Mammalian ion channels are becoming increasingly well characterized, and progress in sodium channel research has been summarized recently in Anger et al, J.

Med. Chem. (2001) 44,115-137. Sodium channels are recognised as valid targets for pain therapeutics, and blockade of sodium channels can be useful in the treatment of a range of pain syndromes (see for example Black et al, Progress in Pain Research and Management (2001), 21 (NeurbpamicPain : Pam6physiology and Treatment), 19- 36).

It has now surprisingly been found that compounds of the general formula (I) set out below act as inhibitors of sensory neurone specific sodium channels.

Accordingly, the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, wherein: - X is -N- or -CH-; n is from 0 to 3 ; each Ri is the same or different and is a hydroxy, amino, halogen, Cl-C6 alkyl, Ci-C6 haloalkyl, C,-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, Cl-C6 haloalkoxy, Cl-C6 alkylthio, Cl-C6 haloalkylthio, (C1C6 alkyl) amino or di (Cl-C6

alkyl) amino group ; - p is 0 or 1 ; -Rl/is cyano,-NR/-CO-(C1-C4 alkyl),-NR/-S (0) 2-(CI-C4 alkyl),-CO2H,- S (0) 2OH, -CO2-(C1-C4 alkyl), -O-S(O)2-(C1-C4 alkyl) or-N [S (0) 2-(CI-C4 alkyl)] 2, wherein R is hydrogen or a Cl-C4 alkyl group; - m is 1, 2 or 3 ; and - R2 is either (a) -L-A, wherein L is a direct bond or a Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety and A is C6-Coo aryl, C3-C6 carbocyclyl, a 5-to 10-membered heteroaryl group or a 5-to 10-membered heterocyclic group, (b) -L-CR (A) 2 or-L-CH=C (A) 2 wherein R is hydrogen or Cl-C4 alkyl, L is as defined above and each A is the same or different and is as defined above, (c) -L'-Het-A', wherein Het is -O-, -S- or -NR'-, A' is -L-A, -L-CR (A) 2 or-L- CH=C (A) 2, R' is H or-L-A, L' is a Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above, (d) -L-CO-NR3R4 or -L-CS-NR3R4, wherein L is as defined above and either (i) R3 and R4, together with the N atom to which they are attached, form a 5-to 10-membered heteroaryl or heterocyclyl group or (ii) R3 represents-L-H or A'wherein L and A/are as defined above, and R4 represents -L'-H, -L'-CO- A',-L'-S(O)-A',-L'-S(O)2-A',-L'-Het-A',-NR-CO-N(A)2, -N(A)2, -A-Het-A, -A/,-L-CR (LA) 2 or-L-CH=C (LA) 2 wherein each L is the same or different, each A is the same or different, and L', L, R, A and A/are as defined above, (e) -CO-L-NR3R4 or-CS-L-NR3R4 wherein L, R3 and R4 are as defined above, (f)-CO-A/or-CS-A/wherein A/is as defined above, (g) -L'-O-N=C (A) 2 or-CO-L/-O-N=C (A) 2 wherein L/is as defined above and each A is the same or different and is as defined above, or (h)-L/-NR-CO-NR3R4 or-L/-NR-CS-NR3R4, wherein L', R, R3 and R4 are as defined above, wherein said aryl, carbocyclyl, heteroaryl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6-membered

heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1,2 or 3 substituents which are the same or different and are selected from Cl-C4 alkyl, Cl-C4 haloalkyl, halogen, hydroxy, amino, (Cl-C4 alkyl) amino, di (Cl-C4 alkyl) amino, Cl-C4 alkoxy, Ci-C4 haloalkoxy, C1-C4 alkylthio, Cl-C4 haloalkylthio, -NH-CO-(C1-C4 alkyl), -CO-(C1-C4 alkyl), -CO2-(C1-C4 alkyl), 5-or 6-membered heteroaryl, phenyl and-CHPh2 substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, Cl-C2 alkyl groups, Cl-C2 alkoxy groups and-NH-CO- (CI-C2 alkyl) groups, provided that (a) when R2 is-L-A, A is other than a benzimidazolyl group, and (b) when R2 is-CO-A or-CS-A, A is other than a pyrazolopyrimidinyl or pyrazolyl group.

Typically, the compounds of the invention are compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: - X is -N -or -CH-; - n is from 0 to 3; -pipo ; each Ri is the same or different and is a hydroxy, amino, halogen, Cl-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl-C6 alkylthio, C1-C6 haloalkylthio, (ClC6 alkyl) amino or di (Cl-C6 alkyl) amino group; - m is 1, 2 or 3 ; and - R2 is either (a) -L-A, wherein L is a direct bond or a Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety and A is C6-Clo aryl, C3-C6 carbocyclyl, a 5-to 10-membered heteroaryl group or a 5-to 10-membered heterocyclic group, (b) -L-CR (A) 2 or-L-CH=C (A) 2 wherein R is hydrogen or C1-C4 alkyl, L is as defined above and each A is the same or different and is as defined above, (c) -L'-Het-A', wherein Het is -O-, -S- or -NR'-, Ais-L-A,-L-CR (A) 2 or-L- CH=C (A) 2, R is H or-L-A, L is a Cl-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above, (d)-L-CO-NR3R4 or-L-CS-NR3R4, wherein L is as defined above and either (i)

R3 and R4, together with the N atom to which they are attached, form a 5-to 10-membered heteroaryl or heterocyclyl group or (ii) R3 represents-L-H or A'wherein L and A'are as defined above, and R4 represents-L/-H,-L/-CO-A, A', -L-CR (LA) 2 or-L-CH=C (LA) 2 wherein each L is the same or different, each A is the same or different, and L', L, R, A and A'are as defined above, (e)-CO-L-NR3R4 or-CS-L-NR3R4 wherein L, R3 and R4 are as defined above, (f)-CO-A/or-CS-A/wherein A/is as defined above, or (g)-L/-O-N=C (A) 2 or-CO-L/-O-N=C (A) 2 wherein Lazzis as defined above and each A is the same or different and is as defined above, wherein said aryl, carbocyclyl, heteroaryl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6-membered heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1,2 or 3 substituents which are the same or different and are selected from Cl-C4 alkyl, Cl-C4 haloalkyl, halogen, hydroxy, Cl-C4-alkoxy, Ci-C4 haloalkoxy, C1-C4 alkylthio, Cl-C4 haloalkylthio, phenyl and-CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms, provided that (a) when R2 is-L-A, A is other than a benzimidazolyl group and (b) when R2 is-CO-A or-CS-A, A is other than a pyrazolopyrimidinyl or pyrazolyl group.

As used herein, a Cl-C6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as Cl-C4 alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. A divalent alkyl moiety (or alkylene moiety) can be attached via the same carbon atom, by adjacent carbon atoms or by non-adjacent carbon atoms.

As used herein, a C2-C6 alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, such as a C2-C4 alkenyl group or moiety, for example ethenyl, propenyl and butenyl. Typically, an alkenyl group or moiety is saturated except for one double bond. A divalent alkenyl moiety (or alkenylene moiety) can be attached via the same carbon atoms, via adjacent carbon atoms or via non-adjacent carbon atoms.

As used herein, a C2-C6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, such as a C2-C4 alkynyl group or moiety, for example ethynyl, propynyl and butynyl. Typically, an alkynyl group or moiety is saturated except for one triple bond. A divalent alkynyl moiety (or alkynylene moiety) can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.

As used herein, a C6-Clo aryl group or moiety is typically a phenyl or naphthyl group or moiety. It is preferably a phenyl group or moiety.

As used herein, a 5-to 10-membered heteroaryl group is a 5-to 10- membered aromatic ring, such as a 5-or 6-membered ring, containing at least one heteroatom, for example 1,2 or 3 heteroatoms, selected from 0, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazyl, thiadiazolyl, thiazolyl and pyrazolyl groups. Thienyl, triazolyl, pyridyl, thiazolyl and imidazolyl groups are preferred.

Pyrrolyl groups are also preferred.

- As used herein, a halogen is typically chlorine, fluorine, bromine or iodine- and is preferably chlorine or fluorine. As used herein, a said Cl-C6 alkoxy group is typically a said Cl-C6 alkyl group attached to an oxygen atom. A said Cl-C6 alkylthio group is typically a said Cl-C6 alkyl group attached to a thio group.

As used herein, a Cl-C6 haloalkyl group is typically a said Cl-C6 alkyl group, for example a Cl-C4 alkyl group, substituted by one or more said halogen atoms.

Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl groups include perhaloalkyl groups such as-CX3 wherein X is a said halogen atom.

Particularly preferred haloalkyl groups are-CF3 and-CC13, As used herein, a Cl-C6 haloalkoxy group is typically a said Cl-C6 alkoxy group, for example a Cl-C4 alkoxy-group, substituted by one or more said halogen atoms. Typically, it is substituted by 1,2 or 3 said halogen atoms. Preferred haloalkoxy groups include perhaloalkoxy groups such as-OCX3 wherein X is a said halogen atom. Particularly preferred haloalkoxy groups are-OCF3 and-OCC13.

As used herein, a Cl-C6 haloalkylthio group is typically a said Cl-C6 alkylthio group, for example a Cl-C4 alkylthio group, substituted by one or more said halogen atoms. Typically, it is substituted by 1,2 or 3 said halogen atoms. Preferred

haloalkylthio groups include perhaloalkylthio groups such as-SCX3 wherein X is a said halogen atom. Particularly preferred haloalkylthio groups are-SCF3 and -SCC13.

As used herein, a C3-C6 carbocyclyl group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring, having from 3 to 6 carbon atoms.

Preferably it is a saturated group, i. e. a C3-C6 cycloalkyl group. Examples include cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, a 5-to 10-membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated Cs-Clo carbocyclic ring in which one or more, for example 1,2 or 3, of the carbon atoms are replaced by a moiety selected from N, O, S, S (O) and S (0) 2. Preferably, only one carbon atom is replaced with a-S (O)-or - S (0) 2- moiety. More preferably, a 5-to 10-membered heterocyclyl group or moiety is a non-aromatic, saturated or unsaturated Cs-Cto carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S.

Saturated heterocyclyl groups are preferred. Examples of suitable-- heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, 1,4 dioxanyl, 1,3 dioxolanyl and homopiperidinyl groups. Further examples of suitable heterocyclyl groups include thiomorpholino, S-oxo-thiomorpholino and S, S-dioxo-thiomorpholino groups.

Preferred heterocyclyl groups are piperidinyl, morpholinyl, piperazinyl and homopiperidinyl groups. Further preferred heterocyclyl groups are thiomorpholino, S-oxo-thiomorpholino and S, S-dioxo-thiomorpholino groups.

Typically, when a said aryl, carbocyclyl, heteroaryl or heterocyclyl group is fused to two cyclic moieties selected from phenyl rings and 5-to 6-membered heterocyclyl and heteroaryl groups, said cyclic moieties are fused directly to the aryl, carbocyclyl, heteroaryl or heterocyclyl group. Typically, the two cyclic moieties are not fused together.

Preferably 0,1 or 2 of the said substituents on an aryl, heteroaryl, carbocyclyl or heterocyclyl group are selected from-NH-CO-(Ci-C4 alkyl),-CO-(Cz-C4 alkyl), - C02- (CI-C4 alkyl), 5-or 6-membered heteroaryl, phenyl and-CHPh2 substituents.

Typically, the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Rl, R2, R3 and R4 are unsubstituted or are substituted by

1,2 or 3 substituents which are the same or different and are selected from halogen, Cl-C4 alkyl, hydroxy, amino, (CI-C4 alkyl) amino, Ci-C4 alkoxy, Cl-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkylthio, Ci-C4 haloalkylthio, -NH-CO-(C1-C2 alkyl), -CO- (CI-C2 alkyl), -CO2-(C1-C2 alkyl), 5-membered heteroaryl, phenyl and -CHPh2 substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, Cl-C2 alkyl groups, Cl-C2 alkoxy groups and -NH-CO-(C1-C2 alkyl) groups.

More typically, the above substituents are selected from halogen, Cl-C4 alkyl, hydroxy, Cl-C4 alkoxy, Ci-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, phenyl and-CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms.

Preferably, the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Rl, R2, R3 and R4 are unsubstituted or are substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Cl- C4 alkyl, hydroxy, amino, Cl-C2 alkoxy, Cl-C2 haloalkyl, Ci-C2 haloalkoxy, Cl-C2 haloalkylthio, -NH-CO-(C1-C2 alkyl), -CO-(C1-C2 alkyl), -CO-(C1-C2 alkyl), oxadiazolyl, phenyl and-CHPh2 substituents, the oxadiazolyl and phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, methyl groups, methoxy groups and-NH-CO-CH3 groups. Preferably, these preferred substituents are selected from halogen, C1-C2 alkyl, hydroxy, Cl-C2 alkoxy, Cl-C2 haloalkyl, Cl-C2 haloalkoxy, Cl-C2 haloalkylthio, phenyl and-CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from fluorine and chlorine atoms.

Typically, X is-CH-.

Typically, n is 0 or 1.

Preferably, each R1 is the same or different and is a hydroxy, amino, halogen, Cl-C4 alkyl, Cl-C4 haloalkyl, Cl-C4 alkoxy, C2-C4 alkenyloxy, Ci-C4 haloalkoxy, Cl- C4 alkylthio or Cl-C4 haloalkylthio group. Typically, in this preferred embodiment each R1 is the same or different and is a hydroxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, Cl-C4 alkoxy, Cl-C4 haloalkoxy, Cl-C4 alkylthio or Cl-C4 haloalkylthio group.

More preferably, each R1 is the same or different and is C1-C2 alkyl, C2-C3 alkenyloxy, amino, hydroxy or Cl-C2 alkoxy. Typically, in this more preferred embodiment each Ri is the same or different and is Cl-C2 alkyl, hydroxy or Cl-C2 alkoxy.

Typically, Ri is cyano,-NH-CO- (Cl-C4 alkyl),-NH-S (0) 2- (C1-C4 alkyl),-O- S (0) 2-(Cz-C4 alkyl),-S (0) 2-OH or-N-[S (0) 2-(C1-C4 alkyl)] 2. Preferably, Riz ils cyano,-NH-CO-CH3,-NH-S (0) 2-CH3, -O-S (0) 2-CH3,-N- [S02-CH3] 2 or-S (0) 20H.

Typically p is 0 and R1 is located meta to the fused heterocycle, or on the phenyl carbon atom nearest the N atom. Thus, the compound of formula (I) is typically a compound of formula Typically, each L moiety in the R2 substituent is the same or different and represents a direct bond or a Cl-C6 alkyl moiety. Preferably, each L is the same or different and represents a direct bond or a Cl-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, for example-CH (CH3)- or -CH2-CH(CH3)-.

Typically each L''moiety in the R2 substituent is the same or different and represents a Cl-C6 alkyl moiety, preferably a Cl-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, for example-CH (CH3)- or -CH2-CH (CH3) -.

Typically, each A moiety in the R2 substituent is the same or different and represents a C6-Clo aryl, C3-C6 cycloalkyl, 5-or 6-membered heterocyclyl or 5-or 6- membered heteroaryl group, which group is (a) unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl-C4 alkyl, Cl-C4 haloalkyl, halogen, hydroxy, amino, (C1-C4 alkyl) amino, di (CI-C4 alkyl) amino, Cl-C4 alkoxy, Ci-C4 haloalkoxy, Cl-C4 alkylthio, Cl-C4 haloalkylthio,-NH-CO- (C1-C2 alkyl), phenyl and halophenyl substituents and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6-membered heterocyclyl or heteroaryl groups. For the avoidance of doubt, said preferred substituents on the moiety A are themselves unsubstituted.

More typically, each A moiety in the R2 substituent is the same or different and represents a C6-Clo aryl, C3-C6 cycloalkyl, 5-or 6-membered heterocyclyl or 5- or 6-membered heteroaryl group, which group is (a) unsubstituted or substituted by 1,2 or 3 substituents selected from Cl-C4 alkyl, Cl-C4 haloalkyl, halogen, hydroxy, Cl-C4 alkoxy, Ci-C4 haloalkoxy, Cl-C4 alkylthio, Ci-C4 haloalkylthio, phenyl and halophenyl substituents and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6-membered heterocyclyl or heteroaryl groups.

Further, each A moiety in the R2 substituent is typically the same or different and is a phenyl, thienyl, triazolyl, pyridyl, pyrrolyl, pyrrolidinyl, 4-H-pyranyl, cyclopentyl, imidazolyl, thiazolyl or piperidyl group which is (a) unsubstituted or substituted by one or two substituents selected from halogen, C1-C2 haloalkyl, C1-C2 haloalkoxy, C1-C2 haloalkylthio, phenyl, Ci-C2 alkyl, Cl-C2 alkoxy, amino, hydroxy and-NH-CO- (C1-C2 alkyi) groups and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6-membered heteroaryl moieties.

More typically, each A moiety in the R2 substituent is the same or different and is a phenyl, thienyl, triazolyl, pyridyl, cyclopentyl, imidazolyl, thiazolyl or piperidyl group which is (a) unsubstituted or substituted by one or two substituents selected from halogen, Cl-C2 haloalkyl, Cl-C2 haloalkoxy, Cl-C2 haloalkylthio, phenyl, C1-C2 alkyl, Cl-C2 alkoxy and hydroxy groups and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6-membered heteroaryl moieties.

Preferably, each A moiety in the R2 substituent is a phenyl, thienyl, triazolyl, pyridyl, fluorenyl, thiazolyl, tetrahydroisoquinolinyl, 9H-carbazolyl, indolinyl, 9H- xanthenyl or benzimidazolyl group, which group is unsubstituted or substituted by one or two substituents selected from halogen, Cl-C2 alkyl, hydroxy, amino, Cl-C2 alkoxy, Cl-C2 haloalkyl, Cl-C2 haloalkoxy, Cl-C2 haloalkylthio, -NH-CO-CH3 and phenyl substituents. More typically, in this preferred embodiment, each A moiety is a phenyl, thienyl, triazolyl, pyridyl, fluorenyl, thiazolyl, tetrahydroisoquinolinyl or benzimidazolyl group, which group is unsubstituted or substituted by one or two substituents selected from halogen, Cl-C2 alkyl, hydroxy, Cl-C2 alkoxy, Cl-C2 haloalkyl, Cl-C2 haloalkoxy, Cl-C2 haloalkylthio and phenyl substituents.

Typically, each R substituent in each-CR (A) 2 moiety is the same or different and is hydrogen or methyl.

Typically, each Het moiety in the R2 substituent is-0-,-S-or-NR/-wherein R/is hydrogen, Cl-C4 alkyl, phenyl or -(C1-C4 alkyl) -phenyl. More preferably, each Het moiety in the R2 substituent is-O-or-NR'-wherein R/is hydrogen, Cl-C4 alkyl or benzyl.

When R3 and R4, together with the N atom to which they are attached, form a heteroaryl or heterocyclyl group, the heteroaryl or heterocyclyl group is typically (a) monocyclic, (b) fused to one or two phenyl rings or (c) a morpholino group which is fused to a phenyl ring and to a 1H-pyrazolyl group.

Typically, when R3 and R4, together with the N atom to which they are attached, form a heterocycle, they form a 5-to 7-membered heterocyclyl group.

Preferably, they form a morpholino, thiomorpholino, S-oxo-thiomorpholino, S, S- dioxo-thiomorpholino, pyrrolidinyl, piperazinyl or homopiperidinyl ring which is (a) optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6- membered heteroaryl rings, and (b) unsubstituted or substituted by 1 or 2 substituents selected from Ci-C4 alkyl, Cl-C4 haloalkyl, Cl-C4 alkoxy, Ci-C4 alkylthio, halogen, phenyl, -CHPh2, -CO-(C1-C2 alkyl), -CO2-(C1-C2 alkyl) and 5- to 6- membered heteroaryl substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, Cl-C2 alkyl groups, Cl-C2 alkoxy groups and-NH-CO-(Cz-Cz alkyl) groups.

More typically, when R3 and R4, together with the N atom to which they are attached, form a heterocycle, they form a morpholino, piperazinyl or homopiperidinyl ring which is (a) unsubstituted or substituted by 1 or 2 substituents selected from C1-C4 alkyl, Cl-C4 haloalkyl, halogen, phenyl and-CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms and (b) optionally fused to one or two phenyl rings.

Typically, when R3 and R4 do not together form a heterocycle, R3 represents <BR> <BR> <BR> <BR> hydrogen, Cl-C4 alkyl, phenyl,- (Cl-C4 alkyl) -phenyl or-(Cl-C4 alkyl)-CHPh2. More typically, when R3 and R4 do not together form a heterocycle, R3 represents <BR> <BR> <BR> <BR> hydrogen, C1-C4 alkyl, -(C1-C4 alkyl) -phenyl or- (Ci-C4 alkyl)-CHPh2. Preferably, the phenyl moieties in R3 are unsubstituted or substituted by a hydroxy group. More preferably, R3 is unsubstituted.

More preferably, R3 represents hydrogen, Cl-C4 alkyl or an unsubstituted benzyl, phenyl, hydroxyphenyl or-(Cl-C2 alkyl)-CHPh2 group. Most preferably R3

represents hydrogen, Cl-C4 alkyl or an unsubstituted benzyl or- (C1-C2 alkyl)-CHPh2 group.

Typically, when R3 and R4 do not together form a heterocycle, R4 represents Cl-C4 alkyl, A, -(C1-C4 alkyl)-A, -(CH2)m-CH (A) 2,-CH [ (CH2) mA] 2,- (CH2) m-CO-A, -(CH2)m-O-CH (A) 2,- (CH2) m-S-CH (A) 2,- (CH2) m-S )-CH (A) 2,- (CH2) m-S (0) 2- CH (A) 2, -NH-CO-N (A) 2, -N (A) 2 or-A-O-A, wherein each A is the same or different and is as defined above and m is 0, 1, 2,3 or 4. More typically, when R3 and R4 do not together form a heterocycle, R4 represents Cl-C4 alkyl, A,- (CI-C4 alkyl) -A, - (CH2) m-CH (A) 2,-CH [(CH2)mA]2 or -(CH2)m-CO-A wherein each A is the same or different and is as defined above and m is 0,1, 2,3 or 4.

Preferably, the A moieties in the R4 substituent are (a) unsubstituted or substituted by 1 or 2 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, amino, Cl-C2 haloalkyl, Cl-C2 haloalkoxy and Cl-C2 haloalkylthio substituents and (b) monocyclic or fused to 1 or 2 phenyl rings. Typically, in this preferred embodiment, the A moieties in the R4 substituent are (a) unsubstituted or substituted by 1 or 2 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, Cl-C2-haloalkyl, Cl-C2 haloalkoxy and Cl-C2 haloalkylthio substituents and (b) monocyclic or fused to 1 or 2 phenyl rings.

More preferably, when R3 and R do not together form a heterocycle, R4 represents Cl-C4 alkyl, fluorenyl, phenyl, pyridyl,- (C1-C4 alkyl)-phenyl,- (CI-C4 alkyl)-(5- to 6- membered heteroaryl), -(CH2)m-(9H-carbazolyl), -(CH2)m-indolinyl, -(CH2)m-(9H-xanthenyl), -(CH2)m-O-CHA''A''', -(CH2)m-S-CHA''A''', -(CH2)m-S(O)- CHA''A''', -(CH2) m-S (0) 2-CHA''A''', -NH-CO-N (phenyl) 2,-N (phenyl) 2, -A''-O-A''', - (CH2)m-CHA''A''', -CH[(CH2)nPh] 2 or- (CH2) p-CO-R, wherein m is 0,1, 2 or 3, All and A are the same or different and each represent phenyl or a 5-or 6-membered heteroaryl group, n is 0,1 or 2, p is 1,2 or 3 and R is a 5-or 6-membered heterocyclic group fused to a phenyl ring, for example a tetrahydroisoquinoline group, the cyclic moieties in said preferred R4 groups being unsubstituted or substituted by a halogen atom, C1-C2 alkyl, hydroxy, amino or Ci-C2 alkoxy group.

More preferably, when R3 and R4 do not together form a heterocycle, R4 represents Cl-C4 alkyl, fluorenyl, -(C1-C4 alkyl)-phenyl, -(C1-C4 alkyl)-(5- to 6- membered heteroaryl),- (CH2)m-CHA''A''' wherein m is 0, 1, 2 or 3 and All and A"" are the same or different and each represent phenyl or a 5-or 6-membered heteroaryl

group, -CH [ (CH2)nPh]2 wherein n is 0,1 or 2, or- (CH2) p-CO-R wherein p is 1,2 or 3 and R is a 5-or 6-membered heterocyclic group fused to a phenyl ring, for example a tetrahydroisoquinoline group, the cyclic moieties in said most preferred R4 groups being unsubstituted or substituted by a halogen atom, Cl-C2 alkyl or Cl-C2 alkoxy group.

Typically, when R2 is defined according to option (a), A is monocyclic.

More typically, A is a monocyclic phenyl or 5-to 6-membered heteroaryl group.

Typically, when R2 is defined according to option (a), L is C1-C4 alkyl and A is a phenyl or 5-or 6-membered heteroaryl group, which group is unsubstituted or substituted by 1,2 or 3 substituents selected from Cl-C4 alkyl, Cl-C4 haloalkyl, halogen, hydroxy, Cl-C4 alkoxy, Cl-C4 haloalkoxy, Cl-C4 alkylthio, Cl-C4 haloalkylthio, phenyl and halophenyl substituents.

Preferably, when R2 is defined according to option (a), it is a- (CI-C4 alkyl)- phenyl group, for example benzyl, or a- (Cl-C4 alkyl)- (5- to 6-membered heteroaryl) group, for example-CH2-thienyl or-CH2-triazolyl, the phenyl and heteroaryl moieties-being unsubstituted or substituted'by 1--or 2 substituents selected from-Cl-C2 haloalkyl, halogen, Cl-C2 haloalkylthio, Cl-C2 haloalkoxy, Cl-C2 alkyl and phenyl substituents.

Typically, when R2 is defined according to option (b), it is-L-CR (A) 2 wherein R and A are as defined above. Preferably, L is Cl-C4 alkyl, R is hydrogen or methyl and each A is the same or different and is a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cl-C2 haloalkyl, Cl-C2 alkyl,-NH-CO-CH3 and hydroxy substituents. More preferably, L is Cl-C4 alkyl, R is hydrogen or methyl and each A is the same or different and is a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Ci-C2 haloalkyl, Cl-C2 alkyl and hydroxy substituents.

Typically, when R2 is defined according to option (c), L is Cl-C4 alkyl, Het is 0, NH or-N (benzyl)- and A'is an unsubstituted -(C1-C4)alkyl-phenyl, -(C1-C4 alkyl) -CHPh2 or-CH=CHPh2 group.

Typically, when R2 is defined according to option (d), L is other than a direct bond. More typically, L is C1-C6 alkyl.

Further, when R2 is defined according to option (d), it is typically-L-CO- NR3R4. More typically, when R2 is defined according to option (d), R2 is- (CH2) q-

CO-NR3R4 wherein q is from 1 to 4, and is preferably 1 or 2, and R3 and R4 are as defined above.

Preferably, when R2 is defined according to option (d), either (i) R3 and R4, together with the N atom to which they are attached, form a 5-to 7-membered heterocyclyl group or (ii) R3 represents hydrogen, Cl-C4 alkyl, phenyl or- (Cl-C4 alkyl) -phenyl and R4 represents Cl-C4 alkyl, A, -(C1-C4 alkyl)-A, -(CH2)m-CH (A) 2, - CH[(CH2)mA]2, -(CH2)m-O-CH(A)2, -(CH2)m-S-CH (A) 2,- (CH2) -S (0)-CH (A) 2, -(CH2)m-S(O) 2-CH (A) 2,-NH-CO-N (A) 2,-N (A) 2 or-A-O-A, wherein each A is the same or different and is as defined above and in is 0,1, 2,3 or 4. Typically, in this preferred embodiment when R2 is defined according to option (d), either (i) R3 and R4, together with the N atom to which they are attached, form a 5-to 7-membered heterocyclyl group or (ii) R3 represents hydrogen, C1-C4 alkyl or -(C1-C4 alkyl)- phenyl and R4 represents Ci-C4 alkyl, A,- (C1-C4 alkyl)-A,- (CH2) m-CH (A) 2 or- CH [(CH2) mA] 2 wherein each A is the same or different and is as defined above and m is 0, 1, 2, 3 or 4.

-More preferably, when-R : 2 is defined according to option (d) either (i) R3-and- R4, together with the N atom to which they are attached, form a morpholino, thiomorpholino, S-oxo-thiomorpholino, S, S-dioxo-thiomorpholino, pyrrolidinyl, piperazinyl or homopiperdinyl ring which is (a) optionally fused to 1 or 2 cyclic moieties selected from phenyl rings and 5-to 6-membered heteroaryl rings and (b) unsubstituted or substituted by 1 or 2 substituents selected from Cl-C4 alkyl, Cl-C4 haloalkyl, Cl-C4 alkoxy, Cl-C4 alkylthio, halogen, phenyl,-CHPh2,-CO- (Ci-C2 alkyl),-CO2-(Cz-C2 alkyl) and 5-to 6-membered heteroaryl substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, Cl-C2 alkyl groups, Cl-C2 alkoxy groups and-NH-CO-(Cz-C2 alkyl) groups or (ii) R3 represents hydrogen, Cl-C4 alkyl or an unsubstituted benzyl, phenyl or hydroxyphenyl group and R4 represents Cl-C4 alkyl, fluorenyl, phenyl, pyridyl, -(C1-C4 alkyl)-phenyl, -(C1-C6 alkyl)-(5- to 6- membered heteroaryl), -(CH2)mCHA''A''', -CH[(CH2)nPh]2, -(CH2)m-(9H-carbazolyl), -(CH2)m-indolinyl, -(CH2)m-(9H-xanthenyl), -(CH2)m-O-CHA''A''', -(CH2)m-S- CHA,- -(CH2)m-S(O)-CHA''A''', -(CH2)m-S(O)2-CHA''A''', -NH-CO-N(phenyl)2, -N(phenyl)2 or -A''-O-A''', wherein m is 0, 1, 2 or 3, All and All'are the same or different and each represent phenyl or a 5-or 6-membered heteroaryl group, and n is

0, 1 or 2, the cyclic moieties in these groups being unsubstituted or substituted by a halogen atom, Cl-C2 alkyl, hydroxy, amino or Cl-C2 alkoxy group.

More preferably when R2 is defined according to option (d) either (i) R3 and R4, together with the N atom to which they are attached, form a morpholino, piperazinyl or homopiperdinyl ring which is (a) unsubstituted or substituted by 1 or 2 substituents selected from Cl-C4 alkyl, Cl-C4 haloalkyl, halogen, phenyl and -CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms and (b) optionally fused to one or two phenyl rings or (ii) R3 represents hydrogen, Cl-C4 alkyl or an unsubstituted benzyl group and R4 represents Cl-C4 alkyl, fluorenyl,-(Cl-C4 alkyl)-phenyl,-(Cl-C6 alkyl)-(5-to 6-membered heteroaryl), -(CH2)mCHA''A''' wherein m is 0,1, 2 or 3 and All and A/// are the same or different and each represent phenyl or a 5-or 6-membered heteroaryl group, or-CH [ (CH2) nPh] 2 wherein n is 0,1 or 2, the cyclic moieties in these groups being unsubstituted or substituted by a Cl-C2 alkyl group.

Typically, when R2 is defined according to option (e), L is a direct bond or a C1-C4 alkyl moiety, for example a methyl moiety, and R3 and R4 are as defined above.

Typically, when R2 is defined according to option (f), A is a said C6-CIo aryl group. Typically, when R2 is defined according to option (f), it is-CO-A. More typically, when R2 is defined according to option (f), it is-CO-L-CH (A) 2 or-CO-L- A, wherein L is as defined above and each A is the same or different and is as defined above.

Preferably, when R2 is defined according to option (f), it is-CO-CH2-CH (R) 2 or-CO-R/, wherein each R is the same or different and is a phenyl or halophenyl moiety and R' is a benzimidazolyl group.

Typically, when R2 is defined according to option (g), it is-CO-L/-O- N=C (A) 2, wherein L''is as defined above and each A is the same or different and is as defined above. Preferably, when R2 is defined according to option (g), it is-CO- CH2-O-N=CR''R''' wherein Rl/and R///are the same or different and each represent an unsubstituted phenyl or pyridyl group.

Typically, when R2 is defined according to option (h), L is Cl-C4 alkyl.

Typically, R is H. Typically, either (i) R3 and R4, together with the N atom to which

they are attached, form a phenothiazine or phenoxazine group or (ii) R3 is hydrogen and R4 is -(CH2)m-CHA''A''' or -A''-O-A''' wherein m is 0, 1, 2 or 3 and A'' and A''' are the same or different and each represent phenyl or a 5-to 6-membered heteroaryl group. Preferably, All and A are both phenyl.

Preferred compounds of formula (I) are those in which: X is-N-or-CH- ; - n is from 0 to 3; - m is 1, 2 or 3 ; - each R1 is the same or different and is a hydroxy, amino, halogen, Cl-C4 alkyl, Cl-C4 haloalkyl, C1-C4 alkoxy, Cl-C4 haloalkoxy, C2-C4 alkenyloxy Cl-C4 alkylthio, or C1-C4 haloalkylthio group; p is 0 or 1 ; - r1' is cyano, -NH-CO-(C1-C4 alkyl), -NH-S(O)2-(C1-C4 alkyl), -O-S(O)2-(C1- C4 alkyl),-S (0) 2-OH or -N[S(O)2-(C1-C4 alkyl] 2; and - R2 is either - (a) L A wherein L is a direct bond or a (Sz-C6 alkyl moiety and A is a C6-C10 aryl, C3-C6 cycloalkyl, 5-or 6-membered heterocyclyl or 5-or 6-membered heteroaryl group, (b) -L-CR (A) 2 or-L-CH=C (A) 2 wherein R is hydrogen or Cl-C4 alkyl, L is as defined above and each A is the same or different and is as defined above, (c) -L'-Het-A', wherein Het is -O-, -S- OR -NR'- wherein R' is hydrogen, C1-C4 alkyl, phenyl or -(C1-C4 alkyl)-phenyl, A' is -L-A, -L-CR (A) 2 or-L- CH=C (A) 2, Lazzis a Cl-C6 alkyl moiety, L is as defined above and each A is the same or different and is as defined above, (d)-L-CO-NR3R4 or-L-CS-NR3R4 wherein L is as defined above and either (i) R3 and R4, together with the nitrogen atom to which they are attached, form a 5-to 7-membered heterocyclyl group or (ii) R3 represents hydrogen, Cl-C4 alkyl, phenyl, -(C1-C4 alkyl) -phenyl or -(C1-C4 alkyl)-CHPh2 and R4 represents Cl-C4 alkyl, A, -(C1-C4 alkyl)-A, -(CH2) m-CH (A) 2, - CH[(CH2)mA]2, -(CH2)m-CO-A, -(CH2)m-O-CH (A) 2,- (CH2) m-S-CH (A) 2, -(CH2)m-S(O)-CH (A) 2,-(CH2) m-S (0) 2-CH (A) 2,-NH-CO-N (A) 2,-N (A) 2 or - A-O-A, wherein each A is the same or different and is as defined above and misO, 1, 2, 3 or 4,

(e) -CO-L-NR3R4 or-CS-L-NR3R4 wherein L, R3 and R4 are as defined above, -CO-A', or -CS-A', wherein A is as defined above, (g) -L'-O-N=C (A) 2,-CO-L-O-N=C (A) 2 wherein L'is as defined above and each A is the same or different and is as defined above, or (h) -L'-NR-CO-NR3R4 or -L'-NR-CS-NR3R4 wherein L', R, R3 and R4 are as defined above, wherein said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6-membered heterocyclyl and heteroaryl groups, and - said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1,2 or 3 substituents which are the same or different and are selected from halogen, Cl-C4 alkyl, hydroxy, amino, (C1-C4 alkyl) amino, Cl-C4 alkoxy, Cl-C4 haloalkyl, Cl-C4 haloalkoxy, Cl-C4 alkylthio, Cl-C4 haloalkylthio, -NH-CO-(C1-C2 alkyl), -CO-(C1-C2 alkyl), -CO2-(C1-C2 alkyl), 5-membered heteroaryl, phenyl and -CHPh2 substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by one or two further substituents selected from halogen atoms, Cl-C2 alkyl groups, Cl-C2 alkoxy groups and-NH-CO- (Cl-C2 alkyl) groups, provided that (a) when R2 is-L-A, A is monocyclic and (b) when R2 is-CO- A or -CS-A', A is a said C6-CIo aryl group.

Further preferred compounds of formula (I) are those in which - X is -CH-; - n is from 0 to 3; - pis0 ; mis 1, 2 or 3 ; each Ri is the same or different and is a hydroxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, or Cl-C4 haloalkylthio group; and - R2 is either (a) -L-A wherein L is a direct bond or a Cl-C6 alkyl moiety and A is a C6-Cio aryl, C3-C6 cycloalkyl, 5-or 6-membered heterocyclyl or 5-or 6-membered heteroaryl group,

(b)-L-CR (A) 2 or-L-CH=C (A) 2 wherein R is hydrogen or Cl-C4 alkyl, L is as defined above and each A is the same or different and is as defined above, (c)-L-Het-A', wherein Het is -O-, -S- or -NR'- wherein R' is hydrogen, Cl-C4 alkyl, phenyl or -(C1-C4 alkyl) -phenyl, A' is -L-A, -L-CR (A) 2 or-L- CH=C (A) 2, Lazzis a Cl-C6 alkyl moiety, L is as defined above and each A is the same or different and is as defined above, <BR> <BR> <BR> <BR> (d) -L-CO-NR3R4 or-L-CS-NR3R4 wherein L is as defined above and either (i) R3 and R4, together with the nitrogen atom to which they are attached, form a 5-to 7-membered heterocyclyl group or (ii) R3 represents hydrogen, Cl-C4 alkyl,- (Cl-C4 alkyl)-phenyl or- (Cl-C4 alkyl)-CHPh2 and R4 represents Cl-C4 alkyl, A,- (Cl-C4 alkyl)-A,- (CH2) m-CH (A) 2, -CH [(CH2)mR]2 or -(CH2)m-CO- A wherein each A is the same or different and is as defined above and m is 0, 1,2, 3 or 4, (e)-CO-L-NR3R4 or-CS-L-NR3R4 wherein L, R3 and R4 are as defined above, -CO-A' or -CS-A' whererin A' is as defined above, or (g) -L'-O-N=C(A)2, -CO-L'-O-N=C(A)2 wherein L' is as defined above and each A is the same or different and is as defined above, wherein said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6-membered heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Ci-C4 alkyl, hydroxy, Cl-C4 alkoxy, Cl-C4 haloalkyl, Cl-C4 haloalkoxy, Cl-C4 alkylthio, Ci-C4 haloalkylthio, phenyl and-CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by one or two halogen atoms, provided that (a) when R2 is defined according to option (a), it is a- (Cl-C4 alkyl)-phenyl group or a -(C1-C4 alkyl)-(5- to 6-membered heteroaryl) group, the phenyl and heteroaryl moieties being unsubstituted or substituted by 1 or 2 substituents selected from Cl-C2 haloalkyl, halogen, Cl-C2 haloalkylthio, C1-C2 haloalkoxy, C1-C2 alkyl and phenyl substituents and (b) when R2 is defined

according to option (f) it is-CO-CH2-CH (R) 2 or -COR', wherein each R is the same or different and is a phenyl or halophenyl moiety and R is a benzimidazolyl group.

More preferred compounds of formula (I) are compounds wherein: X is-N-or-CH- ; nisOorl ; - each R1 is the same or different and is Cl-C2 alkyl, hydroxy or Cl-C2 alkoxy ; - p is 0 or 1 ; - R1' is cyano, -NH-CO-CH3, -NH-S(O)2-CH3, -O-S(O)2-CH3, -N[SO2-CH3]2 or - (0) 2-OH; - m is 1, 2 or 3 ; and - R2 is either (a) -L-A wherein L represents a direct bond or a Cl-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, and A is a phenyl, thienyl, triazolyl, pyridyl, fluorenyl, thiazolyl, tetrahydroisoquinolinyl, 9H-carbazolyl, indolinyl, 9H- xanthenyl or benzimidazolyl group, which group is unsubstituted or substituted-by one. or two substituents selected from halogen, C-i-C2 alkyl,-- hydroxy, amino, Cl-C2 alkoxy, Cl-C2 haloalkyl, Cl-C2 haloalkoxy, Cl-C2 haloalkylthio, -NH-CO-CH3 and phenyl substituents, (b) -L-CR (A) 2 or-L-CH=C (A) 2 wherein R is hydrogen or methyl, L is as defined above and each A is the same or different and is as defined above, (c)-L/-Het-A/wherein Het is-0-or-NR-wherein R/is hydrogen, Cl-C4 alkyl or benzyl, A' is -L-A, -L-CR (A) 2 or-L-CH=C (A) 2, L/is a Cl-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above, (d)-L-CO-NR3R4 wherein L is as defined above and either (i) R3 and R4, together with the nitrogen atom to which they are attached, form a morpholino, thiomorpholino, S-oxo-thiomorpholino, S, S-dioxo-thiomorpholino, pyrrolidinyl, piperazinyl or homopiperidinyl ring which is (a) optionally fused to one or two cyclic moieties selected from phenyl rings and 5-to 6- membered heteroaryl rings, and (b) unsubstituted or substituted by one or two substituents selected from Cl-C4 alkyl, Cl-C4 haloalkyl, Cl-C4 alkoxy, Cl-C4 alkylthio, halogen, phenyl,-CHPh2,-CO- (Cl-C2 alkyl),-C02- (CI-C2 alkyl) and 5-to 6-membered heteroaryl substituents, the phenyl and heteroaryl

moieties in said substituents being unsubstituted or substituted by one or two further substituents selected from halogen atoms, Cl-C2 alkyl groups, Cl-C2 alkoxy groups and-NH-CO- (CI-C2 alkyl) groups, or (ii) R3 represents hydrogen, Cl-C4 alkyl or an unsubstituted benzyl, phenyl, hydroxyphenyl or -(Cl-C2 aLkyl)-CHPh2 group and R4 represents C1-C4 alkyl, fluorenyl, phenyl, phridyl, -(C1-C4 alkyl)-phenyl, -(C1-C4 alkyl)-(5- to 6-membered heteroaryl), -(CH2) m-(9H-carbazolyl),-(CH2) m-indolinyl,-(CH2) m-(9H-xanthenyl), - (CH2)m-O-CHA''A''', -(CH2)m-S-CHA''A''', -(CH2)m-S(O)-CHA''A''', -(CH2)m- S (0) 2-CHA''A''', -NH-CO-N(phenyl)2, -N(phenyl) 2 or -A''-O-A''', -(CH2)m- CHA''A''', -CH[(CH2)nPh] 2 or -(CH2)p-CO-R where m is 0,1, 2 or 3, All and Alla are the same or different and each represent phenyl or a 5-or 6- membered heteroaryl group, n is 0,1 or 2, p is 1,2 or 3 and R is 5-or 6- membered heterocyclic group fused to a phenyl ring, for example a tetrahydroisoquinoline group, the cyclic moieties in said R4 groups being unsubstituted or substituted by a halogen atom, Cl-C2 alkyl, hydroxy, amino or C1-C2 alkoxy group, (e)-CO-L-NR3R4 or-CS-L-NR3R4 wherein L, R3 and R4 are as defined above, -CO-A' or -CS-A' where A' is as defined above, (g) -CO-L'-O-N=C (A) 2 wherein L is as defined above and each A is the same or different and is as defined above; or (h)-L/-NR-CO-NR3Rß or-L/-NR-CS-NR3R4 wherein 1 !, R, R3 and R4 are as defined above, provided that when R2 is-L-A, A is monocyclic.

Further preferred compounds of formula (I) compounds of formula (1 a) wherein - n is 0 or 1; each Ri is the same or different and is Cl-C2 alkyl, hydroxy or Cl-C2 alkoxy; mis 1, 2 or 3 ; and - R2 is either

(a) -L-A wherein L represents a direct bond or a Cl-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, and A is a phenyl, thienyl, triazolyl, pyridyl, fluorenyl, thiazolyl, tetrahydroisoquinolinyl or benzimidazolyl group, which group is unsubstituted or substituted by one or two substituents selected from halogen, C1-C2 alkyl, hydroxy, Cl-C2 alkoxy, Cl-C2 haloalkyl, Cl-C2 haloalkoxy, Cl-C2 haloalkylthio and phenyl substituents, (b) -L-CR (A) 2 or-L-CH=C (A) 2 wherein R is hydrogen or methyl, L is as defined above and each A is the same or different and is as defined above, (c)-L/-Het-Az wherein Het is-O-or-NR/-wherein R/is hydrogen, Cl-C4 alkyl or benzyl, A' is -L-A, -L-CR (A) 2 or-L-CH=C (A) 2, L''is a Cl-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above, (d)-L-CO-NR3R4 wherein L is as defined above and either (i) R3 and R4, together with the nitrogen atom to which they are attached, form a morpholino, piperazinyl or homopiperidinyl ring which is (a) substituted or unsubstituted by one or two substituents selected from Ci-C4 alkyl, Ci-C4 haloalkyl, halogen, phenyl and-CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by one or two halogen atoms and (b) optionally fused to one or two phenyl rings, or (ii) R3 represents hydrogen, Cl-C4 alkyl or an unsubstituted benzyl or-CH2-CH2-CHPh2 group and R4 represents Cl-C4 alkyl, fluorenyl,-(C,-C4 alkyl)-phenyl,-(Cl-C4 alkyl)- (5- to 6-membered heteroaryl),- (CH2)m-CHA''A''' where m is 0,1, 2 or 3 and All and Alla are the same or different and each represent phenyl or a 5-or 6-membered heteroaryl group, -CH [ (CH2) nPh] 2, wherein n is 0,1 or 2, or-(CH2) p-CO-R wherein p is 1,2 or 3 and R is 5-or 6-membered heterocyclic group fused to a phenyl ring, for example a tetrahydroisoquinoline group, the cyclic moieties in said R4 groups being unsubstituted or substituted by a halogen atom, Cl-C2 alkyl or Cl-C2 alkoxy group, (e) -CO-L-NR3R4 or-CS-L-NR3R4 wherein L, R3 and R4 are as defined above, -CO-A' or CS-A' wherein A' is as defined above, or (g)-CO-L/-O-N=C (A) 2 wherein L/is as defined above and each A is the same or different and is as defined above,-

provided that when R2 is defined according to option (a) it is a benzyl,-CH2- thienyl or-CH2-triazolyl group, the phenyl and heteroaryl moieties being unsubstituted or substituted by 1 or 2 substituents selected from Cl-C2 haloalkyl, halogen, Cl-C2 haloalkylthio, Cl-C2 haloalkoxy, Cl-C2 alkyl and phenyl substituents.

Examples of these particularly preferred compounds of the invention include: 1. 2- (3, 5-bis-trifluoromethyl-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-6-ol 2. 2- (2-chloro-6-fluoro-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 3. 2-(2,5-difluoro-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 4. 2- (3, 5-difluoro-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 5. 2-(4-trifluoromethylsulfanyl-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 6. 2- (3, 5-bis-trifluoromethyl-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 7. 2- (2-dibenzylamino-ethyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 8. 2- [4, 4-bis- (4-fluoro-phenyl)-butyl]-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 9. 2- [4, 4-bis- (4-hydroxy-3, 5-dimethyl-phenyl)-pentyl]-1, 2,3, 4-tetrahydro- isoquinolin-8-ol <BR> <BR> <BR> <BR> 10. 2-(8-hydroxy-3, 4-dihydro-LH-isoquinolin-2-yl)-1-(3-phenyl-2, 3-dihydro-t benzo [1, 4] oxazin-4-yl) -ethanone 11. 2-(2-benzyloxy-propyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 12. 2- (2, 2-diphenyl-ethyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 13. N-benzhydryl-2- (3, 4-dihydro-lH-isoquinolin-2-yl)-acetamide 14. 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-N- (9H-fluoren-9-yl)-acetamide <BR> <BR> <BR> <BR> 15. N- (l-benzyl-2-phenyl-ethyl)-2- (3, 4-dihydro-lH-isoquinolin-2-yl)-acetamide 16. 2-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(1,2-diphenyl-ethyl)-a cetamide 17. 2- (3, 4-dihydro-1 H-isoquinolin-2-yl)-N- (3, 3-diphenyl-propyl)-acetamide 18. N-benzhydryl-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetamide 19. N- (9H-fluoren-9-yl)-2- (8-methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)- acetamide 20. N-benzyl-2-(8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-phe nyl- acetamide 21. N- (3, 3-diphenyl-propyl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 22. N, N-dibenzyl-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetamide 23. 2-thiophen-2-yhnethyl-1, 2,3, 4-tetrahydro-isoquinolin-8-ol

24. N-benzhydryl-2- (8-hydroxy-3, 4-dihydro-1H-isoquinolin-2-yl)-acetamide 25. N-benzyl-2-(8-hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-phenyl- acetamide 26. N- (9H-fluoren-9-yl)-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 27. N- (3, 3-diphenyl-propyl)-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 28. 2- (5-phenyl-2H- [1, 2,3] triazol-4-ylmethyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol 29. 1- (3, 4-dihydro-lH-isoquinolin-2-yl)-2- (2, 2-diphenyl-ethylamino)-ethanone 30. 1-(3,4-dihydro-1H-isoquinolin-2-yl)-2-(3,3-diphenyl-propylam ino)-ethanone 31. 1- (3, 4-dihydro-lH-isoquinolin-2-yl)-2- [ [2- (3, 4-dihydro-lH-isoquinolin-2-yl)- 2-oxo-ethyl]- (3, 3-diphenyl-propyl)-amino]-ethanone 32. 2-dibenzylamino-1-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanone 33. N-(3,3-diphenyl-propyl)-2-(7-methoxy-3,4-dihydro-1H-isoquino lin-2-yl)- acetamide 34. N,N-dibenzyl-2-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-a cetamide dibenzyl- [2- (7-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]-amine 35. 2- (2, 2-diphenyl-ethyl) -1,2, 3, 4-tetrahydro-isoquinoline 36. 2-(2, 2-diphenyl-ethyl)-8-methoxy-1, 2,3, 4-tetrahydro-isoquinoline 37. 2- [4, 4-bis- (4-fluoro-phenyl)-butyl]-1, 2,3, 4-tetrahydro-isoquinoline 38. 2- [4, 4-bis- (4-fluoro-phenyl)-butyl]-8-methoxy-1, 2,3, 4-tetrahydro- isoquinoline 39. 1-(3, 4-dihydro-lH-isoquinolin-2-yl)-3, 3-bis-(4-flúoro-phenyl)-propan-1-one 40. 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-N- [l- (5-methyl-thiazol-2-yl)-ethyl]- acetamide 41. 2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- [l- (5-methyl-thiazol-2-yl)- ethyl]-acetamide 42. (3, 3-diphenyl-propyl)- [2- (7-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- ethyl]-amine 43. 2-(benzhydryl-amino)-1-(3,4-dihydro-1H-isoquinolin-2-yl)-eth anone 44. dibenzyl- [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]-amine 45. [2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethy]-(3,3-diphenyl-pro pyl)-amine

46. 2- {(2, 2-diphenyl-ethyl) - [2- (8-methoxy-3, 4-dihydro-IH-isoquinolin-2-yl)-2- oxo-ethyl]-amino}-1-(8-methoxy-3,4-dihydro-1H-isoquinolin-2- yl)-ethanone 47. 2- {benzhydryl- [2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-2-oxo- ethyl]-amino}-1- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone 48. 2-(benzhydryl-amino)-1-(8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- ethanone 49. 2-(2, 2-diphenyl-ethylamino)-1-(8-methoxy-3, 4-dihydro-lH-isoquinolin-2- yl)-ethanone 50. (1H-benzoimidazol-5-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-me thanone 51. N- (2, 2-diphenyl-ethyl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 52. 1- (4-benzhydryl-piperazin-1-yl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2- yl)-ethanone 53. 1- {4- [bis- (4-fluoro-phenyl)-methyl]-piperazin-1-yl)-2- (8-methoxy-3, 4- dihydro-lH-isoquinolin-2-yl)-ethanone 54. 1-(4-benzhydryl-piperazin-1-yl)-2-(3,4-dihydro-1H-isoquinoli n-2-yl)- ethanone 55. 1-f4- [bis- (4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2- (3, 4-dihydro-IH- isoquinolin-2-yl)-ethanone 56. 2- (1, 3-dihydro-isoindol-2-yl)-N- (2, 2-diphenyl-ethyl) -acetamide 57. 1- (4-benzhydryl-piperazin-1-yl)-2- (1, 3-dihydr6-isoindol-2-yl)-ethanone 58. 1- {4- [bis- (4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2- (1, 3-dihydro-isoindol- 2-yl)-ethanone 59. 2-benzhydrylideneaminooxy-1- (3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone 60. 2-(3, 4-dihydro-lH-isoquinolin-2-yl)-N-(2, 2-diphenyl-ethyl)-acetamide 61. 2- (1, 3-dihydro-isoindol-2-yl)-N- (3, 3-diphenyl-propyl)-acetamide 62. N-(3, 3-diphenyl-propyl)-3-(8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- propionamide 63. 2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (phenyl-pyridin-2-yl- methyl)-acetamide 64.3, 4-dihydro-1H-isoquinoline-2-carbothioic acid (2, 2-diphenyl-ethyl)-amide 65. N-benzhydryl-2- (1, 3-dihydro-isoindol-2-yl)-acetamide 66.3, 4-dihydro-lH-isoquinoline-2-carbothioic acid benzhydryl-amide

67. 8-methoxy-3, 4-dihydro-1H-isoquinoline-2-carbothioic acid benzhydryl- amide 68. 8-methoxy-3, 4-dihdyro-1H-isoquinoline-2-carbothioic acid (2,2-diphenyl- ethyl)-amide 69. 2-benzhydrylideneaminooxy-1-(8-methoxy-3,4-dihydro-1H-isoqui nolin-2- yl)-ethanone 70. 2-(di-pyridin-2-yl-methyleneaminooxy)-1-(8-methoxy-3,4-dihyd ro-1H- isoquinolin-2-yl)-ethanone 71. 2-(8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-phenyl-2, 3-dihydro- benzo [1, 4] oxazin-4-yl)-ethanone 72. 2- (8-methoxy-3, 4-dihydro-1 H-isoquinolin-2-yl)-1-phenoxazin-10-yl- ethanone 73. 1-(10, 11-dihydro-dibenzo [b, fgazepin-5-yl)-2-(8-methoxy-3, 4-dihydro-1H- isoquinolin-2-yl)-ethanone 74. 2- [3- (2, 2-diphenyl-vinyloxy)-propyl]-8-methoxy-1, 2,3, 4-tetrahydro- isoquinoline 75. 4-methoxy-1, 3-dihydro-isoindole-2-carbothioic acid benzhydryl-amide 76. 7-methoxy-1, 3,4, 5-tetrahydro-benzo [c] azepine-2-carbothioic acid benzhydryl-amide 77. 7-methoxy-1, 3,4, 5-tetrahydro-benzo [c] azepine-2-carbothioic acid (2,2- diphenyl-ethyl)-amide 78. N, N-diisopropyl-2-(8-methoxy-3,4-dihydro-1H-sioquinolin-2-yl)- acetamide 79. N, N-dibenzyl-2- (8-methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-acetamide 80. N-benzhydryl-2- (4-methoxy-1, 3-dihydro-isoindol-2-yl)-acetamide 81. N-(4, 4-diphenyl-butyl)-2-(8-methoxy-3, 4-dihydro-1 H-isoquinolin-2-yl)- acetamide <BR> <BR> <BR> <BR> <BR> 82. N-(4, 4-diphenyl-butyl)-2-(. 4-methoxy-1, 3-dihydro-isoindol-2-yl)-acetamide 83. N-benzhydryl-2- (7-methoxy-1, 3,4, 5-tetrahydro-benzo [c] azepin-2-yl)- acetamide 84. N-(2,2-diphenyl-ethyl)-2-(7-methoxy-1, 3,4, 5-tetrahydro-benzo [c] azepin-2- yl)-acetamide 85. N- (3, 3-diphenyl-propyl)-2- (7-methoxy-1, 3,4, 5-tetrahydro-benzo [c] azepin-2- yl)-acetamide 86. NN-dibenzyl-2- (7-methoxy-1, 3,4, 5-tetrahydro-benzo [c] azepin-2-yl)- acetamide 87. N,N-dibenzyl-3-(8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-p ropionamide 88. N- (3, 3-diphenyl-propyl)-2- (4-methoxy-1, 3-dihydro-isoindol-2-yl) -acetamide 89. N- (2, 2-diphenyl-ethyl)-2- (4-methoxy-1, 3-dihydro-isoindol-2-yl)-acetamide 90. 2- (1, 3-Dihydro-isoindol-2-yl)-N- (2, 2-diphenyl-ethyl) -acetamide 91. N, N-Dibenzyl-2-(8-ethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetamide 92. N-(4,4-Diphenyl-butyl)-2-(8-ethoxy-3,4-dihydro-1H-isoquinoli n-2-yl)- acetamide 93. 2-(8-Ethoxy-3, 4-dihydro-1 H-isoquinolin-2-yl)-1-(3-phenyl-2, 3-dihydro- benzo [1,4] oxazin-4-yl)-ethanone 94. N- (3-Benzhydryloxy-propyl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 95. 2-(1,3-Dihydro-isoindol-2-yl)-N-(3,3-diphenyl-propyl)-acetam ide 96. N- (2-Benzhydrylsulfanyl-ethyl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2- yl}-acetamide 97. 2-(8-Allyloxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(3, 3-diphenyl-propyl)- acetamide 98. 2- (4-Amino-1, 3-dihydro-isoindol-2-yl)-N- (2, 2-diphenyl-ethyl)-acetamide 99. 2-(4-Amino-1,3-dihydro-isoindol-2-yl)-N-(3, 3-diphenyl-propyl) -acetamide 100. 2- (4-Amino-1, 3-dihydro-isoindol-2-yl)-N- (4, 4-diphenyl-butyl) -acetamide 101. 2- (4-Amino-1, 3-dihydro-isoindol-2-yl)-N, N-dibenzyl-acetamide 102. 2- [4, 4-Bis- (4-fluoro-phenyl)-butyl]-2, 3-dihydro-lH-isoindol-4-ylamine 1 03. N-[2-(Diphenyl-methanesulfinyl)-ethyl]-2-(8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-acetamide 104. N-[2-(Diphenyl-methanesulfonyl)-ethyl]-2-(8-methoxy-3,4-dihy dro-1H- isoquinolin-2-yl)-acetamide 105. 2-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(1-phenyl-et hyl)-acetamide 106. 2-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-(1-phenyl-ethyl)-aceta mide 107. 2-(Benzhydryl-amino)-1-(1,3-dihydro-isoindol-2-yl)-ethanone 108. 2-(8-Amino-3,4-dihydro-1H-isoquinolin-2-yl)-N-benzhydryl-ace tamide 109. 2- (8-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (4, 4-diphenyl-butyl) - acetamide 110. 2- [4, 4-Bis- (4-fluoro-phenyl)-butyl]-1, 2,3, 4-tetrahydro-isoquinolin-8-ylamine 111. 2- (8-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (2, 2-diphenyl-ethyl)- acetamide 112. 2- (8-Acetylamino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (4, 4-diphenyl-butyl) - acetamide 113. N- [3, 3-Bis- (4-methoxy-phenyl)-propyl]-2- (1, 3-dihydro-isoindol-2-yl)- acetamide 114. N- [3, 3-Bis- (4-methoxy-phenyl)-propyl]-2- (3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 115. N- [3, 3-Bis- (4-methoxy-phenyl)-propyl]-2- (8-methoxy-3, 4-dihydro-IH- isoquinolin-2-yl)-acetamide 116. N- [3- (3, 4-Bis-acetylamino-phenyl)-3-phenyl-propyl]-2- (3, 4-dihydro-lH- isoquinolin-2-yl)-acetamide 117. N-(4, 4-Diphenyl-butyl)-2-(8-methanesulfonylamino-3, 4-dihydro-lH- isoquinolin-2-yl)-acetamide 118. N- [Bis- (4-fluoro-phenyl)-methyl]-2- (1, 3-dihydro-isoindol-2-yl)-acetamide 119. N- [Bis- (4-fluoro-phenyl)-methyl]-2- (3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 120. N- [Bis- (4-fluoro-phenyl)-methyl]-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2- yl)-acetamide 121. N- [Bis- (4-fluoro-phenyl)-methyl]-2- (6, 7-dimethoxy-3, 4-dihydro-1H- isoquinolin-2-yl)-acetamide 122. 3- (5-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (3, 3-diphenyl-propyl) - propionamide 123. 2-(5-Amino-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2, 2-diphenyl-ethyl) - acetamide 124. 2- (Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (4, 4-diphenyl-butyl)- acetamide 125. 3-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(3, 3-diphenyl-propyl) - propionamide 126. 2- (6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(2, 2-diphenyl-ethyl)- acetamide 127. 3- (8-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (3, 3-diphenyl-propyl) - propionamide <BR> <BR> <BR> <BR> 128. N- (3-Carbazol-9-yl-propyl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 129. N- (3-Carbazol-9-yl-propyl)-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide 130. N- [3- (5-Chloro-2-methyl-indol-1-yl)-propyl]-2- (8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-acetamide 131. N- [3- (5-Chloro-2-methyl-indol-1-yl)-propyl]-2- (8-hydroxy-3, 4-dihydro-1H- isoquinolin-2-yl)-acetamide 132. 2-(8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10-yl-ethanone 133. 1-Benzhydryl-3-[2-(8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl )-ethyl]- thiourea 134. 1-Benzhydryl-3- [2- (6,7-dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]- thiourea- 135. 1-Benzhydryl-3- [2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]-urea 136. 1-Benzhydryl-3- [2- (6,7-dimethoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-ethyl]- urea 137. 1-(2,2-Diphenyl-ethyl)-3-[2-(8-methoxy-3,4-dihydro-1H-isoqui nolin-2-yl)- ethyl]-thiourea 138. 1- [2-(6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]-3- (2, 2-diphenyl- ethyl)-thiourea 139. 2- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenothiazin-10-yl-ethanone 140. 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-l-phenothiazin-10-yl-ethanone 141. 1- (2-Chloro-phenothiazin-10-yl)-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2- yl)-ethanone 142. 1- (2-Chloro-phenothiazin-10-yl)-2- (8-methoxy-3, 4-dihydro-1 H-isoquinolin-2- yl)-ethanone 143. 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-l- (5-oxo-5H-51ambda*4*- phenothiazin-10-yl)-ethanone 144. 2- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10-yl-ethanone 145. 2-(8-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-trifluoro methyl- phenothiazin-10-yl)-ethanone 146. 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1- (2-trifluoromethyl- phenothiazin-10-yl)-ethanone 147. 1- (2-Acetyl-phenothiazin-10-yl)-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2- yl)-ethanone 148. 1- (2-Acetyl-phenothiazin-10-yl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2- yl)-ethanone 149. 2- (8-Hydroxy-3, 4-dihydro-1H-isoquinolin-2-yl)-N, N-diphenyl-acetamide 150. 2- (8-Methoxy-3, 4-dihydro-IH-isoquinolin-2-yI)-N, N-diphenyl-acetamide <BR> <BR> <BR> <BR> 151. 2- (6, 7-Dimethoxy-3, 4-dihydro- lH-isoqumolin-2-yl)-1- (5, 5-dioxo-5H-<BR> <BR> <BR> <BR> <BR> 51ambda*6*-phenothiazin-10-yl)-ethanone 152. 2-(6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenothiazin-10-yl- ethanone 153. 1- (2-Chloro-phenothiazin-10-yl)-2- (6, 7-dimethoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethanone 154. 2- (6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-(2-trifluoromethyl- phenothiazin-10-yl)-ethanone 155. 1- (2-Acetyl-phenothiazin-10-yl)-2- (6, 7-dimethoxy-3, 4-dihydro-1H- isoquinolin-2-yl)-ethanone 156. 2- (6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-l- (2-methylsulfanyl- phenothiazin-10-yl)-ethanone 157. 2- (6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1- (5-oxo-5H-51ambda*4*- phenothiazin-10-yl)-ethanone 158. 2-(8-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-methylsul fanyl- phenothiazin-10-yl)-ethanone 159. 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1- (2-methylsulfanyl- phenothiazin-10-yl)-ethanone 160. Phenothiazine-10-carboxylic acid [2-(8-hydroxy-3,4-dihydro-1H-isoquinolin-2- yl)-ethyl]-amide 161. Phenothiazine-10-carboxylic acid [2-(6, 7-dimethoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide 162. Phenothiazine-10-carboxylic acid [2- (8-methoxy-3, 4-dihydro-lH-isoquinolin- 2-yl)-ethyl]-amide 163. Phenoxazine-10-carboxylic acid [2- (S-hydroxy-3, 4-dihydro-IH-isoquinolin-2- yl)-ethyl]-amide 164. Phenoxazine-10-carboxylic acid [2- (8-methoxy-3, 4-dihydro-1H-isoquinolin-2- yl)-ethyl]-amide 165. Phenoxazine-10-carboxylic acid [2- (6, 7-dimethoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide 166. N- [3, 3-Bis- (4-fluoro-phenyl)-propyl]-3- (8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-propionamide 167. (8-Hydroxy-3, 4-dihydro-1 H-isoquinolin-2-yl)-acetic acid N', N'-diphenyl- hydrazide 168. (8-Methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-acetic acid N', N'-diphenyl- hydrazide 169. (6,7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetic acid N', N'-diphenyl- hydrazide 170. 4- [2- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3, 4-dihydro-2H- benzo [1, 4] oxazine-2-carboxylic acid ethyl ester 171. 4-[2-(8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3, 4-dihydro-2H- benzo [1, 4] oxazine-2-carboxylic acid ethyl ester 172. 2-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(4-phenoxy-p henyl)- acetamide 173. 2- (5, 8-Dihydro-6H- [ 1, 7] naphthyridin-7-yl)-l-phenoxazin-10-yl-ethanone 174. 1- [2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]-3- (4-phenoxy- phenyl)-urea 175. 2-(8-Amino-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenoxazin-10- yl-ethanone 176. 2-(8-Hydroxy-3, 4-dihydro-I H-isoquinolin-2-yl)-N-(4-hydroxy-phenyl)-N- phenyl-acetamide 177. N- (4-Hydroxy-phenyl)-2- (8-meth6xy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- phenyl-acetamide 178. 2-(1,3-Dihydro-isoindol-2-yl)-1-phenoxazin-10-yl-ethanone 179. 2-(8-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(9H-xanthen- 9-yl)- acetamide 180. 2- (8-Methoxy-3, 4-dihydro-1 H-isoquinolin-2-yl)-N- (9H-xanthen-9-yl)- acetamide 181. 2- (5, 8-Dihydro-6H- [1, 7] naphthyridin-7-yl)-N,N-diphenyl-acetamide 182. 2-(8-Methoxy-,4-dihydro-1H-isoquinolin-2-yl)-N,N-bis-(4-meth oxy-phenyl)- acetamide <BR> <BR> <BR> <BR> <BR> 183. 2- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N, N-bis- (4-methoxy-phenyl)- acetamide 184. 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (2-phenoxy-phenyl)- acetamide 185. 2-(8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(2-phenoxy-phenyl)- acetamide 186. 1- [ (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetyl]-4, 4- diphenylsemicarbazide 187. 2-(8-Methoxy-3, 4-dihydro-1 H-isoquinolin-2-yl)-1-[2-(5-methyl- [1, 3,4] oxadiazol-2-yl)-2, 3-dihydro-benzo [1,4]oxazin-4-yl]-ethanone 188. N- (3-Amino-pyridin-2-yl)-N- (2-hydroxy-phenyl)-2- (8-methoxy-3, 4-dihydro- <BR> <BR> <BR> <BR> lH-isoquinolin-2-yl)-acetamide<BR> <BR> <BR> <BR> <BR> <BR> 189. 3-(8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10-yl-propan-1- one 190. 3-(8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10-yl-propan-1- one 191. Methanesulfonic acid 2-(2-oxo-2-phenoxazin-10-yl-ethyl)-1, 2,3, 4-tetrahydro- isoquinolin-8-yl ester 192. 1- (2, 3-Dihydro-benzo [1, 4]oxazin-4-yl)-2-(8-methoxy-3,4-dihydro-1H- isoquinolin-2-yl)-ethanone 193. 2-(7-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10-yl-ethanone <BR> <BR> <BR> <BR> 194. 2-(6-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10-yl-ethanone 195. 2-(5-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenoxazin-1 0-yl-ethanone 196. 2- (4-Methoxy-1, 3-dihydro-isoindol-2-yl)-1-phenoxazin-10-yl-ethanone 197. N-Methanesulfonyl-N- [2- (2-oxo-2-phenoxazin-10-yl-ethyl)-1, 2,3, 4-tetrahydro- isoquinolin-8-yl]-methanesulfonamide 198. N-[2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-yl]- methanesulfonamide 199. 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1- (1-methyl-lH-4-oxa-1, 2,9- triaza-cyclopenta [b] naphthalen-9-yl)-ethanone 200. 2- (8-Methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-1-phenoxazin-10-yl-propan-1- one 201. Phenoxazine-10-carboxylic acid [2- (5, 8-dihydro-6H- [1, 7] naphthyridin-7-yl)- ethyl]-amide 202. 2-(4-Hydroxy-1,3-dihydro-isoindol-2-yl)-1-phenoxazin-10-yl-e thanone 203. Methanesulfonic acid 2-(2-oxo-2-phenoxazin-10-yl-ethyl)-2, 3-dihydro-lH- isoindol-4-yl ester 204. 1-Carbazol-9-yl-2-(8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl )-ethanone 205. 2-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methyl-2, 3-dihydro- benzo[1, 4] oxazin-4-yl)-ethanone 206. 1- (3-tert-Butyl-2, 3-dihydro-benzo [1, 4] oxazin-4-yl)-2- (8-methoxy-3, 4-dihydro- ~ lH-isoquinolin-2-yl)-ethanone 207. 1- (11H-Dibenzo[b,f][1, 4] oxazepin-10-yl)-2- (8-methoxy-3, 4-dihydro-IH- isoquinolin-2-yl)-ethanone 208. 1-(3-Ethyl-2, 3-dihydro-benzo [1, 4] oxazin-4-yl)-2- (8-methoxy-3, 4-dihydro-IH- isoquinolin-2-yl)-ethanone 209. 2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-1, 2,3, 4-tetrahydro-isoquinoline-8-sulfonic acid 210. N- [2- (2-Oxo-2-phenoxazin-10-yl-ethyl)-2, 3-dihydro-1H-isoindol-4-yl]- methanesulfonamide 211. 1- (3-tert-Butyl-2, 3-dihydro-benzo [1, 4] oxazin-4-yl)-2- (8-hydroxy-3, 4-dihydro- 1 H-isoquinolin-2-yl)-ethanone 212. 2-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-[3-(4-methox y-phenyl)-2, 3- dihydro-benzo [1,4] oxazin-4-yl]-ethanone 213. 1- [3- (2, 5-Dimethoxy-phenyl)-2, 3-dihydro-benzo [1, 4] oxazin-4-yl]-2- (8- methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-ethanone 214. N- (4-4- [2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3, 4-dihydro- 2H-benzo [1, 4] oxazin-3-yl}-phenyl)-acetamide

215. 1- [3- (4-Fluoro-phenyl)-2, 3-dihydro-benzo [1, 4] oxazin-4-yl]-2- (8-methoxy-3, 4- dihydro-lH-isoquinolin-2-yl)-ethanone 216. 1- [3- (3, 4-Dimethoxy-phenyl) -2, 3-dihydro-benzo [1, 4] oxazin-4-yl]-2- (8- methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone 217. 2- (4-Methoxy-1, 3-dihydro-isoindol-2-yl)-1-phenoxazin-10-yl-propan-1-one 218. 1- (1, 3-Dihydro-isoindol-2-yl)-2-phenoxazin-10-yl-ethanone 219. 2- (4-Chloro-1, 3-dihydro-isoindol-2-yl)-1-phenoxazin-10-yl-ethanone 220. 2- (2-Oxo-2-phenoxazin-10-yl-ethyl)-2, 3-dihydro-1 H-isoindole-4-carbonitrile and pharmaceutically acceptable salts thereof.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic,. benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e. g. sodium or potassium) and alkali earth metal (e. g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.

The compounds of the invention can contain one or more chiral centres. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non- racemic mixtures and pure enantiomers and/or diastereoisomers.

Preferred compounds of the invention are optically active isomers. Thus, for example, preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.

The compounds of formula (I) may be prepared by conventional routes, for example those set out in any of schemes 1 to 10 shown below.

Compounds of formula (1) in which m is 2 and X, Ri, n and R2 are defined as above (reaction scheme 1) may be prepared from compounds of formula (2) and compounds of formula (3) where X is a leaving group, typically chlorine, using

standard methods such as reaction in the presence of a base, for example potassium carbonate. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 95°C. Compounds of formula (2) may be prepared from compounds of formula (4) by standard methods familiar to those skilled in the art such as reduction in the presence of platinum oxide.

Alternatively, compounds of formula (2) may be prepared from compounds of formula (5) and formaldehyde by standard methods such as the Pictet-Spengler cyclisation.

Compounds of formula (4) are known compounds or may be prepared by standard methods such as cyclisation of compounds of formula (6) according to the published procedure (Bioorg. Med. Chem. 7 (1999) 2647-2666).

Scheme 1 Compounds of formula (1) in which m is 1 and X, Rl, n and R2 are defined as above (reaction scheme 2) may be prepared from compounds of formula (2) and compounds of formula (3) where X is a leaving group, typically chlorine, using standard methods such as reaction in the presence of a base for example potassium carbonate. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 95°C.

Compounds of formula (2) may be prepared from compounds of formula (7) where X is a leaving group, preferably bromine, by standard methods familiar to

those skilled in the art such as alkylation in the presence of an amine. Alternatively, compounds of formula (2) can be prepared from compounds of formula (7) where X is OH converted into a better leaving group such as a mesylate under standard alkylating conditions familiar to those skilled in the art. Compounds of formula (7) may be prepared from dimethylaryl compounds (8) by bromination using a brominating reagent, for example N-bromosuccinimide. Alcohols (9) may be prepared from acids (10) by standard methods such as reduction in the presence of lithium aluminium hydride.

Scheme 2 Compounds of formula (I) in which m is 3 and X, Ri, n and R2 are defined as above (reaction scheme 3) may be prepared from compounds of formula (2) and compounds of formula (3) where X is a leaving group, typically chlorine, using standard methods such as reaction in the presence of a base for example potassium carbonate. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 95°C.

Compounds of formula (2) where m is 3 may be prepared from compounds of formula (11) by reduction in the presence of a metal hydride for example lithium aluminium hydride. Compounds of formula (11) may be prepared from tetralones (12) by standard methods familiar to those skilled in the art such as the Schmidt reaction. Alternatively, compounds of formula (11) may be prepared from tetralones

(12) by standard methods familiar to those skilled in the art such as the Beckmann rearrangement or further methods as outlined e. g. in Alicyclic Chemistry, (Martin Grossel, Oxford University Press). Tetralones (12) are either known compounds or can be prepared by analogy with known methods.

Scheme 3 When R2 is-L-A and L is other than a direct bond, or when R2 is-L-CR (A) 2, the reaction between the compounds of formulae (2) and (3) in schemes 1,2 and 3 is typically performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 80°C. When R2 is-L-A and L is a direct bond, the reaction between the compounds of formulae (2) and (3) is typically effected by Buchwald coupling.

Thus, X in the formula (3) is typically bromine or iodine.

The compounds of formula (3) are known compounds, or may be prepared by known methods. For example, compounds of formula (3) in which R2 is-(CH2) 2- CH (A) 2 can be prepared by the reduction of compounds of formula (14) in the presence of a reducing agent such as lithium aluminium hydride followed by halogenation in the presence of a halogenating agent such as PBr3 (reaction scheme 4). Compounds of formula (14) may be prepared from diarylethenylacids (15) by reduction in the presence of a reducing agent such as palladium. Diarylethenylacids may be prepared from ketones (16) by standard methods familiar to those skilled in the art such as Wittig reaction.

Scheme 4

Compounds of formula (3) in which R2 is-L-CH=C (A) 2 where L and A are defined as above (reaction scheme 5) may be prepared from corresponding carboxylic acids by reduction in the presence of a reducing agent, for example lithium aluminium hydride, followed by halogenation in the presence of a halogenating reagent for example PBr3.

Scheme 5 Compounds of formula (3) wherein 1t2 is-L/-Het-A/can, for example, be prepared from compounds of formula (19) where Y is a leaving group, by reaction with compounds of formula (20) (reaction scheme 6). Compounds of formula (18) in which A is-CHZ (A) 2 may also be prepared from compounds of formula (16) and compounds of formula (20) by standard methods familiar to those skilled in the art.

Thus, when Het is O or S, compounds (16) and (20) can be condensed in the presence of an acid catalyst, for example PTSA. When Het is NH the reaction between compounds (16) and (203-can be effected by standard methods such as reductive amination in the presence of a reducing agent, for example sodium borohydride.

Scheme 6

When R2 is-L-CO-NR3R4 the reaction between the compounds of formulae (2) and (3) in schemes 1 to 3 is typically effected in the presence of a base for example triethylamine. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 80°C.-Further7 compounds of formula (1) wherein R2 is-L-CS-NR3R4 may be prepared from compounds of formula (1) where R2 is-L-CO-NR3R4 by standard methods familiar to those skilled in the art such as sulphonation in the presence of Lawesson's reagent.

Compounds of formula (3) in which R2 is-L-CO-NR3R4 can be prepared from amines (22) and compounds of formula (23), in which (I is Cl or OH, under standard amide coupling reaction conditions (reaction scheme 7). Typically, where X''is Cl, the reaction is effected in the presence of triethylamine.

Scheme 7

A further method for preparing compounds of formula (1) wherein X, m, R and n are defined as above and R2 is-CO-L-NR3R4 involves the reaction of amides (24) and amines (22) where X is a leaving group, preferably chlorine, using standard methods such as reaction in the presence of a base for example triethylamine (reaction scheme 8). Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 80°C. Amides (24) may be prepared from amines (2) and acids (23), wherein X is Cl or OH, under standard 'amide coupling reaction conditions. Typically, where X is Cl, the reaction is effected in the presence of triethylamine.

Alternatively, compounds of formula (1) where R2 is-CO-L-NR3R4, L is a direct bond and R4 is hydrogen may be prepared from amines (2) by standard methods familiar to those skilled in the art such as alkylation with isocyanates (25).

Similarly, compounds of formula (1) where R2 is-CS-L-NR3R4 and L is a direct bond may be prepared from amines (2) by standard methods such as alkylation with isothiocyanates (26).'Compounds of formula (1) wherein R2 is-CS-L-NR3R4 can, of course, be prepared from compounds of formula (1) where R2 is -L-CO-NR3R4 by standard methods familiar to those skilled in the art such as sulphonation using Lawesson's reagent.

Scheme 8

When R2 is-CO-A the reaction between the compounds of formulae (2) and (3) in schemes 1,2 and 3 is typically effected in the presence of a coupling agent such as EDC/HOBT, HATU or HBTU. Compounds of formula (1) wherein R2 is -CS-A/can, of course, be prepared from compounds of formula (1) where R2 is-CO- A by standard methods familiar to those skilled in the art such as reaction with Lawesson's reagent.

Compounds of formula (3), wherein R2 is-CO-L/-O-N=C (A) 2 or-L/-O- N=C (A) 2 may be prepared from ketones (16) and hydroxylamine by standard methods familiar to those skilled in the art (reaction scheme 9). In reaction scheme 9, X and e represent leaving groups, for example chlorine.

Further, an additional method of preparing compounds of formula (I) in which R2 is-CO-L/-O-N=C (A) 2 or-L/-O-N=C (A) 2 involves the reaction of a compound of formula (31) or (3 la), wherein X is a leaving group, typically chlorine, and oximes (29) by standard methods as previously described. Compounds of formulae (31) and (31 a) may be prepared from amines (2) and compounds of formulae (30) or (30a) under standard amide coupling conditions as previously described.

Scheme 9

The compounds of the invention are found to be inhibitors of sensory neurone specific sodium channels. The compounds of the invention are therefore therapeutically useful. Accordingly, the present invention provides a compound of the formula (1), as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body. Also provided is a pharmaceutical composition comprising a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free.

Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.

The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the invention are-compositions suitable for oral administration, for example tablets and capsules.

Compositions suitable for oral administration may, if required, contain a colouring or flavoring agent. Typically, a said capsule or tablet comprises from 5 to 500 mg, preferably 10 to 500 mg, more preferably 15 to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.

One preferred route of administration is inhalation. The major. advantages of inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.

Preferred pharmaceutical compositions of the invention therefore include those suitable for inhalation. The present invention also provides an inhalation device containing such-a pharmaceutical composition. Typically said device is a

metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler. Typically, said propellant is a fluorocarbon.

Further preferred inhalation devices include nebulizers. Nebulizers are devices capable of delivering fine liquid mists of medication through a"mask"that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages.

Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound of the invention without a propellant.

Typically, said inhalation device contains a spacer. A spacer is a device which enables individuals to inhale a greater amount of medication directly into the lower airways, where it is intended to go, rather than into the throat. Many spacers fit on the end of an inhaler; for some, the canister of medication fits into the device.

Spacers with withholding'chambers and one-way valves prevent medication from escaping into the air. Many people, especially young children and the elderly, may have difficulties coordinating their inhalation with the action necessary to trigger a puff from a metered dose inhaler. For these patients, use of a spacer is particularly recommended.

Another preferred route of administration is intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. Drugs can be delivered nasally in smaller doses than medication delivered in tablet form.

By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter-patient variability. Nasal delivery devices further allow medication to be administered in precise, metered doses. Thus, the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.

A further preferred route of administration is transdermal administration. The present invention therefore also provides a transdermal patch containing a compound

of the invention, or a pharmaceutically acceptable salt thereof. Also preferred is sublingual administration. The present invention therefore also provides a sub- lingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof.

A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e. g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e. g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e. g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e. g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or fihn coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable, carrier, e. g. sterile water, olive oil, ethyl oleate, glycols, e. g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

The compounds of the present invention are therapeutically useful in the treatment or prophylaxis of conditions involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone. Said condition may be one of hypersensitivity for example resulting from a concentration of SNS channels at the

site of nerve injury or in axons following nerve injury, or may be sensitisation of the neurone for example at sites of inflammation as a result of inflammatory mediators.

Said compounds of the invention are therefore most preferred for their use in the treatment or prophylaxis of any condition involving hypersensitivity or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone.

Accordingly, the present invention also provides the use of a compound of the formula (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of a condition involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone, more specifically hypersensitivity of a sensory neurone or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone. Also provided is a method of treating a patient suffering from or susceptible to a condition involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone, more specifically hypersensitivity of a sensory neurone or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone, which method comprises administering to said patient'an effective amount of a compound of formula (1), or a' pharmaceutically acceptable salt thereof.

The term treatment in this context is deemed to cover any effect from a cure of said condition to alleviation of any or all of the symptoms. The compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence or severity of said conditions.

Specific conditions in which SNS channels are present and believed to be involved include pain, for example chronic and acute pain, hypersensitivity disorders such as bladder dysfunction and bowel disorders which may or may not also have associated pain, and demyelinating diseases.

SNS sodium channels are known to mediate pain transmission. Typically, the compounds of the invention are therefore used as analgesic agents. SNS specific sodium channels have been identified as being particularly important in the transmission of pain signals. The compounds of the invention are accordingly particularly effective in alleviating pain. Typically, therefore, said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain. The compounds of the invention are effective in alleviating both chronic and acute pain.

Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease. A discussion of acute pain can be found at Halpern (1984) Advances in Pain Research and Therapy, Vol. 7, p. 147. Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper part of the nervous system. Examples of acute pains which can be alleviated with the compounds of the invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.

Chronic pain is generally understood to be pain that persists beyond the usual course of an acute disease or beyond a reasonable time for an injury to heal. A discussion of chronic pain can be found in the Halpern reference given above. Chronic pain is sometimes a result of persistent dysfunction of the nociceptive pain system. Examples of chronic pains which can be alleviated with the compounds of the invention include trigeminal neuralgia, post-herpetic neuralgia (a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease), diabetic neuropathy, causalgia, "phantom limb"pain, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, pain associated with cancer, pain associated with HIV, neuropathic pain, migraine and other conditions associated with chronic cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, spinal cord injury pain, central pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia.

Some of the chronic pains set out above, for example, trigeminal neuralgia, diabetic neuropathic pain, causalgia, phantom limb pain and central post-stroke pain, have also been classified as neurogenic pain. One non-limiting definition of neurogenic pain is pain caused by dysfunction of the peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease. The compounds of the invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain Examples of bowel disorders which can be treated or prevented with the compounds of the invention include inflammatory bowel syndrome and inflammatory bowel disease, for example Crohn's disease and ulcerative colitis.

Examples of bladder dysfunctions which can be treated or prevented with the compounds of the invention include bladder hyper reflexia and bladder inflammation, for example interstitial cystitis, overactive (or unstable) bladder (OAB), more specifically urinary incontinence, urgency, frequency, urge incontinence and nocturia. The compounds of the invention can also be used to alleviate pain associated with bladder hyper reflexia or bladder inflammation.

Examples of demyelinating diseases which can be treated or prevented with the compounds of the invention are those in which SNS channels are known to be expressed by the demyelinated neurones and which may or may not also have associated pain. A specific example of such a demyelinating disease is multiple sclerosis. The compounds of the invention can also be used to alleviate pain associated with demyelinating diseases such as multiple sclerosis.

The compounds of the invention have additional properties as they are capable of inhibiting voltage dependent sodium channels. They can therefore be used, for example, to protect cells against damage or disorders which results from overstimulatibn of sodium channels.

The compounds of the invention are useful in the treatment and prevention of peripheral and central nervous system disorders. They can therefore additionally be used in the treatment or prevention of an affective disorder, an anxiety disorder, a behavioural disorder, a cardiovascular disorder, a central or peripheral nervous system degenerative disorder, a central nervous system injury, a cerebral ischaemia, a chemical injury or substance abuse disorder, a cognitive disorder, an eating disorder, an eye disease, Parkinson's disease or a seizure disorder.

Examples of affective disorders which can be treated or prevented with the compounds of the invention include mood disorders, bipolar disorders (both Type 1 and Type II) such as seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease, schizophrenia, psychotic disorders, mania and paranoia.

Examples of anxiety disorders which can be treated or prevented with the compounds of the invention include generalised anxiety disorder (GAD), panic disorder, panic disorder with agoraphobia, simple (specific) phobias (e. g. arachnophobia, performance anxiety such as public speaking), social phobias, post- traumatic stress disorder, anxiety associated with depression, and obsessive

compulsive disorder (OCD).

Examples of behavioural disorders which can be treated or prevented with the compounds of the invention include behavioural and psychological signs and symptoms of dementia, age-related behavioural disorders, pervasive development disorders such as autism, Asperger's Syndrome, Retts syndrome and disintegrative disorder, attention deficit disorder, aggressivity, impulse control disorders and personality disorder.

Examples of cardiovascular disorders which can be treated or prevented with the compounds of the invention include cardiac arrthymia, atherosclerosis, cardiac arrest, thrombosis, complications arising from coronary artery bypass surgery, myocardial infarction, reperfusion injury, intermittant claudication, ischaemic retinopathy, angina, pre-eclampsia, hypertension, congestive cardiac failure, restenosis following angioplasty, sepsis and septic shock.

Examples of central and peripheral nervous system degenerative disorders which can be treated or prevented with the compounds of the invention include corticobasal degeneration, disseminated sclerosis, Freidrich's ataxia, mdtomeurone diseases such as amyotrophic lateral sclerosis and progressive bulbar atrophy, multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathies such as diabetic neuropathy, tabes dorsalis, drug-induced neuropathy and vitamin deficiency, systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy and spasticity.

Examples of central nervous system injuries which can be treated with the compounds of the invention include traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injuries, raised intracranial pressure, cerebral oedema, hydrocephalus and spinal cord injury.

Examples of cerebral ischaemias which can be treated or prevented with the compounds of the invention include transient ischaemic attack, stroke, for example thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke or lacunar stroke, subarachnoid haemorrhage, cerebral vasospasm, peri-natal asphyxia, drowning, cardiac arrest and subdural haematoma.

Examples of chemical injuries and substance abuse disorders which can be treated or prevented with the compounds of the invention include drug dependence, for example opiate dependence, benzodiazepine addition, amphetamine addiction

and cocaine addiction, alcohol dependence, methanol toxicity, carbon monoxide poisoning and butane inhalation.

Examples of cognitive disorders which can be treated or prevented with the compounds of the invention include dementia, Alzheimer Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntingtons Disease, Lewy body Dementia, Senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome and dementia pugilans.

Examples of eating disorders which can be treated or prevented with the compounds of the invention include anorexia nervosa, bulimia, Prader-Willi syndrome and obesity.

Examples of eye diseases which can be treated or prevented with the compounds of the invention include drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrhage, retinitis pigmentosa, acute glaucoma, in particular acute normal tension glaucoma, chronic glaucoma, in particular chronic normal tension glaucoma, macular degeneration, retinal artery occlusion and retinitis.

Examples of Parkinson's diseases which can be treated or prevented with the compounds of the invention include drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese or carbon monoxide poisoning), Dopa-responsive dystonia-Parkinsonism, posttraumatic Parkinson's disease (punch-drunk syndrome), Parkinson's with on-off syndrome, Parkinson's with freezing (end of dose deterioration) and Parkinson's with prominent dyskinesias.

Examples of seizure disorders which can be treated or prevented with the compounds of the invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures), generalised seizures, including generalised tonicclonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).

The compounds of the present invention are also useful in the treatment and prevention of tinnitus.

A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.001 to 50 mg per kg of body weight, for example 0. 01 to 10 mg, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.

The following Examples illustrate the invention. They do not, however, limit the invention in any way. In this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting SNS specific sodium channels. A negative result in any one particular assay is not determinative.

EXAMPLES The HPLC analysis of Examples 1 to 8,14 to 29,32 to 35,40 to 44 and 98 to 223 was conducted in the following manner: Solvent: MeCN/H20/0. 05% NH3, 5-95% gradient H20-6 min; Column: Phenomenex 50 x 4.6 mm i. d. , C18 reverse phase; and Flow rate: 1.5 mL/min, unless indicated otherwise.

The HPLC analysis of Examples 9 to 13,30, 31,36 to 39 and 45 to 48 was conducted in the following manner: Solvent: MeCN/H20/0. 05% N H3, 5-95% gradient H20-lOmin ; Column: Phenomenex 50 x 4.6 mm i. d., C18 reverse phase; and Flow rate: 1. 5mL/min, unless indicated otherwise.

The HPLC analysis of Examples 49 to 56,58, 59 and 61 to 97 was conducted in the following manner: Solvent: MeCN/H20/0. 05% NH3, 5-95% gradient H20-6min ; Column : Xterra 50 x 4.60 i. d., C18 reverse phase; and Flow rate: 1. 5mL/min, unless indicated otherwise.

The HPLC analysis of Example 60 was conducted in the following manner : Solvent : MeCN/H2O/0.05% NH3, 5-95% gradient H20-lOmin ; Column : Xterra 50 x 4.60 i. d., C18 reverse phase; and Flow rate: 1. 5mL/min.

Example 1: N-Benzhydryl-2-chloro-acetamide To a stirred solution of aminodiphenylmethane (Aldrich A5,360-5) (4.36g, 25.3 mmol) in CH2C12 (50 mL) was added Et3N (Aldrich 47, 128-3) (2. 81g, 27.77 mmol).

The reaction mixture was cooled to approximately 10°C and chloroacetylchloride (Aldrich 10, 449-3) (3.14g, 27.83 mmol) was added drop-wise over 5 min. The reaction mixture was stirred for 2h and quenched by the addition of distilled H20 (50 mL). The layers were separated and the organic layer washed with brine (50 mL), dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by flash column chromatography to afford the title compound as a white solid (0.78g, 12%): HPLC retention time 3. 67min. Mass Spectrum (ES+) m/z 260 (M+H).

The following compounds were synthesized from the appropriate diphenylalkylamine and chloroacetylchloride according to the method described above: 2-Chloro-N-(2, 2-diphenyl-ethyl)-acetamide ; 2-Chloro-N- (3, 3-diphenyl-propyl)-acetamide ; N-Benzyl-2-chloro-N-phenyl-acetamide; N, N-Dibenzyl-2-chloro-acetamide; 2-Chloro-N- (9H-flurenyl-9-yl)-acetamide ; N, N-Dibenzyl-3-chloro-propionamide ; 2-Chloro-l- (3, 4-dihydro-IH-isoquinolin-2-yl)-ethanone ; and 2-Chloro-1- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone.

Example 2: 2-Chloro-N- (4, 4-diphenyl-butyl)-acetamide To a stirred solution of l-Bromo-3, 3-diphenylpropane (Acros 27191231) (2g, 7. 27mmol) in dimethyl sulphoxide (5 mL) was added potassium cyanide (Aldrich 20, 781-0) (6. 57g, 8. 73mmol). The reaction mixture was stirred at room temperature for 19h and quenched by the addition of distilled H20 (20 mL). The resulting solution was extracted with EtOAc (3 x 20 mL) the combined organic layers dried (Na2SO4), filtered and the solvent removed in vacuo. The resulting residue was dissolved in anhydrous tetrahydrofuran (25 mL) and borane-tetrahydrofuran complex (Aldrich 17,619-2) (1M, 27 mL, 27mmol) was added drop wise over 5min. The reaction mixture was heated at reflux for 2h, cooled to 0°C and quenched with CH30H (10 mL). The solvent was removed in vacuo and the residue azeotroped with CH30H (3 x 15 mL). The residue was dissolved in CH2C12 (20 mL) and Et3N (1.39g, 13. 69mmol) was added. The reaction mixture was cooled to approximately 10°C and chloroacetylchloride (Aldrich 10,449-3) (1. 55g, 12. 44mmol) was added drop-wise over 5min. The reaction mixture was stirred for 4h and quenched with distilled H2O (20 mL). The organic layer was separated, dried (MgS04) and the solvent removed in vacuo. The residue was purified by flash column chromatography to afford the title compounds a viscous oil (1. 8g, 85%): HPLC retention time 4. 04min. Mass Spectrum (ES+) m/z 302 (M+H).

Example 3: 3-Chloro-N- (3, 3-diphenyl-propyl)-propionamide To a stirred solution of 3,3 Diphenylpropylamine (Acros 15948-0250) (6. 5g, 30.7mmol) in CH2CI2 (50 mL) was added Et3N (Aldrich 47, 128-3) (2. 81g, 27.77 mmol). The reaction mixture was cooled to approximately 10°C and 3- chloropropionyl chloride (Aldrich C6, 912-8) (4.29g, 30. 7mmol) was added drop- wise over 5 min. The reaction mixture was stirred for 2h and quenched by the addition of distilled H2O (50 mL). The layers were separated and the organic layer washed with brine (50 mL), dried (Na2S04) and the solvent remove in vacuo. The residue was purified by flash column chromatography and recrystallisation from EtOAc to afford the title compound as a white solid (3. 1g, 33%) : HPLC retention time 3.98min. Mass Spectrum (ES+) m/z 302 (M+H).

Example 4 : 8-Methoxyisoquinoline Ref : Y. Yoshida et al Bioorg. Med. Chem. 7 (1999) 2647-2666.

To a 1 L round bottom flask, equipped with a Dean-Stark trap, was added 2- methoxybenzaldehyde (Aldrich 10,962-2) (23. 8g, 175mmol) in benzene (850 mL).

To this stirred solution was added 2,2-dimethoxyethylamine (Aldrich 12,196-7) (18. 3g, 175 mmol). The reaction mixture was refluxed for 5h, cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in tetrahydrofuran (238 mL) and cooled to c. a.-10°C, (external temperature maintained between-8°C to-10°C with acetone/card-ice). To this cooled solution was added ethyl chloroformate (Aldrich 18,589-2) (18. 9g, 174 mmol) over c. a, 5 min. The reaction mixture was allowed to warm to room temperature and treated with trimethyl phosphite (Aldrich T7, 970-7) (25 mL, 212 mmol). The reaction mixture was stirred at room temperature for 60h, and evaporated in vacuo to give an oil. This oil was dissolved in CH2Cl2 (238 mL) and cooled to 0°c (external temperature), treated with titanium tetrachloride (Aldrich 20, 856-6) (200 g, 1.0 mol) over c. a.

8min, warmed to room temperature, heated at reflux for 3h, cooled to room temperature and stirred. overnight. The reaction mixture was diluted with CH2C12

(800mL) and cooled to c. a. 0°C and basified with 30% sodium hydroxide solution.

The neutralised mixture was filtered through celite/sand diluting with c. a. 5 L of CH2C12. The CH2C12 layer was separated and dried over MgS04, filtered and the solvent removed in vacuo. The resulting brown oil is purified by flash column chromatography using CH2C12/CH30H, 90/10, v/v as mobile phase to give the title compounds a red oil (19.7 g, 70%). 1H NMR (400MHZ, DMSO-d6) # 4.02 (3H), 7.12 (1H), 7.55 (1H), 7.75 (1H,), 7.8 (1H), 8.50 (1H), 9. 55 (1H).

Example 5: Isoquinolin-8-ol Ref : Y. Yoshida et al Bioorg. Med. Chem. 7 (1999) 2647-2666.

To a stirred solution of 8-methoxyisoquinoline (7. 0g, 44mmol) in anhydrous CH2C12 (60 mL) cooled in an ice bath, was added over 0. 5h, boron tribromide, 1M in CH2C12 (Aldrich 21,122-2) (219 mL, 219 mmol). The reaction mixture was warmed to room temperature, heated at reflux for 2h, cooled to-78°C, and decomposed by the addition of CH30H (150 mL). The reaction mixture was warmed to room temperature, heated at reflux for 0. 5h and the solvent removed in vacuo. The residue was azeotrope with CH30H (3 x 100 mL) and suspended in H20 (150 mL). To this suspension was added CH2C12 (300 mL) and with vigorous stirring neutralised to c. a.

7.0 with ammonia (0. 88). The CH2C12 layer was separated and the aqueous layer extracted with CH2C12 (2 x 200 mL). The combined layers were dried (Na2S04) and the solvent removed in vacuo. The residue was purified by flash column chromatography to give the title compounds a pale yellow solid. (6.87g, 98%). 1H NMR (400MHz, DMSO-d6) 6 7.10 (1H), 7.45 (1H), 7. 65. (1H,), 7.75 (1H), 8.50 (1H), 9.50 (1H), 10.90 (1H).

Example 6: 1, 2,3, 4-Tetrahydro-isoquinolin-8-ol acetate salt US Patent 3,575, 983 To a stirred solution of Isoquinolin-8-ol (2. 0g, 13. 8mmol) in ethanol (120 mL) was added acetic acid (2 mL) and platinum (IV) oxide (Aldrich 45,992-5) (0.2g). The

reaction mixture was hydrogenated at ca. 4bar for 18h. The catalyst was filtered off and the solvent removed in vacuo to give the title compound as a tan solid (5.2g, 92%): HPLC retention time 2. 0min. Mass Spectrum (ES+) m/z 150 (M+H).

Example 7: 8-Methoxy-1, 2,3, 4-tetrahydro-isoquinoline acetate salt Prepared according to the method described in Example 6: HPLC retention time 3. 33min. Mass Spectrum (ES+) m/z 164 (M+H).

Example 8 : 2-(2-Dibenzylamino-ethyl) 1, 2,3, 4-tetrahydro-isoquinolin-8-ol) To a stirred suspension of 1, 2,3, 4-Tetrahydro-isoquinolin-8-ol acetate salt (l. Og, 4. 78mmol) in MeCN (50mL) was added N- (chloroethy) dibenzylamine hydrochloride (Aldrich 29,136-6) (1.42g, 4. 78mmol), tetrabutylammonium iodide (Aldrich 14,077- 5) (0.29g, 0. 79mmol) and potassium carbonate (Acros) (0.66g, 4.78mmol). The reaction mixture was heated at 95°C for 7h and cooled to room temperature, filtred and the solvent removed in vacuo. The residue was dissolved in CH2C12 (80mL), washed with H20 (25mL), dried (Na2SO4) and the solvent remove in vacuo. The residue was purified by flash column chromatography using CH2C12/CH30H/ ammonia, 95/5/0. 2, v/v/v, as mobile phase to give the title co7npoundas a low melting solid (0.71g, 39%) : 1H NMR (400MHZ, CDC13) 8n 2.6-2. 9 (8H), 3.55 (2H), 3.65 (4H), 6.5 (1H), 6. 95 (1H), 7.2-7. 5 (11H). HPLC retention time 7. 27min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 9: 2- [4, 4-Bis- (4-fluoro-phenyl)-butyl]-1, 2,3, 4-tetrahydro-isoquinoline Prepared according to the method described in Example 8. HPLC retention time 8. 29min. Mass Spectrum (ES+) m/z 378 (M+H).

Example 10: 2- [4, 4-Bis- (4-fluoro-phenyl)-butyl]-8-methoxy-1, 2, 3,4-tetrahydro- isoquinoline

Prepared according to the method described in Example 8. HPLC retention time 8. 39min. Mass Spectrum (ES+) m/z 408 (M+H).

Example 11: 2- (2, 2-Diphenyl-ethyl)-1, 2,3, 4-tetrahydro-isoquinoline-8-ol To a stirred solution of 1, 2,3, 4-Tetrahydro-isoquinolin-8-ol acetate salt (0.120g, 0, 57mmol) in CH30H (5mL) was added Et3N (Aldrich 47,128-3) (0. 058g, 0. 57mmol). The reaction mixture was stirred for 0. 5h, diphenylacetaldehyde (Aldrich D20-245-0) (0. 113g, 0. 57mmol) in CH30H (5mL), and sodium cyanoborohydride (Aldrichl5, 615-9) (0.036g, 0.57mmol) was added. The reaction mixture was stirred for 18h. The solvent was removed in vacuo and the residue was purified by flash column chromatography using CH2C12/. CH30H, 95/5 w to afford the title compound as a white solid (0.032g, 17%). HPLC retention time 3. 21min.

Mass Spectrum (ES+) m/z 330 (M+H).

Example 12: 2-(2, 2-Diphenyl-ethyl) 1, 2,3, 4-tetrahydro-isoquinoline Prepared according to the method described in Example 11 but with CH2C12 as the reaction solvent. HPLC retention time 4.96min. Mass Spectrum (ES+) m/z 314 (M+H).

Example 13 : 2- (2, 2-Diphenyl-ethyl)-8-methoxy-1, 2,3, 4-tetrahydro-isoquinoline Prepared according to the method described in Example 11 but with CH2Cl2 as the reaction solvent. HPLC retention time 4.96min. Mass Spectrum (ES+) m/z 344 (M+H).

Example 14: N-Benzyhydryl-2- (3, 4-dihydro-lH-isoquinolin-2-yl)-acetamide To a stirred solution of 1,2, 3,4-Tetrahydroisoquinoline (AldrichA5, 5560-8) (0. 133g, lmmol) in MeCN (l SmL) was added potassium carbonate (Acros P/4120/50) 0. 138g, lmmol)), tetrabutlylammonium iodide (Aldrich 14,077-5) (0.074g, 0. 02mmol). To this suspension was added N-Benzhydryl-2-chloro-acetamide (0.259g, lmmol) in MeCN (lOmL). The reaction mixture was heated at reflux for 8h,

cooled to room temperature and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography using iso-hexane. EtOAc as mobile phase to afford the title compound as a clear oil (0.256g, 72%). HPLC retention time 4. Mass Spectrum (ES+) m/z 357 (M+H).

Example 15: 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-N- (9H-fluorenyl)-acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 34min. Mass Spectrum (ES+) m/z 355 (M+H).

Example 16: N, N-Dibenzyl-2- (3, 4-dihydro-lH-isoquinolin-2yl)-acetamide Prepared according to the method described in Example. 14. HPLC retention time 4. 41min. Mass Spectrum (ES+) m/z 371 (M+H).

Example 17 : N-BenzyI-2- (3, 4-dihydro-lH-isoquinoIin-2-yI)-N-phenyI-acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 24min. Mass Spectrum (ES+) m/z 357 (M+H).

Example 18 : 2- (3, 4-Dihydro-lH-isoquinolin-2yl)-N- (3, 3-diphenyl-propyl)- acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 35min. Mass Spectrum (ES+) m/z 385 (M+H).

Example 19: N-Benzhydryl-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 30min. Mass Spectrum (ES+) m/z 387 (M+H).

Example 20: N- (9H-Fluorenyl-9-yl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinoline- 2-yl)-acetamide

Prepared according to the method described in Example 14. HPLC retention time 4. 20min. Mass Spectrum (ES+) m/z 385 (M+H).

Example 21: N-Benzhydryl-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- phenyl-acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 15min. Mass Spectrum (ES+) m/z 387 (M+H).

Example 22: N-(3, 3-Diphenyl-propyl)-2-(8-methoxy-374-dihydro-lH- isoquinolin-2-yl)-acetamide Prepared according to the method described in Example 14 : HPLC retention time 4. 22min. Mass Spectrum (ES+) m/z 415 (M+H).

Example 23: N, N-Dibenzyl-2-(8-hydroxy-3,3-dihydro-1H-isoquinolin-2-yl)- acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 21min. Mass Spectrum (ES+) m/z 387 (M+H).

Example 24: N-Benzhydryl-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 03min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 25: N-Benzyl-2- (8-hydroxy-3, 4-dihydro-IH-isoquinolin-2-yl)-N- phenyl-acetamide Prepared according to the method described in Example 14. HPLC retention time 3. 99min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 26: N- (9H-fluoren-9-yl)-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin-2- yl)-acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 02min. Mass Spectrum (ES+) m/z 371 (M+H).

Example 27: N- (3, 3-Diphenyl-propyl)-2- (8-hydroxy-3, 4-dihydro-lH-isoquinolin- 2-yl)-acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 10min. Mass Spectrum (ES+) m/z 401 (M+H).

Example 28: 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-N- [l- (5-methyl-thiazol-2-yl)- ethyl]-acetamide Prepared according to the method described in Example 14. HPLC retention time 3. 73min. Mass Spectrum (ES+) m/z 316 (M+H).

Example 29: 2-(8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-[1-(5-methyl- thiazol-2-yl)-ethyl]-acetamide Prepared according to the method described in Example 14. HPLC retention time 3. 21min. Mass Spectrum (ES+) m/z 332 (M+H).

Example 30: 1- (3, 4-Dihydro-lH-isoquinoline-2-yl-3, 3-bis- (4-fluoro-phenyl)- propan-l-one To a stirred solution of 1,2, 3,4-Tetrahydroisoquinoline (AldrichA5, 5560-8) (0.102g, 0. 76mmol) in CH2C12 (5mL) was added 3, 3-Bis- (4-fluro-phenyl)-propionyl chloride (0.107g, 0. 33mmol). The reaction mixture was stirred for 5h and the solvent removed in vacuo. The residue was purified by flash column chromatography using CH2Cl2as mobile phase followed by preparative HPLC to give the title compound as an oil

(3.4mgs, (2%). HPLC retention time 4. 39min. Mass Spectrum (ES+) m/z 378 (M+H).

Example 31: 2-(BenZhydryl-amino)-1-(3, 4-dihydro-lH-isoquinolin-2-yl)- ethanone To a stirred solution of2-Chloro-l- (3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone (0. 150g, 0. 71mmol) in acetonitril was added of aminodiphenylmethane (Aldrich A5, 360-5) (0.131g, 0.71mmol), tetrabutlylammonium iodide (Aldrich 14,077-5) (0.53g, 0. 14mmol) and potassium carbonate (Acros) (0.99g, 0. 71mmol). The reaction mixture was heated at reflux for 5h and cooled to room temperature and the solvent removed in vacuo. The residue was purified by column chromatography using EtOAc/iso-hexane, 1/1, v/v, to give the title compound as a colourless oil (0. lOg, 39%). HPLC retention time 6. 65min. Mass Spectrum (ES+) m/z 357 (M+H) : Example 32: 1- (3, 4-Dihydro-1H-isoquinolin-2-yl)-2- (2, 2-diphenyl-ethylamino)- ethanone To a stirred solution of 2-Chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanone (0.209g, l. Ommol) was added (0.197g, l. Ommol), 2, 2-Diphenylpropyamine (Aldrich D20-670-9) (0. 2113g, l. Ommol) tetrabutlylammonium iodide (Aldrich 14,077-5) (0.369g, 0. 074mmol) and potassium carbonate (Acros) (0.99g, 0. 71mmol). The reaction mixture was heated at reflux for 18h, cooled to room temperature and the solvent removed in vacuo. The residue was purified by column chromatography using EtOAc/iso-hexane, 1/3, v/v, to give the title compound as a colourless oil (0.047g, 12 %). HPLC retention time 4. 24min. Mass Spectrum (ES+) m/z 385 (M+H).

Example 33: 1-(3, 4-Dihydro-lH-isoquinolin-2-yl)-2-[[2-(3, 4-dihydro-lH- isoquinolin-2-yl)-2-oxo-ethyl]-(3x3-diphenyl-propyl)-amino]- ethanone Prepared according to the method described in Example 31. HPLC retention time 4.70min. Mass Spectrum (ES+) m/z 558 (M+H).

Example 34 : 1- (3, 4-Dihydro-lH-isoquinolin-2-yl)-2- (3, 3-diphenyl-propylamino)- ethanone Prepared according to the method described in Example 31. HPLC retention time 4. 30min. Mass Spectrum (ES+) m/z 385 (M+H).

Example 35: 2-Dibenzylamino-l- (3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 31. HPLC retention time 4. 72min. Mass Spectrum (ES+) m/z 371 (M+H).

Example 36: 2-{(2, 2-Diphenyl-ethyl)-l2-S-methoxy-3, 4-dihydro-lH-isoquinolin- 2-yl)-2-oxo-ethyl]-amino}-lH-isoquinolin-2yl)-ethanone Prepared according to the method described in Example 31. HPLC retention-time- 4. 75min. Mass Spectrum (ES+) m/z 604 (M+H).

Example 37: 2- Benzhydryl- [2- (8-methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]-amino}-1-(8-mthoxy-,4-dihydro-1H-isoquinolin-2-yl )-ethanone Prepared according to the method described in Example 31. HPLC retention time 7.57min. Mass Spectrum (ES+) m/z 560 (M+H).

Example 38: 2-(Benzhydryl-amino)-1-(8-methoxy-3,4-dihydro-1H-isoquinolin e- 2-yl)-ethanone Prepared according to the method described in Example 31. HPLC retention time 6. 18min. Mass Spectrum (ES+) m/z 387 (M+H).

Example 39: 2-(2, 2-Diphenyl-ethylamino)-1-(8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethanone

Prepared according to the method described in Example 31. HPLC retention time 6. 65min. Mass Spectrum (ES+) m/z 401 (M+H).

Example 40: 2-(1,3-Dihydro-isoindol-2-yl)-N-(3,3-diphenyl-propyl)-acetam ide To a stirred solution of isoindoline (Aldrich 51,557-4) (0.25g, 2. 1mmol) in MeCN (15mL) was added 2-Chloro-N- (3, 3-diphenyl-propyl) -acetamide (0.60g, 2. 1mmol), tetrabutlylammonium iodide (Aldrich 14,077-5) (0.16g, 0.42mmol) and Et3N) (Aldrich 47,128-3) (600al, 2. 1mmol). The reaction mixture was heated at reflux for 4h and cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in CH2C12 (lOOmL), washed with H20 (20mL), dried (Na2S04) and the solvent remove in vacuo. The residue was purified by flash column chromatography using EtOAc/iso-hexane, 1/1 as mobile phase to give the title compounds a tan solid (0. 25g ; 32%).. HPLC retention time 4.33min. Mass Spectrum (ES+) m/z 371 (M+H).

Example 41: N-Benzhydryl-2- (1, 3-dihydro-isoindol-2-yl)-acetamide Prepared according to the method described in Example 40. HPLC retention time 4.32min. Mass Spectrum (ES+) m/z 343 (M+H).

Example 42: 2-Benzhydrylideneaminooxy-1-(3,4-dihydro-1H-isoquinoline-2-y l)- ethanone To a suspension of sodium hydride 60% dispersion in mineral oil (Aldrich 2,344-1) in dimethyl foramide (2mL) cooled in an ice bath was added benzophenone oxime (Lancaster 0817) (0.47g, 2. 39mmol). The reaction mixture was removed from the ice bath and stirred at room temperature for 0. 5h. To this solution was added 2-Chloro-l- (3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone (0. 5g, 2. 39mmol) in dimethyl formamide (lmL). The reaction was stirred for 18h, diluted with H20 (30mL), extracted with Et20 (50mL), dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by preparative HPLC (Solvent : MeCN/H20/0. 05% NH3, 5-95% gradient H20-6min. Column: Phenomenex 50 x 4.6 mm i. d., C18 reverse phase.

Flow rate: 15mL/min.) to give the title compound as a glass (0.44g, 55%). HPLC retention time 4. 53min. Mass Spectrum (ES+) m/z 371 (M+H).

Example 43: 2-lDenZhydrylideneaminooxy-1-(8-methoxy-3, 4-dihydro-lH- isoquinoline-2-yl)-ethanone Prepared according to the method described in Example 42. HPLC retention time 4. 48min. Mass Spectrum (ES+) m/z 401 (M+H).

Example 44: 2-(Di-pyridin-2-yl-methyleneaminooxy)-1-(8-methoxy-3, 4-dihydro- lH-isoquinoline-2-yl)-ethanone Prepared according to the method described in Example 42. HPLC retention time 3. 50min. Mass Spectrum (ES+) m/z 403 (M+H).

Example 45: 2-(5-Phenyl-2H-[1,2,3]triazol-4-ylmethyl)-1,2, 3, 4-tetrahydro- isoquinolin-8-ol 5-Phenyl-2H-[1,2,3]-triazole-4-carbaldehyde: To a stirred solution of phenylacetylene (Aldrich 11,770-6) (5. 1g, 50 mmol) in anhydrous tetrahydrofuran (125 mL) at-40°C under nitrogen was added dropwise over c. a 2 min nButyl lithium (Aldrich 18,617-1) (31.3 mL, . 50 mmol) whilst maintaining the temperature (internal) between-35°C to-40°C with external cooling. To this solution was added anhydrous dimethyl formamide (7.75 mL) and the reaction mixture allowed to warm to room temperature, stirred for 0. 5h and quenched by pouring into a rapidly stirred biphasic solution of 10% potassium dihydrogen phosphate (270 mL) and methyl tert-butyl ether (250 mL), cooled to c. a.

- 5°C. The layers were separated and the aqueous layer back extracted with methyl tert-butyl ether (100 mL). The combined organic layers were washed with H20 (2 x 200 mL), dried (MgS04) and evaporated to dryness in vacuo to give a yellow oil which was purified by flash column chromatography to give 6. 1 g of a pale yellow oil. A solution of this oil (3. 1g in dimethyl sulphoxide (17.5 mL) was added to a

vigorously stirred solution of sodium azide (Aldrich 19,993-1) (1.79g, 27.5 mmol) over c. a. 10 min whilst maintaining the temperature (internal) between 20 to 25°C.

The reaction mixture was stirred for a further O. 5h and quenched by pouring into a rapidly stirred biphasic solution of 15% potassium dihydrogen phosphate (150 mL) and methyl tert-butyl ether (160 mL). The organic layer was separated and washed with H20 (2 xlOO mL). The aqueous layers were re-extracted with methyl tert-butyl ether (100 mL) and the combined organic layers dried over (MgSO4) and evaporated in vacuo to afford the title compound as an off white solid (3. 1g, 65%) : IH NMR (400MHz, CDC13) 8H 7.46-7. 59 (3H), 7.66-7. 89 (2H), 10.14 (1H), 16. 08 (1H,).

2-(S-Phe7Zyl-2H-[1, 2, 3] triazol-4-ylinethyl)-1, 2, 3, 4-tetraliydro-isoquinolin-8-ol : To a stirred solution of 1, 2,3, 4-Tetrahydro-isoquinolin-8-ol acetate salt (0.120g, 0, 57mmol) in CH30H (5mL) was added Et3N (Aldrich 47,128-3) (0. 058g, 0. 57mmol). The reaction mixture was stirred for 0. 5h, 5-phenyl-2H- [1, 2,3]-triazole- 4-carbaldehyde (0. 025g, 0. 14mmol) in CH3OH (5mL), and sodium cyanoborohydride (Aldrichl5, 615-9) (0.009g, 0. 14mmol) was added. The reaction mixture was heated at reflux for 5h, cooled to room temperature and the solvent removed in vacuo. The residue was purified by flash column chromatography using EtOAc/iso-hexane 1/1, v/v as mobile phase to afford the title compound as a viscous oil (0.004g, 10%). HPLC retention time 2. 54min. Mass Spectrum (ES+) m/z 306 (M+H).

Example 46: [2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-(3,3-diphenyl-pr opyl)- amine To a stirred solution of 2-(3o4-Dihydro-lH-isoquinolin-2yl)-N-(3, 3-diphenyl-propyl) - acetamide : (0. 184g, 0. 047mmol) in tetrahydrofuran (lOmL) was added lithium aluminium hydride 1M in Et2O (Aldrich 21, 279-2) (lOmL, lOmmol). The reaction mixture was heated at reflux 8h, cooled to room temperature and stirred for 18h. The reaction mixture was quenched with CH2Cl2 (30mL) and sodium hydroxide solution (2M, 4mL). The CH2C12 layer was separated, washed with H20 dried (Na2S04) and the solvent removed in vacuo. The residue was purified by preparative HPLC

(Solvent: MeCN/H20/0. 05% NHs, 5-95% gradient H2O-10min. Column.

Phenomenex 50 x 19 mm i. d., C18 reverse phase. Flow rate: 15mL/min.), to give the title compound as a pale yellow oil (0.007g, 3.9%). HPLC retention time 7. 76min.

Mass Spectrum (ES+) m/z 371 (M+H).

Example 47: Dibenzyl- [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]-amine Prepared according to the method described in Example 46. HPLC retention time 8. 48min. Mass Spectrum (ES+) m/z 357 (M+H).

Example 48 : 2-(2-Benzyloxy-propyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol To a stirred solution of 2-Benzyloxypropionic acid (0. 318g, 1.76mmol) in CH2Cl2 (3mL) was added oxalyl chloride (Aldrich 0-880-1) (1.12g, 8. 83mmol). The reaction mixture was stirred at room temperature for 5h and the solvent and excess reagent removed in vacuo. The residue was dissolved-in CH2Cl2 (2mL) and added to a-stirred solution of 1, 2,3, 4-Tetrahydro-isoquinolin-8-ol acetate salt (0.367g, 3.52mmol), Et3N (Aldrich 47, 128-3) (0.356g, 3.52mmol) in CH2C12 (2mL) and the reaction mixture was stirred overnight. The reaction mixture was diluted with 5% hydrochloric acid (5mL), separated and me organic layer washed with H20 (SmL), brine (5mL), dried, (Na2SO4) and the solvent remove in vacuo. The residue (0.147g) was dissolved in tetrahydrofuran (2mL) and Lithium aluminium hydride (Aldrich 21, 277-6) (1M in THF, lmL, lmmol). The reaction mixture was heated at reflux for 2h, cooled to room temperature and diluted with CH2Cl2 (lOmL). The mixture was extracted with H20 (5mL x 2), brine (5mL), dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography to afford the title compound as a oil (0. 073g,. 52%).. HPLC retention time 3.1 Imin. Mass Spectrum (ES+) m/z 298 (M+H).

Example 49: 4-Methoxy-1, 3-dihydro-1H-isoindole-2-carbothioic acid benzhydryl-amide 2-Benzyl-4-methoxy-2, S-dihydro-2H-isoindole :

2,3-Dimethylanisole (Acros, 15999) (12.5 g, 91. 8 mmol), N-bromosuccinimide (Aldrich, B8, 125-5) (32.6 g, 183. 5 mmol) and benzoyl peroxide (Lancaster, 13174) (300 mg) were refluxed in CC14 (200 mL) for 20 hrs. The reaction was cooled and the insoluble material removed by filtration. The solid was washed with CC14 and the combined filtrate concentrated in vacuo to afford a yellow solid which was used without further purification. The yellow solid and benzyltriethylammonium chloride (Acros, 16402) (0.75 g, 3.3 mmol) were dissolved in a mixture of 50% aqs NaOH (40 mL) and toluene (175 mL). To the solution was added drop-wise, benzylamine (Aldrich, 18, 570-1) (91.8g, 101 mmol) over 15mins at ambient temperature. Once addition was complete, the reaction was stirred for 24hrs at rt. The organic layer was separated, washed with brine (3 x 100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified via flash chromatography, eluting with EtOAc/ isohexane (1: 15) to afford 2-benzyl-4-methoxy-2, 3-dihydro-lH-isoindole as a red oil. Yield 6. 5g (30%). HPLC retention time 4. 21min. Mass spectrum (ES+) m/z 240 (M + H).

4-Methoxy-2, 3-dihydro-IH isoindole : 2-Benzyl-4-methoxy-2, 3-dihydro-lH-isoindole (1.9g, 7. 94mmol) was dissolved in CH30H (50mL) and placed in a 250mL autoclave. 10% Palladium on activated charcoal (Acros, 19503) (300mg) was added and the reaction was hydrogenated at 3. 5bar for 24hrs. When complete, the catalyst was separated via filtration, and the solvent was removed in vacuo. The residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (1: 4) to afford 4-methoxy-2, 3-dihydro-lH-isoindole as a beige solid. Yield 0.720g (61%). HPLC retention time, 3.07min. Mass spectrum (ES+) m/z 150 (M + H).

4-Methoxy-1, 3-dihydro-IH isoifzdole-2-carbothioic acid benzhydryl-amide 2-Benzyl-4-methoxy-2, 3-dihydro-lH-isoindole (50mg, 0. 335mmol) and benzhydryl isothiocyanate (Fluorochem, 18194) (75mg, 0. 335mmol) were stirred in toluene (2mL) for 24hrs at ambient temperature. The solvent was removed in vacuo and the

residue was purified via flash chromatography eluting with EtOAc/isohexane (1: 4) to afford the title compound as a white solid. Yield 95mg (76%). HPLC retention time 4. 50min. Mass spectrum (ES+) m/z 375 (M + H).

Example 50: 3, 4-Dihydro-lH-isoquinoline-2-carbothioic acid benzhydryl-amide Prepared according to the method described in Example 49. HPLC retention time, 4. 49min. Mass spectrum (ES+) m/z 359 (M + H).

Example 51: 3, 4-Dihydro-1H-isoquinoline-2-carbothioic acid (2, 2-diphenyl- ethyl)-amide Prepared according to the method described in Example 49: HPLC retention time, 4.59min. Mass spectrum (ES+) m/z 373 (M + H).

Example 52 : 8-Methoxy-3,4-dihydro-1H-isoquinolin-2-carbothioic acid (2, 2- diphenyl-ethyl)-amide Prepared according to the method described in Example 49. HPLC retention time 4. 53min. Mass spectrum (ES+) m/z 403 (M + H).

Example 53: 3, 4-Dihydro-lH-isoquinoline-2-carbothioic acid benzhydryl-amide Prepared according to the method described in Example 49. HPLC retention time 4. 51min. Mass spectrum (ES+) m/z 389 (M + H).

Example 54: 7-Methoxy-1, 3,4, 5-tetrahydro-benzo [c] azepin-2-carbothioic acid benzhydryl-amide Prepared according to the method described in Example 49. HPLC retention time 4. 46min. Mass spectrum (ES+) m/z 403 (M + H).

Example 55: 7-Methoxy-1, 3,4, 5-tetrahydro-benzo [c] azepin-2-carbothioic acid (2, 2-diphenyl-ethyl)-amide Prepared according to the method described in Example 49. HPLC retention time 4. 53min. Mass spectrum (ES+) m/z 417 (M + H).

Example 56: Example 2: N-Benzhydryl-2- (4-methoxy-1, 3-dihydro-isoindol-2- yl)-acetamide A solution of 2-benzyl-4-methoxy-2, 3-dihydro-lH-isoindole (75 mg, 0.50 mmol), K2CO3 (69mg, 0. 50mmol) and tetrabutylammonium iodide (Aldrich, 14, 077-5) (37mg, O. lmmol) in MeCN (3 mL) was stirred at rt for 30 mins. N-Benzhydryl-2- chloro-acetamide (130 mg, 0.5 mmol) was added and the reaction was refluxed for 5 hrs. The reaction mixture was allowed to cool, diluted with MeCN (5 mL), and the solids removed by filtration. The solvent was removed in vacuo and the residue purified via flash chromatography eluting with EtOAc/isohexane (l : 2)'t0 afford the title compound as a pale green solid. Yield 60 mg (32%). HPLC retention time 4.24min. Mass spectrum (ES+) m/z 373 (M + H).

Example 57: N- (2, 2-Diphenyl-ethyl)-2- (. 4-methoxy-1, 3-dihydro-isoindol-2-yl)- acetamide Prepared according to the method described in Example 56. HPLC retention time 3. 10min (Solvent: MeCN/H20/0. 05% HCOOH, 5-95% gradient H20-6min. Column Xterra 50 x 4.60 i. d., C18 reverse phase. Flow rate: 1. 5mL/min.). Mass spectrum (ES+) m/z 387 (M + H).

Example 58: N- (3, 3-Diphenyl-propyl)-2- (4-methoxy-1, 3-dihydro-isoindol-2-yl)- acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 32min. Mass spectrum (ES+) m/z 401 (M + H).

Example 59: N- (4, 4-Diphenyl-butyl)-2- (4-methoxy-1, 3-dihydro-isoindol-2-yl)- acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 41min. Mass spectrum (ES+) m/z 415 (M + H).

Example 60: 2-(3, 4-Dihydro-lH-isoquinolin-2-yl)-N-(2, 2-diphenyl-ethyl)- acetamide Prepared according to the method described in Example 56. HPLC retention time 6. 71min. Mass spectrum (ES+) m/z 371 (M + H).

Example 61: N-(2,2-Diphenyl-ethyl)-2-(8-methoxy-3,4-dihydro-1H-isoquinol in- 2-yl)-acetamide Prepared according-to-the method described in Example 56. HPLC retention time 4. 57min. Mass spectrum (ES+) m/z 401 (M + H).

Example 62: 1-(4-benzhydryl-piperazin-1-yl)-2-(8-methoxy-3,4-dihydro-1H- isoquinolin-2-yl)-ethanone 1-(4-Benzhydryl-piperazin-1-yl)-2-chloro-ethanone : A solution of 1-benzhydryl-piperazine (Acros, 12293) (5. 05g, 20mmol) and Et3N (2.22g, 22mmol) in CH2Cl2 (20 mL) was cooled to 5°C using an ice/H20 cooling.

Chloroacetyl chloride (Aldrich, 10,449-3) (2. 5g, 22mmol) in CH2C12 (5mL) was added drop wise such that the temperature remained below 20°C. Once addition was complete, the reaction was stirred for for a further 18hrs at ambient temperature.

Deionised H20 (50 mL) was added and stirring continued for a further lhr. The organic layer was separated, washed with brine (3 x 100 mL), dried (MgSO4) and concentrated in vacuo to afford 1- (4-benzhydryl-piperazin-1-yl)-2-chloro-ethanone as a brown oil, which was used without further purification. Yield 6.8g (95%).

HPLC retention time, 4. 22min. Mass spectrum (ES+) m/z 329 (M + H).

1-(4-Benzhydryl-piperazin-1-yl)-2-(8-methoxy-3,4-dihydro-1H- isoquinolin-2-yl)- ethanone : Prepared according to the method described in Example 55. HPLC retention time, 4. 77min. Mass spectrum (ES+) m/z 456 (M + H).

Example 63: l- {4- [Bis- (4-fluoro-phenyt)-methyl]-piperazin-l-yl}-2- (8-methoxy- 3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone 1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-chloro -ethanone: Prepared according to the method described in Example 62. HPLC retention time 4. 26min. Mass spectrum (ES+) m/z 365 (M + H).

1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-(8- methoxy-3,4-dihydro-1H- isoquinolin-2-yl)-etlaa7zone : Prepared according to the method described in Example 55. HPLC retention time 4. 74min. Mass spectrum (ES+) m/z 492 (M + H).

Example 64: 1- (4-Benzhydryl-piperazin-1-yl)-2- (3, 4-dihydro-lH-isoquinolin-2- yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 71min. Mass spectrum (ES+) m/z 426 (M + H).

Example 65: 1-f 4- [Bis- (4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2- (3, 4-dihydro- 1H-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 66min. Mass spectrum (ES+) m/z 461 (M + H).

Example 66: 2- (1, 3-Dihydro-isoindol-2-yl)-N- (2, 2-diphenyl-ethyl)-acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 28min. Mass spectrum (ES+) m/z 357 (M + H).

Example 67: 1- (4-Benzhydryl-piperazin-1-yl)-2- (1, 3-dihydro-isoindol-2-yl)- ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 50min. Mass spectrum (ES+) m/z 41-2 (M + H).

Example 68 : 1- {4- [Bis- (4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2- (1, 3-dihydro- isoindol-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4 : 52mnr. 1HNMR- (400 MHz (CD3) 2SO)#H2.20-2.25 (4H), 3. 40-3. 55-(6H), 3. 90- (4H), 4.40 (1H), 7.05-7. 20 (8H), 7. 35-7. 45 (4H). Mass spectrum (ES+) m/z 448 (M +H).

Example 69: 2-(8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(phenyl-pyri din- 2-yl-methyl)-acetamide 2-Chloro-N-(phenyl-pyridin-2-yl-methyl)-acetamide: Prepared according to the method described in Example 1. Yield 600mg (98%).

HPLC retention time 3. 40min. Mass spectrum (ES+) m/z 261 (M + H).

2- (8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(phenyl-pyridi n-2-yl-methyl)- acetamide: Prepared according to the method described in Example 56. HPLC retention time 4. 15min. Mass spectrum (ES+) m/z 388 (M + H).

Example 70: 2- (8-Hydroxy-3, 4-dihydro-1H-isoquinolin-2-yl)-1- (3-phenyl-2, 3- dihydro-benzo [1, 4] oxazin-4-yl)-ethanone 2- (2-Nitro-phenoxy)-l-phenyl-ethanone : A solution of 2-nitrophenol (Aldrich, N1, 970-2) (13.9 g, 100 mmol) and K2CO3 (15.2 g, 10 mmol) was stirred in MeCN (50 mL) at rt for 30mins. KI (1. 83 g, 11 mmol) was added in one portion followed by phenacyl bromide (Lancaster, 6260) (19. 9g, 100mmol) in portions. After addition the reaction was stirred for 24hrs at RT, and poured onto ice/H20 (lltr) with stirring. The solid was separated via filtration and washed with H20. The solid was dried and recrystallized ex IPA (300mL) to afford 2- (2-nitro-phenoxy)-l-phenyl-ethanone as cream coloured crystals. Yield 20g (80%). HPLC retention time 3.83min. Mass spectrum (ES+) m/z 258 (M + H).

3-Phenyl-3, 4-dihydro-2H-berazo [1, 4Joxazine : To a stirred solution of sodium hypophosphite (Aldrich, 24,366-3) (50g) in deionised H20 (200mL) and THE (200mL) containing 2- (2-nitro-phenoxy)-1-phenyl-ethanone (10g, 39mmol) was added 10% Palladium on activated charcoal (Acros, 19503) (lg).

The reaction was stirred at RT for 18hrs sodium hypophosphite (Aldrich, 24, 366-3) (50g) and 10% Palladium on activated charcoal (Acros, 19503) (lg) was added and the reaction was stirred for a further 18hrs at RT. The catalyst was filtered off and the two phase mixture was diluted with deionised Ha0 and extracted with Et20 (x3). The combined extracts were washed with H20 and dried over MgSO4. The solvent was removed in vacuo to afford 3-phenyl-3,4-dihydro-2H-benzo [1, 4 oxazine as a red oil which was used without further purification. Yield 8. 2g (100%).

2-Chloro-1-(3-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl)-ethanone: Prepared according to the method described in Example 62. HPLC retention time 3. 91min (Solvent: MeCN/H20/0. 05% HCOOH, 5-95% gradient H20-6min. Column : Xterra 50 x 4.60 i. d. , C18 reverse phase. Flow rate: 1. 5mL/min.). 1H NMR (400 MHz (CD3) 2SO) #H4. 45-4. 55 (2H), 4.80 (1H), 4.95 (1H), 5. 80 (1H), 6.80 (1H), 6.90

(1H), 7.00 (1H), 7.20-7. 25 (1H), 7.30-7. 35 (4H), 7.80 (1H). Mass spectrum (ES+) m/z 288 (M + H).

2-(8-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-phenyl-2, 3-dihydro- benzo [1,4] oxazin-4-yl)-ethanone: Prepared according to the method described in Example 56. HPLC retention time 6. 30min (Solvent: MeCN/H20/0. 05% NH3, 5-95% gradient H20-lOmin. Column: Xterra 50 x 4.60 i. d., C18 reverse phase. Flow rate: 1. 5mL/min.). 1H NMR (400 MHz (CD3) 2SQ) OH2. 60-2.70 (4H), 3.45-3. 65 (4H), 4.35 (1H), 4.90 (1H), 5.95 (1H), 6.50 (1H), 6.55 (1H), 6.75 (1H), 6.85-6. 90 (2H), 6.95-7. 00 (1H), 7.15 (1H), 7.20- 7. 30 (4H), 8.00 (1H), 9.30 (1H). Mass spectrum (ES+) m/z 401 (M + H).

Example 71: 2-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-phenyl-2, 3- dihydro-benzo [1, 4] oxazin-4-yl)-etlianone Prepared according to the method described in Example 56. HPLC retention time 4. 49min. Mass spectrum (ES+) m/z 415 (M + H).

Example 72: 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoazin-10- yl-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 53min. Mass spectrum (ES+) m/z 387 (M + H).

Example 73 : 1-(10,11-Dihydro-dibenzo [b, f] azepin-5-yl)-2- (8-methoxy-3, 4- dihydro-lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 37min. Mass spectrum (ES+) m/z 399 (M + H).

Example 74: N, N-Dibenzyl-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide

Prepared according to the method described in Example 56. HPLC retention time 4.57min. Mass spectrum (ES+) m/z 401 (M + H).

Example 75: N, N-Diisopropyl-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide Prepared according to the method described in Example 56. HPLC retention time 4.26min. Mass spectrum (ES+) m/z 305 (M + H).

Example 76: N- (4, 4-Diphenyl-butyl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin- 2-yl)-acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 55min. Mass spectrum (ES+) m/z 429 (M + H).

Example 77: N- (3, 3-Diphenyl-propyl)-2- (8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-propionamide Prepared according to the method described in Example 56 with the following modification: the reaction was refluxed for 24hrs. HPLC retention time 4. 36min.

Mass spectrum (ES+) m/z 429 (M + H).

Example 78: N, N-Dibenzyl-3- (8-methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)- propionamide Prepared according to the method described in Example 56 with the following modification: the reaction was refluxed for 24hrs. HPLC retention time 4. 45min.

Mass spectrum (ES+) m/z 415 (M + H) Example 79: 2- [3- (2, 2-Diphenyl-vinyloxy)-propyl]-8-methoxy-1, 2,3, 4- tetrahydro-isoquinoline

1- (3-Bromopropyloxy)-2, 2-diphenylethene : Dipehenyl-acetaldehyde (Aldrich, D20, 425-0) (1g, 5. 1mmol) was dissolved in CH2C12 (lOmL) and tetrabutylammonium bromide (Aldrich, 19,311-9) (161mg, 0. 5mmol) was added followed by 1. 2MNaOH solution (lOmL) and 1,3- dibromopropane (Aldrich, 12,590-3) (5.14g, 25. 5mmol) with vigorous stirring. The reaction was stirred at RT for 18hrs and acidified with 2M HCl (lOmL). The organic phase was separated and washed well with H2O, before being dried (MgS04). The solvent was removed in vacuo and the residue was purified via flash chromatography eluting with EtOAc/isohexane (3: 97) to afford a colourless oil. Yield 890mg (55%).

2-[3-(2,2-Diphenyl-vinyloxy)-propyl]-8-methoxy-1,2, 3, 4-tetrahydro-isoquinoline: Prepared according to the method described in Example 5. HPLC retention time 5. 02min. 1H NMR (400 MHz CDClH 2. 0 (2H), 2.65-2. 70 (4H), 2.85-2. 90 (2H), 3. 55 (2H), 3.80 (3H), 4.00-4. 05 (2H), 6 : 55 (1H), 6. 65 (1H), 6. 70 (1H) 7. 10 (1-H) ; 7.18-7. 24 (4H), 7.25-7. 35 (4H), 7. 38-7. 44 (2H). Mass spectrum (ES+) m/z 400 (M + H).

Example SO : N-Benzhydryl-2- (7-methoxy-1, 3, 4, 5-tetrahydro-benzo [c] azepin-2- yl)-acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 40min. Mass spectrum (ES+) m/z 401 (M + H).

Example 81: N- (2, 2-Diphenyl-ethyl) 2- (7-methoxy-1, 3,4, 5-tetrahydro- benzo [c] azepin-2-yl)-acetamide.

Prepared according to the method described in Example 56. HPLC retention time 4. 39min. Mass spectrum (ES+) m/z 415 (M + H).

Example 82: N-(3,3-Diphenyl-propyl)2-(7-methoxy-1, 3,4, 5-tetrahydro- benzo [c] azepin-2-yl)-acetamide

Prepared according to the method described in Example 56. HPLC retention time 4. 47min. Mass spectrum (ES+) m/z 429 (M + H).

Example 83 : N, N-Dibenzyl-2- (7-methoxy-1, 3,4, 5-tetrahydro-benzo azepin-2- yl)-acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 47min. Mass spectrum (ES+) m/z 415 (M + H).

Example 84 : 2-Thiophen-2-ylmethyl-1, 2, 3, 4-tetrahydro-isoquinolin-8-ol A solution of 1, 2,3, 4-tetrahydro-isoquinolin-8-ol acetic acid salt (75 mg, 0.358 mmol) and Et3N (36mg, 0. 358mmol) in CH30H (2 mL) was stirred at ambient temperature for 30mins. 2-Thiophenecarboxaldehyde (Aldrich T3, 240-9) (40mg, 0. 358mmol) was-added and the reaction was stirred for 2hrs-at room temperature.

Sodium cyanoborohydride (Aldrich, 15, 615-9) (23mg, 0.358mmol) was added and the reaction was stirred at RT for 18hrs. The solvent was removed in vacuo and the residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (2: 98) to afford the title compoundas a white solid. Yield 28mg (32%). HPLC retention time, 3. 43min. 1H NMR (400 MHz (CD3) 2SO) OH 2.70-2. 75 (2H), 2. 85-2. 90 (2H), 3. 60 (2H), 3.95 (2H), 6. 50-6. 60 (2H), 6.90-6. 95 (1H), 6.95-7. 0 (1H), 7.05 (1H), 7.35 (1H).

Mass spectrum (ES+) m/z 246 (M + H).

Example 85: (1H-Benzoimidazol-5-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)- methanone To a solution of 5-benzimidazolecarboxylic acid (Aldrich, 29,678-3) (324mg, 2mmol) in CH2Cla/DMF, (9: 1) (lOmL) was added: 1,2, 3, 4-tetrahydro-isoquinoline (Aldrich, T1, 300-5) (320mg, 2. 4mmol), Et3N (404mg, 4mmol), 1- hydroxybenzotriazole (Acros, 16916) (405mg, 3mmol) and 1- [3- (dimethylamino)- propyl]-3-ethyl-carbodiimide (ACT, RC8102) (460mg, 2. 4mmol) and the reaction was stirred at RT for 18hrs. The reaction mixture was diluted with EtOAc (10 mL),

washed (5% citric acid), (sat. sodium bicarbonate), and (brine). The organic layer was dried (MgS04) and concentrated in vacuo. The residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (5: 95) to afford the title compound as a brown oil. Yield l5mg (3%). HPLC retention time 3.09min. Mass spectrum (ES+) m/z 278 (M + H).

Example 86 : N- (3, 3-Diphenyl-propyl)-2- (7-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-acetamide [2-(4-methoxy-phenyl)-ethyl]-carbamic acid methyl ester : 4-Methoxyphenethylamine (Aldrich, 18,730-5) (25.8g, 171mmol) and Et3N (20.7g, 205mmol) were dissolved in anhydrous THF (lltr) and cooled to 0°C. Methyl chloroformate (Aldrich, M3,530-4) 80. 8g, 855mmol) was added drop wise keeping the temperature at 0°C. After addition the reaction was stirred at 0°C for a further - 2hrs and at RT for 18hrs. Deionised H20 (250mL) was added aic-the resulting° solution was extracted into Et20 (400mL) and EtOAc (2x300mL). The combined extracts were washed with brine (3x500mL) and 1M HC1 (3x400mL). The organic layer was dried over dried MgSO4 and the solvent was removed in vacuo to afford a yellow oil which quickly solidified. This was slurried in isohexane, filtered and washed with isohexane to afford [2- (4-methoxy-phenyl)-ethyl]-carbamic acid methyl ester as a white solid, which was used without further purification. Yield 29g (83%).

7-Methoxy-3, 4-dihydro-2H-isoqui7zolin-l-one : Phosphorous pentoxide (Fisher, P/3000/53) (14.2g, 50mmol) was added in portions to methanesulphonic acid (Avocado, 13565) (25mL), and the mixture was heated to 130°C. [2- (4-Methoxy-phenyl)-ethyl]-carbamic acid methyl ester (5.23g, 25mmol) was added in portions and the mixture was heated at 140°C for a further Ihr. The reaction was allowed to cool to ca. 80°C and it was carefully added to ice with rapid stirring. This solution was extracted with CH2C12 (3x5OmL) and the combined extracts were washed with brine (2x50mL), dried (MgS04) and the solvent removed in vacuo. The residue was purified via flash chromatography eluting with

MeOH/CH2Cl2 (10: 90) to afford 7-methoxy-3, 4-dihydro-2H-isoquinolin-l-one.

Yield 3.3g (75%). HPLC retention time 3. 41min (Solvent: MeCN/H20/0.05% HCOOH, 5-95% gradient H2O-10min. Column : Xterra 50 x 4.60 i. d., C18 reverse phase. Flow rate: 1. SmL/min.). Mass spectrum (ES+) m/z 178 (M + H).

7-Methoxy-1, 2,3, 4-tetrahydro-isoquinoliyae hydrochloride : Lithium aluminium hydride, l. OM solution in THF (Aldrich, 21,277-6) (22mL, 22mmol) was added drop wise to 7-methoxy-3, 4-dihydro-2H-isoquinolin-l-one (3. 0g, 17mmol) in THF (25mL) at RT. After addition the reaction was refluxed for 3hrs. The reaction was cooled to 0°C and quenched by the careful addition of deionised H20 (1mL), 10% OH solution (lmL) and deionised H20 (3mL). The basic suspension was filtered through celite and extracted into EtOAc (3xl50mL).

The combined extracts were dried over MgS04 and the solvent was removed in vacuo. The residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (10: 90) to afford 7-methoxy-1, 2, 3,4-tetrahydro-isoquinoline. This was dissolved in EtOAc (lOmL) and hydrogen chloride, 2. 0m solution in Et2O (Aldrich, 45,518-0) (lOmL) was added drop wise, which formed a white ppte. The solid was filtered off and washed with Et20 to afford 7-methoxy-1,2, 3, 4-tetrallydro- isoquinoline hydrochloride as a white solid. Yield 1.4g (42%). HPLC retention time, 3. 05min. Mass spectrum (ES+) m/z 164 (M + H).

N-(3,3-Diphenyl-propyl)-2-(7-methoxy-3,4-dihydro-1H-isoquino lin-2-yl)-acetamide; 7-Methoxy-1, 2,3, 4-tetrahydro-isoquinoline hydrochloride (200mg, lmmol) was stirred in MeCN (lOmL) with K2CO3 (276mg, 2mmol) and TBAI (Aldrich, 14,077- 5) (74mg, 0. 2mmol) for 30mins. 2-Chloro-N- (3, 3-diphenyl-propyl)-acetamide (288mg, I mmol) was added and the reaction was refluxed for 24hrs. The reaction was cooled, diluted with MeCN (lOmL) and the insoluble material was removed via filtration. The solvent was removed in vacuo and the residue was purified via flash chromatography eluting with EtoAc/isohexane (1: 4) to afford the title compound as an orange oil. Yield 150mg (36%) HPLC retention time, 4. 45min. Mass spectrum (ES+) m/z 415 (M + H).

Example 87: N, N-Dibenzyl-2- (7-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- acetamide Prepared according to the method described in Example 86. HPLC retention time 4. 53min. Mass spectrum (ES+) m/z 401 (M + H).

Example 88 : Dibenzyl- [2- (7-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]- amine Lithium aluminium hydride, 1. OM solution in THF (Aldrich, 21,277-6) (0.42mL, 0.42mmol) was added drop wise to N, N-Dibenzyl-2-(7-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl) -acetamide (140mg, 0.35mmol). After addition the reaction was refluxed for 3hrs. The reaction was cooled to 0°C and quenched by the careful addition of deionised H2O (lmL), 10% NaOH solution (1mL) and deionised H20 (3mL). The basic suspension was filtered through celite and extracted into EtOAc (3xl50mL). The combined extracts were dried over MgS04 and the solvent was removed in vacuo. The residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (10: 90) to afford Dibenzyl- [2- (7-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amine. HPLC retention time 5. 13min. Mass spectrum (ES+) m/z 387 (M + H).

Example 89: (3, 3-Diphenyl-propyl)- [2- (7-methoxy-3, 4-dihydro-lH-isoquinolin- 2-yl) -ethyl] amine Prepared according to the method described in Example 88. HPLC retention time, 4. 91min. Mass spectrum (ES+) m/z 401 (M + H).

Example 90 : 2-(3,5-Bis-trifluoromethyl-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin- 6-ol A solution of 1, 2,3, 4-Tetrahydro-isoquinolin-6-ol (0.05 g, 0.13 mmol), 1- bromomethyl-3,5-bis-trifluoromethyl-benzene (0. 041 g, 0. 13 mmol) and K2C03

(0. 018 g, 0.13 mmol) in MeCN (2 mL) was shaken at ambient temperature for 16 hours. The reaction was filtered through a plug of cotton wool, concentrated in vacuo and purified by flash chromatography to afford the title compound. HPLC retention time, 1.26 min. Mass spectrum (ES+) m/z 376 (M + H).

Example 91: 2- (2-Chloro-6-fluoro-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol Prepared according to the method described in Example 90. HPLC retention time 0.97 min. Mass spectrum (ES+) m/z 292 (M + H).

Example 92: 2- (2, 5-Difluoro-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol Prepared according to the method described in Example 90. HPLC retention time, 1. 26 min. Mass spectrum (ES+) m/z 276 (M + H).

Example-93 : 2-(3, 5-Difluoro-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin-8-ol Prepared according to the method described in Example 90. HPLC retention time 0.97 min. Mass spectrum (ES+) m/z 276 (M + H).

Example 94: 2- (4-Trifluoromethylsulfanyl-benzyl)-1, 2, 3, 4-tetrahydro- isoquinolin-8-ol Prepared according to the method described in Example 90. HPLC retention time 1.24 min. Mass spectrum (ES+) m/z 340 (M + H) : Example 95: 2-(3, 5-Bis-trifluoromethyl-benzyl)-1, 2,3, 4-tetrahydro-isoquinolin- 8-ol Prepared according to the method described in Example 90. HPLC retention time, 1.27 min. Mass spectrum (ES+) m/z 376 (M + H).

Example 96: 2- [4, 4-Bis- (4-fluoro-phenyl)-butyl]-1, 2,3, 4-tetrahydro-isoquinolin- 8-ol Prepared according to the method described in Example 90. HPLC retention time 1.46 min. Mass spectrum (ES+) m/z 394 (M + H).

Example 97: 2- [4, 4-Bis- (4-hydroxy-3, 5-dimethyl-phenyl)-pentyl]-1, 2,3, 4- tetrahydroisoquinolin-8-ol Prepared according to the method described in Example 90. HPLC retention time 1.41 min. Mass spectrum (ES+) m/z 460 (M + H).

Example 98: N, N-Dibenzyl-2- (8-ethoxy-3, 4-dihydro-lH-isoquinolin-2- yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4.72min. Mass Spectrum (ES+) m/z 415 (M+H).

Example 99: N-(4,4-Diphenyl-butyl)-2-(8-ethoxy-3,4-dihydro-1H-isoquinoli n-2- yl) acetamide Prepared according to the method described in Example 14 : HPLC retention time 4. 68min. Mass Spectrum (ES+) m/z 443 (M+H).

Example 100: 2- (8-Ethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1- (3phenyl-2, 3- dihydro-benzo [1, 4] oxazin-4-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 60min. Mass Spectrum (ES+) m/z 429 (M+H).

Example 101: N- (3-Benzhydryloxy-propyl)-2- (8-methoxy-3, 4-dihydro-1H- isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4.43min. Mass Spectrum (ES+) m/z 445 (M+H).

Example 102: 2- (1, 3-Dihydro-isoindol-2-yl)-N- (3, 3-diphenyl-propyl) acetamide Prepared according to the method described in Example 40. HPLC retention time 4. 33min. Mass Spectrum (ES+) m/z 371 (M+H).

Example 103: N- (2-Benzhydrylsulphanyl-ethyl)-2- (8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 55min. Mass Spectrum (ES+) m/z 447(M+H).

Example 104: 2- (8-Allyloxy-3, 4-dihydro-IH-isoquinolin-2-yl)-N- (3, 3-diphenyl- propyl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 59min. Mass Spectrum (ES+) m/z 441 (M+H).

Example 105: 2- (4-Amino-1, 3-dihydro-isoindol-2-yl)-N- (2, 2-diphenyl- ethyl) acetamide Prepared according to the method, described in Example 14. HPLC retention time 3. 93min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 106 : 2- (4-Amino-1, 3-dihydro-isoindol-2-yl)-N- (3, 3-diphenyl- propyl) acetamide

Prepared according to the method described in Example 14. HPLC retention time 4. 02min. Mass Spectrum (ES+) m/z 386 (M+H).

Example 107: 2- (4-Amino-1, 3-dihydro-isoindol-2-yl)-N- (4, 4-diphenyl- butyl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 14min. Mass Spectrum (ES+) m/z 400 (M+H).

Example 108 : 2- (4-Amino-1, 3-dihydro-isoindol-2-yl)-N, N-dibenzylacetamide Prepared according to the method described in Example 14. HPLC retention time 4. 03min. Mass Spectrum (ES+) m/z 372 (M+H).

Example 109: 2-[4,4-Bis-(4-fluorophenyl)-butyl]-2,3-dihydro-1H-isoindol-4 - lamine- Prepared according to the method described in Example 14. HPLC retention time 4. 50min. Mass Spectrum (ES+) m/z 379 (M+H).

Example 110: N- [2- (Diphenylmethanesulphinyl)-ethyl]-2- (8-methoxy-3, 4- dihydro-lH-isoquinolin-2-yl) acetamide <BR> <BR> <BR> <BR> <BR> N- [2- (Diphenylmethanesulphinyl)-ethyl]-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin- 2-yl) acetamide was prepared from N- (2-benzhydrylsulphanyl-ethyl)-2- (8-methoxy- 3, 4-dihydro-lH-isoquinolin-2-yl) acetamide (leq) and mCPBA (leq) in CH2Ck to afford the title compound. HPLC retention time 3. 85min. Mass Spectrum (ES+) m/z 463 (M+H).

Example 111 : N- [2- (Diphenylmethanesulphonyl)-ethyl]-2- (8-methoxy-3, 4- dihydro-lH-isoquinolin-2-yl) acetamide

N- [2-(Diphenylmethanesulphonyl)-ethyl]-2-(8-methoxy-3,4-dihydr o-1H-isoquinolin- 2-yl) acetamide was prepared from N- (2-benzhydrylsulphanyl-ethyl)-2- (8-methoxy- 3, 4-dihydro-lH-isoquinolin-2-yl) acetamide (1eq) and mCPBA (2eq) in CH2C12 to afford the title compound. HPLC retention time 3. 26min. Mass Spectrum (ES+) m/z 479 (M+H).

Example 112: 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (lphenyl- ethyl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 04min. Mass Spectrum (ES+) m/z 325 (M+H).

Example 113: 2-(3, 4-Dihydro-lH-isoquinolin-2-yl)-N-(lphenyl-ethyl) acetamide Prepared according to the method described in Example 14. HPLC retention time 3.99min. Mass Spectrum (ES+) m/z 295 (M+H).

Example 114: 2-(BenZhydryl-amino)-1-(1, 3-dihydro-isoindol-2-yl) -ethanone Prepared according to the method described in Example 14. HPLC retention time 4. 12min. Mass Spectrum (ES+) m/z 343 (M+H).

Example 115: 2- (8-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- benzhydrylacetamide Prepared according to the method described in Example 14. HPLC retention time 3. 99min. Mass Spectrum (ES+) m/z 372 (M+H).

Example 116: 2- (8-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (4, 4-diphenyl- butyl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 13min. Mass Spectrum (ES+) m/z 414 (M+H).

Example 117: 2- [4, 4-Bis- (4-fluorophenyl)-butyl]-1, 2,3, 4-tetrahydro-isoquinolin- 8-amine Prepared according to the method described in Example 14. HPLC retention time 4.60min. Mass Spectrum (ES+) m/z 393 (M+H).

Example 118 : 2- (8-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (2, 2-diphenyl- ethyl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 1 Imin. Mass Spectrum (ES+) m/z 386 (M+H).

Example 119: 2-(8-Acetylamino-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(4, 4- diphenyl-butyl) acetamide 2- (8-Acetylamino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (4, 4-diphenyl- butyl) acetamide was prepared from 2- (8-amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (4,4-diphenyl-butyl) acetamide (1 eq. ) and acetylchloride (1 eq) in CH2Cl2 to afford the title compound. HPLC retention time 4. 21min. Mass Spectrum (ES+) m/z 456 (M+H).

Example 120: N- [3, 3-Bis- (4-methoxyphenyl)-propyl]-2- (1, 3-dihydro-isoindol-2- yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4.30min. Mass Spectrum (ES+) m/z 431 (M+H).

Example 121: N- [3, 3-Bis- (4-methoxyphenyl)-propyll-2- (3, 4-dihydro-lH- isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4.42min. Mass Spectrum (ES+) m/z 445 (M+H).

Example 122: N- [3, 3-Bis- (4-methoxyphenyl)-propyll-2- (8-methoxy-3, 4-dihydro- 1H-isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 31min. Mass Spectrum (ES+) m/z 475 (M+H).

Example 123: N- [3- (3, 4-Bis-acetylaminophenyl)-3phenyl-propyl]-2- (3, 4- dihydro-lH-isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 3. 67min. Mass Spectrum (ES+) m/z 499 (M+H).

Example 124: N- (4, 4-Diphenyl-butyl)-2- (8-methanesulphonylamino-3, 4- dihydro-lH-isoquinolin-2-yl) acetamide <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> N- (4, 4-Diphenyl-butyl)-2- (8-methanesulphonylamino-3, 4-dihydro-1 H-isoquinolin-2- yl) acetamide was prepared from 2- (8-amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (4,4-diphenyl-butyl) acetamide (1 eq), methanesulphonylchloride (1 eq) and triethylamine (leq) in CH2C12 to afford the title compound. HPLC retention time 3. 99min. Mass Spectrum (ES+) m/z 492 (M+H).

Example 125: N- [Bis- (4-fluorophenyl) methyl]-2- (1, 3-dihydro-isoindol-2- yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 28min. Mass Spectrum (ES+) m/z-379 (M+H).

Example 126: N- [Bis- (4-fluorophenyl) methyl]-2- (3, 4-dihydro-1H-isoquinolin-2- yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 42min. Mass Spectrum (ES+) m/z 393 (M+H).

Example 127: N-[Bis-(4-fluorophenyl)methyl]-2-(8-methoxy-3,4-dihydro-1H- isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 44min. Mass Spectrum (ES+) m/z 423 (M+H).

Example 128 : N- [Bis- (4-fluorophenyl) methyl]-2- (6, 7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 13min. Mass Spectrum (ES+) m/z 453 (M+H).

Example 129 : 3- (5-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (3, 3-diphenyl- propyl) propionamide Prepared according to the method described in Example 14. HPLC retention time 3. 87min. Mass Spectrum (ES+) m/z 414 (M+H).

Example 130: 2-(5-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(2, 2-diphenyl- ethyl) acetamide Prepared according to the method described in Example 14. HPLC retention time 3.90min. Mass Spectrum (ES+) m/z 386 (M+H).

Example 131: 2- » imethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(4, 4-diphenyl- butyl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 25min. Mass Spectrum (ES+) m/z 459 (M+H).

Example 132 : 3- (6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(3, 3- diphenyl-propyl) propionamide

Prepared according to the method described in Example 14. HPLC retention time 4. 01min. Mass Spectrum (ES+) m/z 459 (M+H).

Example 133: 2- (6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(2, 2- diphenyl-ethyl) acetamide Prepared according to the method described in Example 14: HPLC retention time 4. 07min. Mass Spectrum (ES+) m/z 431 (M+H).

Example 134: 3- (8-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (3, 3-diphenyl- propyl) propionamide Prepared according to the method described in Example 14. HPLC retention time 3. 97min. Mass Spectrum (ES+) m/z 414 (M+H).

Example 135: N- (3-Carbazol-9-yl-propyl)-2- (8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 47min. Mass Spectrum (ES+) m/z 428 (M+H).

Example 136: N- (3-Carbazol-9-yl-propyl)-2- (8-hydroxy-3, 4-dihydro-lH- isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4.07min. Mass Spectrum (ES+) m/z 414 (M+H).

Example 137 : N-j3- (5-Chloro-2-methyl-indol-1-yl)-propyl]-2- (8-methoxy-3, 4- dihydro-lH-isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 48min. Mass Spectrum (ES+) m/z 426 (M+H).

Example 138: N- [3- (5-Chloro-2-methyl-indoI-1-yl)-propyl]-2- (8-hydroxy-3, 4- dihydro-lH-isoquinolin-2-yl) acetamide Prepared according to the method described in Example 14. HPLC retention time 4. 06min. Mass Spectrum (ES+) m/z 413 (M+H).

Example 139: 1-Benzhydryl-3- [2- (8-methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)- ethyl]-thiourea l-Benzhydryl-3-[2-(8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl3-thiourea was prepared from 2-(8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylamine (leq) and benzhydryl isothiocyanate (leq) in CH2C12 to afford the title compound. HPLC retention time 4. 55min. Mass Spectrum (ES+) m/z 432 (M+H).

Example 140: 1-Benzhydryl-3-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin- 2- yl)-ethyl]-thiourea Prepared according to the method described in Example 139. HPLC retention time 4.23min. Mass Spectrum (ES+) m/z 462 (M+H).

Example 141: 1-Benzhydryl-3-[2-(8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl )- ethyl]-urea Prepared according to the method described in Example 139. HPLC retention time 4. 18min. Mass Spectrum (ES+) m/z 416 (M+H).

Example 142: 1-Benzhydryl-3- [2- (6, 7-dimethoxy-3, 4-dihydro-lH-isoquinolin-2- yl)-ethyl]-urea Prepared according to the method described in Example 139. HPLC retention time 3. 86min. Mass Spectrum (ES+) m/z 446 (M+H).

Example 143 : 1-(2,2-Diphenyl-ethyl)-3-[2-(8-methoxy-3,4-dihydro-1H- isoquinolin-2-yl)-ethyl]-thiourea Prepared according to the method described in Example 139. HPLC retention time 4. 55min. Mass Spectrum (ES+) m/z 446 (M+H).

Example 144: 1-[2-(6, 7-Dimethoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3- (2, 2-diphenyl-ethyl)-thiourea Prepared according to the method described in Example 139.'HPLC retehtion'time" 4.23min. Mass Spectrum (ES+) m/z 476 (M+H).

Example 145 : 2- (8-Hydroxy-3, 4-dihydro-lH-MoquinoHn-2-yI)-l-phenothiazm- 10-yl-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 06min. Mass Spectrum (ES+) m/z 389 (M+H).

Example 146: 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenothiazin- 10-yl-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 56min. Mass Spectrum (ES+) m/z 403 (M+H).

Example 147: 1-(2-Chloro-phenothiazin-10-yl)-2-(8-hydroxy-3,4-dihydro-1H- isoquinolin-2-yl)-ethanone

Prepared according to the method described in Example 56. HPLC retention time 4. 33min. Mass Spectrum (ES+) m/z 4.23 (M+H).

Example 148 : 1- (2-Chloro-phenothiazin-10-yl)-2- (8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 82min. Mass Spectrum (ES+) m/z 438 (M+H).

Example 149: 2-(8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-(5-oXo-5H- 51ambda*4*-phenothiazin-10-yl)-ethanone Prepared according to the method described in Example 110. HPLC retention time 3. 94min. Mass Spectrum (ES+) m/z 419 (M+H).

Example 150 : 2-(8-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenoxazin-1 0- yl-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 12min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 151: 2- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-l- (2- trifluoromethyl-phenothiazin-10-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 40min. Mass Spectrum (ES+) m/z 457 (M+H).

Example 152: 2-(8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-(2- trifluoromethyl-phenothiazin-10-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 83min. Mass Spectrum (ES+) m/z 471 (M+H).

Example 153: 1-(2-Acetyl-phenothiazin-10-yl)-2-(8-hydroxy-3,4-dihydro-1H- isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 3. 93min. Mass Spectrum (ES+) m/z 431 (M+H).

Example 154: 1- (2-Acetyl-phenothiazin-10-yl)-2- (8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 37min. Mass Spectrum (ES+) m/z 445 (M+H).

Example 155: 2- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N, N- diphenylacetamide Prepared according to the method-described in Example 56. HPLC retention time 3.75min. Mass Spectrum (ES+) m/z 359 (M+H).

Example 156: 2- (8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N,N- diphenylacetamide Prepared according to the method described in Example 56. HPLC retention time 4. 22min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 157: 2- (6, 7-Dimethoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-1- (5, 5-dioxo- 5H-51ambda*6*-phenothiazin-10-yl)-ethanone Prepared according to the method described in Example 111. HPLC retention time 3. 76min. Mass Spectrum (ES+) m/z 465 (M+H).

Example 158: 2- (6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolim-2-yl)-1- phenothiazin-10-yl-ethanone

Prepared according to the method described in Example 56. HPLC retention time 4. 19min. Mass Spectrum (ES+) m/z 433 (M+H).

Example 159: 1- (2-Chloro-phenothiazin-10-yl)-2- (6, 7-dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4.46min. Mass Spectrum (ES+) m/z 468 (M+H).

Example 160: 2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2- trifluoromethyl-phenothiazin-10-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 53min. Mass Spectrum (ES+) m/z 501 (M+H). <BR> <BR> <BR> <BR> <BR> <BR> <P>'Example 161 : l= (2-AcetyI-phenotMazin-10-yl)-2- (6, 7-dimethoxy-3, 4-dihydro-"<BR> <BR> <BR> <BR> <BR> lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 06min. Mass Spectrum (ES+) m/z 475 (M+H).

Example 162: 2-(6, 7-Dimethoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-1-(2- methylsulphanyl-phenothiazin-10-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 40min. Mass Spectrum (ES+) m/z 479 (M+H).

Example 163: 2- (6, 7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1- (5-oxo-5H- 51ambda*4*-phenothiazin-10-yl)-ethanone Prepared according to the method described in Example 110. HPLC retention time 3. 56min. Mass Spectrum (ES+) m/z 449 (M+H).

Example 164: 2-(8-Hydroxy-3, 4-dihydro-1H-isoquinolin-2-yl)-1-(2- methylsulphanyl-phenothiazin-10-yl)-ethanone Prpeared according to the method described in Example 56. HPLC retention time 4. 26min. Mass Spectrum (ES+) m/z 435 (M+H).

Example 165: 2- (8-Methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-1- (2- methylsulphanyl-phenothiazin-10-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 70min. Mass Spectrum (ES+) m/z 449 (M+H).

Example 166: Phenothiazine-10-carboxylic acid [2- (8-hydroxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide Prepared according-to the method described in Example 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 3. 86min. Mass Spectrum (ES+) m/z 418 (M+H).

Example 167: Phenothiazine-10-carboxylic acid [2-(6, 7-dimethoxy-3, 4-dihydro- lH-isoquinolin-2-yl)-ethyl]-amide Prepared according to the method described in Example 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 4.04min. Mass Spectrum (ES+) m/z 357 (M+H).

Example 168 : Phenothiazine-10-carboxylic acid [2- (8-methoxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide Prepared according to the method described in Example 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 4. 62min. Mass Spectrum (ES+) rn/z 357 (M+H).

Example 169: Phenoxazine-10-carboxylic acid [2- (8-hydroxy-3, 4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide Prepared according to the method described in Example 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 4.61min. Mass Spectrum (ES+) m/z 432 (M+H).

Example 170: Phenoxazine-10-carboxylic acid [2- (8-methoxy-3, 4-dihydro-IH- isoquinolin-2-yl)-ethyl]-amide Prepared according to the method described in Example 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 3. 84min. Mass Spectrum (ES+) m/z 402 (M+H).

Example 172: Phenoxazine-10-carboxylic acid [2- (6, 7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl) ;-ethyl]-amide- Prepared according to the method described in Example 56 with the following modification : tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 4. 26min. Mass Spectrum (ES+) m/z 416 (M+H).

Example 173: N- [3, 3-Bis- (4-fluorophenyl)-propyl]-3- (8-methoxy-3, 4-dihydro- 1H-isoquinolin-2-yl) propionamide Prepared according to the method described in Example 56. HPLC retention time 3.9min. Mass Spectrum (ES+) m/z 465 (M+H).

Example 174: (8-Hydroxy-3, 4-dihydro-1H-isoquinolin-2-yl)-acetic acid N', N'- diphenyl-hydrazide Prepared according to the method described in Example 56. HPLC retention time 3. 42min. Mass Spectrum (ES+) m/z 374 (M+H).

Example 175: (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetic acid N', N'- diphenyl-hydrazide Prepared according to the method described in Example 56. HPLC retention time 3. 85min. Mass Spectrum (ES+) m/z 388 (M+H).

Example 176: (6,7-Dimethoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetic acid N', N'-diphenyl-hydrazide Prepared according to the method described in Example 56. HPLC retention time 3.55min. Mass Spectrum (ES+) m/z 418 (M+H).

Example 177: 4- [2- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3, 4- dihydro-2H-benzo [1, 4] oxazine-2-carboxylic acid ethyl ester Prepared according to the method described in Example 56. HPLC retention time 4. 01min. Mass Spectrum (ES+) m/z 397 (M+H).

Example 178 : 4- [2- (-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3, 4- dihydro-2H-benzo [1, 4] oxazine-2-carboxylic acid ethyl ester Prepared according to the method described in Example 56. HPLC retention time 4. 22min. Mass Spectrum (ES+) m/z 411 (M+H).

Exampe 179: 2-(8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(4- phenoxyphenyl) acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 18min. Mass Spectrum (ES+) m/z 389 (M+H).

Example 180: 2- (5, 8-Dihydro-6H- [1, 7] naphthyridin-7-yl)-1-phenoxazin-10-yl- ethanone

Prepared according to the method described in Example 56 with the following modification: triethylamine was used as base. HPLC retention time 3. 1min. Mass Spectrum (ES+) m/z 358 (M+H).

Example 181 : 1- [2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethyl]-3- (4- phenoxyphenyl)-urea Prepared according to the method described in Example 139. HPLC retention time 3. 5min. Mass Spectrum (ES+) m/z 418 (M+H).

Example 182 : 2- (8-Amino-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10-yl- ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 09min. Mass Spectrum (ES+) m/z 372 (M+H).

Example 183 : 2-(8-Hydroxy-3, 4-dillydro-1H-isoquinolin-2-yl)-N-(4- hydroxyphenyl)-Nphenylacetamide Prepared according to the method described in Example 56. HPLC retention time 3. 98min. Mass Spectrum (ES+) m/z 375 (M+H).

Example 184: N- (4-Hydroxyphenyl)-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin- 2-yl)-Nphenylacetamide Prepared according to the method described in Example 56. HPLC retention time 4. 54min. Mass Spectrum (ES+) m/z 433 (M+H).

Example 185: 2- (1, 3-Dihydro-isoindol-2-yl)-1-phenoxazin-10-yl-ethanone Prepared according to the, method described in Example 56. HPLC retention time 4. 44min. Mass Spectrum (ES+) m/z 343 (M+H).

Example 186 : 2-(8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N-(9H-xanthen-9- yl) acetamide Prepared according to the method described in Example 56. HPLC retention time 3.96min. Mass Spectrum (ES+) m/z 387 (M+H).

Example 187 : 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (9H-xanthen-9- yl) acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 56min. Mass Spectrum (ES+) m/z 401 (M+H).

Example 188: 2- (5, 8-Dihydro-6H- [l, 7] naphthyridm-7-y !)-N, N- diphenylacetamide Prepared accordingto thewmethod-described in Example 56-with-the-following- modification :- triethylamine was used as base. HPLC retention time 3.44min. Mass Spectrum (ES+) m/z 344 (M+H).

Example 189 : 2- (8-Methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-N, N-bis-(4- methoxyphenyl) acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 22min. Mass Spectrum (ES+) m/z 433 (M+H).

Example 190: 2-(8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N, N-bis-(4- methoxyphenyl) acetamide Prepared according to the method described in Example 56. HPLC retention time 3.63min. Mass Spectrum (ES+) m/z 419 (M+H).

Example 191: 2-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2- phenoxyphenyl) acetamide

Prepared according to the method described in Example 56. HPLC retention time 4.77min. Mass Spectrum (ES+) m/z 389 (M+H).

Example 192: 2- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-N- (2- phenoxyphenyl) acetamide Prepared according to the method described in Example 56. HPLC retention time 4. 17min. Mass Spectrum (ES+) m/z 375 (M+H).

Example 193: 1- [ (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetyl]-4, 4- diphenylsemicarbazide Prepared according to the method described in Example 56. HPLC retention time 3.76min. Mass Spectrum (ES+) m/z 431 (M+H).

Example 194: 2- (8-Methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-1- [2- (5-methyl- [1, 3, 4] oxadiazol-2-yl)-2, 3-dihydro-benzo [1, 4] oxazin-4-yl]-ethanone Prepared according to the method described in Example 56. HPLC retention time 3.76min. Mass Spectrum (ES+) m/z 431 (M+H).

Example 195: N- (3-Amino-pyridin-2-yl)-N- (2-hydroxyphenyl)-2- (8-methoxy-3, 4- dihydro-lH-isoquinolin-2-yl) acetamide Prepared according to the method described in Example 56. HPLC retention time 3. 79min. Mass Spectrum (ES+) m/z 405 (M+H).

Example 196: 3- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10- yl-propan-1-one Prepared according to the method described in Example 56. HPLC retention time 4. 52min. Mass Spectrum (ES+) m/z 401 (M+H).

Example 197: 3- (8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10- yl-propan-1-one Prepared according to the method described in Example 56. HPLC retention time 3. 93min. Mass Spectrum (ES+) m/z 387 (M+H).

Example 198 : Methanesulphonic acid 2- (2-oxo-2-phenoxazin-10-yl-ethyl)- 1,2, 3, 4-tetrahydro-isoquinolin-8-yl ester Prepared according to the method described in Example 124. HPLC retention time 4.23min. Mass Spectrum (ES+) m/z 452 (M+H).

Example 199: 1- (2, 3-Dihydro-benzo [1, 4] oxazin-4-yl)-2- (8-methoxy-3, 4-dihydro- 1H-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 07min. Mass Spectrum (ES+) m/z 339 (M+H).

Example 200: 2-(7-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenoxazin-1 0- yl-ethanone Prepared according to the method described in Example 56. HPLC retention time 3. 88min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 201: 2-(6-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10- yl-ethanone Prepared according to the method described in Example 56. HPLC retention time 3. 83min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 202: 2- (5-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1-phenoxazin-10- yl-ethanone

Prepared according to the method described in Example 56. HPLC retention time 3. 89min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 203 : 2- (4-Methoxy-1, 3-dihydro-isoindol-2-yl)-1-phenoxazin-10-yl- ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 36min. Mass Spectrum (ES+) m/z 373 (M+H).

Example 204: N-Methanesulphonyl-N- [2- (2-oxo-2-phenoxazin-10-yl-ethyl)- 1, 2,3, 4-tetrahydro-isoquinolin-8-yl]-methanesulphonamide Prepared according to the method described in Example 124. HPLC retention time 4. 04min. Mass Spectrum (ES+) m/z 528 (M+H).

Example 205: N- [2- (2-Oxo-2-phenoxazin-10-yl-ethyl)-1, 2,3, 4-tetrahydro- isoquinolin-8-yl]-methanesulphonamide Prepared according to the method described in Example 124. HPLC retention time 2. 95min. Mass Spectrum (ES+) m/z 450 (M+H).

Example 206: 2-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-(1-methyl-1H -4- oxa-1, 2, 9-triaza-cyclopenta [b] naphthalen-9-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 1 lmin. Mass Spectrum (ES+) m/z 391 (M+H).

Example 207: 2- (8-Methoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-1-phenoxazin-10- yl-propan-1-one Prepared according to the method described in Example 56. HPLC retention time 4. 98min. Mass Spectrum (ES+) m/z 401 (M+H).

Example 208: Phenoxazine-10-carboxylic acid [2- (5, 8-dihydro-6H- [1, 7] naphthyridin-7-yl)-ethyl]-amide Prepared according to the method described in Example 56 with the following modification: triethylamine was used in place of potassium carbonate. HPLC retention time 4. 98min. Mass Spectrum (ES+) m/z 401 (M+H).

Example 209: 2-(4-Hydroxy-1, 3-dihydro-isoindol-2-yl)-1-phenoxazin-10-yl- ethanone Prepared according to the method described in Example 56. HPLC retention time 3. 73min. Mass Spectrum (ES+) m/z 359 (M+H).

Example 210: Methanesulphonic acid 2- (2-oxo-2-phenoxazin-10-yl-ethyl)-2, 3- dihydro-TH-isoindol-4-yl ester Prepared according to the method described in Example 124. HPLC retention time 4. 18min. Mass Spectrum (ES+) m/z 437 (M+H).

Example 211: 1-Carbazol-9-yl-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)- ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 86min. Mass Spectrum (ES+) m/z 371 (M+H).

Example 212: 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1- (3-methyl-2, 3- dihydro-benzo [1, 4] oxazin-4-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 26min. Mass Spectrum (ES+) m/z 353 (M+H).

Example 213: 1- (3-tert-Butyl-2, 3-dihydro-benzo [1, 4] oxazin-4-yl)-2- (8-methoxy- 3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4.79min. Mass Spectrum (ES+) m/z 395 (M+H).

Example 214: 1- (11H-Dibenzo [b, f] [1, 4] oxazepin-10-yl)-2- (8-methoxy-3, 4- dihydro-lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 44min. Mass Spectrum (ES+) m/z 401 (M+H).

Example 215: 1-(3-Ethyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-(8-methoxy-3 , 4- dihydro-lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC'retention time 4. 40min. Mass Spectrum (ES+) m/z 367 (M+H).

Example 216 : 2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-1, 2,3, 4-tetrahydro- isoquinoline-8-sulphonic acid Prepared according to the method described in Example 56. HPLC retention time 2. 39min. Mass Spectrum (ES+) m/z 437 (M+H).

Example 217: N-[2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-2, 3-dihydro-lH-isoindol- 4-yl]-methanesulphonamide Prepared according to the method described in Example 124. HPLC retention time 2. 86min. Mass Spectrum (ES+) m/z 436 (M+H).

Example 218: 1- (3-tert-Butyl-2, 3-dihydro-benzo [1, 4] oxazin-4-yl)-2- (8-hydroxy- 3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone

Prepared according to the method described in Example 56. HPLC retention time 4. 11min. Mass Spectrum (ES+) m/z 381 (M+H).

Example 219: 2- (8-Methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-1- [3- (4- methoxyphenyl)-2, 3-dihydro-benzo [1, 4] oxazin-4-yl]-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 51min. Mass Spectrum (ES+) m/z 445 (M+H).

Example 220: 1- [3-(2,5-Dimethoxyphenyl)-2,3-dihydro-benzo[1, 4] oxazin-4-yl]-2- (8-methoxy-3, 4-dihydro-IH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 69min. Mass Spectrum (ES+) m/z 475 (M+H).

Example 221: N-(4-{4-[2-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-acety l]- 3,4-dihydro-2H-benzo [1, 4] oxazin-3-yl} phenyl) acetamide Prepared according to the method described in Example 56. HPLC retention time 3. 88min. Mass Spectrum (ES+) m/z 472 (M+H).

Example 222: 1- [3- (4-Fluoropenyl)-2, 3-dihydro-benzofl, 4] oxazin-4-yl]-2- (8- methoxy-3, 4-dihydro-1 H-isoquinolin-2-yl)-ethanone Prepared =according to the method described in Example 56. HPLC retention time 4. 57min. Mass Spectrum (ES+) m/z 433 (M+H).

Example 223: 1- [3- (3, 4-Dimethoxyphenyl)-2, 3-dihydro-benzo [1, 4] oxazin-4-ylj-2- (8-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4. 29min. Mass Spectrum (ES+) m/z 475 (M+H).

Biological Screening Inhibition of Human Navl. 8 stably expressed in SH-SY-SY cells A SH-SY-5Y neuroblastoma cell line stably expressing the human Navl. 8 (have. 8) ion channel was constructed. This cell line has been used to develop a medium to high throughput assay for determining the ability of test compounds to inhibit membrane depolarisation mediated via the hNavl. 8 channel.

SH-SY-SY have. 8 are grown in adherent monolayer culture using 50: 50 Ham's F-12/EMEM tissue culture medium supplemented with 15% (v/v) foetal bovine serum; 2mM L-glutamine, 1% NEAA and 600, ug. ml~l Geneticin sulphate.

Cells are removed from the tissue culture flask using trypsin/EDTA and re-plated into black walled, clear bottom 96-well assay plates at 50, 000cells. well-124 hours prior to assay.

On the day of assay the cell assay plates are washed to remove cell culture "medium using a sodium free assay buffer (145mM tetramethyrammonium chloride ; 2mM calcium chloride; 0. 8rnM magnesium chloride hexahydrate; lOmM HEPES ; lOmM glucose ; 5mM potassium chloride, pH 7.4). Fluorescent membrane potential dye solution (FLIPRTM membrane potential dye, Molecular Devices Corporation), containing ICjjM ofapyrethroid to prevent channel inactivation and 250nM tetrodotoxin (TTX) to reduce interference from TTX-sensitive sodium channels present in the cell line. Test compound, initially dissolved in dimethyl sulfoxide but further diluted in sodium free buffer, is added to achieve the final test concentration range of 100µM - 0.05µM.

Cell plates are incubated for 30 minutes at room temperature to allow equilibration of dye and test compound. Plates are then transferred to a fluorescence plate reader for fluorescence measurement using an excitation wavelength of 530nm whilst measuring fluorescence emission at 565nm. Baseline fluorescence levels are first determined before the addition of a sodium containing buffer (220mM sodium chloride; 2mM calcium chloride; 0. 8mM magnesium chloride hexahydrate; 10mM HEPES; 10mM glucose; 5mM potassium chloride. pH 7.4) to cause membrane depolarisation in those cells where channel block has not been effected (final sodium

concentration = 72. 5mM). Membrane depolarisation is registered by an increase in fluorescence emission at 565nm.

The change in fluorescence seen in each test well upon the addition of sodium containing buffer is calculated relative to the baseline fluorescence for that well.

This figure is then used for calculating the IC50 for each test compound. The results are set out in Tables 1 and 2 below.

TABLE 1 Compound IC50 Example 91 6. 91 Example 92 5. 27 Example 93 4. 72 Example 94 2. 17 Example 95 1. 71 Example 8 0.41 Example 70 2. 14 Example 48 4.84 Example 11 0. 60 Example 14 1. 59 Example 16 0. 88 Example 17 1. 25 Example 18---0. 68 Example 19 0. 73 Example 21 1. 25 Example 22 0. 81 Example 23 0. 26 Example 24 1. 51 Example 25 1. 07 Example 26 0.67 Example 27 1. 02 Example 45 7. 21 Example 32 0. 23 Example 34 0. 19 Example 33 0.86 Example 35 4. 86 Example 86 1. 46 Example 87 1. 10 Example 88 0.58 Compound Also Example 12 0. 99 Example 13 1. 39 Example 9 0. 43 Example 10 0.48 Example 30 1. 59 Example 29 14. 96 Example 89 0. 49 Example 31 1.85 Example 47 0. 47 Example 46 0. 29 Example 36 2. 80 Example 38 1.39 Example 39 0. 45 Example 61 2.56 Example 62 5. 63 Example 63 15. 84 Example 64 3. 14 Example 65 5. 64 Example 66 2. 05 Example 67 2. 35 Example 68 1.95 Example 42 1.05 Example 60 0. 95 Example 40 0. 97 Example 77 0. 66 Example 69 8. 96 Example 41 7. 02 Example 50 2.74 Example 53 4. 06 Example 52 4.68 Example 43 1.67 Compound Example 96 1. 94 Example 97 1. 06

TABLE 2 The compound numbers in Table 2 refer to those set out at pages 21 to 32 of the description. Compound ICso 90 2. 05 71 2. 18 72 1. 29 73 1. 28 74 1. 80 76 14. 75 78 28. 52 79 1. 02 80 0. 00 81 1. 40 82 1. 06 83 0. 83 84 0. 40 85 1.08 86 0. 49 87 0. 49 88 2. 09 91 6. 98 92 4. 82 94 2. 84 95 0. 53 96 1. 11 97 2. 27 98 6. 76 99 2. 43 Compound ICso 100 0.97 101 4. 26 102 0. 86 103 2. 25 105 15. 89 107 2. 26 108 3. 48 109 1. 80 110 0. 48 111 3.88 112 0. 79 114 10. 62 115 2. 35 116 22. 19 117 1. 36 118 10.23 119 1. 91 120 3. 34 121 3. 45 122 0. 96 123 2. 89 124 0. 59 125 0. 38 126 1. 93 127 0. 65 Compound ICso 128 3. 51 129 2. 48 131 3. 61 132 0. 49 133 0. 60 134 0. 77 135 0. 38 136 2. 11 137 0. 44 138 0. 52 139 1. 25 140 2.33 141 1.85 142 2. 09 143 9. 59 144 0. 50 145 2. 63 147 2. 04 148 5.17 149 9.09 150 1. 79 151 7. 44 152 3. 03 153 5. 31 154 12. 40 155 6. 26 156 2. 37 157 30. 00 158 4. 59 159 20.78 Compound ICso 160 0.95 161 1.11 162 0.97 163 0. 77 164 0. 71 165 1.02 166 0.35 167 4.51 168 2w01 169 29.90 170 1.69 171 1. 75 172 6.27 173 5. 64 174 0.55 175 1.53 176 5.95 178 0.62 180 5.19 181 20.35 182 2.14 183 2.26 184 10v88 185 1.85 186 29.13 187 19*06 188 12. 05 189 0.51 190 0. 53 191 1. 27 Compound ICso 192 9. 06 193 3.17 194 2.89 195 1. 85 196 0. 93 197 3. 83 198 1. 83 199 8.26 200 1. 66 201 6. 09 202 0. 68 203 1. 11 20410. 67 205 4. 63 Compound ICso 206 1. 62 207 0. 94 208 1.68 210 3. 46 211 3. 03 212 5. 06 213 8.24 214 6. 36 215 1. 11 216 4. 31 217 1. 96 218 12.85 219 0. 8 220 0.8