 mmol) and cyclopentanone (40 mg, 0.47 mmol), compound 20 (210 mg, 74%) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.05-1.26(m, 1H), 1.09(br t, J=6.06Hz, 3H), 1.21(t, J=6.64 Hz, 3H), 1.30-1.67(m, 5H), 1.71-1.81(m, 1H), 1.90-2.02(m, 1H), 2.36-2.52(m, 2H), 2.65-2.79(m, 2H), 3.14-3.36(m, 6H), 3.47-3.55(m, 2H), 3.66-3.74(m, 1H), 6.69-6.76(m, 2H), 7.02(dd, J=7.32, 1.27Hz, 1H), 7.16 (ddd, J=8.45, 7.18, 1.76Hz, 1H), 7.27-7.35 (m, 4H). Found: C, 56.62; H, 5.62; N, 6.30. C ₂₈ H ₃₇ N ₃ Ox2.2CF ₃ C, _56.72 ; H, 5.82; N, 6.12% calcd for _CO2Hx0.2H2O .

Compound 21: 4-[[2-(cycloheptylamino)phenyl](piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

Using the same method of compound 9 and using intermediate 6 (200 mg, 0.43 mmol) and cycloheptanone (53 mg, 0.47 mmol), compound 21 (241 mg, 81%) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.05-1.25 (m, 4H), 1.21 (t, J=7.03Hz, 3H), 1.25-1.70 (m, 11H) , 1.8-1.98(m, 1H), 2.36-2.49(m, 2H), 2.67-2.80(m, 2H), 3.13-3.38(m, 6H), 3.51(q, J=6.70Hz, 2H), 6.71 (d, J=8.01Hz, 1H), 6.77 (dt, J=7.42, 1.17Hz, 1H), 7.06 (dd, J=7.62, 1.37Hz, 1H), 7.19 (dq, J=7.42, 1.56Hz, 1H), 7.27-7.35 (m, 4H). Found: C, 57.47; H, 5.91; N, 5.76. Theoretical C of C ₃₀ H ₄₁ N ₃ Ox2.3CF ₃ CO ₂ Hx0.1H ₂ O, 57.42 ; H, 6.06; N, 5.81%.

Compound 22: 4-[(2-{[(benzylamino)carbonyl]amino}phenyl)(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

Using the same method of compound 10 and using intermediate 6 (200 mg, 0.43 mmol) and benzyl isocyanate (63 mg, 0.47 mmol), compound 22 (193 mg, 74%) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.08(t, J=6.64Hz, 3H), 1.23(t, J=6.64Hz, 3H), 2.44(t, J =6.05Hz, 2H), 2.55-2.68(m, 2H), 3.12-3.27(m, 6H), 3.51(br q, J=6.44Hz, 2H), 4.23-4.36(m, 2H), 7.13(dt , J=7.42, 1.37Hz, 1H), 7.17-7.21(m, 3H), 7.22-7.36(m, 8H), 7.56(dd, J=8.20, 0.78Hz, 1H). Measured value: C, 62.35; _H , 5.96; N, _{8.73 .} C _{, 62.44} ; H _{, 5.99} ; N, 8.72%.

Compound 23: N, N-diethyl-4-[[2-(1-naphthylamino)phenyl](piperidin-4-ylidene)methyl]benzamide

Intermediate 6 (200mg, 0.43mmol), bromonaphthalene (116mg, 0.56mmol), Pd ₂ (dba) ₃ (16mg, 0.017mmol), NaO ^t Bu (58mg, 0.60mmol), (±)-BINAP (20mg , 0.034 mmol) in toluene (2.4 mL) was charged to a microwave treatment vial. The vial was flushed with _N2 , capped, and then heated to 110 °C for 5 min with microwave irradiation. The resulting mixture was cooled, concentrated in vacuo, and purified by column chromatography on silica gel, eluting with 1:1 EtOAc:hexanes. The product was dissolved in _CH2Cl2 (10 _mL ), then trifluoroacetic acid (1.3 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 20-45% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 23 (138 mg, 45% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.00(t, J=6.54Hz, 3H), 1.19(t, J=6.74Hz, 3H), 2.54-2.75(m , 4H), 3.08-3.21(m, 4H), 3.23-3.31(m, 2H), 3.42-3.53(m, 2H), 6.78(dd, J=8.01, 0.98Hz, 1H), 6.88(dd, J =7.42, 0.98Hz, 1H), 6.98(dt, J=7.47, 1.27Hz, 1H), 7.11-7.20(m, 5H), 7.23-7.33(m, 3H), 7.42(dq, J=6.83, 1.17 Hz, 1H), 7.47 (d, J=8.20Hz, 1H), 7.56 (d, J=8.40Hz, 1H), 7.80 (d, J=8.20Hz, 1H). Found: C, 66.35; H, 5.04; N, 6.65. _{Calcd for C33H35N3Oxl.4CF3CO2H} C, 66.22; H, _5.65 ; _N , 6.47%.

Compound 24: N,N-Diethyl-4-[{2-[(3-fluorophenyl)amino]phenyl}(piperidin-4-ylidene)methyl]benzamide

Intermediate 6 (200 mg, 0.43 mmol), 3-fluoroiodobenzene (124 mg, 0.56 mmol), Pd ₂ (dba) ₃ (16 mg, 0.017 mmol), NaO ^t Bu (58 mg, 0.60 mmol), (±)- A mixture of BINAP (21 mg, 0.034 mmol) in toluene (2.4 mL) was charged to a microwaved vial. The vial was flushed with _N2 , capped, and then heated to 110 °C for 25 min under microwave irradiation. The resulting mixture was cooled, concentrated in vacuo, and purified by column chromatography on silica gel, eluting with 1:1 EtOAc:hexanes. The product was dissolved in _CH2Cl2 (10 _mL ), then trifluoroacetic acid (1.3 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 15-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 24 (99 mg, 34% yield) as TFA salt. Freeze drying of this material from _CH3CN / _H2O yielded a light gray solid. Purity (HPLC): >95%; ¹ H NMR (400MHz, CD ₃ OD) δ1.00(t, J=6.83Hz, 3H), 1.18(t, J=6.83Hz, 3H), 2.47-2.74(m , 4H), 3.01(q, J=6.83Hz, 2H), 3.14-3.27(m, 4H), 3.46(q, J=5.86Hz, 2H), 6.32-6.39(m, 2H), 6.46-6.50( m, 1H), 6.97-7.05(m, 1H), 7.07-7.32(m, 8H). Found: C, 62.96; H, 5.62; N, 7.17. C ₂₉ H ₃₂ FN ₃ Ox1.2CF ₃ CO ₂ Theoretical for _Hx0.2H2O C, 63.07; H, 5.66; N, 7.03%.

Compound 25: 4-[{2-[(4-chlorophenyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

Intermediate 6 (200 mg, 0.43 mmol), 4-bromochlorobenzene (107 mg, 0.56 mmol), Pd ₂ (dba) ₃ (16 mg, 0.017 mmol), NaO ^t Bu (58 mg, 0.60 mmol), (±)- A mixture of BINAP (21 mg, 0.034 mmol) in toluene (2.4 mL) was charged to a microwaved vial. The vial was flushed with _N2 , capped, and then heated to 110 °C for 5 min with microwave irradiation. The resulting mixture was cooled, concentrated in vacuo, and purified by column chromatography on silica gel, eluting with 2:3 EtOAc:hexanes. The product was dissolved in _CH2Cl2 (10 _mL ), then trifluoroacetic acid (1.3 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 20-50% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to afford compound 25 (139 mg, 46% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.01(t, J=6.83Hz, 3H), 1.18(t, J=6.83Hz, 3H), 2.46-2.75(m , 4H), 3.00(q, J=6.57Hz, 2H), 3.15-3.30(m, 4H), 3.46(q, J=6.70Hz, 2H), 6.64-6.69(m, 2H), 6.98-7.03( m, 2H), 7.06 (dt, J=7.37, 1.27Hz, 1H), 7.15-7.21 (m, 5H), 7.23-7.28 (m, 2H). Measured values: C, 60.39; H, 5.29; N, C, _60.28 ; H _, 5.31; _{N , 6.63} %.

Compound 26: 4-[{2-[cyclohexyl(methyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

To a suspension of Intermediate 6 (175 mg, 0.38 mmol) and cyclohexanone (41 mg, 0.42 mmol) in MeOH (5 mL) was added decaborane (14 mg, 0.11 mmol). The reaction was stirred at room temperature under _N2 overnight, then concentrated in vacuo. The residue was filtered through a short plug of silica gel, eluting with 1:1 EtOAc:hexanes, and concentrated in vacuo. To a solution of the product (206 mg, 0.38 mmol) in MeOH (4 mL) was added formaldehyde (37% in _H2O , 0.084 mL, 1.13 mmol). The reaction was stirred at room temperature for 30 minutes. Decaborane (28 mg, 0.23 mmol) was added and the reaction was stirred at room temperature under _N2 for 1 h, then concentrated in vacuo. The residue was filtered through a short plug of silica gel, eluting with 1:1 EtOAc:hexanes, and concentrated in vacuo. The residue was dissolved in _CH2Cl2 (10 mL) _, then trifluoroacetic acid (1.2 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 5-30% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to afford compound 26 (181 mg, 70% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ0.95(br s, 3H), 1.08(br t, J=6.35Hz, 3H), 1.21(br t, J=6.44 Hz, 3H), 1.18-1.25(m, 2H), 1.45-1.63(m, 3H), 1.70(br s, 2H), 2.39-2.54(m, 2H), 2.71-2.93(m, 5H), 3.02 (br s, 1H), 3.07-3.21(m, 2H), 3.22-3.43(m, 4H), 3.51(br q, J=6.64Hz, 2H), 7.35(s, 5H), 7.50(br s, 3H). Found: C, 52.62; H, 6.35; N, 5.00. Theoretical value of C ₃₀ H ₄₁ N ₃ Ox2.5CF ₃ CO ₂ Hx 3.0H ₂ O C, 52.63; H, 6.25; N, 5.26% .

Compound 27: N,N-Diethyl-4-[(2-{[(4-methylphenyl)sulfonyl]amino}phenyl)(piperidin-4-ylidene)methyl]benzamide

The same method as compound 13 was used except that the residue was purified by reverse phase HPLC (gradient 15-40% _CH3CN in _H2O with 0.1% ) and p-toluenesulfonyl chloride (144 mg, 0.76 mmol) to give compound 27 (181 mg, 76% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.11(br t, J=6.64Hz, 3H), 1.22(br t, J=7.03Hz, 3H), 2.40(s , 3H), 2.42-2.51(m, 1H), 2.51-2.61(m, 2H), 2.73-2.82(m, 1H), 3.22-3.34(m, 5H), 3.39-3.47(m, 1H), 3.49 -3.57(m, 2H), 6.67(dd, J=7.81, 0.98Hz, 1H), 7.11(ddd, J=7.81, 7.03, 1.95Hz, 1H), 7.19-7.29(m, 4H), 7.31(d , J=8.20Hz, 4H), 7.53 (d, J=8.40Hz, 2H). Found: C, 57.97; H, 5.36; N, 6.31. C ₃₀ H ₃₅ N ₃ O ₃ Sx1.4CF ₃ CO ₂ C, 58.01; H, 5.43; N, 6.19% of Theoretical for _Hx0.1H2O .

Compound 28: N,N-Diethyl-4-[(2-{[(2-fluorophenyl)sulfonyl]amino}phenyl)(piperidin-4-ylidene)methyl]benzamide

Using the same method of compound 13 and using intermediate 6 (175 mg, 0.38 mmol) and 2-fluorobenzenesulfonyl chloride (147 mg, 0.76 mmol), compound 28 was obtained as TFA salt (121 mg, 51% yield). This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.11 (br t, J=6.64Hz, 3H), 1.23 (br t, J=6.83Hz, 3H), 2.43-2.61 (m, 3H), 2.73-2.81(m, 1H), 3.22-3.35(m, 5H), 3.39-3.48(m, 1H), 3.53(br q, J=6.96Hz, 2H), 6.71(d, J=7.42Hz, 1H), 7.12(ddd, J=7.91, 6.93, 2.15Hz, 1H), 7.23-7.33(m, 8H), 7.63-7.68(m, 1H), 7.70(dt, J=7.03, 1.76Hz, 1H). Measured value: C, 56.89; H, 5.08; N, 6.33. Theoretical value of C ₂₉ H ₃₂ FN ₃ O ₃ Sx1.2CF ₃ CO ₂ Hx0.2H ₂ O C, 56.96; H, 5.12 ; N, 6.35%.

Compound 29: 4-[{2-[(butylsulfonyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

Using the same method of compound 13 and using intermediate 6 (208 mg, 0.449 mmol) and butane-1-sulfonyl chloride (0.12 mL, 0.93 mmol), compound 29 (95.7 mg, 36% yield) was obtained as TFA salt. Freeze drying of this material from _CH3CN / _H2O yielded a slightly off-white solid. Purity (HPLC): >94%; ¹ H NMR (400MHz, CD ₃ OD) δ0.91(t, J=7.4Hz, 3H), 1.12(br t, J=6.9Hz, 3H), 1.23(br t , J=7.1Hz, 3H), 1.35-1.46(m, 2H), 1.65-1.74(m, 2H), 2.40-2.62(m, 3H), 2.73-2.82(m, 1H), 2.85-3.02(m , 2H), 3.18-3.42(m, 6H), 3.53(br q, J=7.2Hz, 2H), 7.28-7.39(m, 8H). Found values: C, 55.52; H, 5.90; N, 6.73. _{C27H37N3O3Sx1.4CF3CO2Hx0.1H2O Theoretical} C _, 55.48 _; H, 6.03 _{; N} , _6.51 %.

Intermediate 7: 4-[[4-[(diethylamino)carbonyl]phenyl](2-nitrophenyl)methylene]-1-piperidinecarboxylic acid-1,1-dimethylethyl base ester

To a mixture of Intermediate 5 (1000 mg, 2.22 mmol) and 2-nitrophenylboronic acid (556 mg, 3.33 mmol) in toluene (28 mL) and ethanol (6.0 mL) was added 2.0M Na ₂ CO ₃ (4.4 mL) . Tetrakis(triphenylphosphine)palladium (257mg, 0.22mmol) was added and the resulting mixture was heated at 90°C under _N2 overnight. The reaction was then concentrated in vacuo and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The crude product was purified by column chromatography on silica gel, eluting with 1:1 EtOAc:hexanes, to afford intermediate 7 (244 mg, 22% yield) as a brown oil. ¹ H NMR (400MHz, CDCl ₃ ) δ1.12(brs, 3H), 1.22(brs, 3H), 1.45(s, 9H), 2.07-2.15(m, 2H), 2.26-2.36(m, 1H) , 2.41-2.50(m, 1H), 3.20-3.43(m, 4H), 3.45-3.62(m, 4H), 7.22(d, J=8.20Hz, 2H), 7.30(d, J=8.20Hz, 3H ), 7.40-7.46 (m, 1H), 7.58 (dt, J=7.62, 1.17Hz, 1H), 7.90 (dd, J=8.10, 1.07Hz, 1H).

Intermediate 8: 4-[(1-Benzylpiperidin-4-ylidene)(2-nitrophenyl)methyl]-N,N-diethylbenzamide

To a solution of Intermediate 7 (244 mg, 0.49 mmol) in _CH2Cl2 (10 _mL ) was added trifluoroacetic acid (1.3 mL). The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was redissolved _{in CH2Cl2} , then washed with saturated aqueous _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (1x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue and benzaldehyde (0.101 mL, 0.99 mmol) were dissolved in 1,2-dichloroethane (13 mL). Glacial acetic acid (57 μL, 0.99 mmol) was added to the reaction, followed by NaBH(OAc) ₃ (262 mg, 1.24 mmol). The reaction was stirred at room temperature overnight, concentrated in _vacuo , redissolved in _CH2Cl2 , and washed with saturated aqueous _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (1x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The crude product was purified by filtration through a short plug of silica gel, eluting with a _gradient of 100% _CH2Cl2 to 1:9 MeOH/ _CH2Cl2 , to afford intermediate 8 (238 mg, 93% yield ₎ as a dark yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ1.10(br s, 3H), 1.24(br s, 3H), 2.09-2.23(m, 2H), 2.31-2.55(m, 6H), 3.24(br s, 2H), 3.46-3.57(m, 4H), 7.20-7.34(m, 8H), 7.36-7.43(m, 3H), 7.55(dt, J=7.52, 1.37Hz, 1H), 7.87(dd, J= 8.20, 1.17Hz, 1H).

Intermediate 9: 4-((2-aminophenyl){4-[(diethylamino)carbonyl]phenyl}methylene)piperidine-1-tert-butylcarboxylate

To a mixture of Intermediate 5 (1080 mg, 2.39 mmol) and 2-aminophenylboronic acid (426 mg, 3.11 mmol) in toluene (31 mL) and ethanol (6.2 mL) was added 2.0M Na ₂ CO ₃ (4.8 mL). Tetrakis(triphenylphosphine)palladium (276 mg, 0.24 mmol) was added and the resulting mixture was heated at 90 °C under _N2 overnight. The reaction was then concentrated in vacuo and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The crude product was purified by column chromatography on silica gel, eluting with 7:3 EtOAc:hexanes, to afford intermediate 9 (1039 mg, 94% yield) as a brown solid. ¹ H NMR (400MHz, CDCl ₃ ) δ1.12(br s, 3H), 1.23(br s, 3H), 1.46(s, 9H), 2.15-2.27(m, 2H), 2.40-2.51(m, 2H ), 3.22-3.44(m, 4H), 3.46-3.78(m, 6H), 6.69(d, J=7.81Hz, 1H), 6.73(dt, J=7.47, 1.07Hz, 1H), 6.95(dd, J=7.52, 1.46Hz, 1H), 7.09 (dt, J=7.62, 1.56Hz, 1H), 7.21 (d, J=8.20Hz, 2H), 7.31 (d, J=8.20Hz, 2H).

Compound 31: 4-[[2-(acetylamino)phenyl](piperidin-4-ylidene)methyl]-N,N-diethylbenzamide

To a solution of Intermediate 9 (250 mg, 0.54 mmol) in _CH2Cl2 (15 _mL ) was added triethylamine (225 μL, 1.62 mmol) followed by acetyl chloride (50 μL, 0.70 mmol). The reaction was stirred _at room temperature overnight, diluted with _CH2Cl2 , and washed with saturated aqueous _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (1x). The combined organic phases were dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was dissolved in _CH2Cl2 (15 _mL ), then trifluoroacetic acid (1.7 mL) was added. The reaction was stirred at room temperature for 4 hours, then concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 5-30% _CH3CN in _H2O containing 0.1% trifluoroacetic acid). The product was dissolved _{in CH2Cl2} , then washed with saturated aqueous _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (1x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo to afford compound 31 (133 mg, 61% yield ₎ as a colorless solid. ¹ HNMR (400MHz, CDCl ₃ ) δ1.11(br s, 3H), 1.23(br s, 3H), 2.07(s, 3H), 2.09-2.25(m, 2H), 2.51(br t, J=5.47 Hz, 2H), 2.90(t, J=5.57Hz, 2H), 2.96(br t, J=5.47Hz, 2H), 3.26(br s, 2H), 3.53(br s, 2H), 7.06-7.13( m, 2H), 7.15 (d, J = 8.20 Hz, 2H), 7.27-7.35 (m, 4H), 8.22 (d, J = 8.40 Hz, 1H).

Compound 32: Methyl 2-[{4-[(diethylamino)carbonyl]phenyl}(piperidin-4-ylidene)methyl]phenylcarbamate

A mixture of zinc dust (39 mg, 0.59 mmol) and methyl chloroformate (46 μL, 0.59 mmol) in (2 mL) toluene was stirred at room temperature for 1 hour. A solution of Intermediate 9 (250 mg, 0.54 mmol) in toluene (4 mL) was added dropwise to the reaction. The reaction was stirred _at room temperature overnight, diluted with _CH2Cl2 , filtered, and washed with 1N _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (1x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The crude product was purified by column chromatography on silica gel, eluting with 3:1 EtOAc:hexanes. The product was dissolved in _CH2Cl2 (15 _mL ), then trifluoroacetic acid (1.7 mL) was added. The reaction was stirred overnight at room temperature, then concentrated in vacuo. The residue was dissolved in _CH2Cl2 , then washed with _saturated aqueous _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (1x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo to give compound 32 (88 mg, 36% _yield ) as a dark yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ1.11(br s, 3H), 1.23(br s, 3H), 2.11-2.22(m, 2H), 2.50(t, J=5.66Hz, 2H), 2.94( dq, J=24.85, 4.93Hz, 4H), 3.26(br s, 2H), 3.53(br s, 2H), 3.74(s, 3H), 6.84(br s, 1H), 7.01-7.07(m, 2H ), 7.15 (d, J=8.40Hz, 2H), 7.27-7.33 (m, 4H), 8.07 (d, J=7.42Hz, 1H).

Intermediate 10: N,N-Diethyl-4-[(2-nitrophenyl)(piperidin-4-ylidene)methyl]benzamide

To a mixture of Intermediate 5 (5.16 g, 11.7 mmol) and 2-nitrophenylboronic acid (2.93 g, 17.5 mmol) in toluene (125 mL) and ethanol (25 mL) was added 2.0 M Na ₂ CO ₃ (14.6 mL ). Tetrakis(triphenylphosphine)palladium (1.35 g, 1.17 mmol) was added and the resulting mixture was heated at 90 °C under _N2 overnight. Then, the reaction was concentrated in vacuo, and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried _{over Na2SO4} , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with 1:1 EtOAc:hexanes. The material was dissolved in dichloromethane (20 mL), then trifluoroacetic acid (5 mL) was added. The reaction was stirred overnight at room temperature, followed by the addition of saturated aqueous sodium bicarbonate. The two phases were separated and the aqueous phase was extracted with dichloromethane (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo to afford intermediate 10 (1.50 g, 30%) as _a tan solid. ¹ H NMR (400MHz, CDCl ₃ ) δ1.06-1.16(m, 3H), 1.18-1.29(m, 3H), 2.29-2.39(m, 1H), 2.42-2.53(m, 1H), 2.54-2.73 (m, 2H), 2.99-3.10(m, 2H), 3.16-3.29(m, 4H), 3.47-3.59(m, 2H), 7.20(d, J=8.40Hz, 2H), 7.29-7.33(m , 3H), 7.47 (ddd, J=8.20, 7.62, 1.56Hz, 1H), 7.61 (td, J=7.62, 1.37Hz, 1H), 7.92 (dd, J=8.20, 1.17Hz, 1H).

Intermediate 11: 4-[bromo(1-butylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide

To Intermediate 5 (5000 mg, 11.08 mmol) in _CH2Cl2 (100 mL) was added TFA (15 _mL ) at room temperature. The resulting mixture was stirred at room temperature under _N2 for 4 h. Then, the reaction was concentrated in vacuo, and the residue was diluted with saturated NaHCO ₃ . The aqueous phase was extracted with _CH2Cl2 ( _2x ). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. To this crude product in dichloroethane (50 mL) was added butyraldehyde (878 mg, 12.2 mmol) followed by NaBH(OAc) ₃ (3520 mg, 16.62 mmol) at room temperature under nitrogen. The reaction was stirred overnight at room temperature, concentrated in vacuo, redissolved in _CH2Cl2 , and _washed with 2M NaOH solution (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (2x). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with a gradient of 9: _{1 CH2Cl2} /EtOAc to 3: _{2 CH2Cl2} /EtOAc to afford intermediate 11 (1807 mg, 40% yield) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ0.92(t, J=7.32Hz, 3H), 1.07-1.19(m, 3H), 1.20-1.39(m, 4H), 1.42-1.54(m, 2H), 1.57-1.64(m, 1H), 2.24-2.39(m, 6H), 2.55(t, J=5.86Hz, 2H), 2.70(t, J=8.00Hz, 2H), 3.23-3.36(m, 2H) , 3.48-3.62 (m, 2H), 7.31 (d, J=8.00Hz, 2H) 7.35 (d, J=8.00, 2H).

Intermediate 12: 4-{bromo[1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide

Using the same method as Intermediate 11 and using Intermediate 5 (6000 mg, 13.3 mmol) and 4-pyridinecarbaldehyde (3242 mg, 9.24 mmol), Intermediate 12 (3675 mg, 90% yield) was obtained as a pale yellow solid. ¹ H NMR (400MHz, CD ₃ OD) δ1.12(t, J=6.83Hz, 3H), 1.23(t, J=6.93Hz, 3H), 2.27-2.33(m, 2H), 2.38-2.43(m , 2H), 2.57(t, J=5.76Hz, 2H), 2.69-2.75(m, 2H), 3.24-3.34(m, 3H), 3.53(q, J=7.23Hz, 1H), 3.59(s, 2H), 7.36 (s, 4H), 7.42-7.46 (m, 2H), 8.43-8.47 (m, 2H).

Intermediate 13: 4-{bromo[1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide

Using the same method as Intermediate 11 and using Intermediate 5 (4000 mg, 8.87 mmol) and 3-pyridinecarbaldehyde (531.3 mg, 4.96 mmol), Intermediate 13 (2050 mg, 93% yield) was obtained as a light green oil. ¹ H NMR (400MHz, CD ₃ OD) δ1.12(t, J=7.23Hz, 3H), 1.23(t, J=7.23Hz, 3H), 2.25-2.31(m, 2H), 2.37-2.44(m , 2H), 2.57(t, J=5.76Hz, 2H), 2.67-2.74(m, 2H), 3.24-3.34(m, 3H), 3.48-3.57(m, 1H), 3.59(s, 2H), 7.36(s, 4H), 7.38-7.43(m, 1H), 7.80-7.87(m, 1H), 8.43(dd, J=4.88, 1.56Hz, 1H), 8.49(d, J=1.56Hz, 1H) .

Intermediate 14: 4-{bromo[1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide

Using the same method as Intermediate 11 and using Intermediate 5 (5000 mg, 11.0 mmol) and 2-pyridinecarbaldehyde (1140 mg, 10.7 mmol), Intermediate 14 (4096 mg, 87% yield) was obtained as a pale yellow solid. ¹ H NMR (400MHz, CD ₃ OD) δ1.12(t, J=6.93Hz, 3H), 1.23(t, J=7.03Hz, 3H), 2.26-2.32(m, 2H), 2.40-2.46(m , 2H), 2.60(t, J=5.66Hz, 2H), 2.67-2.75(m, 2H), 3.24-3.35(m, 3H), 3.53(q, J=6.96Hz, 1H), 3.66(s, 2H), 7.28-7.33 (m, 1H), 7.36 (s, 4H), 7.54 (d, J = 7.81 Hz, 1H), 7.78-7.84 (m, 1H), 8.44-8.48 (m, 1H).

Compound 30: 4-[(2-aminophenyl)(1-benzylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide

To a solution of intermediate 8 (238 mg, 0.49 mmol) in 4:2:1:1 EtOH/THF/ _H2O / _NH4Cl (aq) was added iron powder (275 mg, 4.92 mmol). The reaction was microwaved at 140°C for 10 minutes, then filtered through celite. The celite was rinsed with EtOAc. The filtrate was concentrated in vacuo, redissolved in EtOAc, and washed with saturated aqueous _NaHCO3 (1x) and brine (1x). The organic phase was collected and the aqueous phase was extracted with EtOAc (1x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by reverse phase HPLC (gradient 10-40% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to afford compound 30 as TFA salt (118 mg, 35% yield). This material was lyophilized from _CH3CN / _H2O to yield a beige solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.09 (br t, J=6.64Hz, 3H), 1.21 (br t, J=6.83Hz, 3H), 2.30-2.63 (m, 3H), 2.84-2.96(m, 1H), 3.00-3.32(m, 4H), 3.51(br q, J=6.77Hz, 4H), 4.32(s, 2H), 6.70(s, 1H) , 6.80-6.89(m, 2H), 7.03-7.19(m, 1H), 7.31(s, 4H) 7.48(s, 5H). Found: C, 60.57; H, 6.01; N, 6.60.C ₃₀ H C, _60.65 ; H _{, 6.12 ; N} , 6.43%.

Compound 33: 4-[[2-(acetylamino)phenyl](1-benzylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide

To a solution of compound 31 (133, 0.33 mmol) and benzaldehyde in 1,2-dichloroethane (9 mL) was added glacial acetic acid (38 μL, 0.66 mmol), followed by NaBH(OAc) ₃ (174 mg, 0.82 mmol ). The reaction was stirred at room temperature overnight, concentrated in _vacuo , redissolved in _CH2Cl2 , and washed with saturated aqueous _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (2x). The combined organic phases were dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 10-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 33 (127 mg, 64% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.09(br s, 3H), 1.20(t, J=6.64Hz, 3H), 1.89(d, J=17.18Hz, 3H), 2.30-2.54(m, 1H), 2.55-2.72(m, 1H), 2.83-3.09(m, 1H), 3.10-3.30(m, 5H), 3.43-3.63(m, 4H), 4.34( d, J=13.28Hz, 2H), 7.11(d, J=7.62Hz, 1H), 7.17(d, J=7.62Hz, 1H), 7.25-7.39(m, 6H), 7.45-7.54(m, 5H ). Found: C, 61.21; H, 5.68; N, 6.00. Theoretical value of C ₃₂ H ₃₇ N ₃ O ₂ x1.7CF ₃ CO ₂ H x 0.3H ₂ O C, 61.19; H, 5.70; N, 6.05 %.

Compound 34: Methyl 2-((1-benzylpiperidin-4-ylidene){4-[(diethylamino)carbonyl]phenyl}methyl)phenylcarbamate

Using the same method as compound 33 and using compound 32 (88 mg, 0.21 mmol) and benzaldehyde (44 mg, 0.42 mmol), compound 34 (81 mg, 62% yield) was obtained as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.08 (br t, J=6.93Hz, 3H), 1.20 (br t, J=6.83Hz, 3H), 2.36-2.64 (m, 3H), 2.81-3.00(m, 1H), 3.00-3.18(m, 2H), 3.20-3.30(m, 2H), 3.45-3.55(m, 4H), 3.57(s, 3H), 4.33 (br d, J=7.03Hz, 2H), 7.14-7.24(m, 4H), 7.26-7.40(m, 4H), 7.48(s, 5H). Found: C, 60.84; H, 5.67; N, 6.17. Theoretical Cp, 60.93; H, 5.74; N, 6.09% for C ₃₂ H ₃₇ N ₃ O 3 x 1.5CF ₃ CO ₂ H x _{0.4H 2} O.

Compound 35: 4-{(2-aminophenyl)[1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl Amide

_Intermediate 10 (0.760 g, 1.93 mmol), 4-chloromethylthiazole hydrochloride (0.493 g, 2.90 mmol) and potassium carbonate (0.533 g, 3.86 mmol) were dissolved in dry DMF ( 20 mL) was stirred for 18 hours. The mixture was concentrated in vacuo, then diluted with dichloromethane. The resulting solution was washed once with saturated aqueous sodium bicarbonate and then once with brine. The organic phase _was dried ( _Na2SO4 ), filtered and concentrated in vacuo. The residue was dissolved in a 4:2:1:1 mixture of ethanol/THF/ _H2O / _NH4Cl (aq) (4 mL) in a microwave vial. Iron powder (1.08 g, 19.3 mmol) was added and the reaction was heated in the microwave at 150°C for 20 minutes, then filtered through celite. The celite was rinsed with ethyl acetate, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with 1% to 5% methanol in dichloromethane to afford the product as a yellow solid (0.321 g, 36%). Some product (115 mg, 0.249 mmol) was purified by reverse phase HPLC (gradient 10-45% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to give compound 35 as TFA salt (89 mg, 19% yield ). This material was lyophilized from _CH3CN / _H2O to yield a yellow solid. HPLC purity: >95% (215nm); >93% (254nm); >99% (280nm); ¹ H NMR (400MHz, CD ₃ OD) δ 1.11 (brt, J=6.44Hz, 3H), 1.23 ( br t, J=7.42Hz, 3H), 2.47-2.59(m, 2H), 2.64-2.76(m, 1H), 2.84-2.98(m, 1H), 3.24-3.33(m, 4H), 3.48-3.59 (m, 4H), 4.53(s, 2H), 6.86-6.97(m, 2H), 7.10-7.21(m, 2H), 7.30-7.37(m, 4H), 7.85(d, J=1.95Hz, 1H ), 9.11 (d, J=1.95Hz, _{1H )} . Measured value: C, _52.11 ; H, _5.21 ; N _{, 7.66} . , 52.05; H, 5.08; N, 7.78%.

Compound 36: 4-{(2-aminophenyl)[1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl Amide

To a solution of Intermediate 10 (0.717 mg, 1.82 mmol) and thiazole-5-carbaldehyde (0.717 mg, 1.82 mmol) in 1,2-dichloroethane (40 mL) was added NaBH(OAc) ₃ (0.656 mg, 3.09 mmol). The reaction was stirred overnight at room temperature, then washed with saturated aqueous NaHCO ₃ (1×). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was dissolved in a 4:2:1:1 mixture of ethanol/THF/ _H2O / _NH4Cl (aq) (4 mL) in a microwave vial. Iron powder (1.08 g, 19.3 mmol) was added and the reaction was heated in the microwave at 150°C for 20 minutes, then filtered through celite. The celite was rinsed with ethyl acetate, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with 1%-5% methanol in dichloromethane to afford the product as an orange solid (0.503g, 64%). Some of the product (150 mg, 0.326 mmol) was purified by reverse phase HPLC (gradient 10-45% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to give compound 36 as TFA salt (108 mg, 30% yield ). This material was lyophilized from _CH3CN / _H2O to yield a yellow solid. HPLC purity: >97% (215nm); >94% (254nm); >99% (280nm); ¹ H NMR (400MHz, CD ₃ OD) δ1.11 (br t, J=7.03Hz, 3H), 1.22 (br t, J=7.03Hz, 3H), 2.41-2.59(m, 2H), 2.63-2.88(m, 2H), 3.24-3.33(m, 4H), 3.33-3.48(m, 2H), 3.48- 3.57(m, 2H), 4.71(s, 2H), 6.72-6.79(m, 1H), 6.83(dd, J=8.01, 0.78Hz, 1H), 6.91-7.01(m, 1H), 7.10(td, J=7.62, 1.37Hz, 1H), 7.32-7.35(m, 4H), 8.08(s, 1H), 9.20(s, 1H). Measured values: C, 51.64; H, 5.14; N, 7.67.C ₂₇ Calcd _{for H32N4O2x2.1CF3CO2Hx1.4H2O} C, _51.67 ; _H , 5.13 _{; N} , 7.72%.

Compound 37: 4-{[2-(acetylamino)phenyl][1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-di Ethylbenzamide

A solution of compound 35 as the free base (103 mg, 0.224 mmol), acetyl chloride (32 μL, 0.448 mmol) and triethylamine (110 μL, 0.726 mmol) in dichloromethane (10 mL) was stirred overnight at room temperature. The solution was diluted with _CH2Cl2 , then washed with saturated aqueous _{NaHCO3 (} 1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (2x). _The combined organic phases were dried over _Na2SO4 , filtered and concentrated. The residue was purified by reverse phase HPLC (gradient 10-45% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 37 (80 mg, 58% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a yellow solid. Purity: >97% (215nm); >94% (254nm); >99% (280nm); ¹ H NMR (400MHz, CD ₃ OD) δ1.11 (br t, J=6.64Hz, 3H), 1.23( br t, J=6.64Hz, 3H), 1.92(s, 3H), 2.36-2.61(m, 2H), 2.63-2.74(m, 2H), 3.21-3.32(m, 6H), 3.48-3.57(m , 2H), 4.55(s, 2H), 7.11-7.23(m, 2H), 7.28-7.39(m, 6H), 7.86(s, 1H), 9.12(d, J=1.76Hz, 1H). Measured value : C, 54.55 _; H _{, 5.48} ; _N , 7.91. Theoretical for C29H34N4O2Sx1.6CF3CO2Hx1.3H2O C, 54.59 _; H, _{5.43 ;} N, 7.91%.

Compound 38: 2-{{4-[(diethylamino)carbonyl]phenyl}[1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene]methyl}phenyl Methyl carbamate

A mixture of zinc dust (15 mg, 0.22 mmol) and methyl chloroformate (17 μL, 0.22 mmol) in (10 mL) toluene was stirred at room temperature for 10 minutes. A solution of compound 35 (103 mg, 0.22 mmol) in toluene (5 mL) was added dropwise to the reaction. The reaction was stirred _at room temperature overnight, diluted with _CH2Cl2 , and washed with saturated aqueous _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by reverse phase HPLC (gradient 10-45% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 38 (26 mg, 18% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a yellow solid. Purity: >87% (215nm); >81% (254nm); >86% (280nm); ¹ H NMR (400MHz, CD ₃ OD) δ1.11 (br t, J=6.64Hz, 3H), 1.23( br t, J=6.64Hz, 3H), 2.38-2.60(m, 2H), 2.63-2.73(m, 2H), 3.21-3.30(m, 6H), 3.50-3.56(m, 2H), 3.60(s , 3H), 4.56(s, 2H), 7.11-7.23(m, 2H), 7.29-7.39(m, 6H), 7.86(s, 1H), 9.11(d, J=1.76Hz, 1H). Measured value : C, 54.55 _; H _{, 5.48} ; N, 7.91. Theoretical for C29H34N4O2Sx1.6CF3CO2Hx1.3H2O C, 54.59 _; H, _{5.43 ;} N _, 7.91%.

Compound 39: 4-{[2-(acetylamino)phenyl][1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl}-N N-diethyl phenylbenzamide

To a solution of compound 31 (0.289 g, 0.713 mmol) and thiazole-5-carbaldehyde (0.129 g, 1.14 mmol) in 1,2-dichloroethane (20 mL) was added NaBH(OAc) ₃ (0.257 g, 1.21 mmol). The reaction was stirred overnight at room temperature, then washed with saturated aqueous NaHCO ₃ (1×). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (2x). The combined organic phases were dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by reverse phase HPLC (gradient 10-45% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 39 (187 mg, 43% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a white solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ 1.11 (br t, J=7.03Hz, 3H), 1.23 (br t, J=6.64Hz, 3H), 1.92(s , 3H), 2.50-2.73(m, 4H), 3.22-3.32(m, 5H), 3.45-3.58(m, 3H), 4.74(s, 2H), 7.13-7.19(m, 2H), 7.20-7.28 (m, 1H), 7.31(d, J=8.40Hz, 2H), 7.32-7.38(m, 3H), 8.09-8.11(m, 1H), 9.19-9.21(m, 1H). Measured value: C, 53.46; _H , 5.22; _N , _{7.30 .} C _, 53.43; H _{, 5.18} ; N, 7.60%.

Compound 40: 2-{{4-[(diethylamino)carbonyl]phenyl}[1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl}phenyl Methyl carbamate

Using the same method as compound 39 and using compound 32 (0.172 g, 0.408 mmol) and thiazole-5-carbaldehyde (74 mg, 0.65 mmol), compound 40 (0.239 mg, 93% yield) was obtained as TFA salt. Freeze drying of this material from _CH3CN / _H2O yielded an off-white solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ1.11 (br t, J=6.25Hz, 3H), 1.23 (br t, J=7.03Hz, 3H), 2.51-2.62 (m, 2H), 2.63-3.08(m, 2H), 3.20-3.35(m, 5H), 3.46-3.57(m, 3H), 3.60(s, 3H), 4.73(s, 2H), 7.18-7.27 H , 5.28; _N , _{7.48 .} C, 52.88; H _{, 5.25} ; N, _7.61 % _.

Compound 41: 4-[(2-aminophenyl)(1-butylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide

To a mixture of Intermediate 11 (1.80 g, 4.44 mmol) and 2-aminophenylboronic acid (792 mg, 5.78 mmol) in toluene (60 mL) and ethanol (13 mL) was added _{2.0M Na2CO3} (10 mL). Tetrakis(triphenylphosphine)palladium (514mg, 0.445mmol) was added, and the resulting mixture was heated at 90°C overnight using a pressure vessel. The reaction was then concentrated in vacuo and the residue was diluted with brine. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a gradient of 3: ₂ EtOAc/ _CH2Cl2 to 100% EtOAc to afford compound 41 (1769 mg, 95% yield) as a pale yellow oil. The oil (200 mg) was repurified by reverse phase HPLC (gradient 10-70% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to give compound 41 as the TFA salt (130 mg). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ HNMR (400MHz, CDCl ₃ ) δ0.98 (t, J=7.03Hz, 3H), 1.04-1.16 (m, 3H), 1.17-1.30 (m, 3H), 1.33 -1.51(m, 2H), 1.61-1.82(m, 2H), 2.29-2.72(m, 2H), 2.83-3.07(m, 2H), 3.07-3.22(m, 3H), 3.23-3.39(m, 3H), 3.42-3.71(m, 4H), 6.79-7.05(m, 2H), 7.08-7.27(m, 2H), 7.33(s, 4H). Measured values: C, 58.08; H, 6.05; N, _{6.63 .} Theoretical for _{C27H37N3Ox1.90C2HO2F3} C, 58.14; H, 6.16 _{; N} , 6.60 _% .

Compound 42: 4-{(2-aminophenyl)[1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide

Using the same method as compound 41 and using Intermediate 12 (1.31 g, 2.95 mmol), 2-aminophenylboronic acid (526 mg, 3.84 mmol), tetrakis(triphenylphosphine)palladium (341 mg, 0.295 mmol), toluene ( 30 mL), ethanol (6 mL) and 2.0M Na ₂ CO ₃ (5 mL), yielding compound 42. The crude product was purified by silica gel column chromatography eluting with EtOAc to afford compound 42 (1.32 g, 98% yield) as a light yellow solid. The solid (400 mg) was repurified by reverse phase HPLC (gradient 10-60% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to give compound 42 as the TFA salt (456.7 mg). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CDCl ₃ ) δ0.96-1.36 (m, 6H), 2.33-2.63 (m, 2H), 2.67-2.91 (m, 2H), 3.15-3.63 (m, 10H), 4.44(s, 2H), 6.88-7.00(m, 2H), 7.08(d, J=7.22Hz, 1H), 7.14-7.23(m, 1H), 7.26-7.40(m, 4H ), 7.74 (d, J=2.93Hz, 2H), 8.77 (s, 2H). Found: C, 55.54; H, 5.05; N, 7.81. C ₂₉ H ₃₄ N ₄ Ox2.4C ₂ HO ₂ F ₃ Theoretical value of x0.1H ₂ O C, 55.61; H, 5.05; N, 7.67%

Compound 43: 4-{(2-aminophenyl)[1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide

Using the same method as compound 41 and using Intermediate 13 (2.05g, 4.64mmol), 2-aminophenylboronic acid (826mg, 6.03mmol), tetrakis(triphenylphosphine)palladium (536mg, 0.464mmol), toluene ( 60 mL), ethanol (12 mL) and 2.0M Na ₂ CO ₃ (10 mL), yielding compound 43. The crude product was purified by silica gel column chromatography eluting with EtOAc to afford compound 43 (1.79 g, 85% yield) as a light yellow solid. This solid (400 mg) was repurified by reverse phase HPLC (gradient 10-60% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 43 as the TFA salt. This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CDCl ₃ ) δ0.96-1.33 (m, 6H), 2.36-2.61 (m, 2H), 2.65-2.92 (m, 2H), 3.16-3.66 (m, 10H), 4.35-4.55(s, 2H), 6.99(d, J=8.20Hz, 2H), 7.11(d, J=6.44Hz, 1H), 7.21(t, J=7.71Hz, 1H) , 7.28-7.39(m, 4H), 7.67(dd, J=7.71, 5.17Hz, 1H), 8.15(d, J=8.01Hz, 1H), 8.74(d, J=23.43Hz, 2H). Measured value : C _, 55.94 _{; H} , _5.11 ; N, _7.91. C, 56.01; H, _{5.13 ;} N, 7.78%

Compound 44: 4-{(2-aminophenyl)[1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide

Using the same method as compound 41 and using Intermediate 14 (4.08g, 9.27mmol), 2-aminophenylboronic acid (1.65g, 12.0mmol), tetrakis(triphenylphosphine)palladium (1.07g, 0.927mmol), Toluene (120 mL), ethanol (24 mL) and 2.0M Na ₂ CO ₃ (20 mL). The crude product was purified by flash column chromatography eluting with EtOAc to afford compound 44 (3.10 g, 74% yield) as a dark yellow solid. This solid (500 mg) was repurified by reverse phase HPLC (gradient 10-70% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to give compound 44 as the TFA salt (487 mg). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ HNMR (400MHz, CDCl ₃ ) δ0.97-1.39 (m, 6H), 2.40-2.65 (m, 2H), 2.69-2.91 (m, 2H), 3.16-3.64 ( m, 10H), 4.38-4.57(m, 2H), 6.70-6.91(m, 2H), 6.98(t, J=6.93Hz, 1H), 7.06-7.19(m, 1H), 7.28-7.38(m, 4H), 7.39-7.54(m, 2H), 7.81-7.97(m, 1H), 8.58-8.74(m, 1H). Found: C, 58.75; H, 5.36; N, 8.62. C ₂₉ H ₃₅ N Theoretical value _{of 4 Ox1.8C2HO2F3x0.3H2O} C, 58.86; H, 5.52; _N , 8.42%

Compound 45: 4-{[2-(acetylamino)phenyl][1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl Amide

Using the same method as compound 41 and using intermediate 12 (590 mg, 1.33 mmol), 2-(acetylaminophenyl) boronic acid (310.6 mg, 1.735 mmol), tetrakis(triphenylphosphine) palladium (154.3 mg, 0.133 mmol), toluene (20 mL), ethanol (5 mL) and 2.0M Na ₂ CO ₃ (3.5 mL) to give compound 45. The crude product was purified by flash column chromatography eluting with EtOAc to afford compound 45 (630 mg, 95% yield) as a pale yellow oil. This oil was repurified by reverse phase HPLC (gradient 10-60% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to afford compound 45 as the TFA salt (443 mg). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CDCl ₃ ) δ0.90-1.37(m, 6H), 1.91(s, 3H), 2.38-2.97(m, 4H), 3.09-3.71(m , 8H), 4.45 (s, 2H), 7.17 (d, J = 8.01 Hz, 2H), 7.23-7.48 (m, 7H), 7.71 (s, 2H), 8.73 (s, 2H).

Compound 46: 4-{[2-(acetylamino)phenyl][1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl Amide

Using the same method as compound 41 and using intermediate 13 (590 mg, 1.33 mmol), 2-(acetylaminophenyl) boronic acid (310.6 mg, 1.735 mmol), tetrakis(triphenylphosphine) palladium (154.3 mg, 0.133 mmol), toluene (20 mL), ethanol (5 mL) and 2.0M Na ₂ CO ₃ (3.5 mL) to give compound 46. The crude product was purified by reverse phase HPLC (gradient 10-40% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 46 as TFA salt (650 mg, 80% yield). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >96%; ¹ HNMR (400MHz, CDCl ₃ ) δ1.02(t, J=6.44Hz, 3H), 1.14(t, J=6.35Hz, 3H), 1.83(s, 3H), 3.10-3.28(m, 10H), 3.35-3.52(m, 2H), 4.37(s, 2H), 7.07(d, J=7.42Hz, 1H), 7.18-7.34(m, 10H), 7.47-7.66( m, 1H), 7.97 (d, J=7.62Hz, 1H). Found: C, 49.11; H, 4.53; N, 6.54. C ₃₁ H ₃₆ N ₄ O ₂ x3.5C ₂ HO ₂ F ₃ x1. Theoretical value of _8H2O C, 49.17; H, 4.68; N, 6.04%

Compound 47: 4-[[2-(acetylamino)phenyl](1-butylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide

To a solution of compound 41 (500 mg, 1.19 mmol) and triethylamine (180 mg, 1.78 mmol) in dichloromethane (1 mL) was added acetyl chloride (110 μL, 1.54 mmol) at 0°C. The resulting mixture was stirred overnight at room temperature. The solution was washed with _H2O . The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (2x). The combined organic phases were dried over MgSO ₄ , filtered and concentrated. The residue was purified by reverse phase HPLC (gradient 10-70% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 47 (267 mg, 49% yield) as TFA salt. This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CDCl ₃ ) δ0.94-1.04 (m, 3H), 1.05-1.15 (m, 3H), 1.17-1.28 (m, 3H), 1.35-1.50 (m, 2H), 1.66-1.80(m, 2H), 1.92(d, J=15.04Hz, 3H), 2.31-2.78(m, 2H), 2.82-3.20(m, 3H), 3.21-3.35(m , 5H), 3.44-3.75(m, 4H), 7.09-7.22(m, 2H), 7.27-7.39(m, 6H). Found values: C, 60.51; H, 6.50; N, 6.43.C ₂₉ H ₃₉ C, 60.75 _; H, 6.45; N, _6.64 % for _{N3O2 x 1.5C2HO2F3} .

Compound 48: 4-{[2-(acetylamino)phenyl][1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl Amide

Compound 48 (111 mg, 20% yield). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >96%; ¹ H NMR (400MHz, CDCl ₃ ) δ0.98-1.36(m, 6H), 1.94(s, 3H), 2.50-2.98(m, 4H), 3.14-3.68(m , 8H), 4.40-4.62(m, 2H), 7.17(d, J=7.81Hz, 2H), 7.24-7.40(m, 7H), 7.41-7.56(m, 2H), 7.90(tJ=7.71Hz, 1H), 8.69 (d, J=4.10Hz, 1H). Found: C, 60.91; H, 5.54; N, 8.46. C ₃₁ H ₃₆ N ₄ O ₂ x1.5C ₂ HO ₂ F ₃ x0.1H ₂ Theoretical values for O C, 61.00; H, 5.68; N, 8.37%.

Compound 49: Methyl [2-((1-butylpiperidin-4-ylidene){4[(diethylamino)carbonyl]phenyl}methyl)phenyl]carbamate

A mixture of zinc dust (17.4 mg, 0.267 mmol) and methyl chloroformate (41 μL, 0.534 mmol) in toluene (2 mL) was stirred at room temperature for 1 hour. A solution of compound 41 (112 mg, 0.267 mmol) in _CH2Cl2 was added dropwise to _the reaction. The reaction was _stirred overnight at 80 °C, diluted with _CH2Cl2 , filtered, and washed with 1 N _NaHCO3 (1x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (1x). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography eluting with 1:1 EtOAc:hexanes to give a colorless oil. This oil was repurified by reverse phase HPLC (gradient 10-60% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 49 (26.3 mg, 17% yield) as the TFA salt. This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ HNMR (400MHz, CDCl ₃ ) δ0.93-1.03 (m, 3H), 1.04-1.15 (m, 3H), 1.17-1.26 (m, 3H), 1.35-1.49 ( m, 2H), 1.63-1.81(m, 2H), 2.34-2.70(m, 2H), 2.79-3.19(m, 3H), 3.20-3.33(m, 5H), 3.43-3.74(m, 7H), 7.17-7.26(m, 3H), 7.26-7.36(m, 4H), 7.46(dd, J=33.4, 7.81Hz, 1H). Found: C, 52.36; H, 5.77; N, _5.77 . Calcd for ₃₉ N ₃ O ₃ x2.7 C ₂ HO ₂ F ₃ C, 52.60; H, 5.35; N, 5.35%.

Compound 50: (2-{{4-[(diethylamino)carbonyl]phenyl}[1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}phenyl)carbamic acid methyl ester

Using the same method as compound 49 and using compound 42 (400 mg, 0.88 mmol), methyl chloroformate (166 mg, 1.76 mmol) and zinc powder (57.5 mg, 0.88 mmol) at 50 °C, compound 50 was obtained. The crude product was purified by flash column chromatography eluting with 1:1 EtOAc/heptane to afford compound 50 (282 mg, 62% yield). This compound was repurified by reverse phase HPLC (gradient 10-60% _CH3CN in _H2O containing 0.1% trifluoroacetic acid) to afford compound 50 as the TFA salt. This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CDCl ₃ ) δ1.09 (t, J=6.35Hz, 3H), 1.16-1.30 (t, J=5.76Hz, 3H), 2.46-2.60 ( m, 2H), 2.62-2.87(m, 2H), 3.15-3.56(m, 8H), 3.59(s, 3H), 4.36-4.54(m, 2H), 7.14-7.36(m, 7H), 7.44( d, J=7.81Hz, 1H), 7.72(d, J=4.49Hz, 2H), 8.59-8.92(m, 2H). Found values: C, 54.48; H, 4.85; N, 7.95. C ₃₁ H ₃₆ C, _54.66 ; H _{, 5.16} ; N _{, 7.20 %} .

Compound 51: (2-{{4-[(diethylamino)carbonyl]phenyl}[1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}phenyl)carbamic acid methyl ester

Using the same method as compound 49 and using compound 43 (500 mg, 1.10 mmol), methyl chloroformate (208 mg, 2.20 mmol) and zinc powder (71.9 mg, 1.10 mmol) at 50 °C, compound 51 was obtained. The crude product was purified by reverse phase HPLC (gradient 10-50% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 51 (335.4 mg, 59% yield) as TFA salt. This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >97%; ¹ H NMR (400MHz, CDCl ₃ ) δ0.95-1.36 (m, 6H), 2.45-2.60 (m, 2H), 2.64-2.88 (m, 2H), 3.20-3.57 (m, 8H), 3.60(s, 3H), 4.39-4.56(m, 2H), 7.15-7.36(m, 8H), 7.44(d, J=11.13Hz, 1H), 7.62-7.76(m, 1H ), 8.16(d, J=7.62Hz, 1H), 8.24(s, 1H), 8.62-8.97(m, 1H). Found: C, 56.77; H, 5.17; N, 7.73. C ₃₁ H ₃₆ N C, _{56.76 ;} H, 5.17 _; N, _7.56 % for _{4O3x2.0C2HO2F3Theoretical} .

Compound 52: (2-{{4-[(diethylamino)carbonyl]phenyl}[1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}phenyl)carbamic acid methyl ester

Using the same method as compound 49 and using compound 44 (500 mg, 1.10 mmol), methyl chloroformate (208 mg, 2.20 mmol) and zinc powder (71.9 mg, 1.10 mmol) at 50 °C, compound 52 was obtained. The crude product was purified by flash column chromatography eluting with 4:1 EtOAc/heptane to afford compound 52 (156.7 mg, 28% yield). This compound was repurified by reverse phase HPLC (gradient 10-60% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 52 as the TFA salt (134 mg). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >97%; ¹ H NMR (400MHz, CDCl ₃ ) δ1.10(t, J=8.00Hz, 3H), 1.22(t, J=7.23Hz, 3H), 2.59(t, J= 6.05Hz, 2H), 2.67-2.93(m, 2H), 3.16-3.57(m, 8H), 3.59-3.72(m, 3H), 4.37-4.62(m, 2H), 7.17-7.38(m, 7H) , 7.39-7.58(m, 3H), 7.82-7.98(m, 1H), 8.24(s, 1H), 8.68(d, J=4.88Hz, 1H). Measured values: C, 58.25; H, 5.72; N _{C , 58.20} ; H, _{5.67 ;} N _{, 7.98} % _.

Compound 53: 4-{(1-butylpiperidin-4-ylidene)[2-(ethylamino)phenyl]methyl}-N,N-diethylbenzamide

To a solution of compound 41 (190 mg, 0.452 mmol) and acetaldehyde (20 mg, 0.452 mmol) in 1,2-dichloroethane (1 mL) was added NaBH(OAc) ₃ (144 mg, 0.678 mmol) at room temperature . The reaction was stirred overnight at room temperature, washed with 2M NaOH solution (2x). The organic phase was collected and the _aqueous phase was extracted with _CH2Cl2 (2x). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 10-65% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 53 (100 mg, 48% yield) as TFA salt. This material was lyophilized from _CH3CN / _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CD ₃ OD) δ0.94-1.02 (m, 3H), 1.02-1.16 (m, 6H), 1.16-1.27 (m, 3H), 1.33- 1.50(m, 2H), 1.64-1.81(m, 2H), 2.30-2.73(m, 3H), 2.84-3.37(m, 10H), 3.43-3.71(m, 4H), 6.61-6.77(m, 2H ), 6.97(dd, J=62.58, 7.71Hz, 1H), 7.16(q, J=7.88Hz, 1H), 7.27-7.38(m, 4H). Found values: C, 62.90; H, 7.33; N, C, _62.89 ; H _{, 7.04} ; N _{, 6.92} % _.

Compound 54: N, N-diethyl-4-{[2-(ethylamino)phenyl][1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}benzidine Amide

Using the same method as compound 53 and using compound 42 (231.1 mg, 0.508 mmol), acetaldehyde (22.4 mg, 0.508 mmol) and NaBH(OAc) ₃ (161.6 mg, 0.763 mmol), compound 54 was obtained. The crude product was purified by reverse phase HPLC (gradient 10-40% _CH3CH in _H2O with 0.1% trifluoroacetic acid) to afford compound 54 as TFA salt (164.7 mg, 67% yield). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ H NMR (400MHz, CDCl ₃ ) δ1.02-1.16(m, 6H), 1.23(t, J=6.54Hz, 3H), 2.51(t, J=5.96Hz, 2H), 2.71-2.89(m, 2H), 2.93-3.05(m, 1H), 3.07-3.20(m, 1H), 3.21-3.61(m, 9H), 4.37-4.53(m, 2H), 6.71- 6.88(m, 2H), 7.04(d, J=6.83Hz, 1H), 7.16-7.26(m, 1H), 7.29-7.43(m, 4H), 7.74(d, J=4.10Hz, 2H), 8.56 -9.00 ( _m , 2H). Found: _{C ,} 56.23 _; H, 5.56; N, 7.54. Theoretical value _{of C31H38N4Ox2.30C2HO2F3x0.80H2OC} , 56.31 _; H , 5.56; N, 7.38%.

Compound 55: N, N-diethyl-4-{[2-(ethylamino)phenyl][1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}benzidine Amide

Using the same method as compound 53 and using compound 43 (360 mg, 0.792 mmol), acetaldehyde (34.9 mg, 0.792 mmol) and NaBH(OAc)3 (251.8 mg, 1.18 mmol), compound 55 was obtained. The crude product was purified by reverse phase HPLC (gradient 10-60% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 55 (85 mg, 15% yield) as TFA salt. This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ HNMR (400MHz, CDCl ₃ ) δ1.03-1.14 (m, 6H), 1.23 (t, J=6.93Hz, 3H), 2.45-2.56 (m, 2H), 2.72 -2.88(m, 2H), 2.90-3.18(m, 2H), 3.20-3.60(m, 9H), 4.38-4.55(m, 2H), 6.78-6.90(m, 2H), 7.08(d, J= 7.81Hz, 1H), 7.19-7.27(m, 1H), 7.30-7.40(m, 5H), 7.62-7.79(m, 1H), 8.16(d, J=7.81Hz, 1H), 8.62-8.98(m , 1H). Found: C _, 55.54; H, 5.59; _N , 7.51 _. Theoretical value of C ₃₁ H ₃₈ N _{4 Ox2.30C2HO2F3x1.40H2O} C, 55.52; H, 5.64; N , 7.27%.

Compound 56: N, N-diethyl-4-{[2-(ethylamino)phenyl][1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}benzidine Amide

Using the same method as compound 53 and using compound 44 (360 mg, 0.792 mmol), acetaldehyde (34.9 mg, 0.792 mmol) and NaBH(OAc) ₃ (251.8 mg, 1.18 mmol), compound 56 was obtained. The crude product was purified by reverse phase HPLC (gradient 10-60% _CH3CN in _H2O with 0.1% trifluoroacetic acid) to afford compound 56 as TFA salt (220 mg, 39% yield). This material was lyophilized from _H2O to yield a colorless solid. Purity (HPLC): >99%; ¹ HNMR (400MHz, CDCl ₃ ) δ1.04-1.16(m, 6H), 1.23(t, J=6.54Hz, 3H), 2.54(t, J=5.96Hz, 2H ), 2.73-2.93(m, 2H), 2.97-3.21(m, 2H), 3.21-3.61(m, 9H), 4.50(s, 2H), 6.70-6.84(m, 2H), 7.02(d, J =7.62Hz, 1H), 7.13-7.24(m, 1H), 7.34(s, 4H), 7.40-7.55(m, 2H), 7.82-7.95(m, 1H), 8.68(d, J=4.30Hz, 1H). Found values: C _{, 61.21 ; H} , _6.22 ; N, _{8.56 .} 8.41%.

Claims (21)

1. Compounds of formula IA, pharmaceutically acceptable salts, diastereomers, enantiomers or mixtures thereof:

in R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-3 alkyl and C _2-9 heterocyclyl-C _1-3 alkyl; wherein said C _1-6 alkyl, C _3-6 cycloalkyl, C _{6 -10} aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-3 alkyl and C _2-9 heterocyclyl-C _1-3 alkyl are optionally selected from one or more -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, - NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR are substituted, wherein R is independently hydrogen or C _1-6 alkyl; R ² , R ³ and R ⁴ are independently selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein said C _1-6 alkyl and C _3-6 cycloalkyl are optionally One or more selected from -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C( =O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR, wherein R is independently hydrogen or C _1-6 alkyl; and R ⁷ is selected from -H, -OH, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _{1- 6} alkyl, C _2-9 heterocyclyl-C _1-6 alkyl, -C(=O)-NR ⁸ R ⁹ , -C(=O)-OR ⁸ , -S(=O)-R ⁸ , -S(=O) ₂ -R ⁸ , -C(=O)-R ⁸ and -SO ₃ H, wherein R ⁸ and R ⁹ are independently selected from -H, C _1-6 alkyl, C _{3- 8} cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl, wherein The C _1-6 alkyl, C 3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 used in _the definition of R ⁷ , R ⁸ or R ⁹ Aryl-C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl are optionally selected from one or more of -R, -NO ₂ , -OR, -Cl, -Br, - I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ of R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O) _NR2 , -NRC(=O)R, and -NRC(=O)-OR The group is substituted, wherein R is independently hydrogen or C _1-6 alkyl. 2. A compound according to claim 1, Wherein R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl and C _2-5 heteroarylmethyl, wherein The C _1-6 alkyl group, C _3-6 cycloalkyl group, benzyl group and C _2-5 heteroarylmethyl group are optionally replaced by one or more selected from C _1-6 alkyl group, halogenated C _{1 -6} alkyl, -CF ₃ , C _1-6 alkoxy, chlorine, fluorine, bromine and iodine are substituted; ^R2 and ^R3 are ethyl; R ⁴ is selected from hydrogen and C _1-3 alkyl; R ⁷ is selected from -H, -OH, phenyl, C _3-5 heterocyclyl, phenyl-C _1-3 alkyl, C _3-5 heterocyclyl-C _1-3 alkyl, C _1-6 Alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-3 alkyl, -C(=O)-NR ⁸ R ⁹ , -C(=O)-OR ⁸ , -S (=O)-R ⁸ , -S(=O) ₂ -R ⁸ , -C(=O)-R ⁸ and -SO ₃ H, wherein R ⁸ and R ⁹ are independently selected from -H, phenyl, C _3-5 heterocyclyl, phenyl-C _1-3 alkyl, C _3-5 heterocyclyl-C _1-3 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _{3 -7} cycloalkyl-C _1-3 alkyl, wherein the phenyl, C _3-5 heterocyclyl, phenyl-C _1-3 alkyl used in the definition of R ⁷ , R ⁸ and R ⁹ , C _3-5 heterocyclyl-C _1-3 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl- _{C 1-3} alkyl is optionally replaced by one or Substituted by multiple groups selected from C _1-6 alkyl, halogenated C _1-6 alkyl, -CF ₃ , C _1-6 alkoxy, chlorine, fluorine, bromine and iodine. 3 - according to the compound of claim 1, Wherein R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl , thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and N-oxo-pyridylmethyl, wherein the C _1-6 alkane Base, C _3-6 cycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl , thiazolylmethyl and N-oxo-pyridylmethyl are optionally replaced by one or more selected from C _1-6 alkyl, halogenated C _1-6 alkyl, -CF ₃ , C _1-6 alkoxy , chlorine, fluorine, bromine and iodine groups are substituted; ^R2 and ^R3 are ethyl; ^R is selected from hydrogen and methyl; R ⁷ is selected from -H, C _1-6 alkyl, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _3-7 cycloalkyl, phenyl, C _1-6 alkyl, -C(=O)-NR ⁸ R ⁹ , -S(=O) ₂ -R ⁸ , -C(=O)-OR ⁸ and -C(=O)-R ⁸ , Wherein R ⁸ and R ⁹ are independently selected from -H, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, C _3-7 cycloalkyl, phenyl and C _1-6 alkyl, wherein the phenyl-C _{1-3 alkyl, C 3-7 cycloalkyl} -C _1-3 alkyl, C ₃ used in the definition of R ⁷ , R ⁸ and R ⁹ _-7 cycloalkyl, phenyl, C _1-6 alkyl is optionally replaced by one or more selected from C _1-6 alkyl, halogenated C _1-6 alkyl, -CF ₃ , C _1-6 alkoxy radical, chlorine, fluorine, bromine and iodine radicals. 4. A compound according to claim 1, Wherein ^R is selected from hydrogen, propyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl , thiazolylmethyl and N-oxo-pyridylmethyl; ^R2 and ^R3 are ethyl; ^R is selected from hydrogen and methyl; ^R is selected from -H, ethyl, phenyl, benzyl or phenethyl, naphthyl, fluorophenyl, chlorophenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexyl Methyl, -C(=O)-NH-R ⁸ , -S(=O) ₂ -R ⁸ , -C(=O)-OR ⁸ and -C(=O)-R ⁸ , wherein R ⁸ is selected from from methyl, 2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, methylphenyl, fluorophenyl, butyl, cyclohexyl and cyclohexylmethyl. 5. The compound according to claim 1, wherein said compound is selected from the group consisting of: Compound 1: 4-[2-(benzoylamino)phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide; Compound 2: N-[2-[[4-[(diethylamino)carbonyl]phenyl]-4-piperidinylenemethyl]phenyl]phenylacetamide; Compound 3: 4-[[2-[(cyclohexylcarbonyl)amino]phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide; Compound 4: N-[2-[[4-[(diethylamino)carbonyl]phenyl]-4-piperidinylidenemethyl]phenyl]phenylpropanamide; Compound 5: 4-[[2-[(cyclohexylacetyl)amino]phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide; Compound 6: N, N-diethyl-4-[[2-[(2-phenylethyl)amino]phenyl]-4-piperidinylidenemethyl]benzamide; Compound 7: 4-[[2-[(cyclohexylmethyl)amino]phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide; Compound 8: N, N-diethyl-4-[[2-[(phenylmethyl)amino]phenyl]-4-piperidinylenemethyl]-benzamide; Compound 9: 4-[[2-(cyclohexylamino)phenyl]-4-piperidinylenemethyl]-N,N-diethylbenzamide; Compound 10: N, N-diethyl-4-[[2-[[(phenylamino)carbonyl]amino]phenyl]-4-piperidinylidenemethyl]benzamide; Compound 11: N, N-diethyl-4-[[2-(phenylamino)phenyl]-4-piperidinylidenemethyl]benzamide; Compound 12: N, N-diethyl-4-[[2-(methylphenylamino)phenyl]-4-piperidinylidenemethyl]benzamide; Compound 13: N,N-diethyl-4-[[2-[(benzenesulfonyl)amino]phenyl]-4-piperidinylidenemethyl]benzamide; Compound 14: N, N-diethyl-4-[[2-[[(phenylmethyl)sulfonyl]amino]phenyl]-4-piperidinylidenemethyl]benzamide; Compound 15: N,N-diethyl-4-[4-piperidinylidene[2-[[(2,2,2-trifluoroethyl)sulfonyl]amino]phenyl]methyl]benzyl amides; Compound 16: 4-[{2-[(cyclopentylacetyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 17: 4-[{2-[(cyclopentylcarbonyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 18: N,N-diethyl-4-[{2-[(3-phenylpropyl)amino]phenyl}(piperidin-4-ylidene)methyl]benzamide; Compound 19: 4-[{2-[(2-cyclohexylethyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 20: 4-[[2-(cyclopentylamino)phenyl](piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 21: 4-[[2-(cycloheptylamino)phenyl](piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 22: 4-[(2-{[(benzylamino)carbonyl]amino}phenyl)(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 23: N, N-diethyl-4-[[2-(1-naphthylamino)phenyl](piperidin-4-ylidene)methyl]benzamide; Compound 24: N,N-diethyl-4-[{2-[(3-fluorophenyl)amino]phenyl}(piperidin-4-ylidene)methyl]benzamide; Compound 25: 4-[{2-[(4-chlorophenyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 26: 4-[{2-[cyclohexyl(methyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 27: N,N-Diethyl-4-[(2-{[(4-methylphenyl)sulfonyl]amino}phenyl)(piperidin-4-ylidene)methyl]benzamide ; Compound 28: N, N-diethyl-4-[(2-{[(2-fluorophenyl)sulfonyl]amino}phenyl)(piperidin-4-ylidene)methyl]benzamide; Compound 29: 4-[{2-[(butylsulfonyl)amino]phenyl}(piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 31: 4-[[2-(acetylamino)phenyl](piperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 32: Methyl 2-[{4-[(diethylamino)carbonyl]phenyl}(piperidin-4-ylidene)methyl]phenylcarbamate; Compound 30: 4-[(2-aminophenyl)(1-benzylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 33: 4-[[2-(acetylamino)phenyl](1-benzylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 34: Methyl 2-((1-benzylpiperidin-4-ylidene){4-[(diethylamino)carbonyl]phenyl}methyl)phenylcarbamate; Compound 35: 4-{(2-aminophenyl)[1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl amides; Compound 36: 4-{(2-aminophenyl)[1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl amides; Compound 37: 4-{[2-(acetylamino)phenyl][1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-di Ethylbenzamide; Compound 38: 2-{{4-[(diethylamino)carbonyl]phenyl}[1-(1,3-thiazol-4-ylmethyl)piperidin-4-ylidene]methyl}phenyl Methyl carbamate; Compound 39: 4-{[2-(acetylamino)phenyl][1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl}-N,N-di Ethylbenzamide; Compound 40: 2-{{4-[(diethylamino)carbonyl]phenyl}[1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl}phenyl Methyl carbamate; Compound 41: 4-[(2-aminophenyl)(1-butylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 42: 4-{(2-aminophenyl)[1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide; Compound 43: 4-{(2-aminophenyl)[1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide; Compound 44: 4-{(2-aminophenyl)[1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzamide; Compound 45: 4-{[2-(acetylamino)phenyl][1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl amides; Compound 46: 4-{[2-(acetylamino)phenyl][1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl amides; Compound 47: 4-[[2-(acetylamino)phenyl](1-butylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide; Compound 48: 4-{[2-(acetylamino)phenyl][1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}-N,N-diethylbenzyl amides; Compound 49: Methyl [2-((1-butylpiperidin-4-ylidene){4[(diethylamino)carbonyl]phenyl}methyl)phenyl]carbamate; Compound 50: (2-{{4-[(diethylamino)carbonyl]phenyl}[1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}phenyl)carbamic acid Methyl ester; Compound 51: (2-{{4-[(diethylamino)carbonyl]phenyl}[1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}phenyl)carbamic acid Methyl ester; Compound 52: (2-{{4-[(diethylamino)carbonyl]phenyl}[1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}phenyl)carbamic acid Methyl ester; Compound 53: 4-{(1-butylpiperidin-4-ylidene)[2-(ethylamino)phenyl]methyl}-N,N-diethylbenzamide; Compound 54: N, N-diethyl-4-{[2-(ethylamino)phenyl][1-(pyridin-4-ylmethyl)piperidin-4-ylidene]methyl}benzidine amides; Compound 55: N, N-diethyl-4-{[2-(ethylamino)phenyl][1-(pyridin-3-ylmethyl)piperidin-4-ylidene]methyl}benzidine amides; Compound 56: N, N-diethyl-4-{[2-(ethylamino)phenyl][1-(pyridin-2-ylmethyl)piperidin-4-ylidene]methyl}benzidine amides; and pharmaceutically acceptable salts thereof. 6. A compound according to any one of claims 1-5 for use as a medicament. 7. Use of a compound according to any one of claims 1-5 for the manufacture of a medicament for the treatment of pain, anxiety or functional gastrointestinal disorders. 8. A pharmaceutical composition comprising a compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier. 9. A method of treating pain in a warm-blooded animal, said method comprising the step of administering to said animal in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1-5. 10. A method of treating a functional gastrointestinal disorder in a warm-blooded animal, said method comprising the step of administering to said animal in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1-5. 11. A method for preparing a compound of formula IIA, said method comprising: Reaction of a compound of formula IIIA with ^R5 - _CH2 -X or ^R5 -CHO: wherein X is a halogen; R ⁷ is selected from -C(=O)-OR ⁸ , -S(=O)-R ⁸ , -S(=O) ₂ -R ⁸ and -C(=O)-R ⁸ , wherein R ⁸ is selected from C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclic, C _6-10 aryl-C _1-6 alkyl and C _2-9 heterocyclic Base-C _1-6 alkyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl- C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl are optionally selected from one or more of -R, -NO ₂ , -OR, -Cl, -Br, -I, - F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, - The groups of S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR Substituted, wherein R is independently hydrogen or C _1-6 alkyl; and R ⁵ is selected from C _6-10 aryl and C _2-5 heteroaryl, wherein said C _6-10 aryl and C _2-5 heteroaryl are optionally selected from one or more of -R, - NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(= O)R and -NRC(=O)-OR are substituted by a group, wherein R is independently hydrogen or C _1-6 alkyl. 12. A method for preparing a compound of formula IIA, said method comprising:

Reaction of a compound of formula IVA with ^R7 -X or R7 ^{- OR7} : wherein X is a halogen; R ⁷ is selected from -C(=O)-OR ⁸ and -C(=O)-R ⁸ , wherein R ⁸ is selected from C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl , C _2-9 heterocyclyl, C _6-10 aryl-C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-6 alkyl and C _2-9 heterocyclyl-C _1-6 alkyl Optionally selected from one or more of -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH , -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, Substituted by groups of -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR, wherein R is independently hydrogen or C _1-6 alkyl; and R ⁵ is selected from C _6-10 aryl and C _2-5 heteroaryl, wherein said C _6-10 aryl and C _2-5 heteroaryl are optionally selected from one or more of -R, - NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(= O)R and -NRC(=O)-OR are substituted by a group, wherein R is independently hydrogen or C _1-6 alkyl. 13. A process for the preparation of compounds of formula VA, Including compounds of the reduced formula VIA,

in R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-3 alkyl and C _2-9 heterocyclyl-C _1-3 alkyl; wherein said C _1-6 alkyl, C _3-6 cycloalkyl, C _{6 -10} aryl, C _2-9 heterocyclyl, C _6-10 aryl-C _1-3 alkyl and C _2-9 heterocyclyl-C _1-3 alkyl are optionally selected from one or more -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , -SH, - NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR are substituted, wherein R is independently hydrogen or C _1-6 alkyl; and R ² and R ³ are independently selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein said C _1-6 alkyl and C _3-6 cycloalkyl are optionally replaced by one or more one selected from -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH, -NH ₂ , - SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O) Substituted with groups of NR ₂ , -NRC(=O)R and -NRC(=O)-OR, wherein R is independently hydrogen or C _1-6 alkyl. 14. Compounds of formula I, their pharmaceutically acceptable salts, diastereomers, enantiomers and mixtures thereof:

in R ¹ is selected from hydrogen, C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _{6- 10} aryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C _6-10 aryl-C _1-3 alkyl and optionally substituted C _2-9 heterocyclyl-C _1-3 alkyl; n is 0, 1 or 2; m is 0, 1 or 2; R ² , R ³ and R ⁴ are independently selected from hydrogen, optionally substituted C _1-6 alkyl and optionally substituted C _3-6 cycloalkyl; R ⁵ and R ⁶ are independently selected from -R, -NO ₂ , -OR, -Cl, -Br, -I, -F, -CF ₃ , -C(=O)R, -C(=O)OH , -NH ₂ , -SH, -NHR, -NR ₂ , -SR, -SO ₃ H, -SO ₂ R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR ₂ , -NRC(=O)R and -NRC(=O)-OR, wherein R is independently hydrogen or C _1-6 alkyl; and R ⁷ is selected from -H, -OH, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _{2 -9} heterocyclyl, optionally substituted C _6-10 aryl-C _1-6 alkyl, optionally substituted C _2-9 heterocyclyl-C _1-6 alkyl, -C(=O)- NR ⁸ R ⁹ , -C(=O)-OR ⁸ , -S(=O)-R ⁸ , -S(=O) ₂ -R ⁸ , -C(=O)-R ⁸ and -SO ₃ H , wherein R ⁸ and R ⁹ are independently selected from -H, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally Substituted C _2-9 heterocyclyl, optionally substituted C _6-10 aryl-C _1-6 alkyl and optionally substituted C _2-9 heterocyclyl-C _1-6 alkyl. 15. A compound according to claim 14, Wherein ^R is selected from hydrogen, C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl and optionally substituted C _3-6 cycloalkyl; ^R2 and ^R3 are ethyl; R ⁴ is selected from hydrogen and C _1-3 alkyl; R ⁷ is selected from -H, -OH, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _{3- 5} heterocyclyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkyl-C _{1- 3} alkyl, -C(=O)-NR ⁸ R ⁹ , -C(=O)-OR ⁸ , -S(=O)-R ⁸ , -S(=O) ₂ -R ⁸ , -C( =O)-R ⁸ and -SO ₃ H, wherein R ⁸ and R ⁹ are independently selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl -C _1-3 alkyl, optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, Optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl; and n and m are 0. 16. A compound according to claim 14, Wherein R ¹ is selected from hydrogen and C _1-6 alkyl-OC(=O)-; ^R2 and ^R3 are ethyl; ^R is selected from hydrogen and methyl; R ⁷ is selected from -H, phenyl-C _1-3 alkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _3-6 cycloalkyl, phenyl, optionally substituted C _{1- 6} alkyl, -C(=O)-NR ⁸ R ⁹ , -S(=O) ₂ -R ⁸ and -C(=O)-R ⁸ , wherein R ⁸ and R ⁹ are independently selected from -H, Phenyl-C _1-3 alkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _3-6 cycloalkyl, phenyl and optionally substituted C _1-6 alkyl; and n and m are 0. 17. The compound according to claim 14, wherein ^R1 is hydrogen; ^R2 and ^R3 are ethyl; ^R is selected from hydrogen and methyl; R ⁷ is selected from -H, phenyl, benzyl or phenethyl, cyclohexyl, cyclohexylmethyl, -C(=O)-NH-R ⁸ , -S(=O) ₂ -R ⁸ and -C (=O)-R ⁸ , wherein R ⁸ is selected from 2,2,2-trifluoroethyl, phenyl, benzyl or phenethyl, cyclohexyl and cyclohexylmethyl; and n and m are 0. 18. A method for preparing a compound of formula II, said method comprising:

Reaction of a compound of formula III with X ¹ -C(=O)-R ¹⁰ :

in R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl and optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl; X ¹ is selected from -OH, -OR ¹¹ , -OC(=O)-R ¹¹ , -Cl, -Br and -I, wherein R ¹¹ is C _1-6 alkyl; R ² , R ³ and R ⁴ are independently selected from hydrogen, optionally substituted C _1-6 alkyl, and optionally substituted C _3-6 cycloalkyl; and R ¹⁰ is selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclic Base-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl . 19. A method of preparing a compound of formula IV, said method comprising:

Reaction of a compound of formula V with R ¹² -C(=O)-R ¹³ :

in R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl and optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl; R and ^R are independently selected from hydrogen, optionally substituted C _1-6 alkyl ^, and optionally substituted C _3-6 cycloalkyl; and R ¹² and R ¹³ are independently selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl; or R ¹² and R ¹³ together form part of a C _3-6 cycloalkyl ring or a C _3-5 heterocyclyl ring. 20. A method of preparing a compound of formula VI, said method comprising:

Reaction of a compound of formula V with R ¹⁴ -NCO:

in R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl or optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl; R and ^R are independently selected from hydrogen, optionally substituted C _1-6 alkyl ^, and optionally substituted C _3-6 cycloalkyl; and R ¹⁴ is selected from optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl. 21. A method of preparing a compound of formula VII, said method comprising: Reaction of a compound of formula VIII with R ¹⁶ -X ² : in R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl and optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl; R ² and R ³ are independently selected from hydrogen, optionally substituted C _1-6 alkyl and optionally substituted C _3-6 cycloalkyl; X ^is selected from I, Br and Cl; R ^is selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclic Base-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl ;and R ¹⁶ is selected from optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclyl, optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl, any substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl. 22. A method of preparing a compound of formula IX, said method comprising:

The compound of formula III is reacted with ^X3 -S(=O) ₂ - ^R17 : in R ¹ is selected from C _1-6 alkyl-OC(=O)-, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally Substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl and optionally substituted C _3-5 heterocyclyl-C _1-3 alkyl; X ³ is selected from -OH, -OR ¹¹ , -Cl, -Br and -I, wherein R ¹¹ is C _1-6 alkyl; R ² , R ³ and R ⁴ are independently selected from hydrogen, optionally substituted C _1-6 alkyl, and optionally substituted C _3-6 cycloalkyl; and R ^is selected from -H, optionally substituted phenyl, optionally substituted C _3-5 heterocyclyl, optionally substituted phenyl-C _1-3 alkyl, optionally substituted C _3-5 heterocyclic Base-C _1-3 alkyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkyl-C _1-3 alkyl .