ZA200404333B

ZA200404333B - 3,4-Dihydro-1H-isoquinoloin-2-Yl-Derivatives.

Info

Publication number: ZA200404333B
Application number: ZA200404333A
Authority: ZA
Inventors: Jan Kehler; Anders Poulsen; Berith Bjornholm; Friedrich Kroll; Morten Bang Norgaard
Original assignee: Lundbeck & Co As H
Priority date: 2001-12-19
Filing date: 2004-06-02
Publication date: 2005-06-02
Also published as: BR0215037A; AR037855A1; PL371851A1; IS7299A; CO5601017A2; KR20040068306A; UA81755C2

Description

3,4-dihydro-1H-isoquinolin-2-yl-derivatives ‘ Field of the Invention , 5 The compounds of the present invention belong to a novel class of 3,4-dihydro- 1H-isoquinolin-2-yl-derivatives having affinity for the neurokinin 2 (NK2) receptor. The compounds are NK2-antagonists and are useful in the treatment of those diseases where an

NK2-receptor is implicated like asthma and a CNS-disease. These novel 3,4-dihydro- 1H-isoquinolin-2-yl-derivatives are capable of penetrating the blood brain barrier and therefore useful in treating a variety of CNS diseases.

Background of the invention

Three tachykinins, Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are widely distributed throughout the peripheral and central nervous systems. The biological effects of these neuropeptides are carried out via binding to their preferred receptors, NK1,

NK2 and NK3 (Guard, S. and Watson, S. P. Neurochem. Int. 1991, 18, 149). Substance P displays highest affinity for the NK1 receptors, whereas NKA and NKB bind preferentially to NK2 and NK3 receptors, respectively. The selectivities of the endogenous ligands for their respective receptors are not absolute (reviewed in Regoli, D. et al. Pharmacol. Rev. 1994, 46, No. 4, 551 plus Bremer, A. A. et al. Eur J Pharmacol 2001, 423, 143). The three receptor subtypes belong to the G-protein-coupled receptor super family and have been cloned in various species including mice, rats and humans (Giardina, G. A. M. et al. Drugs of the Future 1997, 22, 1235 and references herein).

Activation of the tachykinin receptors influences a broad array of biological actions, including pain transmission, vasodilation, smooth muscle contraction, secretion of saliva, bronchoconstriction, activation of the immune system (inflammatory pain), neurogenic " inflammation and neurotransmission (Patacchini, R. et Maggi, C.A. Eur J Pharmacol. 2001, 429, 13; Longmore, J. et al. Can J Physiol Pharmacol 1997, 75, 612; Giardina, G. A. M. et : al. Drugs of the Future 1997, 22, 1235 and references herein).

Expression of NK2 receptors in human is somewhat controversial. The receptor is generally expressed in low amounts in CNS, and autoradiographic studies have failed to show NK?2 receptors in the human brain. A recent reverse transcription-polymerase chain reaction (RT- ,

PCR) study, however, has revealed a detectable expression of NK2 receptor mRNA in various human brain regions including caudate nucleus, putamen, hippocampus, substantia ) nigra and cerebral cortex (Bensaid, M et al. Neurosci Lett 2001, 303, 25).

Up-regulation of the preprotachykinin (PPT) genes and mRNAs for the neurokinin receptors occurs both in animal models of disease (Fischer, A. et al. J Clin Invest 1996, 98, 2284) and in human diseases, such as asthma (Adcock, I. M. et al. J Mol Endocrino 1993, 11,1).

NK antagonists have been and are under investigations for the treatment of a vast amount of both CNS related and peripheral diseases. A number of pre-clinical studies have been performed to assess the involvement of NK1 and NK2 receptors mediation and modulation of diseases related to anxiety and/or depression (Griebel, G. Et al. Psycopharmacology, 2001, 158, 241; Walsh, D. M. et al. Psychopharmacology 1995, 121, 186; Rupniak, N. M. et al. Neuropharmacology 2000, 39, 1413; Rupniak, N. M. et Kramer, M.S. TiPS 1999, 20, 485;; Giardina, G. A. M. et al. Drugs of the Future 1997, 22, 1235, and references in these).

These studies indicate that NK2 antagonists will be useful in treating or preventing a variety of brain disorders including depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalised anxiety disorder, social anxiety disorder, panic anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder, psychosis, and Huntington’s disease as well as Parkinson’s disease, adjustment disorders, pain, emesis, migraine, epilepsia, obesity, asthma and cerebrovascular disease. However, peripheral diseases such as inflammation, inflammatory bowel disease, hypertension, arthritis, cardiovascular diseases, neuritis, neuralgia, urticaria, incontinence, gastrointestinal diseases, influenza, allergy, pulmonary allergy and carcinoma / tumural growth may also be addressed by NK2 antagonists. 30 .

US 3,994,891 discloses tetrahydroisoquinolines of the general formula

» . N ©) /

R wherein R is hydrogen or methyl, and G is NH or CH2. The dihydroxy compounds are described as effective vasodilators, whereas the dimethoxy compounds are intermediates in the manufacture of the dihydroxy compounds.

Hence, there is a desire for novel compounds that are antagonists at the NK2 receptor.

Summary of the Invention

The objective of the present invention is to provide compounds that are antagonists at the

NK2 receptor.

A further objective of the present invention is to provide compounds with such activities which have improved solubility, metabolic stability and/or bioavailability compared to prior art compounds.

Accordingly, the present invention relates to novel compounds of formula I

Rea R® pi /

Rb N /~\ . N .

Ra m 77 a\ \ 4 - 3 R3 RS

R4 R5 wherein

R' is a group R''CO-, R''CS-, R!'SO,-, R''OCO-, R''SCO- or R''CO-CR'*R">- wherein ,

R" is Ci.z-alkyl, Cye-alkenyl, C,¢-alkynyl, Csg-cycloalkyl, Cs.3-cycloalkyl-C) ¢-alkyl, aryl, aryl-C,¢-alkyl, heteroaryl, heteroaryl-C, ¢-alkyl, tetrahydropyranyl, ’ 1,2,3,4-tetrahydronaphtalenyl, or 4H-benzo[1,3]dioxinyl optionally substituted with halogen wherein each of said Cy.¢-alkyl, aryl, heteroaryl and Ci g-cycloalkyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, Ci¢-alkyl, C,¢-alkoxy, aryl-Cj.¢-alkoxy, C)¢-alkylsulfanyl, aryl and aryloxy wherein said aryl and aryloxy independently are unsubstituted or substituted with one or more halogen, and R'? and R" independently are hydrogen or C,¢-alkyl; or R'is a group R"“RPNCO-, R"“R"NCS-, wherein R'* and R'® are independently hydrogen,

Ciealkyl, Cy¢-alkenyl, Cj¢-alkynyl, Cis-cycloalkyl, Cjs-cycloalkyl-C,¢-alkyl, aryl or aryl-C,¢-alkyl, wherein each of said Cj¢-alkyl, aryl and Css-cycloalkyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C;¢-alkyl and C,¢-alkoxy, or R'* and R'® together with the

N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group;

Ris selected from hydrogen, trifluoromethyl and C, ¢-alky];

R*R% RR”, R™, R® and R® are independently selected from hydrogen, halogen, cyano, nitro, C,¢-alkyl, C¢-alkenyl, Cy¢-alkynyl, Css-cycloalkyl, Css-cycloalkyl-C,¢-alkyl, amino, Cjg¢-alkylamino, di-(Ci.¢-alkyl)amino, C,-alkylcarbonyl, aminocarbonyl,

Cj¢-alkylaminocarbonyl, di-(C,.¢-alkyl)aminocarbonyl, Ci—¢-alkoxy, C,¢-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C, ¢-alkylsulfonyl; m is 2-6;

Ris benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclic aryl or heteroaryl } wherein each benzyl, benzoyl, aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C.s-alkyl, C,¢-alkenyl, C,s-alkynyl,

Cs.g-cycloalkyl, Css-cycloalkyl-C,s-alkyl, amino, C;¢-alkylamino, di-(C;.¢-alkyl)amino,

Ci.¢-alkylcarbonyl, aminocarbonyl, C,¢-alkylaminocarbonyl, di-(C,_¢-alkyl)aminocarbonyl,

Ci-¢-alkoxy, C,s-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and . trifluoromethylsulfonyl, : 5 QisC,NorCR', wherein R'® is selected from hydrogen, halogen, cyano, nitro, C,¢-alkyl, C,¢-alkenyl,

Cae-alkynyl, Cjg-cycloalkyl, Cs.s-cycloalkyl-C,¢-alkyl, amino, Ci-¢-alkylamino, di- (Ci¢-alkyl)amino, C,.¢-alkylcarbonyl, aminocarbonyl, C,¢-alkylaminocarbonyl, di- (Cj-alkyl)aminocarbonyl, Ci-s-alkoxy, Cj¢-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl, a group ~NR*®*COR?' wherein R* is hydrogen or C,.¢-alkyl and R*' is Ci.s-alkyl, a group -COOR'® wherein R' is hydrogen or

Cis-alkyl, or a group —CONR'’R!® wherein R'” and R'® independently are selected from hydrogen and C.¢-alkyl orR' and R"® together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl is unsubstituted or substituted with a C,_¢-alkyl; or R’ and R"® together with the carbon to which they are attached form a cyclic structure selected from the group comprising:

B

A )=0 y~* A? Ng CL

A3 NN

Xo Q' ING L »=0

Q

1) 2) 3)

Jig

Ee av by [ 4) wherein Q’ is the carbon shared with the piperidine ring, so that said cyclic structure together with said piperidine ring form a spiro structure; and

X, Y, and Z are independently chosen from O; NR’; CRZR*, S(O). and a bond; wherein

R" is selected from hydrogen, C,-alkyl, C,¢-alkenyl, Cz6-alkynyl, C;g-cycloalkyl,

Cs.g-cycloalkyl-C;_¢-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R"® .

Is a group R¥S0,-, R*0CO- or R¥SCO- wherein R® is Cig-alkyl, C,¢-alkenyl,

Cagalkynyl, Cig-cycloalkyl, Cig-cycloalkyl-Cic-alkyl or aryl, or R" is a group ‘

R*'R*’NCO- or R*'R?NCS-, wherein R?' and R? are independently hydrogen, C,_¢-alkyl,

C,.-alkenyl, Cy 4-alkynyl, Csg-cycloalkyl, Cs.s-cycloalkyl-C, ¢-alkyl, or aryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from Ci¢-alkyl or halogen; or R?' and R*? together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; R* and R* are independently selected from hydrogen, halogen, cyano, nitro, C;-alkyl, C,¢-alkenyl, Cs-¢-alkynyl, Cs.g-cycloalkyl,

Cs.s-cycloalkyl-C,.¢-alkyl, aryl, heteroaryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C,¢-alkyl or halogen, amino, C;s-alkylamino, a group NR¥R* wherein R*® and R? are independently selected from C,;¢-alkyl

Ci-alkylcarbonyl, aminocarbonyl, C,¢-alkylaminocarbonyl, di~(C,¢-alkyl)aminocarbony],

Ci¢-alkoxy, C;-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and

C,.c-alkylsulfonyl or R* and R% together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, or R? and R* together is oxo; and n is 0, 1 or 2; provided that no more than one of X, Y and Z may be a bond, and provided that two adjacent groups X, Y or Z may not at the same time be selected from O and S; and

A', A%, A’ and A* are independently selected from N and CR?’ wherein R? is hydrogen, halogen, cyano, nitro, C,_¢-alkyl, Ca-alkenyl, C,.¢-alkynyl, Cs s-cycloalkyl, Cig-cycloalkyl-

C,¢-alkyl, Ci.¢-alkylcarbonyl, aminocarbonyl, C-¢-alkylaminocarbony]l, di- (C,¢-alkyl)aminocarbonyl, Ci¢-alkoxy, C,¢-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl C;-alkylsulfonyl amino or a group

NR*R?’ wherein R*® and R® are independently selected from hydrogen and C,.¢-alkyl or

R? and R? together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group; provided that only one of A', A?, A? . and A? may be N; and the dotted line emanating from Q is a bond when Q is C, and no bond when Q is CR'® or N;

or a pharmaceutically acceptable acid addition salt thereof. ; Detailed Description of the Invention \ 5 The Ci.-alkyl groups defined for R'! are preferably selected from C,.j¢-alkyl, more preferred C, s-alkyl, and most preferred Cj g-alkyl.

In one embodiment, the present invention relates to such compounds wherein Q is CR'’, and

R’ and R'? together with the carbon to which they are attached form a bicyclic structure: z A

CX i

X ZA3 ~Q' A¢ 1), wherein Q’ is the carbon shared with the piperidine ring, so that said bicyclic structure together with said piperidine ring form a spiro structure; and

X,Y and Z are independently chosen from O; NR'’; CR®R* and S(O), wherein R' is selected from hydrogen, Cl-alkyl, C,¢-alkenyl, Cygs-alkynyl, Cs.g-cycloalkyl,

Cjs-cycloalkyl-C).¢-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R" is a group R¥S0,-, R??0CO- or R¥SCO- wherein R? is C,¢-alkyl, Cy¢-alkenyl,

Ca¢-alkynyl, Cig-cycloalkyl, Ci.g-cycloalkyl-Ci¢-alkyl or aryl, or RY is a group

RYRZ”NCO-, R¥'R*NCS-, wherein R*' and R* are independently hydrogen, C,.¢-alkyl,

Cs.¢-alkenyl, Cy ¢-alkynyl, C;s-cycloalkyl, Cj.s-cycloalkyl-C,¢-alkyl or aryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C,_¢-alkyl or halogen; or R* and R* together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; R? and R* are independently selected from hydrogen, halogen, cyano, nitro, C,-alkyl, Cz ¢-alkenyl, Cy.s-alkynyl, C;_s-cycloalkyl, y C;.s-cycloalkyl-C,_¢-alkyl, aryl, heteroaryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C,.s-alky! or halogen, amino, C,_¢-alkylamino, a ) group NR*R*® wherein R* and R? are independently selected from C;.-alkyl or R? and

R?® together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, C¢-alkylcarbonyl, aminocarbonyl,

C).¢-alkylaminocarbonyl, di-(C,.¢-alkyl)aminocarbonyl, Ci-s-alkoxy, Ci-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl, and C;¢-alkylsulfonyl or R® and R%* together is 0x0; and n is 0, 1 or 2; and a bond; provided that no more than one of X,Yand Z - may be a bond, and provided that two adjacent groups X, Y or Z may not at the same time be selected from O and S; and ®

A', A’, A’ and A* are independently selected from N and CR?’ wherein R? is hydrogen, halogen, cyano, nitro, C,¢-alkyl, Cy.¢-alkenyl, Cy -alkynyl, C;.3-cycloalkyl, Ci.g-cycloalkyl-

Ci¢-alkyl, amino, a group NR*R? wherein R*® and R? are independently selected from hydrogen and C,¢-alkyl or R*® and R” together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, C 1-6-alkylcarbonyl, aminocarbonyl, C,s-alkylaminocarbonyl, di-(C,.s-alkyl)aminocarbonyl, C_¢-alkoxy,

C.¢-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C,-alkylsulfonyl; provided that only one of A', A%, A’ and A* maybeN.

In a preferred embodiment, the present invention relates to such compounds wherein X, Y and Z are selected from one of the combinations: X is oxygen, Y is a bond and Z is

CRP®R*. X is CRZR* Y is a bond and Z is oxygen; X is NR", Y is a bond and Z is

CR¥R*; Xis CRPR*,Y is a bond and Z is NR'’; X is CO, Y is a bond and Z is NR'; X is

SO,, Y is a bond and Z is NR'?; X is SO, Y is a bond and Z is NR"; X is CR¥R* Yisa bond and Z is S; X is CR®R*, Y is a bond and Z is SO; X is CR®R*, Y is a bond and Z is

SO,; wherein R" is hydrogen, acetyl or methylsulfonyl and R*® and R* are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl.

In another preferred embodiment, the present invention relates to such compounds wherein -X-Y-Z- together form a group selected from: -O-CR®R?**-, -CR*R**-0-, -NR'*-CR*R?*., -CR¥R*NR"-, -CO-NR"-, -SO-NR"-, -SO-NR"-, -CR¥™R™S., -CR¥R*SO -CR¥R?-S0,-; wherein R" is hydrogen, acetyl or methylsulfonyl tyl and R** and R** are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl. .

In another preferred embodiment, the present invention relates to such compounds wherein

A’ is N or CR?” wherein R? is halogen, cyano, nitro, a group NR*R* wherein R® and RY are independently selected from hydrogen and C;.¢-alkyl or R?® and R*® together with the N- atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or , morpholinyl group, C,¢-alkylcarbonyl, aminocarbonyl, C,.s-alkylaminocarbonyl, di- (Ci.¢-alkyl)aminocarbonyl, Ci-¢-alkoxy, hydroxy, trifluoromethyl, difluoromethyl, ’ 5 fluoromethyl, trifluoromethylsulfonyl or C,.¢-alkylsulfonyl.

Al A AZ and A? are independently selected from CR?" wherein R” is as defined above.

In a more preferred embodiment, the present invention relates to such compounds wherein bicyclic structure described above is selected from the group comprising:

R2¥ R27 R1¢

N

Q R27" ( ( ©

Q' Q Q

R27 R27" a) b) c) wherein R'? is acetyl or methylsulfonyl, R%*" is hydrogen or methyl, R* is hydrogen or fluoro, R?"" is hydrogen, fluoro, methyl or isopropyl, R¥" is hydrogen, fluoro or trifluoromethyl.

In another embodiment, the present invention relates to such compounds wherein R’ and R'° together with the carbon to which they are attached form a cyclic structure selected from the group comprising:

B

= 0 : a N J

N~ o O° °N . o—! . Q Q 2) 3) 4)

wherein Q’ is the carbon shared with the piperidine ring, so that said cyclic structure together with said piperidine ring form a spiro structure

In yet another embodiment, the present invention relates to such compounds wherein R’ is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl or mono- or bicyclic aryl or heteroaryl * wherein each benzyl, benzoyl, aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C.s-alkyl, C,¢-alkenyl, C, s-alkynyl,

Css-cycloalkyl, Csg-cycloalkyl-Cy.¢-alkyl, amino, C;.¢-alkylamino, di-(C;.6-alkyl)amino,

Cy-alkylcarbonyl, aminocarbonyl, C;.-alkylaminocarbonyl, di-(C1_-alkyl)aminocarbonyl,

C-alkoxy, C,¢-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.

In yet another embodiment, the present invention relates to such compounds wherein R’ is 2,3-dihydrobenzofuran-7-yl, benzyl or benzoyl wherein said benzyl or benzoyl is unsubstituted or substituted with one or more halogens in the phenyl groups, or R’ is mono- or bicyclic aryl or heteroaryl selected from the group comprising phenyl, indolyl, pyridyl, thiophenyl and benzisoxazolyl, wherein each aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C;¢-alkyl, C,s-alkenyl,

Cyealkynyl, Csg-cycloalkyl, Cjs-cycloalkyl-C,¢-alkyl, amino, C,s-alkylamino, di- (Cyg-alkyl)amino, Ci¢-alkylcarbonyl, aminocarbonyl, Cj¢-alkylaminocarbonyl, di- (Cl _g-alkyl)aminocarbonyl, Ci-s-alkoxy, C,¢-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.

In a preferred embodiment, the present invention relates to such compounds wherein said mono- or bicyclic aryl or heteroaryl is selected from the group comprising phenyl, indol- 3-yl and benzisoxazol-3-yl wherein said phenyl, indol-3-yl or benzisoxazol-3-yl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C;.¢-alkyl,

C.¢-alkenyl, C,¢-alkynyl, Cs.3-cycloalkyl, Cs.s-cycloalkyl-C, ¢-alkyl, amino, .

Cj.¢-alkylamino, di-(Ci.¢-alkyl)amino, C,¢-alkylcarbonyl, aminocarbonyl,

Cig-alkylaminocarbonyl, di-(Cl.¢-alkyl)aminocarbonyl, Ci-s-alkoxy, Ci¢-alkylthio, . hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.

In an even more preferred embodiment, the present invention relates to such compounds wherein said optional substituents are selected from the group comprising halogen, phenyl . and methyl. ) 5 In yet another embodiment, the present invention relates to such compounds wherein Q is

CR' wherein R' is selected from hydrogen, C,.c-alkylcarbonyl, hydroxy, a group -NR**COR?! wherein R* is hydrogen or C,_¢-alkyl and RY is Ci.6-alkyl, a group _COOR'¢ wherein R'® is C,.¢-alkyl, or a group —CONR'’'R'® wherein R'” and R'® together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl are unsubstituted or substituted with a

Ci.¢-alkyl.

In a preferred embodiment, the present invention relates to such compounds wherein R!? is selected from hydrogen, acetyl, hydroxy, a group -NR**COR*' wherein R* is hydrogen and

R*' is methyl, a group -COOR!® wherein R'® is ethyl, or a group -CONR'’R'® wherein R"” and R'® together with the nitrogen to which they are attached form a piperidinyl or a 4-methylpiperazinyl.

In another preferred embodiment, the present invention relates to such compounds wherein mis 2,3 or 4, more preferred m is 2.

In yet another embodiment, the present invention relates to such compounds wherein R' is a group R''CO-, R''OCO- wherein R'" is Cig-alkyl, Css-cycloalkyl, Css-cycloalkyl-

Ci¢-alkyl, phenyl, phenyl-C,¢-alkyl, pyridyl, furanyl, benzo[1,2,5]Joxadiazolyl, quinoxalinyl, benzo[b]thiophenyl or naphthalenyl wherein each of said Cjg¢-alkyl, phenyl, pyridyl and furanyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C,.¢-alkyl, C,¢-alkoxy, phenyl and phenoxy wherein said phenyl and phenoxy independently are unsubstituted or substituted with one halogen; or R'is a group R'"“R'>’NCO-, wherein R'* and R"® are independently . 30 hydrogen, Ci¢-alkyl, aryl, or aryl-C,_¢-alkyl, wherein each of said C,-alkyl and aryl groups independently are unsubstituted or substituted with one substituent selected from the group comprising halogen and C,.¢-alkoxy.

In yet another embodiment, the present invention relates to such compounds wherein R? is hydrogen.

In yet another embodiment, the present invention relates to such compounds wherein R? is hydrogen. :

In yet another embodiment, the present invention relates to such compounds wherein R* is hydrogen or methoxy.

In yet another embodiment, the present invention relates to such compounds wherein R’ is hydrogen or methoxy.

In yet another embodiment, the present invention relates to such compounds wherein R° is hydrogen.

In yet another embodiment, the present invention relates to such compounds wherein R7 and R’is hydrogen.

In yet another embodiment, the present invention relates to such compounds wherein R? and R®is hydrogen.

Preferred compounds of the invention are compounds number 1-209 as disclosed in the experimental section as well as the compounds in the following list: 1-(1-{2-[4-(5-Fluoro-] H-indol-3-yl)-piperidin-1-y1}-ethyl}-5-chloro-3,4-dihydro- 1 H-isoquinolin-2-yl1)-1-(4-fluoro-phenyl)methanone, 1-cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl} -5-chloro- 3,4-dihydro- 1 H-isoquinolin-2-yl)methanone, } 1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl}-ethyl} - 5-chloro-3,4-dihydro-H-isoquinolin-2-yl)methanone, : 1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - 5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone,

1-cyclopentyl-1-(1- {2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]}- ethyl}-5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, . 1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro{isobenzofuran-1(3H),4'-piperidine- 1'-yl}-ethyl}-5-chloro-3,4-dihydro- / H-isoquinolin-2-yl)methanone, " 5 N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl} - 4-(3-fluoropheny!)-piperidin-4-yl]acetamide,

N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3 4-tetrahydro-isoquinolin-1-y1]-ethyl}- 4-(3-fluorophenyl)-piperidin-4-yl]Jacetamide,

N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}- 4-phenylpiperidin-4-yl]acetamide,

N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-phenylpiperidin-4-yl]acetamide, 1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl]- 5-chloro-3,4-dihydro- 1 H-isoquinolin-2-yl} methanone, 1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-/H-indol-3,4'-piperidin-1'-yl]ethyl]- 5-chloro-3,4-dihydro- 1 H-isoquinolin-2-yl} methanone, 1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro /H-indol-3,4'-piperidin-1'-yl]- ethyl]-5-chloro-3,4-dihydro- / H-isoquinolin-2-yl} methanone, 1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-/ H-indol-3,4'-piperidin-1'-yl]- ethyl]-5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl }methanone, 1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-/ H- isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1 H- isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 5-chloro-3,4-dihydro-/H-isoquinolin-2-yl)-methanone, 1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 5-chloro-3,4-dihydro- / H-isoquinolin-2-yl)methanone,

1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine- 1 "-yl]-ethyl}- 5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl)-methanone, 1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4"-piperidine-1 "-yl]-ethyl}- : 5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(5-fluoro-/H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro- ) 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, 1-cyclopentyl-1-(1-{2-[4-(5-fluoro-1 H-indol-3-yl)-piperidin-1-yl]-ethyl} -3 ,4-dihydro- 5-fluoro-/H-isoquinolin-2-yl)methanone, 1-cyclopentyl-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1 "-yl]-ethyl}- 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'"-piperidine-1 "-yl]-ethyl}- 3,4-dihydro-5-fluoro- / H-isoquinolin-2-yl)methanone, 1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine-1 -yl]- ethyl} -3,4-dihydro-5-fluoro-7 H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4"-piperidine- 1'-yl]ethyl}-3,4-dihydro-5-fluoro-1 H-isoquinolin-2-yl)methanone,

N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin- 1 -yl]-ethyl}- 4-(3-fluorophenyl)-piperidin-4-yl]acetamide,

N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-(3-fluorophenyl)-piperidin-4-yl]acetamide,

N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl } - 4-phenylpiperidin-4-ylJacetamide,

N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-phenylpiperidin-4-yl]acetamide, l-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-/H-indol-3,4'-piperidin-1'-yl]ethyl]- 3.,4-dihydro-5-fluoro-1 H-isoquinolin-2-yl}methanone, 1-(4-fluorophenyl)-1- {1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4"-piperidin-1'-yl]ethyl]- 3,4-dihydro-5-fluoro- H-isoquinolin-2-yl}methanone, } 1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro /H-indol-3,4"-piperidin-1'-yl]- ethyl]-3,4-dihydro-5-fluoro- H-isoquinolin-2-yl} methanone, 1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro- / H-indol-3,4'-piperidin-1'-y]- ethyl]-3,4-dihydro-5-fluoro- / H-isoquinolin-2-yl }methanone,

1-cyclopentyl-1-(1- {2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 5-fluoro- 1 H-1soquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1- {2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 5-fluoro- 1 H-isoquinolin-2-yl)methanone, ’ 5 1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin- 1-yl]-ethyl}-3,4-dihydro-5-fluoro-

I H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl}-ethyl}-3,4-dihydro-5-fluoro-

IH-isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-5-fluoro-/H-isoquinolin-2-yl)-methanone, 1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl } - 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)methanone, 1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl}-ethyl} - 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)-methanone, l-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(5-fluoro-/H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, 1-cyclopentyl-1-(1-{2-[4-(5-fluoro-/ H-indol-3-yl)-pipendin-1-yl]-ethyl}-5,6-dichloro- 3,4-dihydro-/H-isoquinolin-2-yl)methanone, 1-cyclopentyl-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl } - 5,6-dichloro-3,4-dihydro- 1 H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, l-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]- ethyl}-5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1- {2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]ethyl}-5,6-dichloro-3,4-dihydro- / H-isoquinolin-2-yl)methanone,

N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl } - . 30 4-(3-fluorophenyl)-piperidin-4-yl]acetamide,

N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1 -yl]-ethyl}- 4-phenylpiperidin-4-yl]acetamide,

N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1 -yl]-ethyl}- : 4-phenylpiperidin-4-yl]acetamide, l-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro- H-indol-3,4"-piperidin-1 "-yl]ethyl]- ‘ 3,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl} methanone, 1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4'-piperidin-1 ‘-yl]ethyl]- 5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl} methanone, 1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-S-fluoro /H-indol-3,4'-piperidin-1"-yl]- ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl} methanone, 1-(4-fluoropheny!l)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-/ H-indol-3,4'-piperidin-1'-y1]- ethyl]-5,6-dichloro-3,4-dihydro- / H-isoquinolin-2-yl} methanone, 1-cyclopentyl-1-(1- {2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl} - 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro- 1 H-1soquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)-methanone, 1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - 5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)-methanone, 1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl}-ethyl} - 5,6-dichloro-3,4-dihydro-1 H-isoquinolin-2-yl)methanone, 1-(1-{2-[4~(5-fluoro- H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-

IH-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, . 1-cyclopentyl-1-(1-{2-[4-(5-fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl} -5,6-difluoro- 3,4-dihydro-/H-isoquinolin-2-yl)methanone,

1-cyclopentyl-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - 5,6-difluoro-3,4-dihydro-7 H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 5,6-difluoro-3,4-dihydro-1 H-isoquinolin-2-yl)methanone, : 5 l-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'"-piperidine-1'-yl]- ethyl}-5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]ethyl}-5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone,

N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-(3-fluorophenyl)-piperidin-4-ylJacetamide,

N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3 4-tetrahydro-isoquinolin-1-yl}-ethyl} - 4-(3-fluorophenyl)-piperidin-4-ylJacetamide,

N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-phenylpiperidin-4-yl]acetamide,

N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl } - 4-phenylpiperidin-4-yl]acetamide, 1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl]- 5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl }methanone, 1-(4-fluorophenyl)-1- {1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl}- 5,6-difluoro-3,4-dihydro-/H-isoquinolin-2-yl}methanone, 1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro /H-indol-3,4"-piperidin-1'-yl]- ethyl]}-5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl }methanone, 1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-/ H-indol-3,4"-piperidin-1'-yl}- ethyl]-5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl} methanone, 1l-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-y1]-ethyl}-5,6-difluoro- 3,4-dihydro-7 H-isoquinolin-2-yl)methanone, 1-(4-fluorophenyl)-1-(1- {2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}- 5,6-difluoro-3,4-dihydro-/H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,

1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4"-piperidine-1 '-yl]-ethyl}- 5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl)-methanone, 1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4"-piperidine-1 "-yl]-ethyl}- 5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, l-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl}-ethyl} - ’ 5,6-difluoro-3,4-dihydro- / H-isoquinolin-2-yl)-methanone, and 1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - 5,6-difluoro-3,4-dihydro- / H-isoquinolin-2-yl)methanone.

The compounds of the invention are NK; receptors antagonists having a human NK, binding affinity (IC50) of 5 uM or less, typically of 1 pM or less, preferably of 200 nM or less, more preferred of 50 nM or less and most preferred of 10 nM or less.

Accordingly, the compounds of the invention are considered useful in treating a variety of

CNS diseases such as depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalised anxiety disorder, social anxiety disorder, panic anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder, psychosis and Huntington’s disease as well as

Parkinson’s dementia, adjustment disorders, pain, emesis, migraine, epilepsia, obesity and cerebrovascular disease.

In particular, the compounds of the invention are considered useful in the treatment of depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalised anxiety disorder, social anxiety disorder, panic anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder and psychosis.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.

In a further aspect, the present invention provides the use of a compound of formula I as defined above or an acid addition salt thereof for the manufacture of a pharmaceutical . preparation for the treatment of the above mentioned disorders. : 5 The compounds of the general formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention. Throughout the specification and claims, reference to specific compounds refers to the racemates unless otherwise indicated.

The term C,-alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, and 2-methyl-1-propyl. The terms C,.s-alkyl, C;_jo-alkyl and C,.;z-alkyl, respectively, refer similarly to branched or unbranched alkyl group having from one to eight, ten or twelve carbon atoms inclusive, respectively.

Similarly, C;.¢-alkenyl and C,¢-alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond, respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The term C;-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.

Halogen means fluoro, chloro, bromo or iodo.

As used herein, the term acyl refers to a formyl, C,s-alkylcarbonyl, arylcarbonyl, aryl-

Ci¢-alkylcarbonyl, Cs.s-cycloalkylcarbonyl or a Cj.s-cycloalkyl-C;¢-alkyl-carbonyl group, and the term thioacyl is the corresponding acyl group, in which the carbonyl group is replaced with a thiocarbonyl group.

The terms C,¢-alkoxy, Css-cycloalkyl-C ¢-alkyl, C,s-alkylsulfonyl, C;s-alkylamino,

Cj.¢alkylcarbonyl, and the like, designate such groups in which the C,¢-alkyl and the

C.g-cycloalkyl group are as defined above.

The term aryl refers to a carbocyclic aromatic group, such as phenyl or naphthyl, in particular phenyl.

The term heteroaryl refers to 5-membered monocyclic rings such as 1 H-tetrazolyl, 3H-1,2,3-oxathiazolyl, 3H-1,2,4-oxathiazolyl, 3H-1,2,5-oxathiazolyl, 1,3,2-oxathiazolyl, ’ 1,3,4-oxathiazolyl, 1,4,2-oxathiazolyl, 3H-1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,4,2-dioxazolyl, 3H-1,2,3-dithiazolyl, 3H-1,2,4-dithiazolyl, 1,3,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1H-imidazolyl, 1H-pyrazolyl, 1H-pyrrolyl, furanyl, thienyl, 1H-pentazole; 6-membered monocyclic rings such as 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, 4H-1,3,5-oxathiazinyl, 1,4,2-oxathiazinyl, 1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl, 4H-1,3,2-dioxazinyl, 4H-1,3,5-dioxazinyl, 1,4,2-dioxazinyl, 2H-1,5,2-dioxazinyl, 1,2,3-dithiazinyl, 1,2,4-dithiazinyl, 4H-1,3,2-dithiazinyl, 4H-1,3,5-dithiazinyl, 1,4,2-dithiazinyl, = 2H-1,5,2-dithiazinyl, 2H-1,2,3-oxadiazinyl, 2H-1,2,4-oxadiazinyl, 2H-1,2,5-oxadiazinyl, 2H-1,2,6-oxadiazinyl, 2H-1,3,4-oxadiazinyl, 2H-1,3,5-oxadiazinyl, 2H-1,2,3-thiadiazinyl, 2H-1,2,4-thiadiazinyl, 2H-1,2,5-thiadiazinyl, 2H-1,2,6-thiadiazinyl, 2H-1,3,4-thiadiazinyl, 2H-1,3,5-thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-1,2-oxazinyl, 2H-1,3-oxazinyl, 2H-1,4-oxazinyl, 2H-1,2-thiazinyl, 2H-1,3-thiazinyl, 2H-1,4-thiazinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, 2H-pyranyl, 2H-thiinyl; and to bicyclic rings such as 3H-1,2,3-benzoxathiazolyl, 1,3,2-benzodioxazolyl, 3H-1,2,3-benzodithiazolyl, 1,3,2-benzodithiazolyl, benzfurazanyl, 1,2,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, 1H-benzotriazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, 1 H-benzimidazolyl, 1H-indazolyl, 3H-1,2-benzoxathiolyl, 1,3-benzoxathiolyl, 3H-2,1-benzoxathiolyl, 3H-1,2-benzodioxolyl, 1,3-benzodioxolyl 3H-1,2-benzodithiolyl, 1,3-benzodithiolyl, 1H-indolyi, 2H-isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl, 2-benzothienyl, 1H-2,1-benzoxazinyl, 1H-2,3-benzoxazinyl, 2H-1,2-benzoxazinyl, 2H-1,3-benzoxazinyl, , 2H-1,4-benzoxazinyl, ) 2H-3,1-benzoxazinyl, 1H-2,1-benzothiazinyl, 1H-2,3-benzothiazinyl, 2H-1,2-benzothiazinyl, 2H-1,3-benzothiazinyl, 2H-1,4-benzothiazinyl, 2H-3,1-benzothiazinyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl,

quinolyl, 1H-2-benzopyranyl, 2H-1-benzopyranyl, 1H-2-benzothiopyranyl or 2H-1-benzothiopyranyl.

The acid addition salts of the compounds of the invention are pharmaceutically acceptable ’ 5 salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The pharmaceutical compositions of this invention, or those which are manufactured in accordance with this invention, may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.

Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.

The total daily dose is usually in the range of about 0.05 - 500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.

The compounds of the invention may be prepared as follows: 1) Alkylating a piperazine, piperidine or tetrahydropyridine of formula III with an alkylating derivative of formula II:

Réa RS pi

R™ J R? L

R7a -

RS N AQ .

Ré \ y/ \

R9

R4 R® 11) (1m wherein R'-R’ and Q are as previously defined and L is a leaving group such as e.g. halogen, mesylate or tosylate; 2) Reductive alkylation of an amine of formula III with a reagent of formula IV:

Rss R8® pd /

R7b N R2

Ra

R3 RS / \

N A

Ré - R9

Iv) (II) wherein R'-R’® and Q are as previously defined and E is an aldehyde or an activated carboxylic acid, 3) Acylating an amine of formula V by the use of a carboxylic acid and a coupling reagent, an activated ester, an acid chloride, an isocyanate, carbamoyl chloride or by a two-step procedure by treatment with phosgene followed by addition of an amine: :

Ra Re . R3 R6

R* RS o wherein R'-R’ and Q are as previously defined, whereupon the compound of formula I 1s isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.

The alkylation according to method 1) is conveniently performed in an organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature.

Alternatively, the alkylation can be performed at a fixed temperature, which is different from the boiling point, in one of the above-mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO), or N-methylpyrrolidin-2-one (NMP), preferably in the presence of a base. The alkylating agents of formula II can be prepared by methods analogues to those described in the examples or can be synthesised by applying methods described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John

Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions. The amines of formula III are either commercially available or have been described in the literature or can be prepared by methods analogues to those described in the literature e.g. Marxer et al. J. Org. Chem. 1975, 40, 1427, by

Parham et al. J. Org. Chem. 1976, 41, 2628 and by Bauer et al. J. Med. Chem. 1976, 19, 1315, Maligres et al. Tetrahedron 1997, 53, 10983, and by Cheng et al. Tet. Lett. 1997, 38, 1497, Chen, Meng-Hsin; Abraham, John A. Tetrahedron Lett. 1996, 37, 5233-5234 and . Slade, P.D. et al. J. Med. Chem. 1998, 41, 1218-1235, or can be synthesised by methods described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John

Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions.

The reductive alkylation according to method 2) is performed by standard literature methods or as described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John

Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions. The reaction can be performed in two steps, e.g. coupling of amines of formula III with a reagent of formula IV by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with a coupling reagents such as e.g. dicyclohexyl carbodiimide, followed by reduction of the resulting amide with lithium aluminium hydride or alane. The carboxylic acids of formula IV are either commercially available or can be prepared by methods analogues to those described in the literature (e.g. Tet. Lett. 37, 1996, pp. 5453-5456; Tet. Lett. 35, 1994, pp. 6567-6570; J. Med. Chem. 25, 1982, pp. 1235-1240; Synthesis 1987, pp. 474-477).

The acylation according to method 3) is conveniently performed by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with coupling reagents such as e.g. dicyclohexyl carbodiimide. When the acylating reagent is carbamoyl chlorides or isocyanates, the acylation produces urea derivatives. The urea derivatives can also be prepared by a two-step procedure consisting of treatment with phosgene followed by addition of an amine.

The intermediate compounds of formula V are prepared as described in methods 1) and 2), wherein R%-R’, Q, L and E are as previously defined, and R' is a protection group. This protection group may be chosen from those protection group generally used for protection of amino groups. Those skilled in the art will know to select appropriate protection groups and how to protect and deprotect the amines with these protection groups.

Experimental Section .

Melting points were determined on a Biichi SMP-20 apparatus and are uncorrected.

Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with

IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (C18 column 4.6 x 30 mm with a particle size of 3.5 um) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 4 min at 2 mL/min. Purity was determined by integration of the UV trace ) 5 (254 nm). The retention times, R,, are expressed in minutes.

Mass spectra were obtained by an alternating scan method to give molecular weight information. The molecular ion, MH+, was obtained at low orifice voltage (5-20V) and fragmentation at high orifice voltage (100-200V).

Preparative LC-MS-separation was performed on the same instrument. The LC conditions (C18 column 20 x 50 mm with a particle size of 5 pm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection. '"H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.9%D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, g=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dg=double quartet, tt=triplet of triplets, m=multiplet. NMR signals corresponding to acidic protons are generally omitted.

For column chromatography silica gel of type Kieselgel 60, 230-400 mesh ASTM was used.

For ion-exchange chromatography (SCX, 1 g, Varian Mega Bond Elut®, Chrompack cat.

No. 220776) was used. Prior use of the SCX-columns was pre-conditioned with 10% : solution of acetic acid in methanol (3 mL).

Preparation of intermediates

Alkylating reagents of the formula II 1.(RS)-1 -(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert-butyl ester :

Tetrahydrosioquinolinic acid (10 g) was suspended in tetrahydrofuran THF (100 mL).

Triethyl amine (9.1 mL) and di-tert-butyl dicarbonate (14.3 g) was added and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo, redissolved in ethyl acetate (250 mL) and washed twice with and aqueous 0.5 M KHSO4-solution (200 mL), dried over magnesium sulphate and evaporated in vacuo to give 1-carboxymethyl- 3,4-dihydro-1H-isoquinoline-2-carboxylic acid terr-butyl ester in quantitative yield as a clear oil which crystallised upon standing. The protected amino acid was dissolved in dry tetrahydrofuran under nitrogen, cooled to 0 °C and 1M borane in tetrahydrofuran (41.5 mL) was added slowly under nitrogen during 15 min. The mixture was warmed to room temperature and stirred for 1h. Excess borane was carefully destroyed by slow addition of 50 mL of a 1:1 mixture of water/tetrahydrofuran. The mixture was made alkaline to pH=12 by addition of saturated potassium carbonate and extracted with diethylether (2 x 50 mL).

The combined organic phase were dried (magnesium sulphate) and evaporated in vacuo to give 1-(2-Hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as a clear oil (8.4 g). The protected aminoalcohol was dissolved in dry tetrahydrofuran (150 mL) together with triethylamine (5.6 mL) and cooled to 0 °C under nitrogen.

Methanosulfonyl chloride (2.64 mL) in dry THF (30 mL) was added dropwise during 15 min and the mixture was warmed to room temperature and stirred for 30 min. After filtration and concentration in vacuo the clear oily residue was dissolved in acetone (300 mL), lithium bromide (14.6 g) was added and the mixture was heated to reflux for 1 h. The mixture was filtered, evaporated in vacuo and the product purified by column chromatography on silicagel using as eluent ethyl acetate/heptane (1:1) and fractions containing the product was pooled and evaporated in vacuo to give (RS)-1-(2-Bromo-ethyl)- 3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert-butyl ester as a clear oil (8 g) which crystallised upon standing. .

The following compound was prepared in a similar way:

(RS)-1-(2-Bromo-ethyl)-6,7-dimethoxy-3,4-dihydro- I H-isoquinoline-2-carboxylic acid- tert-butyl ester

Piperidines of the formula II1 : 5

The piperidine-derivatives of formula III, wherein X is oxygen, Z is CR’R' Y is a bond,

A', A? and A* are CH, A’ is CR", i.e. spiro[isobenzofuran-1(3H),4"-piperidines] are prepared according to the methods described by Marxer et al. J. Org. Chem. 1975, 40, 1427, by Parham et al. J. Org. Chem. 1976, 41, 2628 and by Bauer et al. J. Med. Chem. 1976, 19, 1315.

The following compounds were prepared in a similar way: 6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine], 6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine], 6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'-piperidine], 6-trifluoromethyl-3-methylspiro[isobenzofuran-1(3H),4'-piperidine],

S-methylspiro[isobenzofuran-1(3H),4'-piperidine], 6-fluoro-3-isobutylspiro[isobenzofuran-1(3H),4'-piperidine], 6-fluoro-3-cyclohexylspiro[isobenzofuran-1(3H),4'-piperidine] and 6-fluoro-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4'-piperidine]

The piperidine-derivatives of formula III, wherein X is CR°R'?, Z is NR®, Y is a bond, A’,

A? and A* are CH, A’ is CR" and R'" is fluoro or trifluoromethyl, are prepared according to the methods described by Maligres et al. Tetrahedron 1997, 53, 10983, and by Cheng et al.

Tet. Lert. 1997, 38, 1497.

The following compound was prepared in a similar way: 1-Acetyl-5-fluoro-spiro[2,3-dihydro- /H-indol-3,4'-piperidine].

The piperidine-derivatives of formula III, wherein the X is CR’R'?, Z is oxygen, Y is a bond, A', A* and A* are CH, A? is CR!., i.e. 2,3-dihydro-spiro(benzofuran-3,4'-piperidines), are prepared according to the methods described by Chen, Meng-Hsin; Abraham, John A.

Tetrahedron Lett. 1996, 37, 5233-5234 and Slade, P.D. et al. J. Med. Chem. 1998, 41, 1218-

The following compounds were prepared in a similar way: 2,3-Dihydro-5-fluorospiro[benzofuran-3,4'-piperidine] and 2,3-dihydro-5,6-difluorospiro[benzofuran-3,4'"-piperidine]

The substituents R® -R!! are introduced by applying suitably substituted starting compounds to methods analogous to the above mentioned.

Amines of the formula V

An amine of formula V was prepared by the following procedure:

A mixture of an amine of formula III (1 mmol), (RS)-1-(2-Bromo-ethyl)-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid-tert-butyl ester (1.3 mmol) and potassium carbonate (1.3 mmol) in acetonitrile (20 mL) were heated to 85 °C for 6 h. The mixture was cooled to room temperature and evaporated in vacuo to give an yellow oily residue. The product was redissolved in dichloromethane (10 mL) and anisole (0.26 mL) and trifluoroacetic acid (10 mL) were added and the mixture stirred at room temperature for 90 min. The mixture was evaporated in vacuo. The product was either purified by chromatography or used directly in the next step without purification.

The following compounds were purified by chromatography before further use: (RS)- 1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-1,2,3,4-tetrahydro- isoquinoline (RS)-1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 1,2,3,4-tetrahydroisoquinoline )

Enantiomeric forms of Amines of the formula V .

Enantiomer 1 and enantiomer 2 of N-{4-(3-Fluoro-phenyl)-1-[{2-(1,2,3 4-tetrahydro- isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamide

Racemic N-{4-(3-fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-y1)-ethyl]-piperidin- 4-yl} acetamide was subjected to resolution by chiral HPLC using a Gilson SF3 supercritical fluid chromatography system equipped with chiralcelOD columns (4.6 mm x 25 cm for analytical and 10 mm x 25 cm for preparative runs). The particle size in the columns was 10 ] 5 um. A solution of the racemic compound N-{4-(3-fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro- isoquinolin-1-yl)-ethyl]-piperidin-4-yl} acetamide (1 g) in methanol (1 mL) was injected in 40 pL portions on a preparative column. The column was eluted with carbondioxide — modifier (75:25). The modifier was 2-propanol with diethylamine (0.5%) and trifluoracetic acid (0.5%). The flow was 18.9 mL/min at 20 Mpa. Fraction collection was triggered by

UV-detection (210 nM). The fractions containing the separate products were pooled and evaporated in vacuo which gave the enantiomers. The first eluted enantiomer is called

Enantiomer 1 and the second eluted is called Enantiomer 2 of N-{4-(3-fluoro-phenyl)- 1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl} acetamide. The enantiomers were measured by HPLC to have an enantiomeric excess higher than 95%.

The following enantiomers were prepared in a similar way:

Enantiomer 1 and enantiomer 2 of N-{4-(phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)- ethyl]-piperidin-4-yl}acetamide

Examples

Preparation of the compounds of the invention

The compounds of the present invention were prepared by one of two general methods:

Method A: Alkylating a piperidine of formula III with an alkylating derivative of formula II:

A mixture of a piperidine of formula III (1 mmol), (RS)-1-(2-Bromo-ethyl)-3,4-dihydro- /H-isoquinoline-2-carboxylic acid-tert-butyl ester (1.3 mmol) and potassium carbonate (1.3 mmol) in acetonitrile (20 mL) were heated to 85 °C for 6 h. The mixture was cooled to . room temperature and evaporated in vacuo. The product was purified by chromatography either on silicagel using as eluent ethylacetate/triethylamine (99:1) or by purified by HPLC.

Fractions containing the product were pooled and evaporated in vacuo.

Method B: Acylating an amine of formula V by the use of a carboxylic acid and a coupling reagent, an activated ester, an acid chloride or an isocyanate:

An amine of formula V (prepared as described above; 1 mmol) and triethylamine (5 mmol) : were dissolved in anhydrous acetonitrile (10 mL). An appropriately substituted acid chloride (5 mmol) was added and the reaction mixture stirred at room temperature for 30 min.

Methanol (0.5 mL) was added to the reaction mixture followed by evaporation in vacuo.

The product was purified by chromatography either on silicagel using ethylacetate/triethylamine (99:1) as eluent or by HPLC. Fractions containing the product were pooled and evaporated in vacuo and characterised by HPLC-UV-ELSD-MS. The measured HPLC-retention time, the measured molecular mass and UV- and ELSD-purities are shown in table 1.

The following compounds were made by the methods indicated in table 1. Analytical data are shown in table 1.

Compound 1. 1-(1-{2-[4-(5-Fluoro-/H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-/H-isoquinolin- 2-yl)-1-(4-fluoro-phenyl)methanone 2. 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 3. 1-{2-[4-(5-Fluoro-]/H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1 H-isoquinoline- 2-carboxylic acid phenethyl-amide 4. 1-(1-{2-[4-(5-Fluoro-!H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-/ H-isoquinolin- 2-yl)-1-phenylmethanone 25S. 1-(1-{2-[4-(5-Fluoro-/H-indol-3-yl)-piperidin-1-yl}-ethyl}-3,4-dihydro-1H-isoquinolin- 2-yl)-1-(2-fluoro-phenyl)methanone 6. 1-(1-{2-[4-(5-Fluoro-/H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- I H-isoquinolin- 2-yl)-3-phenyl-propan-1-one 7. 1-{2-[4-(5-Fluoro-/H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-/ H-isoquinoline- 2-carboxylic acid (3-chloro-propyl)amide . 8. 1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-/ H-isoquinoline- 2-carboxylic acid (2-methoxy-phenyl)amide

9. 1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-/ H-isoquinoline- 2-carboxylic acid tert-butyl ester . 10. 3-Chloro-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-y1)-2,2-dimethyl-propan-1-one 12. 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro- / H-isoquinolin-2-yl)methanone 13. 1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-1-(1-{2-[6-fluorospiro[isobenzofuran- 1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro-1 H-isoquinolin-2-yl)methanone 14. 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-1soquinoline-2-carboxylic acid tert-butyl ester 15. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-1soquinolin-2-yl)-1-phenylmethanone 16. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-p-tolylmethanone 17. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl1)-1-(2-methoxy-phenyl)methanone 18. 1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)methanone 19. 1-(2-Fluoro-phenyl!)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]- ethyl}-3,4-dihydro-/H-isoquinolin-2-yl)methanone 20. 1-(2-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl}- ethyl}-3,4-dihydro- / H-isoquinolin-2-yl)methanone 21. 1-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]- ethyl}-3,4-dihydro- I H-isoquinolin-2-yl)methanone 22. 1-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-y1]- ethyl}-3,4-dihydro-1 H-isoquinolin-2-yl)methanone 23. 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid phenethyl amide 24. 1-(1-{2-[6-Fuorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- ] 30 1 H-isoquinolin-2-yl)-1-(4-methoxy-phenyl)methanone 25. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl}-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-3-phenyl-propan-1-one

26. 2-Ethyl-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1 '-yl]-ethyl}- 3,4-dihydro- 1 H-isoquinolin-2-yl)-butan-1-one 27. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1 -yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(3-methoxy-phenyl)methanone 28. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4"-piperidine-1 -yl]-ethyl}-3,4-dihydro- } 1 H-isoquinolin-2-y1)-2-phenylethanone 29. 3-Cyclohexy!-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1 "-yl]-ethyl}- 3,4-dihydro-/ H-isoquinolin-2-yl)-propan-1-one 30. 2-(4-Fluoro-phenyl)-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1 -yl]- ethyl} -3,4-dihydro-/ H-isoquinolin-2-yl)ethanone 31. 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-1soquinoline-2-carboxylic acid (3,4-dichloro-phenyl)amide 32. 1-Cyclopropyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine- 1'-y1]-ethyl} - 3,4-dihydro- / H-isoquinolin-2-yl)methanone 33. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-pyridin-3-yl-methanone 34. 1-[5-(4-Chloro-phenyl)-2-methyl-furan-3-y1]-1-(1- {2-{6-fluorospiro[isobenzofuran- 1(3H),4"-piperidine-1'-yl]-ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl)methanone 35. 2-(4-Chloro-phenyl)-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine- 1'-yl}-ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl)ethanone 36. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'"-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-2-methyl-propan-1-one 37. 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'"-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid (2-ethyl-phenyl)amide 38. N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin- 1 -yl]-ethyl} - 4-(3-fluorophenyl)-piperidin-4-yl]acetamide 39. 1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4"-piperidin- 1'-yl]]-ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl)methanone 40. 1-Cycloheptyl-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl]- 3,4-dihydro-/H-isoquinolin-2-yl} methanone . 41. N-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yi]-ethyl} - 4-phenylpiperidin-4-yl)acetamide

42. 1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-6,7-dimethoxy-1 H-isoquinolin-2-yl)methanone . 43. 1-(4-Fluorophenyl)-1-(1- {2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]-ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl)methanone ‘ 5 44. 1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro- H-indol- 3,4'-piperidin-1’-yl]-ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl)methanone 45. 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone 46. 1-(4-Fluorophenyl)-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro- / H-indol- 3,4'-piperidin-1’-yl]-ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl)methanone 47. 1-Cycloheptyl-1-(1-{2-[4-(2-methyl- / H-indol-3-yl)-piperidin-1-yl}-ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl)methanone 48. 1-Cycloheptyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl} - 3,4-dihydro-1H-isoquinolin-2-yl)methanone 49. 1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 50. 1-Cyclopentyl-1-{1-[spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl]-3,4-dihydro- 1H-isoquinolin-2-yl} methanone 51. 1-Cyclopentyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[ 2,3-dihydro- / H-indol- 3,4"-piperidin-1’-yl]-ethyl}-3,4-dihydro- / H-isoquinolin-2-yl)methanone 52. 1-(4-Fluorophenyl)-1-(1- {2-[6-fluoro-3-methylspiro[isobenzofuran-1 (3H),4'-piperidine- 1'-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 53. 1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]- ethyl}-3,4-dihydro-/H-isoquinolin-2-yl)methanone 54. 1-Cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)methanone 55. 1-Cycloheptyl-1-(1- {2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 56. 1-(1-{2-[4-(4-Chloro-phenyl)-pipendin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)- } 30 1-cycloheptylmethanone 57. 1-Cyclopentyl-1-(1-{2-[S-isopropylspiro[isobenzofuran-1(3H),4"-piperidine-1'-yl}- ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl)methanone

58. N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1 ,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-(3-fluorophenyl)-piperidin-4-yl]acetamide 59. 1-Cycloheptyl-1-{1-[2-(4-phenylpiperidin-1-yl)-ethyl]-3,4-dihydro-1 H-isoquinolin- . 2-yl}methanone 60. 1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1 (3H),4'-piperidine- )

I'-yl]-ethyl}-3,4-dihydro-7H-isoquinolin-2-yl)methanone 61. 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]-ethyl} -3 ,4-dihydro- 1 H-isoquinolin-2-yl)methanone 62. 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1 "-yl]-ethyl}- 3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 63. 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1 -yl]- ethyl}-3,4-dihydro-6,7-dimethoxy- I H-isoquinolin-2-yl)methanone 64. 1-(1-{2-[4-(6-Fluorobenzo[d}isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3 ,4-dihydro- 1 H-1soquinolin-2-yl)-1-(4-fluorophenyl)methanone 65. 1-[1(2-{2-[1-(4-Fluorophenyl)-methanoyl]-1,2,3 4-tetrahydro-isoquinolin-1-yl} -ethyl)- 4-phenylpiperidin-4-yl]-1-piperidin-1-yl-methanone 66. 1-Cyclopentyl-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl}-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 67. 8-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 68. 1-Cycloheptyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]- ethyl} -3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 69. 1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-y1} -ethyl)- 4-phenyl-piperidin-4-y1]-1-(4-methyl-piperazin-1-yl)methanone 70. 1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}- 4-phenyl-piperidine-4-carboxylic acid ethyl ester 71. 1-(1-{2-[2~(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl } - 4-phenyl-piperidin-4-yl)-ethanone 72. 1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine-1'-y1}- ethyl} -3,4-dihydro-6,7-dimethoxy-1 H-isoquinolin-2-yl)methanone . 73. 1-Cyclopentyl-1-(1-{2-[4-(2-methyl-1 H-indol-3-yl)-piperidin-1-yl]-ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl)methanone

74. 1-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-phenyl-piperidin-4-yl)ethanone 75. 1-(4-Fluorophenyl)- 1-(1- {2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 76. 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-yl)- 1-(4-fluoro-phenyl)methanone 77. 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - piperidin-4-yl)-1-(4-fluoro-phenyl)methanone 78. 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin- 1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-(4-methyl-piperazin-1-yl)methanone 79. 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-y1)- 1-cyclopentylmethanone 80. 1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl} - 3,4-dihydro-1H-isoquinolin-2-yl)methanone 81. 1-(4-Fluorophenyl)-1-(1-{2-[piro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)methanone 82. 1-Cyclopentyl-1-(1-{2-[4-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 3,4-dihydro-/ H-isoquinolin-2-yl)methanone 83. 1-(2-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl}-ethyl}-3,4-dihydro-6,7-dimethoxy- / H-isoquinolin-2-yl)methanone 84. N-[4-(3-Fluoro-phenyl)-1-(2- {2-[1-(4-fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-ethyl)-piperidin-4-yl]-acetamide 85. 1-(2-Fluorophenyl)-1-{1-[spiro[2,3-dihydro-/ H-indol-3,4'"-piperidin-1'-yl]ethyl]- 3,4-dihydro-/ H-isoquinolin-2-yl} methanone 86. 1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-/ H-indol- 3,4'-piperidin-1’-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 87. 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin- 1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone 88. 1-{1-[2-(4-Benzyl-piperidin-1-yl)-ethyl]-3,4-dihydro-/ H-isoquinolin-2-yl}- ) 30 1-cycloheptylmethanone 89. 1-(2-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone

90. 1-(1-{2-[(Chloro-trifluoromethyl-phenyl)-hydroxy-piperidin-1-yl] -ethyl}- 6,7-dimethoxy-3,4-dihydro- 1 H-isoquinolin-2-yl)-1-cycloheptylmethanone 91. 1-(1-{2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl} -6,7-dimethoxy- : 3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone 92. 1-Cycloheptyl-1-(1-{2-[4-(2-isopropoxy-phenyl)-piperidin-1 -yl]-ethyl}-3,4-dihydro- 1H-1soquinolin-2-yl)methanone 93. 1-(1-{2-[4-(7-Chloro- / H-indol-3-yl)-piperidin-1-yl]-ethyl} -3,4-dihydro-/ H-isoquinolin- 2-yl)-1-cyclopentylmethanone 94. 1-Cyclopentyl-1-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1 -yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)methanone 95. 1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone 96. N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin- 1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide 97. 1-(4-Fluoro-phenyl)-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro- 1H-isoquinolin-2-yl}methanone 98. 1-(1-{2-[4-(6-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone 99. 1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 100.1-Cycloheptyl-1-{1-[spiro[2,3-dihydro-/ H-indol-3,4"-piperidin-1'-yl]ethyl]- 3,4-dihydro-6,7-dimethoxy- / H-isoquinolin-2-yl} methanone 101.N-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl}- 4-phenyl-piperidin-4-yl)acetamide 102.1-(1-{2-[4-(6-Fluoro-benzo[dJisoxazol-3-yl)-piperidin-1-yl}-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone 103.1-cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 3,4-dihydro-6,7-dimethoxy- / H-isoquinolin-2-yl)methanone 104.1- {2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl}- 4-phenyl-piperidine-4-carboxylic acid ethyl ester . 105.1-(1- {2-[4-(4-Dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone

106.1-Cyclopentyl-1-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-1soquinolin-2-yl)methanone 107.1-[1-(2- {2-[1-(4-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- ethyl)-4-phenyl-piperidin-4-yl]ethanone 108.1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-y1}- ethyl)-4-phenyl-piperidin-4-yl]ethanone 109.1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl1}- ethyl)-4-phenyl-piperidin-4-yl]-1-piperidin-1-yl-methanone 110.1-Cyclopentyl-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin- 2-yl}methanone 111.1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl1]- ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 112.1-(4-Fluoro-phenyl)-1-(1- {2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]- ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 113.1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)methanone 114. 3,3-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2 H-3,4'-piperidine-1'-yl)-] ethyl}- 3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one 115. Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl}- 3,4-dihydro-1H-isoquinoline-2-yl]-methanone 116. Cyclohexyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4'-piperidine-1'-yl)-]Jethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone 117. Cyclohexyl-[1-{2-[spiro(benzofuran-3H-1,4'-piperidine-1'-yl)-] ethyl}-3,4-dihydro- 1H-isoquinoline-2-yl]-methanone 118. Cyclohexyl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-yl)-methanone 119. N-{1-[2-(2-Cyclohexanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]- 4-phenyl-piperidin-4-yl}-acetamide 120. 3,3-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one 121. Cyclohexyl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-methanone

122. Cyclohexyl-(1-{2-[4-(4-dimethylamino-phenyl)-piperidin-1 -yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-methanone 123. 3-Phenyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl} - 3,4-dihydro-1H-isoquinoline-2-yl]-propanone 124. (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl} - 6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone 125. 2-Phenoxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl }- 3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one 126. Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[spiro(5-methyl-isobenzofuran- 3H-1,4"-piperidine-1'-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 127. Cyclohexyl-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-yl)-methanone 128. 2-Propyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl}- 3,4-dihydro-1H-isoquinoline-2-yl]-pentan-1-one 129. 22-Dimethyl-3-chlor-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl}-3,4-dihydro-1H-isoquinoline-2-yl}-propan-1-one 130. Cyclohexyl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone 131. 3,3-Dimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4'-piperidine-1'-yl)-

Jethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one 132. Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]- ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 133. 2-Ethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-butan-1-one 134. 2-Benzyloxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4"-piperidine-1'-yl)-]ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one 135. Benzo[1,2,5]oxadiazol-5-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine- 1'-yl)-] ethyl}-3,4-dihydro-1H-isoquinoline-2-yl}-methanone 136. (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)- cyclohexyl-methanone . 137. 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin- 2-yl)-3,3-dimethyl-butan-1-one

Claims

Patent Claims

N 1. A 3,4-dihydro-1H-isoquinoloin-2-yl-derivative of formula I ’ Rea R® ni Rb { Re /—\ N A R7a m\ . R3 Re Re RS I wherein R'is a group R''CO-, R''CS-, R''SO,-, R"'OCO-, R''SCO- or R''CO-CR'?R"- wherein R'" is Cj.y-alkyl, Cag-alkenyl, Csg-alkynyl, Cig-cycloalkyl, Cjs-cycloalkyl-Cy.¢-alkyl, aryl, aryl-C, ¢-alkyl, heteroaryl, heteroaryl-C,; ¢-alkyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphtalenyl, or 4H-benzo[1,3]dioxiny] optionally substituted with halogen wherein each of said C,¢-alkyl, aryl, heteroaryl and Cs.s-cycloalkyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C,¢-alkyl, C,¢-alkoxy, aryl-C,.¢-alkoxy, Ci.¢-alkylsulfanyl, aryl and aryloxy wherein said aryl and aryloxy independently are unsubstituted or substituted with one or more halogen, and R'? and R" independently are hydrogen or C;¢-alkyl; or R'is a group R"“RNCO-, R"“R'*’NCS-, wherein R'* and R" are independently hydrogen, Cie-alkyl, Cy¢-alkenyl, C,¢-alkynyl, Cjs-cycloalkyl, Cis-cycloalkyl-C¢-alkyl, aryl or aryl-Ci¢-alkyl, wherein each of said C,¢-alkyl, aryl and Csjg-cycloalkyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C,¢-alkyl and C).¢-alkoxy, or R'* and R'® together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group, R? is selected from hydrogen, trifluoromethyl and C,s-alkyl;

R’-R®, R™, R™, R* and R® are independently selected from hydrogen, halogen, cyano, nitro, Ci¢-alkyl, Cisalkenyl, C,.¢-alkynyl, Cjg-cycloalkyl, Cs. 5-cycloalkyl-Cy ¢-alkyl, amino, C,¢-alkylamino, di-(Cj¢-alkyl)amino, C;.¢-alkylcarbonyl, - aminocarbonyl, ' Ci¢-alkylaminocarbonyl, di-(C,.¢-alkyl)aminocarbonyl, Ci-¢-alkoxy, C;-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C,.¢-alkylsulfonyl; ’ m is 2-6; R’ is benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclic aryl or heteroaryl wherein each benzyl, benzoyl, aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C,¢-alkyl, Ca¢-alkenyl, C,¢-alkynyl,

Cs.s-cycloalkyl, Cjs-cycloalkyl-Cy.¢-alkyl, amino, C.s-alkylamino, di-(C,¢-alkyl)amino,

Ci.¢-alkylcarbonyl, aminocarbonyl, C,.¢-alkylaminocarbonyl, di-(C,¢-alkyl)aminocarbonyl, Ci-¢-alkoxy, Cjs-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl; QisC,Nor CRrR'% wherein R'° is selected from hydrogen, halogen, cyano, nitro, C,.-alkyl, C,¢-alkenyl, Cyg-alkynyl, Cjs-cycloalkyl, Cjs-cycloalkyl-Ci¢-alkyl, amino, Ci.¢-alkylamino, di- (Ci¢-alkyl)amino, Cj.¢-alkylcarbonyl, aminocarbonyl, C,g¢-alkylaminocarbonyl, di-

(Ci.s-alkyl)aminocarbonyl, Ci¢-alkoxy, Cis-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, triflucromethylsulfonyl, a group ~-NR**COR?!' wherein R* is hydrogen or C,.¢-alkyl and R*! is Ci-s-alkyl, a group —COOR'® wherein R'S is hydrogen or Cis-alkyl, or a group -CONR''R'® wherein R'7 and R'® independently are selected from hydrogen and C;.¢-alkyl or R'” and R"® together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl is unsubstituted or substituted with a C,_¢-alkyl; or R® and R'? together with the carbon to which they are attached form a cyclic structure : selected from the group comprising:

SS —N Zz Al N< = O CL Y 2A2 Q : IT Cy NN 0 a ah Wa 1), 2), 3), 0 IN omy Q 4) wherein Q’ is the carbon shared with the piperidine ring, so that said cyclic structure together with said piperidine ring form a spiro structure; and X,Y, and Z are independently chosen from O; NR? CR? R**. S(O), and a bond; wherein R' is selected from hydrogen, C¢-alkyl, Cp¢-alkenyl, C,6-alkynyl, C;g-cycloalkyl, Csg-cycloalkyl-C_¢-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R' 1S a group R?°S0,-, R¥?°0CO- or R¥SCO- wherein R® is Ci¢-alkyl, C,¢-alkenyl, Cys-alkynyl, Csg-cycloalkyl, Cjs-cycloalkyl-C,.¢-alkyl or aryl, or RY is a group R*'R*NCO- or R*'R*NCS-, wherein R*' and R* are independently hydrogen, C,.¢-alkyl, Cy¢-alkenyl, Cy6-alkynyl, Cs.s-cycloalkyl, C;.s-cycloalkyl-C,¢-alkyl, or aryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C,¢-alkyl or halogen; or R* and R* together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; R? and R* are independently selected from hydrogen, halogen, cyano, nitro, C;¢-alkyl, C.s-alkenyl, C,¢-alkynyl, Cj.s-cycloalkyl, C;-cycloalkyl-C,.¢-alkyl, aryl, heteroaryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C,.-alkyl or halogen, amino, C,.¢-alkylamino, a group NRPR?* wherein R*® and R* are independently selected from Ci¢-alkyl

C,.¢-alkylcarbonyl, aminocarbonyl, C,¢-alkylaminocarbonyl, di-(C,.¢-alkyl)aminocarbonyl, Ci-¢-alkoxy, C,s-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and

C).¢-alkylsulfonyl or R* and R*® together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, or R? and R** together is oxo; and n is 0, 1 or 2; provided that no more than one of X, Y and Z may be a bond, and provided that two adjacent groups X, Y or Z may not at the same time be selected from 0) and S; and . 5s A', A’, A’ and A* are independently selected from N and CR? wherein R? is hydrogen, halogen, cyano, nitro, Cys-alkyl, C,.¢-alkenyl, C,4-alkynyl, Cis-cycloalkyl, Cs.s-cycloalkyl- Ci-¢-alkyl, Ci ¢-alkylcarbonyl, aminocarbonyl, Ci-alkylaminocarbonyl, di-

(Ci.s-alkyl)aminocarbonyl, Ci¢-alkoxy, Cj¢-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl Ci-alkylsulfonyl amino or a group NR®R?’ wherein R*® and R? are independently selected from hydrogen and C.¢-alkyl or R*® and R? together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group; provided that only one of A!, A%, A’ and A* may be N; and the dotted line emanating from Q is a bond when Q is C, and no bond when Q is CR? or N; or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1 characterised in that Q is CR!®, and R® and R'° together with the carbon to which they are attached form a bicyclic structure: VE TS pe 1), wherein Q’ is the carbon shared with the piperidine ring, so that said bicyclic structure together with said piperidine ring form a spiro structure; and X, Y and Z are independently chosen from O; NR'’; CR**R** and S(O), wherein R" is selected from hydrogen, Clg-alkyl, C,¢-alkenyl, Cy¢-alkynyl, Cs.g-cycloalkyl, :

Cs.3-cycloalkyl-C) ¢-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R'° is a group R¥S0,-, R?®0CO- or R®SCO- wherein R? is Cis-alkyl, Cj.¢-alkenyl, Cye-alkynyl, Cjs-cycloalkyl, Css-cycloalkyl-C;.¢-alkyl, or aryl, or RY is a group

R*'R¥NCO-, R?’R?>NCS-, wherein R?' and RZ are independently hydrogen, Cj.s-alkyl,

Cs.¢-alkenyl, C,6-alkynyl, Cs s-cycloalkyl, Csg-cycloalkyl-C,.¢-alkyl, or aryl, wherein said . aryl 1s unsubstituted or substituted with one or more substituents selected from C,-alkyl or halogen; or R?*' and R* together with the N-atom to which they are linked, form a ' 5 pyrrolidinyl, piperidinyl, or perhydroazepinyl group; R® and R* are independently selected from hydrogen, halogen, cyano, nitro, C.¢-alkyl, C,.s-alkenyl, C,¢-alkynyl, C3 s-cycloalkyl,

Ci.g-cycloalkyl-C, ¢-alkyl, aryl, heteroaryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C;_¢-alkyl or halogen, amino, C,¢-alkylamino, a group NR*R?® wherein R* and R?® are independently selected from C,.¢-alkyl or R* and R® together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl, or morpholinyl group, C,¢-alkylcarbonyl, aminocarbonyl, C,¢-alkylaminocarbonyl, di-(C,.¢-alkyl)aminocarbonyl, Ci-¢-alkoxy, C,-alkylthio, hydroxy, trifluoromethyl, trifluoromethylisulfonyl and C,s-alkylsulfonyl or R® and R* together is oxo; and n is 0, 1 or 2; and a bond; provided that no more than one of X, Y and Z may be a bond, and provided that two adjacent groups X, Y or Z may not at the same time be selected from O and S; and A’, A%, A’ and A? are independently selected from N and CR?’ wherein R*’ is hydrogen, halogen, cyano, nitro, C.¢-alkyl, C,.¢-alkenyl, C;¢-alkynyl, Cs.s-cycloalkyl, C;s-cycloalkyl- C,s-alkyl, amino, a group NR*®R? wherein R?® and R*® are independently selected from hydrogen and C,_¢-alkyl or R28 and R® together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, C,.¢-alkylcarbonyl, aminocarbonyl, C,.¢-alkylaminocarbonyl, di- (C,.¢-alkyl)aminocarbonyl, Ci-¢-alkoxy, C6 alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C,.¢-alkylsulfonyl; provided that only one of A’, A? A? and A* may be N.
3. A compound according to claim 2 characterised in that X, Y and Z are selected from one of the combinations: X is oxygen, Y is a bond and Z is CR®R?*; X is CR¥R¥ Yisa bond and Z is oxygen; X is NR", Y isa bond and Z is CR¥R?*, X is CRZR%, Y is a bond and Zis NR'®; X is CO, Y is a bond and Z is NR'%; X is SO,, Y is a bond and Z is NR"; X is SO, Y is a bond and Z is NR'%; X is CR®R*, Yisabondand Z is S; X is CR®R* Y is a bond and Z is SO; X is CR®R*, Y is a bond and Z is SO»; wherein R'? is hydrogen, acetyl or methylsulfonyl and R® and R* are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl.
4. A compound according to claim 2 characterised in that -X-Y-Z- together form a group selected from: -O-CR¥R*-, -CR®R*-0., -NR'’-CR®R%*., -CR¥®R¥™.NR'’., -CO-NR"-, -80,-NR"-, -SO-NR"-, -CR*R™-§-, -CR®R**-SO-, -CR®R*-S0,-; wherein R' is hydrogen, acetyl or methylsulfonyl and R?> and R** are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl.
5. A compound according to any of claims 2 to 4 characterised in that A® is N or CR?’ wherein R? is halogen, cyano, nitro, a group NR*®R? wherein R® and RZ? are independently selected from hydrogen and C¢-alkyl or R*® and R* together with the N- atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, C,¢-alkylcarbonyl, aminocarbonyl, C;¢-alkylaminocarbonyl, di- (C,¢-alkyl)aminocarbonyl, Ci¢-alkoxy, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl, or C,_¢-alkylsulfonyl.
6. A compound according to any of claims 2 to 5 characterised in that A', A2, A® and A* are independently selected from CR? wherein R* is as defined above.
7. A compound according to claim 2 characterised in that said bicyclic structure is selected from the group comprising: R23 R27 R19 ons R27" CY ° Q Q 9) R27 R27 a) b) c) wherein R'is acetyl or methylsulfonyl, R?> is hydrogen or methyl, R*’ is hydrogen or fluoro, R* is hydrogen, fluoro, methyl or isopropyl, RT” is hydrogen, fluoro or trifluoromethyl.
8. A compound according to claim 1 characterised in that R® and R'° together with the carbon to which they are attached form a cyclic structure selected from the group , comprising: N Coo Op, J ~qf J Cr hme Lg o—/ 2) 3) 4) wherein Q’ is the carbon shared with the piperidine ring, so that said cyclic structure together with said piperidine ring form a spiro structure.
9. A compound according to claim 1 characterised in that R® is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl or mono- or bicyclic aryl or heteroaryl wherein each benzyl, benzoyl, aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C,¢-alkyl, C,¢-alkenyl, C,q-alkynyl, Cjg-cycloalkyl,

Cs.g-cycloalkyl-C, ¢-alkyl, amino, C,_¢-alkylamino, di-(C,.¢-alkyl)amino, C,.¢-alkylcarbonyl, aminocarbonyl, C,s-alkylaminocarbonyl, di-(Cl.¢-alkyl)aminocarbonyl, Ci-¢-alkoxy, Cje-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.
10. A compound according to claim 9 characterised in that R’ is 2,3-dihydrobenzofuran- 7-y1, benzyl or benzoyl wherein said benzyl or benzoyl is unsubstituted or substituted with one or more halogens in the phenyl groups, or R’ is mono- or bicyclic aryl or heteroaryl selected from the group comprising phenyl, indolyl, pyridyl, thiophenyl and benzisoxazolyl, wherein each aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C,¢-alkyl, Cz.6-alkenyl, C,¢-alkynyl, C;g-cycloalkyl, . Ci.g-cycloalkyl-C, ¢-alkyl, amino, C,.¢-alkylamino, di-(Ci_¢-alkyl)amino, C, ¢-alkylcarbonyl, aminocarbonyl, C,-alkylaminocarbonyl, di-(C1l_¢-alkyl)aminocarbonyl, Ci_¢-alkoxy, : Ci.¢-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.
11. A compound according to claim 10 characterised in that said mono- or bicyclic aryl or heteroaryl is selected from the group comprising phenyl, indol-3-yl and benzisoxazol- 3-yl wherein said phenyl, indol-3-yl or benzisoxazol-3-yl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C,¢-alkyl, C,¢-alkenyl, C,s alkynyl, Cssg-cycloalkyl, Css-cycloalkyl-C,¢-alkyl, amino, C,¢-alkylamino, di- (Cis-alkyl)amino, C,e-alkylcarbonyl, aminocarbonyl, C,s-alkylaminocarbonyl, di- (Cl ¢-alkyl)aminocarbonyl, Ci-¢-alkoxy, Cis-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.
12. A compound according to claim 11 characterised in that said optional substituents are selected from the group comprising halogen, phenyl and methyl.
13. A compound according to any of claims 9 to 12 characterised in that Q is CR" wherein R'is selected from hydrogen, C,.¢-alkylcarbonyl, hydroxy, a group -NR**COR?*! wherein R* is hydrogen or C, ¢-alkyl and Ris Ci.¢-alkyl, a group —~COOR'® wherein R'® is C,¢-alkyl, or a group —-CONR''R'® wherein R'” and R' together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl is unsubstituted or substituted with a C,_¢-alkyl.
14. A compound according to claim 13 characterised in that R' is selected from hydrogen, acetyl, hydroxy, a group ~NR*COR?' wherein R* is hydrogen and R* is methyl, a group —-COOR'® wherein R' is ethyl, or a group —-CONR''R'® wherein R' and R" together with the nitrogen to which they are attached form a piperidinyl or a 4-methylpiperazinyl.
15. A compound according to any of claims 1 to 14 characterised in that m is 2,3 or 4.
16. A compound according to claim 15 characterised in that m is 2. i
17. A compound according to any of claims 1 to 16 characterised in that R'is a group R''CO-, R"'OCO- wherein R'' is Csg-alkyl, Csg-cycloalkyl, Cs.s-cycloalkyl-C;¢-alkyl, phenyl, phenyl-C ¢-alkyl, pyridyl, furanyl, benzo[l,2,5]oxadiazolyl, quinoxalinyl, benzo[b]thiophenyl or naphthalenyl wherein each of said Cs¢-alkyl, phenyl, pyridyl and furanyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C;¢-alkyl, C;¢-alkoxy, phenyl and phenoxy ‘ wherein said phenyl and phenoxy independently are unsubstituted or substituted with one halogen; or R' is a group R'*R'>NCO-, wherein R'* and R'* are independently hydrogen, C,. ¢-alkyl, aryl, or aryl-C,¢-alkyl, wherein each of said C,¢-alkyl and aryl groups independently are unsubstituted or substituted with one substituent selected from the group comprising halogen and C,.¢-alkoxy.
18. A compound according to any of claims 1 to 17 characterised in that R? is hydrogen.
19. A compound according to any of claims 1 to 18 characterised in that R® is hydrogen.
20. A compound according to any of claims 1 to 19 characterised in that R* is hydrogen or methoxy.
21. A compound according to any of claims 1 to 20 characterised in that R’ is hydrogen or methoxy. )
22. A compound according to any of claims 1 to 21 characterised in that R®is hydrogen.
23. A compound according to any of claims 1 to 22 characterised in that R’* and R™ is hydrogen.
24. A compound according to any of claims 1 to 23 characterised in that R*® and R¥® is hydrogen.
25. A compound according to claim 1 characterised in that it is selected from the group comprising: 1-(1-{2-[4-(5-Fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-/ H-isoquinolin- 2-yl)-1-(4-fluoro-phenyl)methanone 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl)methanone

1-{2-[4-(5-Fluoro-/H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- H-isoquinoline-

2-carboxylic acid phenethyl-amide

1-(1-{2-[4-(5-Fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl} -3,4-dihydro- / H-isoquinolin- : 2-yl)-1-phenylmethanone

1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1 H-isoquinolin-

2-yl)-1-(2-fluoro-phenyl)methanone

1-(1-{2-[4-(5-Fluoro-! H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin- 2-yl)-3-phenyl-propan-1-one

1-{2-[4-(5-Fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-/ H-isoquinoline-

2-carboxylic acid (3-chloro-propyl)amide 1-{2-[4-(5-Fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl} -3,4-dihydro- I H-isoquinoline- 2-carboxylic acid (2-methoxy-phenyl)amide 1-{2-{4-(5-Fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- / H-isoquinoline- 2-carboxylic acid tert-butyl ester

3-Chloro-1-(1-{2-[4-(5-fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-y1)-2,2-dimethyl-propan-1-one 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone 1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-1-(1- {2-[6-fluorospiro[isobenzofuran-

1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro-1 H-isoquinolin-2-yl)methanone 1-{2-[6-Fluorospiro{isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid tert-butyl ester 1-(1-{2-[6-Fluorospiro{isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-phenylmethanone

1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-p-tolylmethanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro-

1 H-isoquinolin-2-yl)-1-(2-methoxy-phenyl)methanone 1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} -

3,4-dihydro-/H-isoquinolin-2-yl)methanone 1-(2-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl}-ethyl} - 3,4-dihydro-/H-isoquinolin-2-yl)methanone

1-(2-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 3,4-dihydro- / H-isoquinolin-2-yl)methanone 1-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'"-piperidine-1'-yl}-ethyl}- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone : 5 1-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-y1]-ethyl} - 3,4-dihydro-/H-isoquinolin-2-yl)methanone 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid phenethyl amide 1-(1-{2-[6-Fuorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro-

/H-isoquinolin-2-yl)-1-(4-methoxy-phenyl)methanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl)-3-phenyl-propan-1-one 2-Ethyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl)-butan-1-one

1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(3-methoxy-phenyl)methanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl}-ethyl}-3,4-dihydro- 1H-1soquinolin-2-yl)-2-phenylethanone 3-Cyclohexyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl }-

3,4-dihydro-/H-isoquinolin-2-yl)-propan-1-one 2-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}- 3,4-dihydro-/ H-isoquinolin-2-yl)ethanone 1-{2-[6-Fluorospirofisobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid (3,4-dichloro-phenyl)amide

1-Cyclopropyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} -3,4-dihydro- 1H-1soquinolin-2-yl)-1-pyridin-3-yl-methanone 1-[5-(4-Chloro-phenyl)-2-methyl-furan-3-yl]-1-(1- {2-[6-fluorospiro[isobenzofuran-

1(3H),4'-piperidine-1'-yl]-ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl)methanone 2-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-/ H-isoquinolin-2-yl)ethanone

1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl] -ethyl}-3,4-dihydro-

I H-isoquinolin-2-yl)-2-methyl-propan-1-one

1-{2-[6-Fluorospiro[isobenzofuran- 1(3H),4"-piperidine-1'-yl]-ethyl}-3 ,4-dihydro-

1 H-isoquinoline-2-carboxylic acid (2-ethyl-phenyl)amide

N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1 -yl]-ethyl}-

4-(3-fluorophenyl)-piperidin-4-yljacetamide 1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'-piperidin-1 -yl]}- ethyl}-3,4-dihydro-7 H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-{1-[1-acetyl-spiro[2,3-dihydro- H-indol-3,4'-piperidin-1 "-yl]ethyl]-

3,4-dihydro-/H-isoquinolin-2-yl}methanone N-(1- {2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1 -yl]-ethyl}- 4-phenylpiperidin-4-yl)acetamide 1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1 "-yl}-ethyl}- 3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone

1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1 (3H),4'-piperidine- 1'-yl]-ethyl}-3,4-dihydro-1 H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-/ H-indol- 3,4'-piperidin-1°-yl]-ethyl}-3,4-dihydro- / H-isoquinolin-2-yl)methanone 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin- 1-yl]-ethyl} -

4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone 1-(4-Fluorophenyl)-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-/ H-indol- 3,4'-piperidin-1°-yl]-ethyl} -3,4-dihydro- / H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-(1-{2-[4-(2-methyl- H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)methanone

1-Cycloheptyl-1-(1- {2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]- ethyl} -3,4-dihydro-6,7-dimethoxy- / H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-{1-[spiro[2,3-dihydro-] H-indol-3,4"-piperidin-1'-yl]ethyl}-3,4-dihydro-

IH-isoquinolin-2-yl}methanone 1-Cyclopentyl-1-(1- {2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro- / H-indol- 3,4'-piperidin-1’-yl]-ethyl}-3,4-dihydro- / H-isoquinolin-2-yl)methanone

1-(4-Fluorophenyl)-1-(1- {2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'"-piperidine- 1'-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy- / H-isoquinolin-2-yl)methanone . 1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-y1]-ethyl} - 3,4-dihydro-/ H-isoquinolin-2-yl)methanone ' 5 1-Cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4'"-piperidine-1'-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'"-piperidine-1'-yl]- ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl} -3,4-dihydro-1H-isoquinolin-2-yl)- 1-cycloheptylmethanone 1-Cyclopentyl-1-(1-{2-[S-isopropylspiro[isobenzofuran-1(3H),4'-piperidine-1'-yl}-ethyl} - 3,4-dihydro-/ H-isoquinolin-2-yl)methanone N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}- 4-(3-fluorophenyl)-piperidin-4-yl]Jacetamide 1-Cycloheptyl-1-{1-[2-(4-phenylpiperidin-1-yl)-ethyl}-3,4-dihydro-1H-isoquinolin- 2-yl}methanone 1-Cycloheptyl-1-(1- {2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'"-piperidine-1'-yl]- ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1- {2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-[1-(2-{2-[1-(4-Fluorophenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)- 4-phenylpiperidin-4-yl}-1-piperidin-1-yl-methanone : 1-Cyclopentyl-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-

. 30 1H-isoquinolin-2-yl)methanone 8-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3 4-tetrahydro-isoquinolin-1-yl]-ethyl}-1-phenyi- 1,3,8-triaza-spiro{4.5]decan-4-one

1-Cycloheptyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1 (3H),4'-piperidine-1'-yl]- ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1 »2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)- 4-phenyl-piperidin-4-y1]-1-(4-methyl-piperazin- 1-yl)methanone 1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3 ,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-

piperidine-4-carboxylic acid ethyl ester 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1 -yl]-ethyl}- 4-phenyl-piperidin-4-yl)-ethanone 1-Cyclopentyl-1-(1- {2-[6-trifluoromethylspiro[isobenzofuran-1 (3H),4'-piperidine-1'-yl]-

ethyl}-3,4-dihydro-6,7-dimethoxy- / H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl)methanone 1-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin- 1-yl]-ethy1} - 4-phenyl-piperidin-4-yl)ethanone

1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4"-piperidine- 1'-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1 H-isoquinolin-2-yl)- 1-(4-fluoro-phenyl)methanone 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} -

piperidin-4-yl)-1-(4-fluoro-phenyl)methanone 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin- 1-yl1]- ethyl} -4-phenyl-piperidin-4-yl)-1-(4-methyl-piperazin-1-yl)methanone 1-(1-{2-[4~(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-y1)- 1-cyclopentylmethanone

1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl } - 3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(4-Fluorophenyl)-1-(1-{2-[piro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-/H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1- {2-[4-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}-

3,4-dihydro-IH-isoquinolin-2-yl)methanone : 1-(2-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]-ethyl} -3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone

N-[4-(3-Fluoro-phenyl)-1-(2- {2-[1-(4-fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-ethyl)-piperidin-4-yl]-acetamide 1-(2-Fluorophenyl)-1-{1-[spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl]- 3,4-dihydro-1H-isoquinolin-2-yl} methanone 1-Cycloheptyl-1-(1-{2-[S-fluoro-1-methansulfonyl-spiro[2,3-dihydro-/ H-indol- 3,4"-piperidin-1’-yl}-ethyl}-3,4-dihydro-6,7-dimethoxy- H-isoquinolin-2-yl)methanone 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]- ethyl} -4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone 1-{1-[2-(4-Benzyl-piperidin- 1-yl)-ethyl}-3,4-dihydro-/ H-isoquinolin-2-yl}-

l-cycloheptylmethanone 1-(2-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-y1]-ethyl}-3,4-dihydro-6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone 1-(1- {2-[(Chloro-trifluoromethyl-phenyl)-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy- 3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone

1-(1-{2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro- 1 H-isoquinolin-2-yl)-1-cycloheptylmethanone 1-Cycloheptyl-1-(1-{2-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-

1 H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(7-Chloro-1H-indol-3-yl)-piperidin-1-yl}-ethyl} -3,4-dihydro-/ H-isoquinolin-

2-yl)-1-cyclopentylmethanone 1-Cyclopentyl-1-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl}-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone

N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-y1]- ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide 1-(4-Fluoro-phenyl)-1- {1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1 H-isoquinolin- 2-yl}methanone 1-(1-{2-[4-(6-Chloro-! H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-

) 30 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone 1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-yl)methanone

1-Cycloheptyl-1-{1-[spiro[2,3-dihydro-/ H-indol-3,4"-piperidin-1'-yl]ethyl]-3,4-dihydro-

6,7-dimethoxy-/H-isoquinolin-2-yl}methanone

N-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} -

4-phenyl-piperidin-4-yl)acetamide

1-(1-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl}-ethyl}-3,4-dihydro-

1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone

1-cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4'-piperidine-1'-yl}-ethyl}-3,4-dihydro-

6,7-dimethoxy-/ H-isoquinolin-2-yl)methanone

1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-

piperidine-4-carboxylic acid ethyl ester 1-(1-{2-[4-(4-Dimethylamino-phenyl)-piperidin-1-yl}-ethyl}-3,4-dihydro- H-isoquinolin- 2-y1)-1-(4-fluoro-phenyl)methanone 1-Cyclopentyl-1-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-

1 H-isoquinolin-2-yl)methanone

1-[1-(2-{2-[1-(4-Fluoro-phenyl)-methanoyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)- 4-phenyl-piperidin-4-yl]ethanone 1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)- 4-phenyl-piperidin-4-yl]ethanone 1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-

4-phenyl-piperidin-4-yl]-1-piperidin-1-yl-methanone 1-Cyclopentyi-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyi]-3,4-dihydro-1H-isoquinolin- 2-yl}methanone 1-(2-Fluorophenyl)-1-(1-{2-{6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-6,7-dimethoxy- 1 H-isoquinolin-2-yl)methanone

1-(4-Fluoro-phenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl}- ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 1-(4-Fluorophenyl)-1-( {2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 3,4-dihydro-1H-isoquinolin-2-yl)methanone 3,3-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4"-piperidine-1'-yl)-] ethyl} -

3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one : Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl} -3,4-dihydro- 1H-isoquinoline-2-yl]-methanone

Cyclohexyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4"-piperidine-1'-yl)-]ethyl} - 3,4-dihydro-1H-isoquinolin-2-yl)-methanone Cyclohexyl-[1- {2-[spiro(benzofuran-3H-1,4'-piperidine-1'-yl)-] ethyl}-3,4-dihydro- 1H-isoquinoline-2-yl]-methanone : 5 Cyclohexyl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-yl)-methanone N-{1-[2-(2-Cyclohexanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]}-4-phenyl- piperidin-4-yl}-acetamide 3,3-Dimethyl-1-(1- {2-[4-(3-triflucromethyl-phenyl)-piperidin-1-y1]-ethyl }-3,4-dihydro- 1H-isoquinolin-2-yl)-butan-1-one Cyclohexyl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-1soquinolin-2-yl)-methanone Cyclohexyl-(1-{2-[4-(4-dimethylamino-phenyl)-piperidin-1-yl}-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-methanone 3-Phenyl-[1- {2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl}-3,4-dihydro- 1H-isoquinoline-2-yl]-propanone (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl} - 6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone 2-Phenoxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4"-piperidine-1'-yl)-] ethyl}-3,4-dihydro- 1H-isoquinoline-2-yl}-ethan-1-one Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4'-piperidine- 1'-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone Cyclohexyl-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-methanone : 2-Propyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl}-3,4-dihydro- 1H-isoquinoline-2-yl]-pentan-1-one 2,2-Dimethyl-3-chlor-[1- {2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl} - 3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one Cyclohexyl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- } 30 1H-isoquinolin-2-yl)-methanone 3,3-Dimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4'-piperidine-1'-yl)-Jethyl} - 3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one

Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(3 -triflucoromethyl-phenyl)-piperidin-1 -yl]-ethyi}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone 2-Ethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1 H-isoquinolin-2-yl)-butan-1-one

2-Benzyloxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4"-piperidine-1 "-yl)-]ethyl}- } 3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one Benzo[1,2,5]oxadiazol-5-yl-[1- {2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1 “yD]- ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl} -3,4-dihydro-1H-isoquinolin-2-yl)-

cyclohexyl-methanone 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl}-ethyl}-3,4-dihydro- 1H-isoquinolin-2-y1)- 3,3-dimethyl-butan-1-one 3,5,5-Trimethyl-[1- {2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl} - 3,4-dihydro- 1H-isoquinoline-2-yl}-hexan-1-one

3,5,5-Trimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4"-piperidine-1'-yl)-Jethyl} - 3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one 2-Phenoxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4'"-piperidine-1'-yl)-]Jethyl} - 3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl} -3,4-dihydro- 1 H-isoquinolin-2-yl)-

(2,2-dichloro-cyclopropyl)-methanone 2-Benzyloxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4"-piperidine-1'-y1)-] ethyl}- 3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one 1-(1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl} - 6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one

1+(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- IH-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one 3,5,5-Trimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-hexan-1-one 2,2-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4"-piperidine-1'-yl)-] ethyl} -

3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one . 3-Cyclohexyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-propan-1-one

Furan-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl}-3,4-dihydro- 1H-isoquinoline-2-y1}-methanone . N-(4-Phenyl-1-{2-[2-(3,5,5-trimethyl-hexanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- ethyl} -piperidin-4-yl)-acetamide . 5 Quinoxalin-2-yl-[1- {2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl} - 3,4-dihydro- 1H-isoquinoline-2-yl]-methanone 3-Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'"-piperidine-1'-yl)-] ethyl} - 3,4-dihydro-1H-isoquinoline-2-yl}-propan-1-one Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone (Tetrahydro-pyran-4-yl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl}-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone 2-Propyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-y!)-pentan-1-one 2-Ethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-yl)-] ethyl}-3,4-dihydro- 1H-isoquinoline-2-yl]-butan-1-one 3-Phenyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl}-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-propan-1-one 3,3-Dimethyl-1-(1- {2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-butan-1-one (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl} - 6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone 1,2,3,4-tetrahydro-naphthalene-2-yl-(1-{2-{spiro(5-methyl-isobenzofuran- 3H-1,4'-piperidine-1'-yl)-Jethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone (4-Methylsulfanyl-phenyl)-(1- {2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl} - 3,4-dihydro-1H-isoquinolin-2-yl)-methanone 3,5,5-Trimethyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl} -3,4-dihydro- i 30 1H-isoquinolin-2-yl)-hexan-1-one 3-Phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4'-piperidine-1'-yl)-]ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one

Furan-2-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1 -yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-methanone 2-Benzyloxy-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1 -yl]-ethyl}-3,4-dihydro- 1H-isoquinolin-2-yl)-ethanone

1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1 H-isoquinolin-2-yl)- 2-phenoxy-ethanone Quinoxalin-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4"-piperidine-1 "-yl)-]Jethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone 2,2-Dimethyl-1-(1- {2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl] -ethyl}-3,4-dihydro-

1H-isoquinolin-2-yl)-propan-1-one (2,2-Dichloro-cyclopropyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl] -ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone 4-Methylsulfanyl-phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4"-piperidine- 1'-yl)]Jethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone

(2,2-Dichloro-cyclopropyl)-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-methanone 1-(1-{2-[4-(4-Isopropyl-phenyl)-piperidin-1-yl]-ethyl} -3,4-dihydro-1H-isoquinolin-2-y1)- 3,5,5-trimethyl-hexan-1-one 2,2-Dichloro-cyclopropyl-(1-{2-[spiro(isobenzofuran-3H-1,4'-piperidine-1'-yl)-]ethyl} -

3,4-dihydro-1H-isoquinolin-2-yl)-methanone N-(4-Phenyl-1-{2-[2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro- isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide Benzo[1,2,5]oxadiazol-5-yl-(1- {2-[4-(4-chloro-phenyl)-piperidin-1-yl]-ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl)-methanone

N-(1-{2-[2-(3,3-Dimethyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} -4-phenyl- piperidin-4-yl)-acetamide 3-Chloro-2,2-dimethyl-1-(1-{2-[4-(3-triflucromethyl-phenyl)-piperidin-1-yl]-ethyl}- 3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one Tetrahydro-pyran-4-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4'-piperidine-1'-y1)-Jethy1} -

3,4-dihydro-1H-isoquinoline-2-y1]-butan-1-one . 1-(1-{2-[4-(5-Fluoro- 1 H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro- 1H-1soquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,

1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl}-ethyl}- 5-Chloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone,

’ 5 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}- 5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine-1'-yl}- ethyl} -5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1- {2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine-

) 10 1'-yl]-ethyl}-5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin- 1-yl}-ethyl} - 4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-y1]-ethyl} - 4-(3-fluorophenyl)-piperidin-4-ylJacetamide,

N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl} - 4-phenylpiperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl}- 4-phenylpiperidin-4-yljacetamide, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl]-

5-chloro-3,4-dihydro-/H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'"-piperidin-1'-yl]ethyl]- 5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl} methanone, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro /H-indol-3,4'-piperidin-1'-yi]- ethyl]-S-chloro-3,4-dihydro- / H-isoquinolin-2-yl} methanone,

1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1 H-indol-3,4'-piperidin- 1'-yljethyl]-5-chloro-3,4-dihydro-/ H-isoquinolin-2-yl} methanone, 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone,

1-(4-Fluorophenyl)-1-(1- {2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro- 3,4-dihydro-/H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-Fluorobenzo [d]isoxazol-3-yl)-piperidin- 1-yl}-ethyl}-5-chloro-3,4-dihydro- 1H-isoquinolin-2-y1)-1-(4-fluorophenyl)methanone,

1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl} -5-chloro-3,4-dihydro- 1H-1soquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1 "-yl]-ethyl}- . 5-chloro-3,4-dihydro-/H-isoquinolin-2-yl)-methanone,

1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - ) 5-chloro-3,4-dihydro- / H-isoquinolin-2-y)methanone, 1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl1]-ethyl} - 5-chloro-3,4-dihydro-/H-isoquinolin-2-yl)-methanone, 1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} -

5-chloro-3,4-dihydro- / H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(5-Fluoro- 1 H-indol-3-yl)-piperidin-1-yl]-ethyl } -3,4-dihydro-5-fluoro- 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 5-fluoro- I H-isoquinolin-2-yl)methanone,

1s 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}- 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1- {2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-

ethyl}-3,4-dihydro-5-fluoro-/H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]ethyl}-3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)methanone, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl } - 4-(3-fluorophenyl)-piperidin-4-yl]acetamide,

N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl}- 4-phenylpiperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-phenylpiperidin-4-yl]acetamide, , 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl]- 3,4-dihydro-5-fluoro- 1 H-isoquinolin-2-yl} methanone,

1-(4-Fluorophenyl)-1- {1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'-piperidin-1'-yl]ethyl]}- 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl } methanone, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro /H-indol-3,4'-piperidin-1'-yl}- ethyl]-3,4-dihydro-5-fluoro- 1 H-isoquinolin-2-yl } methanone,

’ 5 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-/ H-indol-3,4'-piperidin-1'- yllethyl]-3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl} methanone, 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro- 5-fluoro-/ H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1- {2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-

3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)methanone,

1-(1- {2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin- 1-yl]-ethyl} -3,4-dihydro-5-fluoro- 1H-1soquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro- 1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,

1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}- 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)-methanone, 1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl]-ethyl}- 3,4-dihydro-5-fluoro- 1 H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} -

3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)-methanone, 1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl}-ethyl} - 3,4-dihydro-5-fluoro-/ H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(5-Fluoro-/ H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,

1-Cyclopentyl-1-(1-{2-{4-(5-fluoro- 1 H-indol-3-y!)-piperidin-1-yl]-ethyl}-5,6-dichloro- 3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone,

1-(4-Fluorophenyl)-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} -

5,6-dichloro-3,4-dihydro-/H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]}- ethyl}-5,6-dichloro-3,4-dihydro- / H-isoquinolin-2-yl)methanone,

1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1 (3H),4'-piperidine- 1'-ylJethyl}-5,6-dichloro-3,4-dihydro-1 H-isoquinolin-2-yl)methanone, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-(3-fluorophenyl)-piperidin-4-yl]acetamide,

N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - ’ 4-(3-fluorophenyl)-piperidin-4-yljacetamide, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl}- 4-phenylpiperidin-4-yljacetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} -

4-phenylpiperidin-4-ylJacetamide, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4'"-piperidin-1"-yl]ethyl]- 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl} methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4"-piperidin-1'-yl]ethyl]- 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl} methanone,

1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro /H-indol-3,4"-piperidin-1'-yl}- ethyl]-5,6-dichloro-3,4-dihydro-/H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-/ H-indol-3,4"-piperidin- 1'-yl]ethyi]-5,6-dichloro-3,4-dihydro- / H-isoquinolin-2-yl} methanone, 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylpheny!l)-piperidin-1-yl]-ethyl}-5,6-dichloro-

3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl} - 5,6-dichloro-3,4-dihydro- / H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl}-ethyl}-5,6-dichloro- 3,4-dihydro-/H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,

1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro- 3,4-dihydro-/H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl}-ethyl}- 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)-methanone, 1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-

5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - 5,6-dichloro-3,4-dihydro-/ H-isoquinolin-2-yl)-methanone,

1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(5-Fluoro-1 H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,

: 5 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-/ H-indol-3-yl)-piperidin-1-yl}-ethyl}-5,6-difluoro- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1- {2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 5,6-difluoro-3 4-dihydro-1H-isoquinolin-2-yDmethanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4'-piperidine-1'-yl]-ethyl}-

5,6-difluoro-3,4-dihydro-/H-isoquinolin-2-yl)methanone,

1-Cyclopentyl-1-(1-{2-[6-trifluoromethyispiro[isobenzofuran-1(3H),4"-piperidine-1'-yl]- ethyl} -5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4'-piperidine- 1'-yl]ethyl}-5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone,

N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-ylj-ethyl}- 4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} - 4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl} -

4-phenylpiperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl}- 4-phenylpiperidin-4-yl]jacetamide, 1-Cyclopentyl-1-{1-[1-acetyl-spirof2,3-dihydro-1H-indol-3,4'-piperidin-1'-yl]ethyl]- 5,6-difluoro-3,4-dihydro-/H-isoquinolin-2-yl} methanone,

1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-/ H-indol-3,4"-piperidin-1'-yl]ethyl]- 5,6-difluoro-3,4-dihydro-/H-isoquinolin-2-yl} methanone, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro /H-indol-3,4'"-piperidin-1'-yl]- ethyl]-5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl} methanone,

1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-/ H-indol-3,4'-piperidin-1'-

yl]ethyl]-5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl }methanone, 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylpheny!)-piperidin-1-yl]-ethyl}-5,6-difluoro- 3,4-dihydro-/ H-isoquinolin-2-yl)methanone,

1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl}-ethy1} - 5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl} -5,6-difluoro-3,4-dihydro- 1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,

1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5 ,0-difluoro-3,4-dihydro- } 1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} - 5,6-difluoro-3,4-dihydro-/ H-isoquinolin-2-yl)-methanone, 1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4'-piperidine-1'-yl]-ethyl} -

5,6-difluoro-3,4-dihydro-/H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - 5,6-difluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-methanone, and 1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4"-piperidine-1'-yl]-ethyl} - 5,6-difluoro-3,4-dihydro- / H-isoquinolin-2-yl)methanone.

or from the group comprising the following enantiomers which are prepared by acylation of Enantiomer 2 of the corresponding amines of formula V,

Re Re R™ J R? VERN 7 Nw Ra R3 Ré R¢ RS vv)

wherein R:-R’ and Q are as defined for formula I; and Enantiomer 2 is the slowly eluting of the enantiomer pair by supercritical HPLC at 20 Mpa on a system comprising chiralcelOD columns and an eluent consisting of carbondioxide(75%), 2-propanol(24.75%), diethylamine(0.125%) and trifluoracetic acid(0.125%):

N-(4-(3-Fluoro-phenyl)-1- {2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl1]- ethyl} -piperidin-4-yl)acetamide (Enantiomer) ) N-(4-(3-Fluoro-phenyl)-1- {2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl1]- ethyl}-piperidin-4-yl)acetamide (Enantiomer) : 5 N-[1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl}-4-(3-fluoro- phenyl)-piperidin-4-yl}-acetamide (Enantiomer) N-[1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} -4-(3-fluoro- phenyl)-piperidin-4-yl]-acetamide (Enantiomer) : N-[1- {2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl} -4-(3-fluoro- phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1- {2-[2-(4-isopropyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- ethyl} -piperidin-4-yl)acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1- {2-[2-(4-methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- ethyl} -piperidin-4-yl)acetamide (Enantiomer) N-[1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro- phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-[1-{2-[2-(2-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro- phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl- piperidin-4-yl)acetamide (Enantiomer) N-(1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl}-4-phenyl- piperidin-4-yl)acetamide (Enantiomer) N-[1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro- phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-[1-{2-[2-(Benzo[1,2,5]oxadiazole-5-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- ethyl} -4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1- {2-[2-(naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1- yl}-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-[1-[2-(2-Cyclopentanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-(3-fluoro-

. 30 phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl- piperidin-4-yl)acetamide (Enantiomer)

N-[1-{2-[2-(Benzo[b]thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1 -yl]-ethyl}-4- (3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-[1-{2-[2-(6-Fluoro-4H-benzo[ 1,3]dioxine-8-carbonyl)-1 ,2,3,4-tetrahydro-isoquinolin-1- : yl]-ethyl1}-4-(3-fluoro-phenyl)-piperidin-4-yl]Jacetamide (Enantiomer)

N-[1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} ~4-(3-fluoro- ’ phenyl)-piperidin-4-yl]acetamide (Enantiomer) N-[1-{2-[2-(2-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin- 1-yl}-ethyl} -4-(3-fluoro- phenyl)-piperidin-4-yl]acetamide (Enantiomer) N-(1-{2-[2-(4-Methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1 -yl]-ethyl}-4-phenyl-

piperidin-4-yl)acetamide (Enantiomer) N-[1-{2-[2-(2-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl }-4-(3-fluoro- phenyl)-piperidin-4-yl}-acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- ethyl} -piperidin-4-yl)acetamide (Enantiomer)

N-(1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl- piperidin-4-yl)acetamide (Enantiomer) N-(1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} -4-phenyl- piperidin-4-yl)acetamide (Enantiomer) N-{1-[2-(2-Cycloheptanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-

piperidin-4-yl}-acetamide (Enantiomer) N-(1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} -4-phenyl- piperidin-4-yl)acetamide (Enantiomer) 2-N-(4-(3-Fluoro-phenyl)-1-{2-[2-(3-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin- 1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer)

N-(4-(3-Fluoro-phenyl)-1-{2-[2-(thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin- 1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-pyrazol-1-yl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin- 1-yl}-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-(1-{2-[2-(Naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl} -4-phenyl-

piperidin-4-yl)acetamide (Enantiomer)
26. A pharmaceutical composition comprising a compound of any of claims 1 to 25 in a therapeutically effective amount together with one or more pharmaceutically acceptable . carriers or diluents. ’ 5
27. Use of a compound of any of claims 1 to 25 for the manufacture of a pharmaceutical preparation for the treatment of a disorder in the central nervous system.
28. Use according to claim 27 characterised in that the disorder is selected from the group comprising depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder, psychosis and Huntington’s disease as well as Parkinson’s dementia, adjustment disorders, pain, emesis, migraine, epilepsia, obesity and cerebrovascular disease.
29. Use according to claim 28 characterised in that the disorder is selected from the group comprising depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder and psychosis.
30. Use of a compound of any of claims 1 to 25 in treatment of a disorder in the central nervous system.
31. Use according to claim 30 characterised in that the disorder is selected from the group comprising depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalised anxiety disorder, social anxiety disorder, panic anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder, psychosis and Huntington’s disease as well as Parkinson’s dementia, adjustment disorders, pain, emesis, migraine, epilepsia, obesity and cerebrovascular disease.
32. Use according to claim 31 characterised in that the disorder is selected from the group comprising depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder, , post-traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder and psychosis.