ZA200509246B - Diarylmethylidene piperidine derivatives, preparations thereof and uses thereof - Google Patents

Description

. :

DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES. PREPARATIONS

THEREOF AND USES THEREOF

FIELD OF THE INVENTION

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

BACKGROUND OF THE INVENTION

The & receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the & receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the 8 receptor have also been shown to possess immunomodulatory activities.

The identification of at least three different populations of opioid receptors (i, &and x) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.

With few exceptions, currently available selective opioid § ligands are peptidic in nature and are unsuitable for administration by systemic routes. One example of a non-peptidic 3-agonist is SNC80 (Bilsky E.J. et al., Journal of Pharmacology and .

Experimental Therapeutics, 273(1), pp 359-366 (1995)).

Many § agonist compounds that have been identified in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that many of these 8 agonist compounds show significant convulsive effects when administered systemically.

U.S. Patent No, 6,187,792 to Delorme et al. describes some S-agonists.

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

DESCRIPTION OF THE INVENTION

Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of

Organic Chemistry, Sections 4, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures.

The term "Cama" OF "Cin 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 comprising only carbon and hydrogen atoms up to 14 carbon atoms.

The term “hydrocarbon radical” or "hydrocarbyl" used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.

The term “alkyl” used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms.

The term “alkylene” used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.

The term “alkenyl” used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 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 radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms.

The term “cycloalkyl,” used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.

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

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

The term “aryl” used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g, 4n +2 delocalized electrons) and comprising 5 up to about 14 carbon atoms.

The term “arylene” used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n +2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to link two structures together. . The term “heterocycle” used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s). Heterocycle may be saturated or unsaturated, containing one or more double bonds, and 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 refer to at least two rings share 75 two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.

The term "heteroaromatic used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring- containing structure or molecule has an aromatic character (e.g., 4n +2 delocalized electrons).

The term “heterocyclic group,” “heterocyclic moiety,” “heterocyclic,” or “heterocyclo” used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.

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

The term “heterocyclylene” used alone or as a suffix or prefix, refersto a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.

The term “heteroaryl” used alone oras a suffix or prefix, refersto a heterocyclyl having aromatic character.

The term “beterocylcoalkyl” used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character.

The term “heteroarylene” used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character.

The term “heterocycloalkylene” used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.

The term "six-membered" used as prefix refers to a group having a ring that contains six ring atoms.

The term "five-membered" used as prefix refers to a group having a ring that contains five ring atoms.

A five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N,OandS.

Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, 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-thiadiazoly}, and 1,3,4- oxadiazolyl.

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

Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. 5 The term “substituted” used as a prefix refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more

C.shydrocarbon groups, or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, Cl, Br, 1, and P. Exemplary chemical groups containing one or more heteroatoms include -NO,, -OR, -Cl, -Br, -I, -F, -CFs, -C(=O)R, -C(=0)OH, -NH, -SH, -NHR, NRy, -SR, -SO3H, -SO:R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=O)NR2, -NRC(=O)R, 0x0 (=0), imino (=NR), thio (=5), and oximino (=N-OR), wherein each “R” isa Cishydrocarbyl. For example, substituted phenyl may refer to nitrophenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc. wherein the nitro, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.

The term “substituted” used as a suffix of a first structure, molecule or group, i followed by one or more names of chemical groups refers to a second structure, molecule or group, which is a result of replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups. For example, a “phenyl substituted by nitro” refers to nitrophenyl.

Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5- dihydrofuran tetrahydrofuran, 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, 4,7- dihydro-1,3-dioxepin, and hexamethylene oxide.

In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, 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.

Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine; Phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2- benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine.

In addition to the polycyclic heterocycles described above, heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heteracycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.

Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro- pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3- dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3- dioxepanyl, 4,7-dihydro-1 ,3-dioxepinyl, and hexamethylene oxidyl.

In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3- triazolyl, 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.

Additionally, heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4- benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridiny}, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benziriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, and quinolizidinyl.

In addition to the polycyclic heterocyclyls described above, heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles 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 radicals of the general formula —O-R, wherein R is selected from a hydrocarbon radical. Exemplary alkoxy includes 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 radicals of the general formula -NRR’, wherein R and R’ are independently selected from hydrogen or a hydrocarbon radical.

Halogen includes fluorine, chlorine, bromine and iodine. "Halogenated," used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens. "RT" or "rt" means room temperature. ) In one aspect, the invention provides a compound of formula, a pharmaceutically acceptable salt thereof, diastereomers thereof, enantiomers thereof, and mixtures thereof: 0 Rs Ron 2

RN N

ALYY

X =

N

R1

I wherein

R! is selected from hydrogen, Calkyl-0-C(=0)-, optionally substituted C;. ¢alkyl, optionally substituted Cjcycloalkyl, optionally substituted Ce-10aryl, optionally substituted C,.sheterocyclyl, optionally substituted Cg.10aryl-Ci.3alkyl and optionally substituted C,.sheterocyclyl-Cy.zalkyl; nis0,1or2;mis0,1,0r2;

RZ, R® and R* are, independently, selected from hydrogen, optionally substituted Cy.salkyl, and optionally substituted Ca.scycloalkyl;

RS and R° are, independently, selected from -R, ~NO2, -OR, -Cl, -Br, -1, -F, -CF;, -C(=O)R, -C(=0)OH, -NH, -SH, -NHR, -NR,, -SR, -SO:H, -SO:R, -S(=0)R,

CN, -OH, -C(=0)OR, -C(=O)NR;, -NRC(=O)R, and NRC(=0)-OR, wherein R is, independently, a hydrogen or Cialkyl; and

R’ is selected from —H, -OH, optionally substituted Cjalkyl, optionally substituted Cs.scycloalkyl, optionally substituted Ce.j0aryl, optionally substituted Cagheterocyclyl, optionally substituted Ce. 10aryl-Ci-salkyl, optionally substituted

C,.oheterocyclyl-Cisalkyl, -C(=0)-NR*R’, —C(=0)-O-R%, ~S(=0)-R’, ~S(=0)-R’, -C(=0)-R? and -SO;H, wherein R® and R® are independently selected from -H, optionally substituted C).¢alkyl, optionally substituted Cascycloalkyl, optionally substituted Ce. 10aryl, optionally substituted Ca.oheterocyclyl, optionally substituted

Ce0aryl-Cialkyl, and optionally substituted Cy.sheteracyclyl-Crealkyl.

Particularly, the compounds of the present invention are those of formula I, wherein R! is selected from hydrogen, C;-alkyl-0-C(=0)-, optionally substituted Ci- ¢alkyl, and optionally substituted Cs.¢cycloalkyl;

R2 and R? are ethyl;

R* is selected from hydrogen and Cy.salkyl;

R’ is selected from —H, -OH, optionally substituted phenyl, optionally substituted Cs sheterocyclyl, optionally substituted phenyl-Ci.3alkyl, optionally substituted Cs sheterocyclyl-Cy.salkyl, optionally substituted C.salkyl, optionally substituted Cs.scycloalkyl, optionally substituted Cs.¢cycloalkyl-Cy.salkyl, -C(=0)-N-

RPR,—C(=0)-O-R%, -S(=0)-R’, —§(=0),-R?, -C(=0)-R’ and -SO;3H, wherein R® and

R? are independently selected from -H, optionally substituted phenyl, optionally substituted Cs.sheterocyclyl, optionally substituted phenyl-C.3alkyl, optionally substituted Cs.sheterocyclyl-Cy.salkyl, optionally substituted Ci.¢alkyl, optionally substituted Cs.scycloalkyl, optionally substituted Cscycloalkyl-C.salkyl; and n and m are 0.

More particularly, the compounds of the present invention are those of formula I, wherein R' is selected from hydrogen and C;4alkyl-0-C(=0)-;

R? and R? are ethyl;

R! is selected from hydrogen and methyl;

R is selected from -H, phenyl-Cy_salkyl, Cs.¢cycloalkyl-Cr.aalkyl, Cs. «cycloalkyl, phenyl, optionally substituted Ci-galkyl, -C(=0)-N-R*R’, -S(=0)-R’, and -C(=0)-R®, wherein R® and R® are independantly selected from —H, phenyl-Cy. jalkyl, Ca.cycloalkyl-Cy.zalkyl, Cacycloalkyl, phenyl, and optionally substituted Ci. alkyl; and n and m are 0.

Most particularly, the compounds of the present invention are those of formula 1, wherein

R' is hydrogen;

R? and R? are ethyl;

R* is selected from hydrogen and methyl;

R’ is selected from —H, phenyl, benzyl or phenethyl, cyclohexyl, cyclohexylmethyl, -C(=0)-NH-R?, -S(=0),-R®, and -C(=0)-R®, wherein R® is selected from 2,2,2-triflucroethyl, phenyl, benzyl or phenethyl, cyclohexyl and cyclohexylmethyl; and n and m are 0.

In another aspect, the invention provides a compound of formula IA, a : pharmaceutically acceptable salt thereof, diastereomers thereof, enantiomers thereof, and mixtures thereof:

O

2

RN. N

OPE

X on \

R' 1A wherein

R! is selected from hydrogen, Cy.¢alkyl-0-C(=0)-, Cisalkyl, Ci.cycloalkyl,

Ce.10aryl, Caoheterocyelyl, Ce.10aryl-Cy.zalkyl and C,sheterocyclyl-Cyalkyl; wherein said C1.calkyl, Ciscycloalkyl, Ce 10aryl, Capoheterocyclyl, Cg 10aryl-Ci.aalkyl and

C,sheterocyclyl-Cy.salkyl are optionally substituted with one or more groups selected from -R, -NO;, -OR, -C}, -Br, -1, -F, -CFs, -C(=O)R, -C(=0)OH, -NH,, -SH, -NHR,

NR; -SR, -SO3H, -SO;R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=0)NR;,

NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or

Ciealkyl;

RZ, R? and R* are, independently, selected from hydrogen, C,.calkyl, and

Cs.scycloalkyl, wherein said Ci.alkyl and Ciecycloalkyl are optionally substituted with one or more groups selected from -R, -NO2, -OR, -C}, -Br, -1, -F, -CF3, -C(=O)R, -C(=0)OH, -NH, -SH, -NHR, -NR;, -SR, -SO;H, -SO:R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=O)NR3, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, . 15 independently, a hydrogen or Cisalkyl; and

R is selected from —H, -OH, Cialkyl, Cs.scycloalkyl, Ce.10aryl,

C, sheterocyelyl, Ce.ygaryl-Ci.galkyl, Ca. sheterocyclyl-Cicalkyl, -C(=0)-NR*R’, -C(=0)-O-R%, -S(=0)-R®, -S(=0)-R’, -C(=0)-R® and -SO:H, wherein R® and R’ are independently selected from —H, C.gatkyl, Ca-gcycloalkyl, Ce. aryl, C,.gheterocyclyl,

Cg oaryl-Cirsalkyl, and C,.sheterocyclyl-C.¢alkyl, wherein said C;.¢alkyl,

Cs.scycloalkyl, Csoaryl, Ca.sheterocyclyl, Cs-joaryl-Crealkyl, and Ca oheterocyclyl-

C,alkyl used in defining R., Ror R’ are optionally substituted with one or more groups selected from -R, -NO,, -OR, -Cl, -Br, -L, -F, -CF,, -C(=O)R, -C(=0)OH,

NH, -SH, -NHR, -NRj, -SR, -SO3H, -SO2R, -S(=0)R, -CN, -OH, -C(=0)OR, -C(=0)NRgz, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Cisalkyl.

In one embodiment, the compounds of the present invention are represented by formula IA, wherein R! is selected from hydrogen, C1.6alkyl-O-C(=0)-, Crsalkyl,

Cs.scycloalkyl, benzyl and C,.sheteroarylmethyl, wherein said C,salkyl,

Ca.cycloalkyl, benzyl and C,.sheteroarylmethyl are optionally substituted with one or more groups selected from C).¢alkyl, halogenated C1.salkyl, -CF3, Cy. alkoxy, chloro, fluoro, bromo, and iodo;

R? and R® are ethyl;

R* is selected from hydrogen and Cy.aalkyl;

R’ is selected from —H, -OH, phenyl, Ci.sheterocyclyl, phenyl-Cj.3alkyl,

C;.sheterocyclyl-Cy.salkyl, Crealkyl, Cs.cycloalkyl, Cascycloalkyl-Cy.alkyl, -C(=0)-N-R'R®, -C(=0)-0-R’, -S(=0)-R’, ~§(=0)-R}, -C(=0)-R® and -SOsH, wherein R® and R’ are independently selected from —H, phenyl, Cs.sheterocyclyl, phenyl-Ci.salkyl, Cs.sheterocyclyl-Cyaalkyl, C¢alkyl, Cs.eycloalkyl, Cacycloalkyl-

Ci.;alkyl, wherein said phenyl, Cs. sheterocyclyl, phenyl-Ci.salkyl, Cs.sheterocyclyl-

Cisalkyl, Cialkyl, Cs.scycloalkyl, Cs.reycloalkyl-Cysalkyl used in defining RR? and R® are optionally substituted with one or more groups selected from Cialkyl, halogenated Cj.alkyl, -CF3, C16 alkoxy, chloro, fluoro, bromo, and iodo.

In another embodiment, the compounds of the present invention are represented by formula IA, wherein R! is selected from hydrogen,

C1.salkyl-O-C(=0)-, Ci6alkyl, Ca.cycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and N-oxido-pyridylmethyl, wherein said Cisalkyl,

Ciecycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and N-oxido- pyridylmethyl are optionally substituted with one or more groups selected from

C,.salkyl, halogenated Cysalkyl, -CF3, C1 alkoxy, chloro, fluoro, bromo, and iodo;

R? and R? are ethyl;

R* is selected from hydrogen and methyl;

R is selected from =H, C,alkyl, phenyl-Cy.zalkyl, Cs.;cycloalkyl-Cy.salkyl,

Cs.scycloalkyl, phenyl, Ci.salkyl, -C(=0)-N-R°R’, -S(=0)-R®, -C(=0)-O-R®, and -C(=0)-R%, wherein R® and R’ are independantly selected from —H, phenyl-Cy.salkyl,

Cs .scycloalkyl-Cy.salkyl, Capcycloalkyl, phenyl, and C.salkyl, wherein said phenyl-

C1.salky}, Cascycloalkyl-Cralkyl, Cascycloalkyl, phenyl, Cy6alkyl used in defining rR, R® and R’ are optionally substituted with one or more groups selected from

C.¢alkyl, halogenated Cy6alkyl, -CF3, Cy.¢ alkoxy, chloro, fluoro, bromo, and iodo.

In a further embodiment, the compounds of the present invention are represented by formula IA, wherein R! is selected from hydrogen, propyl, benzyl, thiadiazolylmethyl, pyridyimethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and N-oxido-pyridylmethyl;

R? and R? are ethyl;

R* is selected from hydrogen and methyl;

R7 is selected from ~H, ethyl, phenyl, benzy! or phenethyl, napthyl, fluorophenyl, chlorophenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexylmethyl, -C(=0)-NH-R, -S(=0)-R®, -C(=0)-0-R®, and -C(=0)-R’, wherein R? is selected from methyl, 2,2 2-trifluoroethyl, phenyl, benzyl, phenethyl, methylphenyl, fluorophenyl, butyl, cyclohexyl and cyclohexylmethyl.

It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I or JA. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.

It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula Lor IA. It will further be understood that the present invention encompasses tautomers of the compounds of the formula I or IA.

It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the formula I or IA.

Within the scope of the invention are also salts of the compounds of the formula I or IA. Generally, pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCI or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.

In one embodiment, the compound of formula I or IA above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.

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. This list should however not be interpreted as exhaustive.

Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti-viral agents.

Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and F unctional

Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.

Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation).

Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

Also within the scope of the invention is the use of any of the compounds according to the formula I or IA above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I or IA above, is administered to a patient in need of such treatment.

Thus, the invention provides a compound of formula I or IA, or pharmaceutically acceptable sait or solvate thereof, as hereinbefore defined for use in therapy.

In a further aspect, the present invention provides the use of a compound of formula 1 or IA, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" and "therapeutically" should be contrued accordingly. The term "therapy" within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.

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

In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.

In one embodiment of the invention, the route of administration may be orally, intravenously or intramuscularly.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.

For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid and liquid.

Solid form 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, jubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture 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 by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, tale, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.

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, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.

A therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.

Within the scape of the invention is the use of any compound of formula I or 1A. as defined above for the manufacture of a medicament.

Also within the scope of the invention is the use of any compound of formula or IA for the manufacture of a medicament for the therapy of pain.

Additionally provided is the use of any compound according to Formula I or

IA for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain.

A further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I or IA above, is administered to a patient in need of such therapy.

Additionally, there is provided a pharmaceutical composition comprising a compound of Formulal or IA, ora pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

Particularly, there is provided a pharmaceutical composition comprising a compound of Formula or IA, ora pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.

Further, there is provided a pharmaceutical composition comprising a compound of Formulalor1A, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.

In a further aspect, the present invention provides a method of preparing a compound of formula I or IA.

In one embodiment, the invention provides a process for preparing a compound of formula IL, comprising: oO

RZ

Rr

N R' ng

Oo \

R'

J 11 reacting a compound of formula III with X'-C(=0)-R": 0

R2 oy

Rr ww

Re

N

1

R ,

oI wherein

R! is selected from C.salkyl-0-C(=0)-, optionally substituted C).salkyl, optionally substituted Ca.scycloalkyl, optionally substituted phenyl, optionally substituted Cs sheterocyclyl, optionally substituted phenyl-C;.salkyl and optionally substituted C.sheterocyclyl-Cy.zalkyl; x! is selected from —OH, -OR!!, -0-C(=0)-R", -Cl, -Br and -I, wherein R'!is

Cisalkyl;

RZ Rand R? are, independently, selected from hydrogen, optionally substituted Csalkyl and optionally substituted Cs.¢cycloalkyl; and

RC js selected from —H, optionally substituted phenyl, optionally substituted

Cj.sheterocyclyl, optionally substituted phenyl-C; alkyl, optionally substituted

Cj .sheterocyclyl-Cisalkyl, optionally substituted C;-calkyl, optionally substituted

Cs.scycloalkyl and optionally substituted Cs.scycloalkyl-Cy.zalkyl.

Particularly, the invention provides a process for preparing a compound of formula II as described above, wherein

R! is Cy.alkyl-O-C(=0)-;

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

R?andR® are ethyl;

R* is hydrogen; and

RY is selected from phenyl, phenyl-Ci.satkyl, Csalkyl, Cacycloalkyl and

Cs.scycloalkyl-Cisalkyl.

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

0

R

0 J

Re

NR

R'2 \

R' v reacting a compound of formula V with R!2.c(=0)-R® : 0

R2 oy

R®

NH, \ 1

R , y wherein

R! is selected from Cy.alkyl-O-C(=0)-, optionally substituted Cysalkyl, optionally substituted Cs.scycloalkyl, optionally substituted phenyl, optionally substituted Cs.sheterocyclyl, optionally substituted phenyl-C,.3alkyl and optionally substituted Cs.sheterocyclyl-C;.aalkyl;

R? and R® are, independently, selected from hydrogen, optionally substituted

C;.salky! and optionally substituted Cs ¢cycloalkyl; and

R!? and R" are independently selected from —H, optionally substituted phenyl, optionally substituted Cs sheterocyclyl, optionally substituted phenyl-C;.salkyl,

optionally substituted Cs sheterocyclyl-C;.salkyl, optionally substituted Cisalkyl, optionally substituted C3 ¢cycloalkyl and optionally substituted Cs ¢cycloalky!- .

Ci.aalkyl; or R'? and R'? together form a portion of a Cs ¢cycloalkyl ring or a

Ci sheterocyleyl ring.

Particularly, the invention provides a process for preparing a compound of formula I'V as described above, wherein

R! is Cy ealkyl-O-C(=0)-;

R?andR? are ethyl; and

Rand R® are independently selected from —H, phenyl, phenyl-C;.salkyl,

Crealkyl, Csecycloalkyl and Cascycloatkyl-Cy.salkyl; or R'2 and R" together form a portion of a Ca¢cycloalkyl ring.

In a third embodiment, the present invention provides a process for preparing a compound of formula VI, comprising: 0) 2

TOL

R®

EN

OR CL

N 0)

R

VI reacting a compound of formula V with R'*-NCO:

0] gaele

Re

NH, \

R!

Vv wherein

R! is Cy.salkyl-O-C(=0)-, optionally substituted C,.galkyl, optionally substituted Cs¢cycloalkyl, optionally substituted phenyl, optionally substituted

C.sheterocyclyl, optionally substituted phenyl-Cy.salkyl or optionally substituted

Cs.sheterocyclyl-Cy.alkyl;

R? and R® are, independently, selected from hydrogen, optionally substituted

C1.¢alkyl and optionally substituted Cs.scycloalkyl; and

R" is selected from optionally substituted phenyl, optionally substituted

Cs sheterocyclyl, optionally substituted phenyl-C,.3alkyl, optionally substituted

Cs.sheterocyclyl-Cy.salkyl, optionally substituted Csalkyl, optionally substituted

Cscycloalkyl and optionally substituted Cs.¢cycloalkyl-Cy.salkyl.

Particularly, the invention provides a process for preparing a compound of formula VI as described above, wherein

R'is Cy.alkyl-O-C(=0)-;

R%and R® are ethyl; and

R™ is selected from phenyl, phenyl-Ci.salkyl, C1.6alkyl, Cs¢cycloalkyl and

Cagcycloalkyl-Cysalkyl.

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

0)

RZ hp @

R®

Ni 18 sR

R'S )

Rr yu reacting a compound of formula VIII with RIS-X%

Oo

RZ

IY

Re

R'

N

4

R > yia wherein

R! is selected from C;.¢alkyl-O-C(=0)-, optionally substituted C;.salkyl, optionally substituted Cs.scycloalkyl, optionally substituted phenyl, optionally substituted Cs.sheterocyclyl, optionally substituted phenyl-Cy.3alkyl and optionally substituted Cj.sheterocyclyl-C.3alkyl;

R? and R? are, independently, selected from hydrogen, optionally substituted

C1.¢alkyl and optionally substituted Cs.scycloalkyl;

X? is selected from I, Brand Cl;

RY is selected from —H, optionally substituted phenyl, optionally substituted

Ca sheterocyclyl, optionally substituted phenyl-Ci.3alkyl, optionally substituted

C.sheterocyclyl-C.salkyl, optionally substituted C.ealkyl, optionally substituted

Cs.¢cycloalkyl and optionally substituted Cs.scycloalkyl-Cy.salkyl; and

R'6 is selected from optionally substituted phenyl-Cy.salkyl, optionally substituted Cs sheteracyclyl, optionally substituted Ca.sheterocyclyl-Ci.zalkyl, optionally substituted Cy¢alkyl, optionally substituted Ca¢cycloalkyl and optionally substituted C3 scycloalkyl-Cyalkyl.

Particularly, the invention provides a process for preparing a compound of formula VII as described above, wherein

R! is Cyalkyl-0-C(=0)-;

X2 is selected from -Cl, -Br and -I;

R%?and R® are ethyl;

RY is selected from hydrogen and methyl; and

RS is selected from phenyl, phenyl-Cy.salkyl, Ci.saltkyl, Csgcycloakkyl and

Csecycloalkyl-C,.zalkyl.

In a fifth embodiment, the present invention provides a process for preparing a compound of formula IX, comprising: oO 2

RN :

NTR"

Sh

N ©

R!

IX reacting a compound of formula IIT with X3.8(=0)-R!":

0]

RAVE

Rr

R*

N

4

R ’ ma wherein

R! is selected from Cy.salkyl-O-C(=0)-, optionally substituted Cj-alkyl, optionally substituted Csscycloalkyl, optionally substituted phenyl, optionally substituted C_sheterocycly), optionally substituted phenyl-Cy.3alkyl and optionally substituted Ca.sheterocyclyl-Ci.3alkyl; x? is selected from —OH, -OR', -Cl, -Br and -I, wherein R'' is Ci.salkyl;

R?, R3 and R* are, independently, selected from hydrogen, optionally substituted C,¢alky! and optionally substituted Cacycloalkyl; and

R!7 is selected from —H, optionally substituted phenyl, optionally substituted

Ci.sheterocyclyl, optionally substituted phenyl-C.;alkyl, optionally substituted

Cs sheterocyclyl-Cysalkyl, optionally substituted Ci1.¢alkyl, optionally substituted

Cagcycloalkyl and optionally substituted Cs.scycloalkyl-Cy.salkyl.

Particularly, the invention provides a process for preparing a compound of formula IX as described above, wherein

R! is C .alkyl-O-C(=0)~;

X3 is selected from -Cl, -Br and -I;

R? and R? are ethyl;

R* is hydrogen;

R'7 is selected from phenyl, phenyl-C;.3alkyl, optionally substituted Csalkyl,

Cs.scycloalkyl and C;.scycloalkyl-Cialkyl.

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

O

SAYS.

HNL rR’

N

J

ITA reacting a compound of formula IIIA with R3-CH,-X or R*-CHO: 0) :

OU

HN 7

N

H

IIA wherein X is a halogen;

R is selected from —C(=0)-O-R%, ~S(=0)-R%, ~S(=0),-R’, and -C(=0)-R%, wherein R® is selected from Cj.galkyl, Cs.scycloalkyl, Cs.joaryl, Cs.sheterocyclyl,

Ce.10aryl-Csalkyl, and Casheterocyclyl-Cy.ealkyl, wherein said Ci¢alkyl,

Cs.scycloalkyl, Ceioaryl, Cagheterocyclyl, Cs.10aryl-Ci.¢alkyl, and Cy.oheterocyclyl-

Csalkyl are optionally substituted with one or more groups selected from -R, -NO,,

-OR, -Cl, -Br, -}, -F, -CF3, -C(=O)R, -C(=0)OH, NH, -SH, -NHR, -NR;, -SR, -SO;H, -SO4R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=O)NR2, -NRC(=O)R, and “NRC(=0)-OR, wherein R is, independently, a hydrogen or Cialkyl; and

R? is selected from Cg-joaryl and C,.sheteroaryl, wherein said Ce.10aryl and Cpsheteroaryl are optionally substituted with one or more groups selected from -R, -NO,, -OR, -C}, -Br, -1, -F, -CF3, -C(=O)R, -C(=0)OH, -NH,, -SH, -NHR, -NR;, -SR, -S0;H, -SO:zR, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=0)NR;, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Ci¢alkyl.

In another embodiment, the present invention provides a process for preparing a compound of formula IIA, comprising: 0)

SAE

HN

Rr’

N o

IA reacting a compound of formula IVA with R’-X or R™-0-R": 0]

SASSY

QQ

N p

R IVA wherein X is a halogen;

R’ is selected from —C(=0)-0-R® and -C(=O)R?, wherein R® is selected from

Cialkyl, Cagcycloalkyl, Ce.joaryl, C,.¢heterocyclyl, Ce.10aryl-Ci.6alkyl, and

Ca.oheterocyclyl-Cigalkyl, wherein said Ci4alkyl, Cyscycloalkyl, Ce.roaryl, Cpoheterocyclyl, Ce-10aryl-Ciealkyl, and C,.sheterocyclyl-Ci.¢alkyl are optionally substituted with one or more groups selected from -R, -NO,, -OR, -C}, -Br, -I, -F, -CF3, -C(=O)R, -C(=0)OH, -NH, -SH, -NHR, -NR;, -SR, -SOsH, -SO2R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR;, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Cisalkyl; and

RS is selected from Ce. icaryl and Ca.sheteroaryl, wherein said Cs.ioaryl and

C,.sheteroaryl are optionally substituted with one or more groups selected from -R,

NO,, -OR, -Cl, -Br, 1, -F, -CF3, -C(=O)R, -C(=O)OH, -NH,, -SH, -NHR, -NR3, -SR, -SO3H, -SO,R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=0)NR;, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or C;.¢alkyl.

In a further embodiment, the present invention provides a process of preparing a compound of formula VA, oO 2

Rx N

NH,

N iY

VA comprising reducing a compound of formula VIA,

0

Nasu rR?

NO, \

R!

VIA wherein

R! is selected from hydrogen, C;.galkyl~0-C(=0)-, Cisalkyl, Cs.scycloalkyl, Ce.0aryl, Cysheterocyclyl, Ce 10aryl-Ci.salkyl and Cy.gheterocyclyl-Ci.aalkyl; wherein said Cj.¢alkyl, Cascycloalkyl, Cs.j0aryl, Ca.gheterocyclyl, Cs 10aryl-Ci.3alkyl and

Ca.sheterocyclyl-C.aalkyl are optionally substituted with one or more groups selected from -R, -NO,, -OR, -Cl, -Br, -], -F, -CF3, -C(=0)R, -C(=0)OH, -NH,, -SH, -NHR, “NR, -SR, -SO3H, -SO;R, -S(=0)R, -CN, -OH, -C(=0)OR, -C(=0)NR, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or

Cialkyl; and

R?and R? are, independently, selected from hydrogen, C;4alkyl, and

Ci ¢cycloalkyl, wherein said Cy¢alkyl and Ci.ecycloalkyl are optionally substituted with one or more groups selected from -R, -NO,, -OR, -C}, -Br, -1, -F, -CF3, -C(=O)R, -C(=0)OH, -NH,, -SH, -NHR, -NR3, -SR, -SO3H, -SO;R, -S(=0O)R, -CN, -OH, -C(=0)OR, -C(=0)NR2, -NRC(=0O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or C;¢alkyl.

Particularly, the compounds of the present invention and intermediates used for the preparation thereof can be prepared according to the synthetic routes as exemplified in Schemes 1-18.

Scheme 1 [o] 1. LDA

D —— b ow 0” ~ome N

Intermediate 1 boc 0

MeO . a MeO NaOH HO Br 2 Br

Br

N

N N \ boc boc boc

Intermediate 2 intermediate 3 Intermediate 4 1 [o]

Pas

Pi HO. 2 AN isobutyl chloroformate Br B J ® $ —_— | OH NH,

ESN, ELH — NH,

N PA(PPhy),, Na,CO; toluene/EtOHM,0 N boc ) boc

Intermediate §

Intermediate 8

Scheme 2

QO O

ZN 1) R&COCI R&COH AN CO) 2)

PP NE, or HATU DIPEA J

CH,CL, DMF o

NH, SE ———————— HR 2) Trifluoroacetic acid 0

N CHCl, N boc

Intermediate 6 Compound 1: R®=Ph

Compound 2: R*=CH,Ph

Compound 3: R®=CgH,,

Compound 4: R*=CH,CH,Ph

Compound 5: R®=CH,CH,

Compound 16: R®=CH,CgH,

Compound 17: R:=CH,

Scheme 3 0 0] “SN 1) RE-CHO “ON

Py. NaBH(OAG),, ACOH P. 1,2-Dichloroethane

NH, J —— "NS 2) Trifluoroacetic acid R®

N CH,Cl, N ! H boc

Intermediate 6 Compound 6: Ré=CH,Ph

Compound 7: R®=CgH,,

Compound 8: R=Ph

Compound18: Ré=CH,CH,Ph

Compound 19: R®=CH.CH,,

Scheme 4 lo) [0]

YOO wm Tag

J ByoHya Pp

MeOH

NH, r————————— ee HN. 7 2) Trifiuoroacetic acid

N CH,Cl, N boc

Intermediate € Compound 9: R"=CH,,

Compound 20: R’=CH,

Compound 21: R™=C,H,,

Scheme 5 lo] 0

P 1) R&-NCO P 1,2-Dichloroethane H

NH, _— HN. _N._8 2) Trifluoroacetic acid hg R

N CH,Cl, N o ) H boc

Intermediate 6 Compound 40: R®=Ph

Compound 22: R&=CH,Ph

Scheme 6 0 0 1) R7-Br or R7-

SAYS Pej OU

P BINAP, NaO'Bu tol lo, ee HN. 2) Trfiuoroacetic acid

N CH,CL N ! H boc

Intermediate 6 Compound 11: R’'=Ph

Compound 23: R7=1-Napthyl

Compound 24: R’=3-F-Ph

Compound 25: R’=4-CI-Ph

Scheme 7 (e] [0] 1) R7-Br R7(0)

YOO H.-H 0D

J BINAP, NeOBu °F MeOH P

NH, toluene | N-R’ 2)NaH, Mel, DMF Of BygH,,, HCHO /

N H,0, MeOH N boc 3) Trifluoroacetic acid

CHCl, intermediate 6 Compound 12: R’=Ph

Compound 26: R7=CgH,,

Scheme 8 [oe] 0)

ZN ~~ N

Pp. @ 0) 1) RE-SO,C J pyridine 0

NH, —————t HN. 2) Trifluoroacetic acid & “R®

N CH,CL, N boc

Intermediate 6 Compound 13: R%Ph

Compound 14: R®=CH,Ph

Compound 15: R®*=CH,CF,

Compound 27: R®=4-Me-Ph

Compound 28: R®=2-F-Ph

Compound 29: R®=n-Bu

Scheme 9

QO

ZN HO. ,-OH a ® 0)

Br NO, pe 1. Triftuoroacetic acid

NO, CHCl —————————-tee —_—

N PA(PPhy), N 2 CHO boc Na,CO, (aq) boc

Toluene/EtOH

Intermediate 5 Intermediate 7 NaBH(OAC),, AcOH 1,2-Dichioroethane i I

OL SASS

NO, Fe | NH,

N EtOH/THF/H,O/NH Cla N

Intermediate 8 Compound 30

Scheme 10

AN HO. OH ASN ® 0) 1. ACC}, NEt,, CH,CL,

J Br NH, Pp. or

Zn, CIC(O)OMe, toluene

I NH, — —

J 2. TFA, CHCl,

N PA(PPh), N boc Na,CO, (aq) boc

Toluene/EtOH

Intermediate 5 Intermediate 8

J I a ZN

OU wo COL . 9 .

HN._R HN. __R

Yl — Y © NaBH(OAC),, AcOH N ©

H 1,2-Dichioroethane of

Compound 31: R*=Me

Compound 32: R==0OMe

Compound 33: R%Me

Compound 34: R°*=OMe

Scheme 11 )

AN HO. -OH AN ® 4

P Br NO, py 1.

To, -_—

N Pd(PPh,),, Na,CO, (aq) N boc Toluene/EtOH

Intermediate 5 2 Trifluoroacetic acid Intermediate 10

CH,Cl,

Ne 1. R1°%-CHO, NaBH(OAc), ASN 1,2-Dichloroethane P ® C] or 1

R19-CH,C), K,CO,, DMF NH, - 2. Fe, EtOHTHF/H,ONH,Cl,. N io

Compound 35: R'=4-thiazolyl

Compound 38: R'=5-thiazoly!

Scheme 12

Oo .

ZN 9

UA Oy cr CR? or CI” R Pp ® g

Zn powder

NH, NEt,, CH,CL Toluene | HNO -_—

N 8 oN N : ) N

S <

Ss

Compound 38 Compound 37: R*=Me

Compound 38: R*=OMe

Scheme 13 i I

OU FOL)

R10-CH,CI, K,CO,, DMF J \

HN. _R® or HN __R —————— Y ¥ !

N R1°-CHO, NaBH(OAC), i 1,2-Dichloroethane rR"

Compound 31: R®=Me

Compound 32: R*=OMe Compound 39: Ré=Me, Ri%=5-thiazolyl

Compound 40: R*=OMe, R1*=b-thiazolyl

Scheme 14

Q 0 ’ TN ZN

J Br 4 Trifuoroacetic acid J Br

CH,Cl, et eer eee J

N 2. R10-CHO N boc ko

NaBH(OACc),

Intermediate § 1,2-Dichloroethane intermediate 11 R1%=n-propy!

Intermediate 12 R1°=4-pyridy!

Intermediate 13 R1°=3-pyridyl

Intermediate 14 R°=2-pyridyl o]

HO.,.OH

B AN oo"

NH, —_——

Pd(PPh,), N

Na,CO; (aq)

Toluene/EtOH ro

Compound 44 R'=n-propyl

Compound 42 R'°=4.pyridyl

Compound 43 R1%=3-pyridyl

Compound 44 R%=2.pyridyl

Scheme 156 ]

ASN "Ory a ® 2)

A Br J

Cr T HN” rr etre [e]}

N Pd(PPhy), N gro Na, CO; (29) ro

Toluene/EtOH

Intermediate 12 R'=4.pyridyl Compound 45 R1°=4-pyridyl intermediate 13 R19=3-pyridyl Compound 46 RY=3-pyridyl

Scheme 16 le] 0

OI BASSE

NH, AcCl, NEL, CH,Cl, MN

J a ad

N N ©

Lo) Co

Compound 41: R"%=n-propy! Compound 47: R'*=n-propyl

Compound 44: R1=2-pyridyt Compound 48: R'*=2-pyridy}

Scheme 17 0 (o}

OU TOU

Ln, oor HNO — eee eee

N Zn powder N 0

J Toluene J

R R

Compound 41 R'=n-propyl Compound 49 R'*=n-propyl

Compound 42 R!0=4-pyridyl Compound 50 R=4-pyridyl

Compound 43 R'"°=3-pyridyl Compound 51 R%=3-pyridyl

Compound 44 R¥=2-pyridyl Compound 52 R10=2-pyridyl

Scheme 18 0] 0}

BASS BASS p MeCHO, NaBH(OAc),

NH, 1,2-Dichloroethane HN__~ ——— ee rm ee

N N qo) qo)

Compound 41 R'*=n-propyl Compound 53 R'%=n-propyl

Compound 42 R'=4-pyridyl Compound §4 R1°=4-pyridyl

Compound 43 R1%=3-pyridyl Compound 65 R'%=3-pyridyl

Compound 44 R'°=2-pyridyl : Compound 58 R'°=2-pyridyl

BIOLOGICAL EVALUATION

The compounds of the invention are found to be active towards § receptors in warm-blooded animal, e.g., human. Particularly the compounds of the invention are found to be effective 8 receptor ligands. In vitro assays, infra, demonstrate these surprising activities, especially with regard to agonists potency and efficacy as demonstrated in the rat brain functional assay and/or the human & receptor functional assay. This feature may be related to in vivo activity and may not be linearly correlated with binding affinity. In these in vitro assays, a compound is tested for their activity toward 5 receptors and ICso is obtained to determine the selective activity for a particular compound towards § receptors. In the current context, ICsp generally refers to the concentration of the compound at which 50% displacement of a standard radioactive 8 receptor ligand has been observed.

The activities of the compound towards k and |i receptors are also measured in a similar assay.

In vitro model

Cell culture

Human 2938 cells expressing cloned human x, 8 and p receptors and neomycin resistance are grown in suspension at 37°C and 5% CO in shaker flasks containing calcium-free DMEM10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600 pg/ml geneticin.

Rat brains are weighed and rinsed in ice-cold PBS (containing 2.5mM EDTA, pH 7.4). The brains are homogenized with a polytron for 30 sec (rat) in ice-cold lysis buffer (50mM Tris, pH 7.0, 2.5mM EDTA, with phenylimethylsulfonyl fluoride added just prior use to 0.5MmM from a 0.5M stock in DMSO:ethanol).

Membrane preparation

Cells are pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol), incubated on ice for 15 min, then homogenized with a polytron for 30 sec.

The suspension is spun at 1000g (max) for 10 min at 4°C. The supernatant is saved on ice and the pellets resuspended and spun as before. The supernatants from both spins are combined and spun at 46,000 g(max) for 30 min. The pellets are resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pellets are resuspended in membrane buffer ( 50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes are frozen in dry ice/ethanol and stored at -70°C until use.

The protein concentrations are determined by a modified Lowry assay with sodium dodecyl sulfate.

Binding assays

Membranes are 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 MgCla, 1 mg/ml

BSA (Sigma A-7888), pH 7.4, which is stored at 4°C after filtration through a 0.22 m filter, and to which has been freshly added 5 pg/ml aprotinin, 10 uM bestatin, 10 pM diprotin A, no DTT). Aliquots of 100 pl are added to iced 12x75 mm polypropylene tubes containing 100 pl of the appropriate radioligand and 100 pl of test compound at various concentrations. Total (TB) and nonspecific (NS) binding are determined in the absence and presence of 10 pM naloxone respectively. The tubes are vortexed and incubated at 25°C for 60-75 min, after which time the contents are rapidly vacuum-filtered and washed with about 12 mi/tube iced wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl) through GF/B filters (Whatman) presoaked for at least 2h in 0.1% polyethyleneimine. The radioactivity (dpm) retained on the filters is measured with a beta counter after soaking the filters for at least 12h in minivials containing 6-7 ml scintillation fluid. If the assay is set up in 96-place deep well plates, the filtration is over 96-place PEI-soaked unifilters, which are washed with 3 x 1 ml wash buffer, and dried in an oven at 55°C for 2h. The filter plates are counted in a TopCount (Packard) after adding 50 pl MS-20 scintillation fluid/well.

Functional Assays

The agonist activity of the compounds is measured by determining the degree to which the compounds receptor complex activates the binding of GTP to G-proteins to which the receptors are coupled. In the GTP binding assay, GTP[y]*’S is combined with test compounds and membranes from HEK-293S cells expressing the cloned human opioid receptors or from homogenised rat and mouse brain. Agonists stimulate GTP[y]**S binding in these membranes. The ECso and Ema values of compounds are determined from dose-response curves. Right shifts of the dose response curve by the delta antagonist naltrindole are performed to verify that agonist activity is mediated through delta receptors. The Emax values were determined in relation to the standard & agonist SNC80, i.e., higher than 100% is a compound that have better efficacy than SNC80.

Procedure for rat brain GTP

Rat brain membranes are thawed at 37°C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPyS binding (50 mM Hepes, 20 mM NaOH,

100 mM NaCl, 1 mM EDTA, 5 mM MgCl, pH 7.4, Add fresh: 1 mM DTT, 0.1%

BSA ). 120pM GDP final is added membranes dilutions. The EC50 and Emax of compounds are evaluated from 10-point dose-response curves done in 300pl with the appropriate amount of membrane protein (20pg/well) and 100000-130000 dpm of GTPy™S per well (0.11 -0.14nM). The basal and maximal stimulated binding are determined in absence and presence of 3 pM SNC-80

Data analysis

The specific binding (SB) was calculated as TB-NS, and the SB in the presence of various test compounds was expressed as percentage of control SB.

Values of ICs and Hill coefficient (ny) for ligands in displacing specifically bound radioligand were calculated from logit plots or curve fitting programs such as Ligand,

GraphPad Prism, SigmaPlot, or ReceptorFit. Values of K; were calculated from the

Cheng-Prussoff equation. Mean = S.E.M. values of ICso, K; and ny were reported for ligands tested in at least three displacement curves.

Based on the above testing protocols, we find that the compounds of the present invention are active toward human 5 receptors. Generally, the ICso towards human & receptor for most compounds of the present invention is in the range of 0.48 nM — 17.9 nM. The ECs and %Emax towards human § receptor for these compounds are generally in the range of 18.6 nM -1724 nM and 65 ~ 108, respectively. The ICs towards human k and p receptors for the compounds of the invention is generally in the ranges of 1317 nM- 9739 nM and 261 nM — 9774 nM, respectively.

Receptor Saturation Experiments

Radioligand Kg values are determined by performing the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated Kg (up to 10 times if amounts of radioligand required are feasible). The specific radioligand binding is expressed as pmole/mg membrane protein. Values of K5 and Bmax from individual experiments are obtained from nonlinear fits of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site model.

Determination Of Mechano-Allodynia Using Von Fre Testin

Testing is performed between 08:00 and 16:00h using the method described by Chaplan et al. (1994). Rats are placed in Plexiglas cages on top of a wire mesh bottom which allows access to the paw, and are left to habituate for 10-15 min. The area tested is the mid-plantar left hind paw, avoiding the less sensitive foot pads. The paw is touched with a series of 8 Von Frey hairs with logarithmically incremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 grams; Stoelting, Ill,

USA). The von Frey hair is applied from underneath the mesh floor perpendicular to the plantar surface with sufficient force to cause a slight buckling against the paw, and held for approximately 6-8 seconds. A positive response is noted if the paw is sharply withdrawn. Flinching immediately upon removal of the hair is also considered a positive response. Ambulation is considered an ambiguous response, and in such cases the stimulus is repeated.

Testing Protocol

The animals are tested on postoperative day 1 for the FCA-treated group. The 50% withdrawal threshold is determined using the up-down method of Dixon (1980).

Testing is started with the 2.04 g hair, in the middle of the series. Stimuli are always presented in a consecutive way, whether ascending or descending. In the absence of a paw withdrawal response to the initially selected hair, a stronger stimulus is presented; in the event of paw withdrawal, the next weaker stimulus is chosen.

Optimal threshold calculation by this method requires 6 responses in the immediate vicinity of the 50% threshold, and counting of these 6 responses begins when the first change in response occurs, e.g. the threshold is first crossed. In cases where thresholds fall outside the range of stimuli, values of 15.14 (normal sensitivity) or

0.41 (maximally allodynic) are respectively assigned. The resulting pattern of positive and negative responses is tabulated using the convention, X = no withdrawal; O = withdrawal, and the 50% withdrawal threshold is interpolated using the formula: 50% g threshold = 10%¢*¥%/ 10,000 where Xf= value of the last von Frey hair used (log units); k = tabular value (from

Chaplan et al. (1994)) for the pattern of positive / negative responses; and 8 = mean difference between stimuli (log units). Here 8 = 0.224.

Von Frey thresholds are converted to percent of maximum possible effect (%

MPE), according to Chaplan et al. 1994. The following equation is used to compute %MPE: 9% MPE = Drug treated threshold (g) - allodynia threshold (g) X 100

Control threshold (g) - allodynia threshold (g)

Administration Of Test Substance

Rats are injected (subcutaneously, intraperitoneally, intravenously or orally) with a test substance prior to von Frey testing, the time between administration of test compound and the von Frey test varies depending upon the nature of the test compound.

Writhing Test

Acetic acid will bring abdominal contractions when administered intraperitoneally in mice. These will then extend their body in a typical pattern. When analgesic drugs are administered, this described movement is less frequently observed and the drug selected as a potential good candidate.

A complete and typical Writhing reflex is considered only when the following elements are present: the animal is not in movement; the lower back is slightly depressed; the plantar aspect of both paws is observable. In this assay, compounds of the present invention demonstrate significant inhibition of writhing responses after oral dosing of 1-100 umol/kg. (i) Solutions preparation

Acetic acid (AcOH): 120 pL of Acetic Acid is added to 19.88 ml of distilled water in order to obtain a final volume of 20 ml with a final concentration of 0.6% AcOH. The solution is then mixed (vortex) and ready for injection.

Compound (drug): Each compound is prepared and dissolved in the most suitable vehicle according to standard procedures. (ii) Solutions administration

The compound (drug) is administered orally, intraperitoneally (i.p.) , subcutaneously (s.c.) or intravenously (i.v.)) at 10 ml/kg (considering the average mice body weight) 20, 30 or 40 minutes (according to the class of compound and its characteristics) prior to testing. When the compound is delivered centrally:

Intraventricularly (i.c.v.) or intrathecally (it.) a volume of 5 pL is administered.

The AcOH is administered intraperitoneally (i.p.) in two sites at 10 mbkg (considering the average mice body weight) immediately prior to testing. (iii) Testing

The animal (mouse) is observed for a period of 20 minutes and the number of occasions (Writhing reflex) noted and compiled at the end of the experiment. Mice are kept in individual “shoe box” cages with contact bedding. A total of 4 mice are usually observed at the same time: one control and three doses of drug.

For the anxiety and anxiety-like indications, efficacy has been established in the geller-seifter conflict test in the rat.

For the functional gastrointestina disorder indication, efficacy can be established in the assay described by Coutinho SV et al, in American Journal of

Physiology - Gastrointestinal & Liver Physiology. 282(2):G307-16, 2002 Feb, in the rat.

ADDITIONAL IN VIVO TESTING PROTOCOLS

Subjects and housing

Naive male Sprague Dawley rats (175-200g) are housed in groups ofSina temperature controlled room (22°C, 40-70% humidity, 12-h light/dark). Experiments are performed during the light phase of the cycle. Animals have food and water ad libitum and are sacrificed immediately after data acquisition.

Sample

Compound (Drug) testing includes groups of rats that do not receive any treatment and others that are treated with E. coli lipopolysaccharide(LPS). For the

LPS-treated experiment, four groups are injected with LPS, one of the four groups is then vehicle-treated whilst the other three groups are injected with the drug and its vehicle. A second set of experiments are conducted involving five groups of rats; all of which receive no LPS treatment. The naive group receives no compound (drug) or vehicle; the other four groups are treated with vehicle with or without drug. These are performed to determine anxiolytic or sedative effects of drugs which can contribute to a reduction in USV.

Administration of LPS

Rats are allowed to habituate in the experimental laboratory for 15-20 min prior to treatment. Inflammation is induced by administration of LPS (endotoxin of gram-negative E. coli bacteria serotype 0111:B4, Sigma). LPS (2.4ug) is injected intracerebro-ventricularly (i.c.v.), in a volume of 10pl, using standard stereotaxic surgical techniques under isoflurane anaesthesia. The skin between the ears is pushed rostrally and a longitudinal incision of about lcm is made to expose the skull surface.

The puncture site is determined by the coordinates: 0.8 mm posterior to the bregma, 1.5 mm lateral (left) to the lambda (sagittal suture), and 5 mm below the surface of the skull (vertical) in the lateral ventricle. LPS is injected via a sterile stainless steel needle (26-G 3/8) of 5 mm long attached to a 100-u1 Hamilton syringe by polyethylene tubing (PE20; 10-15 cm). A 4 mm stopper made from a cut needle (20-

G)is placed over and secured to the 26-G needle by silicone glue to create the desired 5mm depth.

Following the injection of LPS, the needle remains in place for an additional 10 s to allow diffusion of the compound, then is removed. The incision is closed, and the rat is returned to its original cage and allowed to rest for a minimum of 3.5h prior to testing.

Experimental setup for air-puff stimulation

The rats remains in the experimental laboratory following LPS injection and compound (drug) administration. At the time of testing all rats are removed and placed outside the laboratory. One ratata time is brought into the testing laboratory and placed in a clear box (9 x9 x 18 cm) which is then placed in 2 sound-attenuating ventilated cubicle measuring 62(w) x35(d) x46(h) cm (BRS/LVE, Div. Tech-Serv

Inc). The delivery of air-puffs, through an air output nozzle of 0.32 cm, is controlled by a system (AirStim, San Diego Intruments) capable of delivering puffs of air of fixed duration (0.2 s) and fixed intensity with a frequency of 1 puff per 10s. A maximun of 10 puffs are administered, or until vocalisation starts, which ever comes first. The first air puff marks the start of recording.

Experimental setup for and ultrasound recording

The vocalisations are recorded for 10 minutes using microphones (G.R.A.S. sound and vibrations, Vedbaek, Denmark) placed inside each cubicle and controlled by LMS (LMS CADA-X 3.5B, Data Acquisition Monitor, Troy, Michigan) software.

The frequencies between 0 and 32000Hz are recorded, saved and analysed by the same software (LMS CADA-X 3.5B, Time Data Processing Monitor and UPA (User

Programming and Analysis).

Compounds (Drugs)

All compounds (drugs) are pH-adjusted between 6.5 and 7.5 and administered at a volume of 4 mlkg. Following compound (drug) administration, animals are returned to their original cages until time of testing.

Analysis

The recording is run through a series of statistical and Fourier analyses to filter (between 20-24kHz) and to calculate the parameters of interest. The data are expressed as the mean + SEM. Statistical significance is assessed using 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 effectiveness. A difference between groups is considered significant with a minimum p value of <0.05.

Experiments are repeated a minimum of two times.

EXAMPLES

The invention will further be described in more detail by the following

Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention.

INTERMEDIATE 1

A mixture of 4-(bromomethyl)benzoic acid, methyl ester (1 1.2 g, 49 mmol) and trimethyl phosphite (25 mL) was refluxed under N, for 5 hrs. Excess trimethyl phosphite was removed by co-distillation with toluene to give INTERMEDIATE 1 in quantitative yield. "HNMR (CDCls) § 3.20 (d, 2H, J=22 Hz, CH), 3.68 (d, 3H 10.8

Hz, OCHs), 3.78 (d, 3H, 11.2 Hz, OCH3), 3.91 (s, 3H, OCHj), 7.38 (m, 2H, Ar-H), 8.00 (d, 2H, J=8 Hz, Ar-H). :

INTERMEDIATE 2: 4-(4-Methoxycarbonyl-benzylidene)-piperidine-1- carboxylic acid tert-butyl ester :

To a solution of INTERMEDIATE 1 in dry THF (200 mL) was added } dropwise lithium diisopropylamide (32.7 mL 1.5 M in hexanes, 49 mmol) at -78 °C.

The reaction mixture was then allowed to warm to room temperature prior to addition of N-tert-butoxycarbonyl-4-piperidone (9.76 g, 49 mmol in 100 mL dry THF). After 12 hrs, the reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were dried over MgSO, and evaporated to give a crude product, which was purified by flash chromatography to provide INTERMEDIATE 2 as a white solid (5.64 g, 35%). IR (NaCl) 3424, 2974, 2855, 1718, 1 688, 1606, 1427, 1362, 1276 cm™'; "HNMR (CDCl) 3 1.44 (s, 9H), 2.31 (t J=5.5 Hz, 2H), 2.42 (t, ]=5.5 Hz, 2H), 3.37 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5

Hz, 2H), 3.87 (s, 3H, OCH), 6.33 (s, 1H, CH), 7.20 (d J=6.7 Hz, 2H, Ar-H), 7.94 (d, 1,=6.7 Hz, 2H, Ar-H); "C NMR (CDCls) 8 28.3, 29.2, 36.19, 51.9, 123.7, 127.8, 128.7, 129.4, 140.5, 142.1, 154.6, 166.8.

INTERMEDIATE 3: 4-Bromo-4-[bromo-(4-methoxvearbonyl-phenyl)-methyl}- piperidine-1-carboxvylic acid tert-butyl ester

To a mixture of INTERMEDIATE 2 (5.2 g, 16 mmol) and K2COs 1.0g)in dry dichloromethane (200 mL) was added a solution of bromine (2.9 g, 18 mmol) in 30 mL CH,Cl, at 0 °C. after 1.5 hrs at room temperature, the solution after filtration of K,CO; was condensed. The residue was then dissolved in ethyl acetate (200 mL), washed with water (200 mL), 0.5 M HC1 (200 mL) and brine (200 mL), and dried over MgSO;4. Removal of solvents provided a crude product, which was recrystallized from methanol to give INTERMEDIATE 3 as a white solid (6.07 g, 78%). IR (NaCl) 3425, 2969, 1725, 1669, 1426, 1365, 1279, 1243 cm’; "HNMR (CDCls) & 1.28 (s, 9H), 1.75 (m, 1H), 1.90 (m, 1H), 2.1 (m, 2H), 3.08 (br, 2H), 3.90 (s, 3H, OCH3), 4.08 (br, 3H), 7.57 (d, J=8.4 Hz, 2H, Ar-H) 7.98 (d, J=8.4 Hz, 2H, Ar-

H); 13C NMR (CDCl) § 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: 4-[bromo-(4-carboxy-phenyl )-methylene]-piperidine-1- carboxylic acid tert-butyl ester

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 hrs. The solid was collected by filtration, and dried overnight under vacuum. The dry salt was dissolved in 40% acetonitrile/water, and was adjusted to pH 2 using concentrated HCI.

INTERMEDIATE 4 (3.8 g, 87%) was isolated as a white powder by filtration. 'H

NMR (CDCl3) 8 1.45 (s, 9H, 'Bu), 2.22 (dd, J=5.5 Hz, 6.1 Hz, 2H), 2.64 (dd, J=5.5

Hz, 6.1 Hz, 2H), 3.34 (dd, J=5.5 Hz, 6.1 Hz, 2H), 3.54 (dd, J=5.5 Hz, 6.1 Hz, 2H), 7.35 (d, J=6.7 Hz, 2H, Ar-H), 8.08 (d, J=6.7 Hz, 2H, Ar-H); BC NMR (CDCl3) 8 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: 4 [bromo-(4-diethylcarbamoyl-phenyl)-methylene]- piperidine-1-carboxvlic acid tert-butyl ester : "To a solution of INTERMEDIATE 4 (1.0 g, 2.5 mmol) in dry dichloromethane (10 mL) at - 20 °C was added isobutylchloroformate (450 mg, 3.3 mmol). After 20 min at -20 °C diethylamine (4 mL) was added and the reaction was allowed to warm to room temperature. After 1.5 hrs the solvents were evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSQOs. Removal of solvents provided a crude product, which was purified by flash chromatography to give INTERMEDIATE 5 as white needles (800 mg, 73%). IR (NaCl) 3051, 2975, 1694, 1633, 1416, 1281, 1168, 1115 om™; "HNMR (CDCl) § 1.13 (br, 3H, CH3), 1.22 (br, 3H, CHa), 1.44 (s, SH, . 'Bu), 2.22 (t, J=5.5 Hz, 2H), 2.62 (t, J=5.5 Hz, 2H), 3.33 (m, 4H), 3.55 (m, 4H), 7.31 (d, J=8.0 Hz, 2H, Ar-H), 7.36 (d, J=8.0 Hz, 2H, Ar-H); ®C NMR (CDCl) 8 12.71, 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.

Claims (30)

1. A compound of formula JA, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof: oO 2 RAYE Rr LR \ R' IA wherein R! is selected from hydrogen, Cy.alkyl-O-C(=0)-, Cy.calkyl, Cascycloalkyl,

Ce. 10aryl, Ca.sheterocyclyl, Cg.joaryl-Cj.zalkyl and Ca.oheterocyclyl-Ci.salkyl; wherein said C.ealkyl, Cascycloalkyl, Ce 10aryl, Cosheteracyelyl, Ce.10aryl-Ciaalkyl and Co. sheterocyclyl-C;.salkyl are optionally substituted with one or more groups selected from -R, -NO,, -OR, -Cl, -Br, -1, -F, -CF3, -C(=O)R, -C(=0)OH, -NH;, -SH, -NHR, -NR,, -SR, -SO3H, -SO4R, -S(=0)R, -CN, -OH, -C(=O)OR, -C(=O)NRg, - NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or

Ci.salkyl; R?% R? and Rare, independently, selected from hydrogen, Cialkyl, and

Cs.scycloalkyl, wherein said Cy.salkyl and Ca scycloalkyl are optionally substituted with one or more groups selected from -R, -NO, -OR, -C}, -Br, -1, -F, -CF;, -C(=O)R, -C(=0)OH, -NHa, -SH, -NHR, -NRy, -SR, -SO;3H, -SO2R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=0)NR;, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or C.alkyl; and R is selected from —H, -OH, C,.¢alkyl, Cs-scycloalkyl, Ce-i0aryl,

C.cheterocyclyl, Cs 10aryl-Cisalkyl, C;oheterocyclyl-Ci.galky], -C(=0)-NR*R’,

-C(=0)-0-R?, ~S(=0)-R%, ~S(=0),-R?, -C(=0)-R® and -SO3H, wherein R® and R® are independently selected from —H, Ciealkyl, Cs seycloalkyl, Ce-icaryl, Ca.gheterocyclyl,

Ce.10aryl-C.galkyl, and Ca.sheterocyclyl-Cyealkyl, wherein said Csalkyl, Cagcycloalkyl, Ce.10aryl, Co sheterocyclyl, Ce.10aryl-C alkyl, and Cy.gheterocyclyl- Cisalkyl used in defining R”, R® or R? are optionally substituted with one or more groups selected from -R, -NOy, -OR, -Cl, -Br, -1, -F, -CF3, -C(=O)R, -C(=0)OH, “NH, -SH, -NHR, -NR;, -SR, -SO;H, -SO:R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=O0)NR;, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Cj.salkyl.

2. A compound according to claim 1, wherein R! is selected from hydrogen, C;6alky!-O-C(=0)-, Cisalkyl, Ca. scycloalkyl, benzyl and C,.sheteroarylmethyl, wherein said C1salkyl, Csgcycloalkyl, benzyl and C,.sheteroarylmethyl are optionally substituted with one or more groups selected from Cyalkyl, halogenated Cy.¢alkyl, -CF3, Ci.s alkoxy, chloro, fluoro, bromo, and iodo; R? and R? are ethyl; R* is selected from hydrogen and C,.3alkyl; R’ is selected from —H, -OH, phenyl, Cs sheterocyclyl, phenyl-C,._salkyl,

Cs.sheterocyclyl-Cy.aalkyl, Ciealkyl, Cs.rcycloatkyl, Cacycloalkyl-Crosalkyl, -C(=0)-N-RPR’, ~C(=0)-0-R?, -S(=0)-R%, ~S(=0);-R®, -C(=0)-R® and -SO:H, wherein R® and R? are independently selected from —H, phenyl, C.sheterocyclyl, phenyl-C.3alkyl, Cs.sheterocyclyl-Cy.;alkyl, Cysalkyl, Cs.xcycloalkyl, Ca.scycloalkyl-

C.1.salkyl, wherein said phenyl, Cs.sheterocyclyl, phenyl-Ci.salkyl, Cs.sheterocyclyl- Chsalkyl, Cpealkyl, Cs.cycloalkyl, Cs.ocycloalkyl-C.salkyl used in defining R’, RS and R® are optionally substituted with one or more groups selected from C,.salkyl, halogenated C.salkyl, -CF3, C1 alkoxy, chloro, fluoro, bromo, and iodo.

3. A compound according to claim 1,

wherein R. is selected from hydrogen, Cy.salky!-0-C(=0)-, Cigalkyl, Ca. scycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pytrolylmethyl, thiazolylmethyl and N-oxido- pyridylmethyl, wherein said C,.¢alkyl, Cs.scycloalkyl, benzyl, thiadiazolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, triazolylmethyl, pyrrolylmethyl, thiazolylmethyl and N-oxido-pyridylmethyl are optionally substituted with one or more groups selected from Ci<alkyl, halogenated C¢alkyl, -CF3, Cis alkoxy, chloro, fluoro, bromo, and iodo; R? and R® are ethyl; R* is selected from hydrogen and methyl; R’ is selected from —H, Ci.alkyl, phenyl-Cy-salkyl, Cs. cycloalkyl-Craalkyl, Csscycloalkyl, phenyl, Crsalkyl, -C(=0)-N-R*R®, -S(=0)R’, -C(=0)-0-R®%, and -C(=0)-R®, wherein R® and R® are independantly selected from -H, phenyl-C.salkyl,

Cj.rcycloalkyl-Ci.alkyl, Cs.seycloalkyl, phenyl, and Ci.salkyl, wherein said phenyl- Cisalkkyl, C3 scycloakkyl-Cisalkyl, Cs.rcycloalkyl, phenyl, C.<alky! used in defining R’, R® and R’ are optionally substituted with one or more groups selected from Ci-salkyl, halogenated Ci¢alkyl, -CF3, Ci alkoxy, chloro, fluoro, bromo, and iodo.

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-oxido-pyridylmethyl; R? and R? are ethyl; R* is selected from hydrogen and methyl; R” is selected from —H, ethyl, phenyl, benzyl or phenethyl, napthyl, fluorophenyl, chlorophenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexylmethyl, -C(=0)-NH-R?, -S(=0)-R?, -C(=0)-0-R’, and -C(=0)-R’, wherein R® is selected from methyl, 2,2 2-trifluorcethyl, phenyl, benzyl, phenethyl, methylphenyl, fluorophenyl, butyl, cyclohexyl and cyclohexylmethyl.

5. A compound according to claim 1, wherein the compound is selected from: COMPOUND 1: A-[[2-(benzoylamino)phenyl]-4-piperidinylidenemethyl]-N,N- diethylbenzamide; COMPOUND 2: N-[2-{[4-[(diethylamino)carbonyl]phenyl]-4- piperidinylidenemethyl]phenyl]benzeneacetamide; COMPOUND 3: 4-[[2-[(cyclohexylcarbonyl)amino]phenyl]-4- piperidinylidenemethyl)-N,N-diethylbenzamide; COMPOUND 4: N-[2-[[4-[(diethylamino)carbonyl]phenyl]-4- piperidinylidenemethyljphenyl]benzenepropanamide; COMPOUND 5: 4-[[2-[(cyclohexylacetyamino]phenyl]-4-piperidinylidenemethyl]- N N-diethylbenzamide; COMPOUND 6: N.N-diethyl-4-[[2-[(2-phenylethyDamino]phenyl]-4- piperidinylidenemethyi}benzamide; COMPOUND 7: 4-{[2-[(cyclohexylmethyl)amino]phenyl]-4- piperidinylidenemethy!]-N,N-diethylbenzamide; COMPOUND 8: N.N-diethyl-4-[[2-[(phenylmethyl)amino]phenyl]-4- piperidinylidenemethyl]-benzamide; COMPOUND 9: 4-{[2-(cyclohexylamino)phenyl}-4-piperidinylidenemethyl}-N.N- diethylbenzamide; COMPOUND 10: N.N-diethyl-4-{[2-{[(phenylamino)carbonyllamino]phenyl]-4- piperidinylidenemethyi}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-[(phenylsulfonyl)amino]phenyI}-4- piperidinylidenemethyl]benzamide;

COMPOUND 14: N.N-diethyl-4-[[2-[[(phenylmethyDsulfonylJamino]phenyl}-4- piperidinylidenemethyl]benzamide; COMPOUND 15: N,N-Diethyl-4-[4-piperidinylidene[2-{[(2,2,2- trifluoroethyl)sulfonyl]amino]phenyljmethylJbenzamide; COMPOUND 16: A-{{2-[(cyclopentylacetylamino]pheny} (piperidin-4- ylidene)methyl]-N,N-diethylbenzamide; COMPOUND 17: 4-[{2-{(cyclopentylcarbonylyamino]phenyl} (piperidin-4- ylidene)methyl}-N,N-diethylbenzamide; COMPOUND 18: N.N-diethyl-4-[{2-[(3-phenylpropyDaminc]phenyl}(piperidin-4- ylidene)methylJbenzamide; COMPOUND 19: 4-[{2-[(2-cyclohexylethyDamino]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)carbonyljamino}phenyl)(piperidin-4- ylidene)methyl]-N,N-diethylbenzamide; COMPOUND 23: N.N-diethyl-4-[[2-(1-naphthylamino)phenyl](piperidin-4- ylidene)methyljbenzamide; COMPOUND 24: N.N-diethyl-4-[{2-[(3-flucrophenyl)amino]phenyl} (piperidin-4- ylidene)methyl]benzamide; COMPOUND 25: 4-[{2-[(4-chlorophenyl)amino]phenyl}(piperidin-4- ylidene)methy!]-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)sulfonyllamino}phenyl)(piperidin-4-ylidene)methylIbenzamide;

COMPOUND 28: N,N-diethyl-4-[(2-{{(2- fluorophenyDsulfonyljamino}phenyl)(piperidin-4-ylidene)methyljbenzamide; COMPOUND 29: 4-{{2-{(butylsulfonyaminoJpheny!} (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)carbonyljphenyl} (piperidin-4- ylidene)methyl]phenylcarbamate; COMPOUND 30: 4-[(2-aminophenyl)(1-benzylpiperidin-4-ylidene)methyl]-N,N- diethylbenzamide; COMPOUND 33: 4{[2-(acetylamino)pheny!}(1-benzylpiperidin-4-ylidene)methyl)- N,N-diethylbenzamide; COMPOUND 34: methyl 2-((1-benzylpiperidin-4-ylidene) {4- [(diethylamino)carbonyljphenyl}methyl)phenylcarbamate; COMPOUND 35: 4-{(2-aminophenyD[1-(1,3-thiazol-4-ylmethyl)piperidin-4- ylidene]methyl}-N N-diethylbenzamide; COMPOUND 36: 4-{(2-aminopheny!)[1-(1,3-thiazol-5-ylmethyl)piperidin-4- ylidene]methy1}-N N-diethylbenzamide; COMPOUND 37: 4-{[2-(acetylamino)phenyl][1-(1,3-thiazol-4-ylmethyl)piperidin-4- ylidene]methyl}-N,N-diethylbenzamide; COMPOUND 38: methyl 2-{{4-[(diethylamino)carbonyl]phenyl}[1-(1 ,3-thiazol-4- ylmethyl)piperidin-4-ylidene)methyl}phenylcarbamate; COMPOUND 39: 4-{[2-(acetylamino)phenyl][1 ~(1,3-thiazol-5-ylmethyl)piperidin-4- ylidene]methyl}-N,N-diethylbenzamide; COMPOUND 40: methyl 2-{{4-[(diethylamino)carbonylJphenyl}[1-(1,3-thiazol-5- ylmethyl)piperidin-4-ylidene]methyl}phenylcarbamate; ’ COMPOUND 41: 4-[(2-aminophenyl)(1-butylpiperidin-4-ylidene)methyl}-N,N- diethyl! benzamide;

COMPOUND 42: A-{(2-aminophenyD)[1-(pyridin-4-ylmethyl)piperidin-4- ylidene]methyl}-N N-diethylbenzamide; COMPOUND 43: 4-{(2-aminopheny})[1-(pyridin-3-ylmethyl)piperidin-4- ylidene}methyl}-N,N-diethylbenzamide; COMPOUND 44: 4-{(2-aminophenyl)[1-(pyridin-2-ylmethyDpiperidin-4- ylidene]methyl} -N,N-diethylbenzamide; COMPOUND 45: 4-{[2-(acetylamino)phenyl][1-(pyridin-4-ylmethyl)piperidin-4- ylidene]methy1}-N,N-diethylbenzamide; COMPOUND 46: 4-{[2-(acetylamino)phenyl][1-(pyridin-3-yimethyl)piperidin-4- ylidene]methyl}-N,N-diethylbenzamide; 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-diethylbenzamide; COMPOUND 49: methyl [2-((1-butylpiperidin-4-ylidene) {4[(diethylamino)carbonyl]phenyl}methyl)phenyl]carbamate; COMPOUND 50: methyl (2-{ {4-[(diethylamino)carbonyljphenyl} [1-(pyridin-4- yimethyl)piperidin-4-ylideneJmethyl}phenyl)carbamate; COMPOUND 51: methyl (2-{ {4-[(diethylamino)carbonyl]pheny1}[1-(pyridin-3- yImethyl)piperidin-4-ylidene]methy! }phenyl)carbamate; COMPOUND 52: methyl (2-{{4-[(diethylamino)carbonyl]pheny1}[1-(pyridin-2- ylmethyl)piperidin-4-ylidene]methyl} phenyl)carbamate; COMPOUND 53: 4-{(1-butylpiperidin-4-ylidene)[2-(ethylamino)phenylJmethy1}- N,N-diethylbenzamide; COMPOUND 54: N,N-diethyl-4- {[2-(ethylamino)phenyl][1-(pyridin-4- ylmethyl)piperidin-4-ylidene]methyl} benzamide; COMPOUND 55: N,N-diethyl-4-{[2-(ethylamino)pheny!][1-(pyridin-3- ylmethyl)piperidin-4-ylidene]methyl } benzamide;

PCT/GB2004/002074 COMPOUND 56: N,N-diethyl-4- {[2-(ethylamino)phenyl]{1-(pyridine-2- ylmethyl)piperidin-4-ylidene]methyl } benzamide; : and pharmaceutically acceptable salts thereof.

6. A compound according to any one of claims 1-5 for use as a medicament.

7. The use of a compound according to any one of claims 1-5 in the manufacture of a medicament for the therapy 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 substance or composition for use in a method for the therapy of pain in a warm-blooded animal, said substance or composition comprising a compound according to any one of claims 1-5, and said method comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of said substance or composition.

10. A substance or composition for use in a method for the therapy of functional gastrointestinal disorders in a warm-blooded animal, said substance or composition comprising a compound according to any one of claims 1-5, and said method comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of said substance or composition.

11. A process for preparing a compound of formula IIA, comprising: AMENDED SHEET

Oo ZN ® 4 Lm R’ N or A reacting a compound of formula ITA with R>-CH;-X or R>-CHO: Q : SAYS

HN. R’ N H MA wherein X is a halogen; Ris selected from —C(=0)-O-R%, —S(=0)-R’, —S(=0);-R’, and -C(=0)-R%, wherein R® is selected from Ci.salkyl, Cascycloalkyl, Ce.10aryl, C,.sheterocyclyl, Ceoaryl-Cirealkyl, and C,.oheterocyclyl-Cy-salkyl, wherein said Calkyl, Cs seycloalkyl, Ceiearyl, Casheterocyclyl, Ce10aryl-Cy.¢alkyl, and Ca.oheterocyclyl- Calkyl are optionally substituted with one or more groups selected from -R, -NO, - OR, -Cl, -Br, -I, -F, -CF3, -C(=O)R, -C(=0)OH, -NHz, -SH, -NHR, -NR3, -SR, - SO;H, -SO3R, -S(=0)R, -CN, -OH, -C(=O)OR, -C(=O)NR;, -NRC(=O)R, and - NRC(=0)-OR, wherein R is, independently, a hydrogen or Ci6alkyl; and

RS is selected from Ceoaryl and Ca.sheteroaryl, wherein said Ce 10aryl and Ca. sheteroary are optionally substituted with one or more groups selected from -R, -NO2, -OR, -C}, -Br, -1, -F, -CF3, -C(FO)R, -C(=0)OH, -NHa, -SH, -NHR, NR, -SR, - SO;H, -SO:R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=O)NR2, NRC(=O)R, and - NRC(=0)-OR, wherein Rs, independently, a hydrogen or Ci¢alkyl.

12. A process for preparing a compound of formula ITA, comprising: oO SAYS le Rr’ J R® IIA reacting a compound of formula IVA with R’-X or R’-O-R": 0 SAVE [ m, N B IVA wherein X is a halogen;

Ris selected from —C(=0)-0-R® and -C(=0)-R%, wherein R® is selected from

C..¢alkyl, Ca.gcycloalkyl, Ce-10aryl, Casheterocyclyl, Ce 10aryl-Cr.6alkyl, and Co. sheterocyclyl-Ci.ealkyl, wherein said Cy.¢alkyl, Ca.scycloalkyl, Ce10aryl, Ca sheterocyclyl, Cg. 10aryl-Ciealkyl, and Ca.sheterocyclyl-Cisalkyl are optionally substituted with one or more groups selected from -R, -NO, -OR, -Cl, -Br, -, -F, CF, -C(=O)R, -C(=0)OH, -NHy, -SH, -NHR, -NR3, -SR, -SOsH, -SO:R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR,, NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Ci.¢alkyl; and RS is selected from Ce.j0aryl and Ca.sheteroaryl, wherein said Ce 10aryl and Casheteroaryl are optionally substituted with one or more groups selected from -R, NOs, -OR, -C}, -Br, 1, -F, -CF3, -C(=O)R, -C(=0)0H, -NH;, -SH, -NHR, -NRy, -SR, -SO3H, -SO4R, -S(=0)R, -CN, -OH, -C(=O)OR, -C(=O)NRg, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Cisalkyl.

13. A process of preparing a compound of formula VA, 0] RZ ny Rr NH, N g R VA comprising reducing a compound of formula VIA,

oO R2 ) Rr No, N iY VIA wherein R! is selected from hydrogen, C1.6alkyl-0-C(=0)-, Ci.calkyl, Cscycloalkyl, Ce caryl, Casheterocyclyl, Ce.10aryl-Ci.;alkyl and C,.oheterocyclyl-Cy.aalkyl; wherein said Csalkyl, Cs.¢cycloalkyl, Ces-10aryl, Casheterocyclyl, Ce-10aryl-Cyaalkyl and

C.sheterocyclyl-Cysalkyl are optionally substituted with one or more groups selected from -R, -NO3, -OR, -Cl, -Br, -I, -F, -CF3, -C(=O)R, -C(=0)OH, -NH,, -SH, -NHR, NR, -SR, -SO3H, -SO2R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=O)NR;, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Cisalkyl; and R? and R? are, independently, selected from hydrogen, Ci¢alkyl, and

C.¢cycloalkyl, wherein said C.alkyl and Cs.geycloalkyl are optionally substituted with one or more groups selected from -R, NO, -OR, -Cl, -Br, -1, -F, -CF3, -C(=0)R, -C(=0)OH, -NH,, -SH, -NHR, -NRy, -SR, -SO;H, -SO4R, -S(=O)R, -CN, -OH, -C(=0)OR, -C(=O)NR;, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Ci.salkyl.

14. A compound of formula I, a pharmaceutically acceptable salt thereof, diasteromers, enantiomers, or mixtures thereof:

0] Rs Ron “ Re fe I Rr I wherein R! is selected from hydrogen, Ci.salkyl-O-C(=0)-, optionally substituted Cy. alkyl, optionally substituted Cacycloalkyl, optionally substituted Ce-10aryl, optionally substituted Ca.sheterocyclyl, optionally substituted Ce.10aryl-Cy.3alkyl and optionally substituted Caoheterocyclyl-Ci.aalkyl; nis0,1or2;mis0, 1, or 2; R% R*and R* are, independently, selected from hydrogen, optionally substituted C;.calkyl and optionally substituted Cs.cycloalkyl; RS and RS are, independently, selected from -R, -NO, -OR, -Cl, -Br, -1, -F, -CF3, -C(=O)R, -C(=0)OH, -NH;, -SH, -NHR, -NR, -SR, -SO3H, -SO:R, -S(=O)R, CN, -OH, -C(=0)O0R, -C(=0)NRz, -NRC(=O)R, and -NRC(=0)-OR, wherein R is, independently, a hydrogen or Cy.¢alkyl; and R is selected from —H, -OH, optionally substituted C,¢alkyl, optionally substituted Cs.gcycloalkyl, optionally substituted Ce.10aryl, optionally substituted

C,.sheterocyclyl, optionally substituted Ce.10aryl-Cy alkyl, optionally substituted

Ca.sheterocyclyl-Cyalkyl, -C(=0)-NR°R’, _C(=0)-0-R%, -§(=0)-R%, -S(=0)-R?, -C(=0)-R® and -SO;H, wherein R® and R® are independently selected from —H, optionally substituted C;.salkyl, optionally substituted Ca.gcycloalkyl, optionally substituted Cg.i0aryl, optionally substituted C;.sheterocyclyl, optionally substituted

Ce.10aryl-Ci.¢alkyl, and optionally substituted C gheterocyclyl-Ci.¢alkyl.

15. A compound according to claim 14, wherein R! is selected from hydrogen, C;.alkyl-O-C(=O)-, optionally substituted C;alkyl, and optionally substituted C;scycloalkyl; R? and R? are ethyl; R* is selected from hydrogen and C.;alkyl; R’ is selected from —H, -OH, optionally substituted phenyl, optionally substituted Cs.sheterocyclyl, optionally substituted phenyl-C;.salkyl, optionally substituted Cs.sheterocyclyl-C;.alkyl, optionally substituted Cysalkyl, optionally substituted Cs.4cycloalkyl, optionally substituted Csscycloalkyl-Craalkyl, -C(=0)-N- R®R®, -C(=0)-0-R?, -S(=0)-R®, —S(=0),-R?, -C(=0)-R® and -SO;H, wherein R® and R? are independently selected from —H, optionally substituted phenyl, optionally substituted Cs sheterocyclyl, optionally substituted phenyl-C;.;alkyl, optionally substituted Cs_sheterocyclyl-Ci.3alkyl, optionally substituted C_salkyl, optionally substituted Cs.¢cycloalkyl, optionally substituted Cs.scycloalkyl-C)_salkyl; and n and m are 0.

16. A compound according to claim 14, wherein R' is selected from hydrogen and C).¢alkyl-O-C(=0)-; R? and R® are ethyl; R* is selected from hydrogen and methyl; R’ is selected from —H, phenyl-Cy.3alkyl, C3 ¢cycloalkyl-Ci_zalkyl, Cs. ecycloalkyl, phenyl, optionally substituted Cy.salkyl, ~C(=0)-N-R*R®, -S(=0),-R®, and -C(=0)-R®, wherein R® and R? are independantly selected from —H, pheny!-C;. salkyl, Cs.scycloalkyl-Ci.3alkyl, Ca¢cycloalkyl, phenyl, and optionally substituted C;. salkyl; and n and m are 0,

17. A compound according to claim 14, wherein R! is hydrogen; R? and R? are ethyl; RY is selected from hydrogen and methyl; R’ is selected from —H, phenyl, benzyl or phenethyl, cyclohexyl, cyclohexylmethyl, -C(=0)-NH-R®, -S(=0)-R®, and -C(=0)-R®, wherein R® is selected from 2,2,2-trifluoroethyl, phenyl, benzyl or phenethyl, cyclohexyl and cyclohexylmethyl; and n and m are 0.

18. A process for preparing a compound of formula II, comprising: 0) R? R® \ R® : ng 0) \ R’ 14 reacting a compound of formula III with X'-C(=0)-R!°:

0] R2 Re R* \ R' m wherein R! is selected from C;.alkyl-O-C(=0)-, optionally substituted Ci.galkyl, optionally substituted Cs ¢cycloalkyl, optionally substituted phenyl, optionally substituted Ca.sheterocyclyl, optionally substituted phenyl-C;.3alkyl and optionally substituted Cs.sheterocyclyl-Ci.aalkyl; x! is selected from —OH, -OR"!, -0-C(=0)-R"!, Cl, -Br and -I, wherein R"' is Cisalkyl; RZ, R? and R! are, independently, selected from hydrogen, optionally substituted Cy_salkyl and optionally substituted Cz.¢cycloalkyl; and Ris selected from —H, optionally substituted phenyl, optionally substituted

Cs.sheterocyclyl, optionally substituted phenyl-C.;alkyl, optionally substituted

Cs.sheterocyclyl-Cy.3alkyl, optionally substituted Csalkyl, optionally substituted Cssecycloalkyl and optionally substituted Cs cycloalkyl-Cisalkyl.

19. A process for preparing a compound of formula IV, comprising:

0) R2 3 $ Re NR R'2 \ R' v reacting a compound of formula V with R2-C(=0)-R" : 0 R2 R> NH, \ 1 R y wherein R! is selected from Cy.alkyl-O-C(=0)-, optionally substituted Cy-salkyl, optionally substituted Cs.¢cycloalkyl, optionally substituted phenyl, optionally substituted Cs sheterocyclyl, optionally substituted phenyl-Cy.3alkyl and optionally substituted Cj.sheterocyclyl-Cj.salkyl; R? and R? are, independently, selected from hydrogen, optionally substituted

Ci.¢alkyl and optionally substituted Cs.scycloalkyl; and R'2 and R" are independently selected from —H, optionally substituted phenyl, optionally substituted Cs.sheterocyclyl, optionally substituted phenyl-C.salkyl,

optionally substituted C;.sheterocyclyl-C alkyl, optionally substituted Ciealkyl, optionally substituted Cs¢cycloalkyl and optionally substituted Cs.scycloalkyl-

Ci.;alkyl, or R'? and R'? together form a portion of a Ci.scycloalkyl ring ora

Ci.sheterocylcyl ring.

20. A process for preparing a compound of formula VI, comprising: 0) RZ oN a3 HN A hl SR" Oo ) R’ iA reacting a compound of formula V with RM.NCO: 0) 2 R Rr? Nw, \ R' y wherein R! is selected from C.galkyl-O-C(=0)-, optionally substituted C.calkyl, optionally substituted Cs.cycloalkyl, optionally substituted phenyl, optionally substituted Cs.sheterocyclyl, optionally substituted phenyl-Cy.3alkyl and optionally substituted Cs.sheterocyclyl-Ci.zalkyl; R? and R? are, independently, selected from hydrogen, optionally substituted

Ci.calkyl and optionally substituted Csccycloalkyl; and R' is selected from optionally substituted phenyl, optionally substituted Cj sheterocyclyl, optionally substituted phenyl-Cy.salkyl, optionally substituted Cs sheterocyclyl-Cy.salkyl, optionally substituted Ci.¢alkyl, optionally substituted

Ca.ccycloalkyl and optionally substituted Cs.scycloalkyl-C.aalkyl.

21. A process for preparing a compound of formula VII, comprising: 0] R SN LY N< 16 14R RS N 4 R AA! reacting a compound of formula VIII with RIX? : 0 R2 h RR NH R'S N R ,

yi wherein R! is selected from C)salkyl-O-C(=0)-, optionally substituted Cycalkyl, optionally substituted Cs¢cycloalkyl, optionally substituted phenyl, optionally substituted Cs.sheterocyclyl, optionally substituted phenyl-C,.3alkyl and optionally substituted Cs.sheterocyclyl-Cy.salkyl; R? and R? are, independently, selected from hydrogen, optionally substituted

Ci.salkyl and optionally substituted C3 scycloalkyl; X2 is selected from I, Br and Cl; RY" is selected from —H, optionally substituted phenyl, optionally substituted

Ca.sheterocyclyl, optionally substituted phenyl-Ci.3alkyl, optionally substituted

Cs.sheterocyclyl-Cisalkyl, optionally substituted Cj.salkyl, optionally substituted Ca¢cycloalkyl and optionally substituted Ca¢cycloalkyl-Ci.salkyl; and R'® is selected from optionally substituted phenyl-C_salkyl, optionally substituted C.sheterocyclyl, optionally substituted Cs_sheterocyclyl-Cy.zalkyl, optionally substituted C;.alkyl, optionally substituted Cs.scycloalkyl and optionally substituted Cj ¢cycloalkyl-Ci.salkyl.

22. A process for preparing a compound of formula IX, comprising: 0] 2 RAG N NTR" RT N 0) 4 R IX reacting a compound of formula III with X3-S(=0)-R"":

PCT/GB2004/002074 0 RZ oy R3 NH R* \ R' Jui wherein R! is selected from C;.¢alkyl-O-C(=0)-, optionally substituted Ci.alkyl, optionally substituted Cs.scycloalkyl, optionally substituted phenyl, optionally substituted Cj.sheterocyclyl, optionally substituted phenyl-C).;alkyl and optionally substituted Cs.sheterocyclyl-Ciaalkyl; X3 is selected from —OH, -ORY, -Cl, -Br and -1, wherein R'! is C,.6alkyl; R?, R® and R* are, independently, selected from hydrogen, optionally substituted Cy.¢alkyl and optionally substituted Ci.scycloalkyl; and R'7 is selected from —H, optionally substituted phenyl, optionally substituted Cssheterocyclyl, optionally substituted phenyl-C;_salkyl, optionally substituted

C.sheterocyclyl-C).aalkyl, optionally substituted C.salkyl, optionally substituted

Cs.scycloalkyl and optionally substituted Cs.¢cycloalkyl-Ci.jalkyl.

23. A method for alleviating pain in a warm-blooded animal, comprising the step of administering to said animal an effective amount of a compound according to any one of claims 1-5.

24. A compound according to any one of claims 1 to 6, or 14 to 17, substantially as herein described and illustrated.

25. Use according to claim 7, substantially as herein described and illustrated. AMENDED SHEET

PCT/GB2004/002074

26. A composition according to claim 8, substantially as herein described and illustrated.

27. A substance or composition for use in a method of treatment according to claim 6 or claim 9 or claim 10, substantially as herein described and illustrated.

28. A process according to any one of claims 11 to 13, or 18 to 22, substantially as herein described and illustrated.

29. A method according to claim 23, substantially as herein described and illustrated.

30. A new compound, a new use of a compound according to any of claims 1 to 5, anew composition, a new process for the preparation of a compound, a substance or composition for a new use in a method of treatment, or a new non-therapeutic method of treatment, substantially as herein described. AMENDED SHEET