KR20040068306A - 3,4-dihydro-1h-isoquinoloin-2-yl-derivatives - Google Patents

Abstract

The present invention relates to novel compounds of formula (I) or pharmaceutically acceptable acid addition salts thereof, wherein the variable groups are as defined in the claims. Compounds of the invention are NK2 antagonists.

Description

3,4-dihydro-1H-isoquinolin-2-yl derivative {3,4-DIHYDRO-1H-ISOQUINOLOIN-2-YL-DERIVATIVES}

Three tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), are widely distributed throughout the peripheral and central nervous system. The biological effects of these neuropeptides are carried out through binding to their preferred receptors NK1, NK2 and NK3 (Guard, S. and Watson, SP Neurochem. Int. 1991 , 18 , 149). Substance P shows the highest affinity for the NK1 receptor, but NKA and NKB preferably bind to the NK2 and NK3 receptors, respectively. The selectivity of endogenous ligands for each of these receptors is not absolute (Review, Regoli, D. et al . , Pharmacol. Rev. 1994 , 46 , No. 4, 551 and Bremer, AA et al., Eur J Pharmacol 2001 , 423 , 143). Three receptor subtypes belong to the G protein-linked receptor upper class and have been cloned in various species, including mice, rats, and humans (Giardina, GAM et al., Drugs of the Future 1997 , 22 , 1235 and herein See).

Activation of tachykinin receptors affects a broad array of biological actions, which include pain transmission, vasodilation, smooth muscle contraction, saliva secretion, bronchial contraction, activation of the immune system (inflammatory pain), neurological inflammation and neurotransmission. (Patacchini, R. et Maggi, CA Eur J Pharmacol. 2001 , 429, 13; Longmore, J. et al., Can J Physiol Pharmacol 1997 , 75 , 612; Giardina, GAM et al., Drugs of the Future 1997 , 22 , 1235 and in luck).

Expression of human NK2 receptors is somewhat controversial. Receptors are typically expressed in small amounts in the CNS, and autoradiography studies have not shown NK2 receptors in the human brain. However, recent reverse transcriptase polymerase chain reaction (RT-PCR) studies have revealed detectable expression of NK2 receptor mRNA in various human brain regions, including tail nucleus, cockle nucleus, hippocampus, melanoma and cerebral cortex (Bensaid, M Et al., Neurosci Lett 2001 , 303 , 25).

Upregulation of preprotakinin (PPT) genes and mRNA for neurokinin receptors has been described in animal models of disease (Fischer, A. et al ., J Clin Invest 1996 , 98 , 2284) and human diseases such as asthma (Adcock, IM et al., J Mol Endocrino 1993 , 11 , 1).

NK antagonists have been studied to treat large amounts of CNS-related and peripheral diseases and are still being studied. Numerous preliminary clinical studies have been conducted to assess the relevance of NK1 and NK2 receptor modulation and regulation in diseases associated with anxiety and / or depression ( Griebel, G. et al., Psycopharmacology, 2001 , 158, 241; Walsh, DM et al., Psychopharmacology 1995 , 121 , 186; Rupniak, NM et al., Neuropharmacology 2000 , 39 , 1413; Rupniak, NM et Kramer, MS TiPS 1999 , 20, 485; Giardina, GAM et al., Drugs of the Future 1997 , 22 , 1235, and these Reference).

These studies have shown that NK2 antagonists have depression, mood swings, bipolar disorder, mood modulation, mixed anxiety depression, general anxiety disorder, social anxiety disorder, panic anxiety disorder, late traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, premenstrual discomfort. It will be useful in treating or preventing disorders, psychosis and Huntington's disease, and various brain diseases including Parkinson's disease, dysregulation, pain, vomiting, migraine, epilepsy, obesity, asthma and cerebrovascular disease. However, peripheral diseases such as inflammation, inflammatory bowel disease, high blood pressure, arthritis, cardiovascular disease, neuritis, neuralgia, urticaria, incontinence, gastrointestinal disease, pandemic, allergy, lung allergy and carcinoma / tumor growth also occur by NK2 antagonists Can be.

US 3,994,891 discloses tetrahydroisoquinoline of the formula:

[Wherein R is hydrogen or methyl and G is NH or CH ₂ ].

Dihydroxy compounds are described as effective vasodilators, but dimethoxy compounds are intermediates in the preparation of dihydroxy compounds.

Accordingly, new compounds that are antagonists at the NK2 receptor are desired.

Compounds of the invention belong to a new class of 3,4-dihydro-1H-isoquinolin-2-yl derivatives having affinity for neurokinin 2 (NK2) receptors. The compound is an NK2-antagonist and is useful for the treatment of diseases involving NK2-receptors, such as asthma and CNS diseases. These novel 3,4-dihydro-1H-isoquinolin-2-yl derivatives can penetrate the blood brain barrier and are therefore useful for the treatment of various CNS diseases.

Summary of the Invention

It is an object of the present invention to provide compounds which are antagonists at the NK2 receptor.

It is another object of the present invention to provide compounds having activity with improved solubility, metabolic stability and / or bioavailability as compared to the compounds of the prior art.

Accordingly, the present invention relates to novel compounds of formula (I) or pharmaceutically acceptable acid addition salts thereof:

[In the meal,

R^OneSilver group R¹¹CO-, R¹¹CS-, R¹¹SO₂-, R¹¹OCO-, R¹¹SCO- or R¹¹CO-CR¹²R¹³Or {in the formula, R¹¹Silver c_1-12Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8-Cycloalkyl-C_1-6-Alkyl, aryl, aryl-C_1-6-Alkyl, heteroaryl, heteroaryl-C_1-64H-benzo [1,3] dioxynyl, which may be substituted by alkyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphthalenyl, or halogen (C_1-6Alkyl, aryl, heteroaryl and C_3-8Each cycloalkyl group is independently unsubstituted, halogen, C_1-6Alkyl, C_1-6-Alkoxy, aryl-C_1-6Alkoxy, C_1-6-Substituted with one or more substituents selected from the group comprising alkylsulfanyl, aryl and aryloxy, wherein the aryl and aryloxy are independently unsubstituted or substituted with one or more halogen), R¹²And R¹³Is independently hydrogen or C_1-6-Alkyl}; R^OneSilver group R¹⁴R¹⁵NCO-, R¹⁴R¹⁵NCS-, where R is¹⁴And R¹⁵Is independently hydrogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8-Cycloalkyl-C_1-6-Alkyl, aryl or aryl-C_1-6-Alkyl or (C_1-6Alkyl, aryl and C_3-8Each cycloalkyl group is independently unsubstituted or halogen, C_1-6Alkyl and C_1-6-Substituted with one or more substituents selected from the group comprising alkoxy), R¹⁴And R¹⁵silver Together with the N-atom to which they are attached form a pyrrolidinyl, piperidinyl or perhydroazinylyl group;

R ² is selected from hydrogen, trifluoromethyl and C _1-6 -alkyl;

R ³ -R ⁶ , R ^7a , R ^7b , R ^8a and R ^8b are hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6- Alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, Independently selected from trifluoromethyl, trifluoromethylsulfonyl and C _1-6 -alkylsulfonyl;

m is 2-6;

R ⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclicaryl or heteroaryl, wherein benzyl, benzoyl, aryl or heteroaryl are each halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, C _{1- 6} -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) Substitution with one or more substituents selected from aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl Can be};

Q is C, N or CR ¹⁰ ;

Wherein R ¹⁰ is hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _{3- 8} -cycloalkyl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6 -alkylcarbonyl, aminocarbonyl, C _{1- 6} -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluorine Rhomethyl, trifluoromethylsulfonyl, the group -NR ³⁰ COR ^{31 wherein} R ³⁰ is hydrogen or C _1-6 -alkyl and R ³¹ is C _1-6 -alkyl, the group -COOR ¹⁶ ( Wherein R ¹⁶ is hydrogen or C _1-6 -alkyl, or a group -CONR ¹⁷ R ¹⁸ (wherein R ¹⁷ and R ¹⁸ are independently selected from hydrogen and C _1-6 -alkyl, or R ¹⁷ and R ¹⁸ can form a piperidinyl, piperazinyl or morpholinyl, together with the nitrogen to which they are attached (the piperidinyl, piperazinyl and morpholinyl is Ring unsubstituted or C _1-6 - from substituted by alkyl)) selected};

Or R ⁹ and R ¹⁰ together with the carbon to which they are attached form a cyclic structure selected from the group comprising:

Wherein Q 'is carbon shared with the piperidine ring such that the cyclic structure forms a spiro structure with the piperidine ring;

X, Y, and Z are O; NR ¹⁹ ; CR ²³ R ²⁴ ; Independently selected from S (O) _n and a bond (R ¹⁹ is hydrogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-Ci_ ₆ -alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R ¹⁹ is a group R ²⁰ SO _2- , R ²⁰ OCO- or R ²⁰ SCO- or (R ²⁰ is C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _{1- 6} -alkyl or aryl, R ¹⁹ is a group R ²¹ R ²² NCO- or R ²¹ R ²² NCS- (R ²¹ and R ²² are independently hydrogen, C _1-6 -alkyl, C _2-6 -al Kenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, or aryl (the aryl is unsubstituted or C _1-6 -alkyl or substituted with one or more substituents selected from halogen); R ²¹ and R ²² are the blood with N- wonjagwa which they are attached pyrrolidinyl, piperidinyl, or tetrahydro-flops ah Jaffe To form a group); R ²³ and R ²⁴ is hydrogen, halogen, cyano, nitro, C _1-6 - alkyl, C _2-6 - alkenyl, C _2-6 - alkynyl, C _3-8 - cycloalkyl, Independently selected from C _3-8 -cycloalkyl-C _1-6 -alkyl, aryl, heteroaryl (the aryl is unsubstituted or C _1-6 -alkyl or halogen, amino, C _1-6 -alkyl Amino, groups NR ²⁵ R ²⁶ (R ²⁵ and R ²⁶ are C _1-6 -alkyl, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1- Independently selected from ₆ -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C _1-6 -alkylsulfonyl Or R ²⁵ and R ²⁶ are substituted with one or more substituents selected from pyridininyl, piperidinyl, perhydroazinyl or morpholinyl group together with the N-atom to which they are attached, R ²³ and R ²⁴ together is oxo; n is 0, 1 or 2; Provided that one or less of X, Y and Z may be a bond provided that two adjacent groups X, Y or Z cannot be selected from O and S at the same time;

A ¹ , A ² , A ³ and A ⁴ are independently selected from N and CR ²⁷ (R ²⁷ is hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylamino Carbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, tri Fluoromethylsulfonyl C _1-6 -alkylsulfonyl amino or groups NR ²⁸ R ²⁹ (R ²⁸ and R ²⁹ are independently selected from hydrogen and C _1-6 -alkyl, or R ²⁸ and R ²⁹ are combined Together with the N-atom form a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group, provided that only one of A ¹ , A ² , A ³ and A ⁴ can be N;

The dotted line from Q is a bond when Q is C and not a bond when Q is CR ¹⁰ or N}].

Detailed description of the invention

The C _1-12 -alkyl group defined for R ¹¹ is preferably selected from C _1-10 -alkyl, more preferably C _1-8 -alkyl, most preferably C _3-8 -alkyl.

In one embodiment, the invention relates to compounds wherein Q is CR ¹⁰ and R ⁹ and R ¹⁰ together with the carbon to which they are attached form the following bicyclic structures:

Wherein Q 'is carbon shared with the piperidine ring such that the bicyclic structure together with the piperidine ring forms a spiro structure;

X, Y and Z are O; NR ¹⁹ ; CR ²³ R ²⁴ and S (O) _n, and are independently selected from bond {R ¹⁹ is hydrogen, C1 _-6 - alkyl, C _2-6 - alkenyl, C _2-6 - alkynyl, C _3-8 - Cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R ¹⁹ is a group R ²⁰ SO _2- , R ²⁰ OCO or R ²⁰ SCO- (R ²⁰ is C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl or aryl, or R ¹⁹ is a group R ²¹ R ²² NCO-, R ²¹ R ²² NCS- (R ²¹ and R ²² are independently hydrogen, C _1-6 -alkyl, C _2-6 -Alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl or aryl (the aryl is unsubstituted or C _1-6- substituted with one or more substituents selected from alkyl or halogen search); R ²¹ and R ²² are the blood with the N- atom to which they are attached pyrrolidinyl, piperidinyl, or tetrahydro-flops ah Jaffe To form a group shown below); R ²³ and R ²⁴ are hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _{3-8 -Cycloalkyl} -C _1-6 -alkyl, aryl, heteroaryl (wherein aryl is unsubstituted or C _1-6 -alkyl or halogen, amino, C _1-6 -alkylamino, a group NR ²⁵ R ²⁶ (R ²⁵ And R ²⁶ is C _1-6 -alkyl, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _{1 -6} -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl, and C _1-6 -alkylsulfonyl, or R ²⁵ and R ²⁶ are selected from Or substituted with one or more substituents selected from the group consisting of a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group together with the attached N-atom, or R ²³ and R ²⁴ are Together is oxo; n is 0, 1 or 2; Provided that at most one of X, Y and Z may be a bond provided that two adjacent groups X, Y or Z cannot be selected from O and S at the same time;

A ¹ , A ² , A ³ and A ⁴ are N and CR ²⁷ {R ²⁷ is hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alky Nyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, groups NR ²⁸ R ²⁹ (R ²⁸ and R ²⁹ are independently from hydrogen and C _1-6 -alkyl. Or R ²⁸ and R ²⁹ together with the N- atom to which they are attached form a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group), C _1-6 -alkylcarbonyl, aminocarbon Carbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, di Fluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C _1-6 -alkylsulfonyl}; Provided that only one of A ¹ , A ² , A ³ and A ⁴ may be N].

In a preferred embodiment, the invention relates to compounds wherein X, Y and Z are selected from one of the following combinations: X is oxygen, Y is a bond, and Z is CR ²³ R ²⁴ ; X is CR ²³ R ²⁴ , Y is a bond, and Z is oxygen; X is NR ¹⁹ , Y is a bond, and Z is CR ²³ R ²⁴ ; X is CR ²³ R ²⁴ , Y is a bond, and Z is NR ¹⁹ ; X is CO, Y is a bond, and Z is NR ¹⁹ ; X is SO ₂ , Y is a bond, and Z is NR ¹⁹ ; X is SO, Y is a bond, and Z is NR ¹⁹ ; X is CR ²³ R ²⁴ , Y is a bond, and Z is S; X is CR ²³ R ²⁴ , Y is a bond, and Z is SO; X is CR ²³ R ²⁴ , Y is a bond, and Z is SO ₂ [wherein R ¹⁹ is hydrogen, acetyl or methylsulfonyl, and R ²³ and R ²⁴ are hydrogen, methyl, isobutyl, cyclohexyl and 4- Independently selected from fluorophenyl].

In another preferred embodiment, the invention relates to compounds wherein -XYZ- together form a group selected from: -O-CR ²³ R ^24- , -CR ²³ R ²⁴ -O-,- NR ¹⁹ -CR ²³ R ^24- , -CR ²³ R ²⁴ -NR ^19- , -CO-NR ^19- , -SO ₂ -NR ^19- , -SO-NR ^19- , -CR ²³ R ²⁴ -S-, -CR ²³ R ²⁴ -SO-, -CR ²³ R ²⁴ -SO ₂ -wherein R ¹⁹ is hydrogen, acetyl or methylsulfonyl, and R ²³ and R ²⁴ are hydrogen, methyl, isobutyl, cyclohexyl and Independently selected from 4-fluorophenyl].

In another preferred embodiment, the invention provides that A ³ is N or CR ²⁷ [R ²⁷ is halogen, cyano, nitro, a group NR ²⁸ R ²⁹ (R ²⁸ and R ²⁹ from hydrogen and C _1-6 -alkyl Independently selected from R ²⁸ and R ²⁹ together with the N-atom to which they are attached form a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group), C _1-6 -alkylcarbonyl, Aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, hydroxy, trifluoromethyl, difluoromethyl, fluoro Methyl, trifluoromethylsulfonyl or C _1-6 -alkylsulfonyl.

In another preferred embodiment, the invention relates to compounds wherein A ¹ , A ² , A ³ and A ⁴ are independently selected from CR ²⁷ wherein R ²⁷ is as defined above. .

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

[Wherein, R ^{19 '} is acetyl or methylsulfonyl, R ^23' is hydrogen or methyl, R ^{27 '} is hydrogen or fluoro, R ^27'' is hydrogen, fluoro, methyl or isopropyl, R ^{27 '''} is hydrogen, fluoro or trifluoromethyl.

In another embodiment, the invention relates to compounds wherein R ⁹ and R ¹⁰ together with the carbon to which they are attached form a cyclic structure selected from the group comprising:

Wherein Q 'is carbon shared with the piperidine ring such that the cyclic structure forms a spiro structure with the piperidine ring.

In another embodiment, the invention provides that R ⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl or mono- or bicyclic aryl or heteroaryl [wherein benzyl, benzoyl, aryl or hetero Each of the aryl is halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl , Di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoro Which may be substituted with one or more substituents selected from methylsulfonyl.

In another embodiment, the invention provides that R ⁹ is 2,3-dihydrobenzofuran-7-yl, benzyl or benzoyl, wherein the benzyl or benzoyl is unsubstituted or substituted with one or more halogens in its phenyl group. , Mono- or bicyclic aryl or heteroaryl, wherein R ⁹ is selected from the group comprising phenyl, indolyl, pyridyl, thiophenyl and benzisoxazolyl, wherein each of the aryl or heteroaryl is halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, C _{1- 6} - alkylamino, di - (C _1-6 -alkyl) amino, C _1-6 -alkyl-carbonyl, aminocarbonyl, C _1-6 -alkyl-aminocarbonyl, di - (C1 _-6 -alkyl) amino and that alkylthio, hydroxy, trifluoromethyl, difluoromethyl, methyl, selected from methyl and trifluoromethyl fluoro-methylsulfonyl-carbonyl, C _1-6 - alkoxy, C _1-6 It may be substituted with one substituent; relates to a compound that would.

In a preferred embodiment, the invention provides that the mono- or bicyclic aryl or heteroaryl is phenyl, indol-3-yl and benzisoxazol-3-yl [the phenyl, indol-3-yl or benzisoxazole-3 -Yl is halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _{1 -6} -alkyl, amino, C _1-6 -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, Di- (Ci_ ₆ -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulphate Which may be substituted with one or more substituents selected from fonyl].

In an even more preferred embodiment, the invention relates to compounds, wherein said optional substituents are selected from the group comprising halogen, phenyl and methyl.

In another embodiment, the invention provides that Q is CR ^{10 wherein} R ¹⁰ is hydrogen, C _1-6 -alkylcarbonyl, hydroxy, —NR ³⁰ COR ³¹ group wherein R ³⁰ is hydrogen or C _{1 -6} -alkyl and R ³¹ is C _1-6 -alkyl), -COOR ¹⁶ group (wherein R ¹⁶ is C _1-6 -alkyl), or -CONR ¹⁷ R ¹⁸ group (wherein R ¹⁷ And R ¹⁸ together with the nitrogen to which they are attached form piperidinyl, piperazinyl or morpholinyl (the piperidinyl, piperazinyl and morpholinyl are unsubstituted or substituted with C _1-6 -alkyl It is related to the compound of the present invention).

In a preferred embodiment, the invention provides that R ¹⁰ is hydrogen, acetyl, hydroxy, a -NR ³⁰ COR ³¹ group (wherein R ³⁰ is hydrogen and R ³¹ is methyl), -COOR ¹⁶ group (wherein R ¹⁶ Is ethyl), or a -CONR ¹⁷ R ¹⁸ group wherein R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form piperidinyl or 4-methylpiperazinyl It is about.

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

In another embodiment, the invention provides that R ¹ is a group R ¹¹ CO—, R ¹¹ OCO— wherein R ¹¹ is C _3-6 -alkyl, C _3-8 -cycloalkyl, C _3-8 -cyclo Alkyl-C _1-6 -alkyl, phenyl, phenyl-C _1-6 -alkyl, pyridyl, furanyl, benzo [1,2,5] oxadiazolyl, quinoxalinyl, benzo [b] thiophenyl or naph Talenyl {The C _3-6 -alkyl, phenyl, pyridyl and furanyl groups are each independently unsubstituted or halogen, C _1-6 -alkyl, C _1-6 -alkoxy, phenyl and phenoxy (the phenyl and Phenoxy is independently substituted or substituted with one or more substituents selected from the group consisting of one halogen; Or R ¹ is a R ¹⁴ R ¹⁵ NCO- group wherein R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl, or aryl-C _1-6 -alkyl (wherein C _1-6- Alkyl and aryl groups are each unsubstituted or substituted with one substituent selected from the group comprising halogen and C _1-6 -alkoxy).

In another embodiment, the invention relates to compounds wherein R ² is hydrogen.

In another embodiment, the present invention relates to compounds wherein R ³ is hydrogen.

In another embodiment, this invention relates to compounds wherein R ⁴ is hydrogen or methoxy.

In another embodiment, this invention relates to compounds wherein R ⁵ is hydrogen or methoxy.

In another embodiment, the invention relates to compounds wherein R ⁶ is hydrogen.

In another embodiment, the invention relates to compounds wherein R ^7a and R ^7b are hydrogen.

In another embodiment, the invention relates to compounds wherein R ^8a and R ^8b are hydrogen.

Preferred compounds of the present invention are the compounds listed below, as well as the first through 209 compounds as disclosed in the experimental section:

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

1-cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro-3 , 4-dihydro- 1H -isoquinolin-2-yl) methanone,

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

1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro -3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

N- [1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Phenyl) -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-phenylpiperidine- 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- 1H -indol-3,4'-piperidin-1'-yl] ethyl] -5-chloro-3 , 4-dihydro- 1H -isoquinolin-2-yl} methanone,

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

1-cyclopentyl-1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indol-3,4'-piperidin-1'-yl] ethyl]- 5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone,

1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indole-3,4'-piperidine-1'- Il] ethyl] -5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone,

1-cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -5-chloro-3,4-dihydro- 1H- Isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -5-chloro-3,4- Dihydro- 1H -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-yl) -1- (4-fluorophenyl) methanone,

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

1- (4-fluorophenyl) -1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1-({2- [6-fluorophospho [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro -3,4-dihydro- 1H -isoquinolin-2-yl) -methanone,

1-cyclopentyl-1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro -3,4-dihydro- 1H -isoquinolin-2-yl) -methanone,

1-cyclopentyl-1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] ethyl} -5-chloro-3,4-di Hydro- 1H -isoquinolin-2-yl) -methanone,

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

1-cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro-5-fluoro- 1H -isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 3,4-dihydro-5-fluoro- 1H -isoquinolin-2-yl) methanone,

1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-5-fluoro- 1H -isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] ethyl} -3,4-dihydro-5-fluoro- 1H -isoquinolin-2-yl) methanone,

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

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

1-cyclopentyl-1- {1- [1-acetyl-spiro [2,3-dihydro- 1H -indol-3,4'-piperidin-1'-yl] ethyl] -3,4-di Hydro-5-fluoro- 1H -isoquinolin-2-yl} methanone,

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

1-cyclopentyl-1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indol-3,4'-piperidin-1'-yl] ethyl]- 3,4-dihydro-5-fluoro- 1H -isoquinolin-2-yl} methanone,

1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indole-3,4'-piperidine-1'- Il] ethyl] -3,4-dihydro-5-fluoro- 1H -isoquinolin-2-yl} methanone,

1-cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-5-fluoro- 1H Isoquinolin-2-yl) methanone,

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

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

1- (4-fluorophenyl) -1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro-5-fluoro- 1H -isoquinolin-2-yl) -methanone,

1- (4-fluorophenyl) -1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-5-fluoro- 1H -isoquinolin-2-yl) methanone,

1-cyclopentyl-1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-5-fluoro- 1H -isoquinolin-2-yl) -methanone,

1-cyclopentyl-1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro-5 -Fluoro- 1H -isoquinolin-2-yl) methanone,

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

1-cyclopentyl-1- (1- {2- [4- (5-fluoro- 1H -indol-3-yl) -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'-piperidin-1'-yl] -ethyl} -5,6-dichloro -3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6 -Dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

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

N- [1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Phenyl) -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-phenylpiperidine- 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- 1H -indol-3,4'-piperidin-1'-yl] ethyl] -5,6-dichloro -3,4-dihydro- 1H -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-5-fluoro- 1H -indol-3,4'-piperidin-1'-yl] ethyl]- 5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone,

1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indole-3,4'-piperidine-1'- Il] ethyl] -5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone,

1-cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) -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- 1H -isoquinolin-2-yl) 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- (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'-piperidin-1'-yl] -ethyl } -5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) -methanone,

1- (4-fluorophenyl) -1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-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'-piperidin-1'-yl] -ethyl} -5,6 -Dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1-cyclopentyl-1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6-dichloro-3, 4-dihydro- 1H -isoquinolin-2-yl) methanone,

1- (1- {2- [4- (5-Fluoro- 1H -indol-3-yl) -piperidin-1-yl] -ethyl} -5,6-difluoro-3,4- Dihydro- 1H -isoquinolin-2-yl) -1- (4-fluoro-phenyl) methanone,

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

1-cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6-di Fluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6 -Difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

N- [1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Phenyl) -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-phenylpiperidine- 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- 1H -indol-3,4'-piperidin-1'-yl] ethyl] -5,6-di Fluoro-3,4-dihydro- 1H -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-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone,

1-cyclopentyl-1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indol-3,4'-piperidin-1'-yl] ethyl]- 5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone,

1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indole-3,4'-piperidine-1'- Il] ethyl] -5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone,

1-cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -5,6-difluoro-3,4-di Hydro- 1H -isoquinolin-2-yl) methanone,

1- (4-Fluorophenyl) -1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -5,6-difluoro- 3,4-dihydro- 1H -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'-piperidin-1'-yl] -ethyl } -5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone,

1- (4-fluorophenyl) -1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6 -Difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) -methanone,

1-cyclopentyl-1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6 -Difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) -methanone, and

1-cyclopentyl-1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6-difluoro- 3,4-dihydro- 1H -isoquinolin-2-yl) methanone.

Compounds of the invention have a human NK ₂ binding affinity (IC50) of 5 μM or less, generally 1 μM or less, preferably 200 nM or less, more preferably 50 nM or less and most preferably 10 nM or less. NK ₂ receptor antagonist.

Thus, the compounds of the present invention are depression, bipolar disorder, bipolar disorder, mood modulation, mixed anxiety depression, general anxiety disorder, social anxiety disorder, panic anxiety disorder, posttraumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, premenstrual It is believed to be useful in the treatment of various CNS diseases such as discomfort disorders, psychosis and Huntington's disease, and Parkinson's dementia, dysregulation, pain, vomiting, migraine, epilepsy, obesity and cerebrovascular disease.

In particular, the compounds of the present invention are depression, bipolar disorder, bipolar disorder, mood modulation, mixed anxiety depression, general anxiety disorder, social anxiety disorder, panic anxiety disorder, posttraumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, premenstrual It is thought to be useful in the treatment of unpleasant disorders and psychosis.

Thus, in another aspect, the invention comprises a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof as defined above, in combination with at least one pharmaceutically acceptable carrier or diluent It provides a pharmaceutical composition.

In another aspect, the present invention provides the use of a compound of formula (I) or an acid addition salt thereof as defined above for the preparation of a pharmaceutical formulation for the treatment of the aforementioned disorders.

Compounds of formula (I) may exist as their optical isomers, and such optical isomers are also included in the present invention. Throughout the description and claims, reference to a specific compound refers to a racemate unless otherwise indicated.

The term C _1-6 -alkyl refers to one to one carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, and 2-methyl-1-propyl 6 refers to a branched or linear alkyl group. Similarly, the terms C _1-8 -alkyl, C _1-10 -alkyl and C _1-12 -alkyl refer to branched or linear alkyl groups having 1 to 8, 10 or 12 carbon atoms respectively.

Similarly, C _2-6 -alkenyl and C _2-6 -alkynyl are one double bond and one triple bond, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl, respectively The group which has C2-C6 containing these is shown.

The term C _3-8 -cycloalkyl denotes a monocyclic or bicyclic carbocyclic ring having 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and the like.

Halogen means fluoro, chloro, bromo or iodo.

As used herein, the term acyl refers to formyl, C _1-6 -alkylcarbonyl, arylcarbonyl, aryl-C _1-6 -alkylcarbonyl, C _3-8 -cycloalkylcarbonyl or C _{Refers to a 3-8} -cycloalkyl-C _1-6 -alkyl-carbonyl group, and the term thioacyl is the corresponding acyl group in which the carbonyl group is substituted with a thiocarbonyl group.

Terms such as C _1-6 -alkoxy, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _1-6 -alkylsulfonyl, C _1-6 -alkylamino, C _1-6 -alkylcarbonyl Represents a group wherein the C _1-6 -alkyl and C _3-8 -cycloalkyl groups are as defined above.

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

The term heteroaryl refers to 1 H -tetrazolyl, 3 H -1,2,3-oxathiazolyl, 3 H -1,2,4-oxazozolyl, 3 H -1,2,5-oxathiazolyl, 1,3,2-oxathiazolyl, 1,3,4-oxathiazolyl, 1,4,2-oxathiazolyl, 3H -1,2,4-dioxazolyl, 1,3,2-di oxazolyl, 1,4,2- de-oxazolyl, 3 H -1,2,3- di-thiazolyl, 3 H -1,2,4- di thiazolyl, 1,3,2- de-thiazolyl, 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, 1 H -1,2,3-triazolyl , 1 H -1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 H -imidazolyl, 1 H -pyrazolyl, 1 H -pyrrolyl, furanyl, tier 5-membered monocyclic rings such as nil, 1 H -pentazole; 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, 4 H -1,3,5-oxathiazinyl, 1,4,2-oxa Thiazinyl, 1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl, 4 H -1,3,2-dioxazinyl, 4 H -1 , 3,5-dioxa possess, 1,4,2- dioxa possess, 2 H -1,5,2- dioxa possess, l, 2,3-di-thiazinyl, 2,4-di-thiazol possess, 4 H -1,3,2- di-thiazinyl, 4 H -1,3,5- di thiazinyl, 1,4,2- de-thiazinyl, 2 H -1,5,2- di possess thiazole , 2H -1,2,3-oxadiazinyl, 2H -1,2,4-oxadiazinyl, 2H- 1,2,5-oxadiazinyl, 2H- 1,2,6-oxa Dia possess, 2 H -1,3,4- oxadiazol possess, 2 H -1,3,5- oxadiazol possess, 2 H -1,2,3- thiadiazol possess, 2 H -1,2,4 - thiadiazol possess, 2 H -1,2,5- thiadiazol possess, 2 H -1,2,6- thiadiazol possess, 2 H -1,3,4- thiadiazol possess, 2 H -1,3 , 5-thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2 H -1,2-oxazinyl, 2 H -1,3 Oxazinyl, 2H- 1,4-oxazinyl, 2H -1,2-thiazinyl, 6-membered monocylics such as 2H -1,3-thiazinyl, 2H- 1,4-thiazinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, 2H -pyranyl, 2H -thiynyl Click ring; And 3 H -1,2,3-benzoxathiazolyl, 1,3,2-benzodioxazolyl, 3 H -1,2,3-benzodithiazolyl, 1,3,2-benzodithiazolyl , Benzfurazanyl, 1,2,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, 1 H -benzotriazolyl 1,2-benzisoxane Zolyl, 2,1-benzisoxazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, 1 H -benzimidazolyl, 1 H -indazolyl, H 3 -1,2- benzoxazol Sati raise, l, 1,3-sati raise, 3 H -2,1- benzoxazol Sati raise, 3 H -1,2- dioxide solril benzo, 1,3-benzo-dioxide solril, 3 H -1,2-benzodithiolyl, 1,3-benzodithiolyl, 1 H -indolyl, 2H -isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl, 2-benzothier Neyl, 1 H- 2,1-benzoxazinyl, 1 H -2,3-benzoxazinyl, 2 H -1,2-benzoxazinyl, 2 H -1,3-benzoxazinyl, 2 H- 1 , 4-benzoxazinyl, 2 H -3,1- benzoxazinyl, 1 H -2,1- benzo thiazinyl, 1 H -2,3- benzo thiazinyl, 2 H -1,2- Ben Thiazinyl, 2 H -1,3- benzo thiazinyl, 2 H -1,4- benzo thiazinyl, 2 H -3,1- benzothiazol possess sour fun carbonyl, possess phthalazine, quinazolinyl, salicylate quinoxaline carbonyl, isoquinolinyl nolil, quinolyl nolil, 1 H -2- benzopyranyl, 2 H -1- benzopyranyl, 1 H -2- benzo thio pyranyl or bicyclic, such as 2 H -1- benzo thio pyranyl Say the ring .

Acid addition salts of the compounds of the present invention are pharmaceutically acceptable salts formed with non-toxic acids. Examples of such organic salts are maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid , Cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and theophylline acetic acid, and 8-halophylline, for example 8-bro Organic salt with moteophylline. Examples of such inorganic salts are inorganic salts with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.

The pharmaceutical compositions of the invention, or pharmaceutical compositions prepared according to the invention, are administered orally by any suitable route, for example in the form of tablets, capsules, powders, syrups, or the like, or in the form of injections. Parenteral administration. For the preparation of such compositions, methods well known in the art can be used, and any pharmaceutically acceptable carrier, diluent, excipient or other additive commonly used in the art can be used.

Conveniently, the compound of the present invention is administered in unit dosage form containing the compound 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, most preferably about 0.1-50 mg of the active compound of the present invention.

Compounds of the present invention can be prepared as follows, and compounds of formula I are also isolated as their free base or pharmaceutically acceptable acid addition salts:

1) alkylation of piperazine, piperidine or tetrahydropyridine of formula III with an alkylated derivative of formula II:

Wherein R ¹ to R ⁹ and Q are as defined above and L is a leaving group such as halogen, mesylate or tosylate;

2) reductive alkylation of an amine of formula III with a reagent of formula IV:

Wherein R ¹ to R ⁹ and Q are as defined above and E is an aldehyde or activated carboxylic acid;

3) by the use of carboxylic acids and coupling agents, activated esters, acid chlorides, isocyanates, carbamoyl chlorides or by a two-step procedure of the addition of amines after treatment with phosgene, Acylation Stages:

Wherein R ¹ to R ⁹ and Q are as defined above.

The alkylation according to method 1) is conveniently carried out at reflux temperature, preferably in an organic solvent such as a boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine). Alternatively, the alkylation is carried out in one of the solvents described above or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one (NMP), preferably In the presence, it can be carried out at a fixed temperature different from the boiling point. Alkylating agents of Formula (II) can be prepared by methods analogous to those described in the examples, or described by Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme- Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. By applying the methods described in standard papers such as New York, that is, known and can be synthesized under reaction conditions appropriate for the reaction. Amines of formula III are either commercially available or described in the literature, such as in Marxer et al . J. Org. Chem. 197 5, 4 0, 1427, by Parham et al . J. Org. Chem. 197 6, 4 1, 2628 and Bauer et al . J. Med. Chem. 197 6, 1 9, 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. 199 6, 3 7, 5233-5234 and Slade, PD et al . J. Med. Chem. 199 8, 4 1, 1218-1235, or by methods similar to those described in Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. By methods described in standard papers such as New York, ie known and can be synthesized under reaction conditions appropriate for the reaction.

Reductive alkylation according to method 2) is carried out by standard literature methods or by Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. As described in standard papers such as New York, that is known and carried out under reaction conditions appropriate for the reaction. The reaction is carried out in two steps, for example by standard methods via carboxylic acid chloride which is an activated ester, or by using a carboxylic acid in combination with a coupling reagent such as dicyclohexyl carbodiimide, After coupling the amine with the reagent of formula IV, the resulting amide can be carried out by reduction with lithium aluminum hydride or alan. Carboxylic acids of formula IV are commercially available or described in, for example, 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).

Acylation according to method 3) is conveniently carried out by standard methods via carboxylic acid chloride which is an activated ester or by using a carboxylic acid in combination with a coupling reagent such as dicyclohexyl carbodiimide. . When the acylation reagent is carbamoyl chloride or isocyanate, acylation produces urea derivatives. Urea derivatives can also be prepared by a two-step procedure consisting of the addition of an amine after phosgene treatment.

Intermediate compounds of formula V are prepared as described in methods 1) and 2) wherein R ² to R ⁹ , Q, L and E are as defined above and R ¹ is a protecting group. It may be selected from protecting groups commonly used for the protection of. Those skilled in the art will know how to select appropriate protecting groups and how to protect and deprotect amines by such protecting groups.

Experiment Division

Melting points were measured on a Buechi SMP-20 apparatus and were not calibrated. Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with an IonSpray source and a Shimadzu LC-8A / SLC-10A LC system. LC conditions (4.6 × 30 mm C18 column with particle size of 3.5 μm), in water / acetonitrile / trifluoroacetic acid (90: 10: 0.05) / water / acetonitrile / in 4 minutes at 2 ml / min. Linear gradient elution to trifluoroacetic acid (10: 90: 0.03). Purity was measured by integration of UV traces (254 nm). Retention time R _t is expressed in minutes.

Mass spectra were obtained by another scanning method for obtaining molecular weight information. Molecular ions MH + were obtained at low inlet voltage (5-20V) and collapsed at high inlet voltage (100-200V).

Preparative LC-MS-separation was performed on the same equipment. LC conditions (C18 column 20 × 50 mm with a particle size of 5 μm), in water / acetonitrile / trifluoroacetic acid (80: 20: 0.05) in water / acetonitrile / in 7 minutes at 22.7 ml / min. Linear gradient elution to trifluoroacetic acid (5: 95: 0.03). Fraction collection was performed by split-flow MS detection.

¹ H NMR spectra were recorded at 500.13 MHz on Bruker Avance DRX500 instrument or at 250.13 MHz on Bruker AC 250 instrument. Deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) was used as the solvent. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for the diversity of the NMR signal: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = helix, dd = doublet, dt = double Triplet, dq = double quartet, tt = triplet of triplets, m = multiplet. NMR signals corresponding to acidic protons are generally omitted. For column chromatography silica gel of Kieselgel 60 type, 230-400 mesh ASTM was used. Ion Exchange Chromatography (SCX, 1 g, Varian Mega Bond Elut , Chrompack cat. No. 220776) was used. Pre-conditioning with 10% solution of acetic acid in methanol (3 mL) before use of SCX-column.

Intermediate manufacturing

Alkylating Reagent of Formula II

1. (RS) -1- (2-Bromo-ethyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert-butyl ester

Tetrahydroisoquinoline acid (10 g) was suspended in tetrahydrofuran THF (100 mL). Triethyl amine (9.1 mL) and di-tert-butyl dicarbonate (14.3 g) were added and the mixture was stirred at rt for 16 h. The mixture was concentrated in vacuo, redissolved in ethyl acetate (250 mL), 0.5 M KHSO₄Washed twice with aqueous solution (200 mL), dried over magnesium sulphate, evaporated under vacuum, 1-carboxymethyl-3,4-dihydro-1H-isoquinoline-2-car as a clear oil which crystallized upon standing. Acid tert-butyl ester was obtained in quantitative yield. 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 for 15 minutes. The mixture was warmed to rt and stirred for 1 h. 50 mL of water / tetrahydrofuran 1: 1 mixture was added slowly to carefully remove excess borane. Saturated potassium carbonate was added to make the mixture alkaline with pH = 12 and extracted with diethyl ether (2 x 50 mL). The combined organic phases were dried (magnesium sulphate) and evaporated under vacuum to give 1- (2-hydroxy-ethyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester was obtained as a clear oil (8.4 g). Protected aminoalcohol was dissolved in dry tetrahydrofuran (150 mL) with triethylamine (5.6 mL) and cooled to 0 ° C. under nitrogen. Metanosulfonyl chloride (2.64 mL) in dry THF (30 mL) was added dropwise for 15 minutes, the mixture was warmed to room temperature and stirred for 30 minutes. After filtration and vacuum concentration, 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 hour. The mixture was filtered, evaporated under vacuum, the product was purified by column chromatography on silica gel using ethyl acetate / heptane (1: 1) as eluent, the fractions containing the product were collected and evaporated under vacuum to crystallize upon standing. (RS) -1- (2-Bromo-ethyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert-butyl ester was provided as a clear oil (8 g).

The following compounds were prepared in a similar manner:

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

Piperidine of Formula III

Piperidine derivatives of formula III, wherein X is oxygen and Z is CR⁹R¹⁰Y is a bond and A^One, A²And A⁴Is CH and A³CR¹¹Spiro [isobenzofuran-1 (3H), 4′-piperidine] to Marxer et al.J. Org. Chem. 1975, 40, 1427, Parham et al.J. Org. Chem. 1976, 41, 2628 and Bauer et al.J. Med. Chem. 1976, 19, 1315].

The following compounds were prepared in a similar manner:

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],

5-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].

Piperidine derivatives of formula III wherein X is CR ⁹ R ¹⁰ , Z is NR ⁸ , Y is a bond, A ¹ , A ² and A ⁴ are CH, A ³ is CR ¹¹ , R ¹¹ is fluoro or trifluoromethyl) [Maligres et al. Tetrahedron 1997, 53, 10983] and Cheng et al . Tet. Lett. 1997, 38, 1497.

The following compounds were prepared in a similar manner:

1-acetyl-5-fluoro-spiro [2,3-dihydro-1H-indole-3,4'-piperidine].

Piperidine derivatives of formula III, wherein X is CR⁹R¹⁰, Z is oxygen, Y is a bond, A^One, A²And A⁴Is CH and A³CR¹¹Ie 2,3-dihydro-spiro (benzofuran-3,4'-piperidine) [Chen, Meng-Hsin; Abraham, John A.Tetrahedron Lett. 1996, 37, 5233-5234 and Slade, P.D. EtcJ. Med. Chem. 1998, 41, 1218-1235.

The following compounds were prepared in a similar manner:

2,3-dihydro-5-fluorospiro [benzofuran-3,4'-piperidine] and

2,3-dihydro-5,6-difluorospiro [benzofuran-3,4'-piperidine].

A similar method as described above was applied to appropriately substituted starting compounds to introduce substituents R ⁸ -R ¹¹ .

Amine of Formula V

An amine of Formula V was prepared by the following method:

Amine of formula III in acetonitrile (20 mL) (1 mmol), (RS) -1- (2-bromo-ethyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert A mixture of -butyl ester (1.3 mmol) and potassium carbonate (1.3 mmol) for 6 hours 85 ℃ Heated to. The mixture was cooled to rt and evaporated in vacuo to give a yellow oily residue. The product was redissolved in dichloromethane (10 mL), anisol (0.26 mL) and trifluoroacetic acid (10 mL) were added and the mixture was stirred at rt for 90 min. The mixture was evaporated in vacuo. The product was purified by chromatography or used directly in the next step without purification.

The following compounds were purified by chromatography before use later:

(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'-piperidin-1'-yl] -ethyl} -1,2,3,4-tetra Hydroisoquinoline.

Enantiomeric Form of the Amine of Formula (V)

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

Racemic N- {4- (3-fluoro-phenyl) -1- [2- (1,2,3,4-tetrahydro-isoquinolin-1-yl) -ethyl] -piperidine-4- The acetamide was subjected to chiral HPLC using a Gilson SF3 supercritical fluid chromatography system equipped with a chiralcel OD column (4.6 mm x 25 cm for analysis and 10 mm x 25 cm for preparative operation). Analyzed. The particle size in the column was 10 μm. Racemic compound N- {4- (3-fluoro-phenyl) -1- [2- (1,2,3,4-tetrahydro-isoquinolin-1-yl) -ethyl] in methanol (1 mL) Piperidin-4-yl} acetamide (1 g) solution was injected in aliquot into 40 μl on a preparative column. The column was eluted with carbon dioxide-modifier (75:25). The modifier was 2-propanol with diethylamine (0.5%) and trifluoroacetic acid (0.5%). The flow rate was 18.9 mL / min at 20 Mpa. Fractionation started with UV-detection (210 nM). Fractions containing the isolated product were combined and evaporated under vacuum to give the enantiomers. The first eluted enantiomer was N- {4- (3-fluoro-phenyl) -1- [2- (1,2,3,4-tetrahydro-isoquinolin-1-yl) -ethyl] -piperi Dien-4-yl} acetamide is called enantiomer 1, and the second eluted enantiomer is called enantiomer 2 of the compound. Enantiomers were measured by HPLC to give excess of enantiomers greater than 95%.

The following enantiomers were prepared in a similar manner:

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

Preparation of Compounds of the Invention

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

Method A: Alkylation of piperidine of Formula III with an alkylated derivative of Formula II:

Piperidine of formula III (1 mmol), (RS) -1- (2-bromo-ethyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid in acetonitrile (20 mL) A mixture of tert-butyl ester (1.3 mmol) and potassium carbonate (1.3 mmol) was heated to 85 ° C. for 6 hours. The mixture was cooled to rt and evaporated under vacuum. The product was purified by chromatography on silica gel using ethyl acetate / triethylamine (99: 1) as eluent or by HPLC. Fractions containing product were combined and evaporated under vacuum.

Method B: Acylation of amines of formula V by the use of carboxylic acids and coupling reagents, activated esters, acid chlorides or isocyanates:

The amine of formula V (prepared as described above; 1 mmol) and triethylamine (5 mmol) were dissolved in anhydrous acetonitrile (10 mL). Properly substituted acid chloride (5 mmol) was added and the reaction mixture was stirred at rt for 30 min. Methanol (0.5 mL) was added to the reaction mixture and then evaporated under vacuum. The product was purified by chromatography on silica gel using ethyl acetate / triethylamine (99: 1) as eluent or by HPLC. Fractions containing product were combined and evaporated under vacuum and characterized by HPLC-UV-ELSD-MS. The measured HPLC-retention time, measured molecular weight, and UV- and ELSD-purity are shown in Table 1.

The following compounds were prepared by the method shown in Table 1. Analytical data is shown in Table 1.

compound

1.1- (1- {2- [4- (5-Fluoro - 1H - indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 1H - iso Quinolin-2-yl) -1- (4-fluoro-phenyl) methanone

2. 1-cyclopentyl-1- (1- {2- [4- (5-fluoro - 1H - indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-di Hydro - 1H - isoquinolin-2-yl) methanone

3. 1- {2- [4- (5-fluoro-1H-Indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-Isoquinoline-2-carboxylic acid phenethyl-amide

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

5. 1- (1- {2- [4- (5-Fluoro - 1H - indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 1H - iso Quinolin-2-yl) -1- (2-fluoro-phenyl) methanone

6. 1- (1- {2- [4- (5-Fluoro - 1H - indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 1H - iso Quinolin-2-yl) -3-phenyl-propan-1-one

7. 1- {2- [4- (5-Fluoro - 1H - indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 1H - 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-1H-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 - 1H - 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 -1H-isoquinolin-2-yl) -2,2-dimethyl-propan-1-one

12. 1-Cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro - 1H - isoquinolin-2-yl) methanone

13. 1- [2- (4-Chloro-phenoxy) -pyridin-3-yl] -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'- Piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

14. 1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinoline 2-carboxylic acid tert-butyl ester

15. 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) -1-phenyl-methanone

16. 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) -1-p- tolyl-methanone

17. 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) -1- (2-methoxy-phenyl) -methanone

18. 1-Cycloheptyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-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'-piperidin-1'-yl]- Ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

20. 1- (2-Chloro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro - 1H-isoquinolin-2-yl) methanone

21. 1- (4-Fluoro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl]- Ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

22. 1- (4-Chloro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

23. 1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinoline 2-carboxylic acid phenethyl amide

24. 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) -1- (4-methoxy-phenyl) -methanone

25. 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-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'-piperidin-1'-yl] -ethyl} -3,4- Dihydro - 1H - isoquinolin-2-yl) -butan-1-one

27. 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-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'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) -2-phenyl-heptanone

29. 3-cyclohexyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro - 1H - isoquinolin-2-yl) -propan-1-one

30. 2- (4-Fluoro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl]- Ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) ethanone

31. 1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinoline 2-carboxylic acid (3,4-dichloro-phenyl) amide

32. 1-Cyclopropyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro - 1H - isoquinolin-2-yl) methanone

33. 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-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-yl] -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

35. 2- (4-Chloro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro - 1H - isoquinolin-2-yl) ethanone

36. 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) -2-methyl-propan-1-one

37. 1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-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 - 1H - isoquinolin-2-yl) methanone

40. 1-cycloheptyl-1- {1- [1-acetyl-spiro [2,3-dihydro - 1H - indol-3,4'-piperidin-1'-yl] ethyl] -3,4 -Dihydro - 1H - isoquinolin-2-yl} methanone

41.N- (1- {2- [2- (1-cycloheptyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenylpiperi Din-4-yl) acetamide

42. 1-Cycloheptyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-6,7-dimethoxy - 1H - 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 - 1H - isoquinolin-2-yl) methanone

44. 1-Cycloheptyl-1- (1- {2- [5-fluoro-1-methanesulfonyl-spiro [2,3-dihydro - 1H - indole-3,4'-piperidine-1 '-Yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

45. 1- (1- {2- [2- (1-cycloheptyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-pi Ferridin-4-yl) -1-piperidin-1-ylmethanone

46. 1- (4-Fluorophenyl) -1- (1- {2- [5-fluoro-1-methanesulfonyl-spiro [2,3-dihydro - 1H - indole-3,4'- Piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

47. 1-Cycloheptyl-1- (1- {2- [4- (2-methyl - 1H - 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-l-yl] -ethyl} -3,4-dihydro-1H- Isoquinolin-2-yl) methanone

49. 1-cyclopentyl-1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

50. 1-cyclopentyl-1- {1- [spiro [2,3-dihydro-1H-indole-3,4'-piperidin-1'-yl] ethyl] -3,4-dihydro- 1H - isoquinolin-2-yl} methanone

51. 1-Cyclopentyl-1- (1- {2- [5-fluoro-1-methanesulfonyl-spiro [2,3-dihydro - 1H - indole-3,4'-piperidine-1 '-Yl] -ethyl} -3,4-dihydro - 1H - 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 - 1H - isoquinolin-2-yl) methanone

53. 1- (2-Fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

54. 1-cycloheptyl-1- (1- {2- [spiro [iso-benzofuran -1 (3H), 4'- piperidin-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'-piperidin-1'-yl] -ethyl} -3,4-dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

56. 1- (1- {2- [4- (4-Chloro-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H-isoquinolin-2-yl)- 1-cycloheptylmethanone

57. 1-Cyclopentyl-1- (1- {2- [5-isopropylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro - 1H - 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-1H-isoquinolin-2-yl} methanone

60. 1-Cycloheptyl-1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro - 1H - isoquinolin-2-yl) methanone

61. 1-Cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) piperidin-1-yl] -ethyl} -3,4-dihydro-1H-isoquinoline- 2-yl) methanone

62. 1-Cyclopentyl-1- (1- {2- [6-fluorophospho [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

63. 1- (4-Fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

64. 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

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-isoquinoline 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'-piperidin-1'-yl] -ethyl} -3 , 4-dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

69. 1- [1- (2- {2- [1- (2-Fluoro-phenyl) -methanoyl] -1,2,3,4-tetrahydro-isoquinolin-1-yl} -ethyl) -4-phenyl-piperidin-4-yl] -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-pi Ferridin-4-yl) -ethanone

72. 1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3 , 4-dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

73. 1-Cyclopentyl-1- (1- {2- [4- (2-methyl-1H-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-pi Ferridin-4-yl) ethanone

75. 1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -Ethyl} -3,4-dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

76. 1- (1- {2- [4- (4-Chloro-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-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} -piperidine-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-1H-isoquinolin-2-yl)- 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- [pyro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3, 4-dihydro - 1H - isoquinolin-2-yl) methanone

82. 1-Cyclopentyl-1- (1- {2- [4-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro - 1H - 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 - 1H - 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 - 1H - indol-3,4'-piperidin-1'-yl] ethyl] -3, 4-dihydro - 1H-isoquinolin-2-yl} methanone

86. 1-Cycloheptyl-1- (1- {2- [5-fluoro-1-methanesulfonyl-spiro [2,3-dihydro - 1H - indole-3,4'-piperidine-1 '-Yl] -ethyl} -3,4-dihydro-6,7-dimethoxy - 1H - 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 - 1H - isoquinolin-2-yl} -1-cycloheptylmethanone

89. 1- (2-Fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -Ethyl} -3,4-dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

90. 1- (1- {2-[(Chloro-trifluoromethyl-phenyl) -hydroxy-piperidin-1-yl] -ethyl} -6,7-dimethoxy-3,4-dihydro -1H-isoquinolin-2-yl) -1-cycloheptylmethanone

91. 1- (1- {2- [4- (4-Chloro-phenyl) -4-hydroxy-piperidin-1-yl] -ethyl} -6,7-dimethoxy-3,4-di Hydro-1H-isoquinolin-2-yl) -1-cycloheptylmethanone

92. 1-Cycloheptyl-1- (1- {2- [4- (2-isopropoxy-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-iso Quinolin-2-yl) methanone

93. 1- (1- {2- [4- (7-Chloro - 1H - indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 1H - isoquinoline 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 - isoquinoline- 2-yl} methanone

98. 1- (1- {2- [4- (6-Chloro - 1H - indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 1H - isoquinoline -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-di Hydro-1H-isoquinolin-2-yl) methanone

100. 1-Cycloheptyl-1- {1- [spiro [2,3-dihydro - 1H - indol-3,4'-piperidin-1'-yl] ethyl] -3,4-dihydro- 6,7-dimethoxy - 1H - isoquinolin-2-yl} methanone

101. N- (1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-pi Ferridin-4-yl) acetamide

102. 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

103. 1-cycloheptyl-1- (1- {2- [spiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 6,7-dimethoxy - 1H - 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 - isoquinoline 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-yl} -ethyl) -4-phenyl-piperidin-4-yl] ethanone

109. 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

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'-piperidin-1'-yl] -ethyl } -3,4-dihydro-6,7-dimethoxy - 1H - isoquinolin-2-yl) methanone

112. 1- (4-fluoro-phenyl) -1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl ] -Ethyl} -3,4-dihydro-1H-isoquinolin-2-yl) -methanone

113. 1- (4-Fluorophenyl) -1-({2- [6-fluorophospho [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3 , 4-dihydro-1H-isoquinolin-2-yl) methanone

114. 3,3-Dimethyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl] -butan-1-one

115. Cyclohexyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H -Isoquinolin-2-yl] -methanone

116. Cyclohexyl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl) -methanone

117. Cyclohexyl- [1- {2- [spiro (benzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H-isoquinoline- 2-day] -methanone

118. Cyclohexyl- (1- {2- [4- (2-methyl-1H-indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-iso Quinolin-2-yl) -Methanone

119. N- {1- [2- (2-cyclohexanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl) -ethyl] -4-phenyl-piperidine-4- Il} -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-isoquinoline-2 -Work) -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-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro- 1H-isoquinolin-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-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro -1H-isoquinolin-2-yl] -ethan-1-one

126. Benzo [1,2,5] oxadiazol-5-yl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-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-1H-isoquinolin-2-yl ) -Methanone

128. 2-propyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl] -pentan-1-one

129. 2,2-Dimethyl-3-chlor- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3 , 4-dihydro-1H-isoquinolin-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'-piperidin-1'-yl)-] ethyl} -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-1 H -isoquinolin-2-yl) -methanone

133. 2-ethyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-iso Quinolin-2-yl) -butan-1-one

134. 2-benzyloxy- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl) -ethan-1-one

135. Benzo [1,2,5] oxadiazol-5-yl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl) -] Ethyl} -3,4-dihydro-1H-isoquinolin-2-yl] -methanone

136. (1- {2- [4- (4-Chloro-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H-isoquinolin-2-yl) -cyclohexyl -Metanon

137. 1- (1- {2- [4- (4-Chloro-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H-isoquinolin-2-yl)- 3,3-dimethyl-butan-1-one

138. 3,5,5-Trimethyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4 -Dihydro-1H-isoquinolin-2-yl] -hexan-1-one

139. 3,5,5-trimethyl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3, 4-dihydro-1H-isoquinolin-2-yl) -hexan-1-one

140. 2-phenoxy- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl) -ethan-1-one

141. (1- {2- [4- (4-Chloro-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H-isoquinolin-2-yl)-(2 , 2-dichloro-cyclopropyl) -methanone

142. 2-benzyloxy- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro -1H-isoquinolin-2-yl] -ethan-1-one

143. 1- (1- {2- [4- (4-chloro-3-trifluoromethyl-phenyl) -4-hydroxy-piperidin-1-yl] -ethyl} -6,7-dimeth Methoxy-3,4-dihydro-1H-isoquinolin-2-yl) -3,3-dimethyl-butan-1-one

144. 1- (1- {2- [4- (2,3-Dihydro-benzofuran-7-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H- Isoquinolin-2-yl) -3,3-dimethyl-butan-1-one

145. 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

146. 2,2-Dimethyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl] -propan-1-one

147. 3-cyclohexyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H- Isoquinolin-2-yl) -propan-1-one

148. Furan-2-yl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl] -methanone

149. N- (4-phenyl-1- {2- [2- (3,5,5-trimethyl-hexanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl } -Piperidin-4-yl) -acetamide

150. Quinoxalin-2-yl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4- Dihydro-1H-isoquinolin-2-yl] -methanone

151. 3-cyclohexyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro -1H-isoquinolin-2-yl] -propan-1-one

152. 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

153. 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

154. (Tetrahydro-pyran-4-yl)-(1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl) -methanone

155. 2-propyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-iso Quinolin-2-yl) -pentan-1-one

156. 2-Ethyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl] -butan-1-one

157. 3-Phenyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-iso Quinolin-2-yl) -propan-1-one

158. 3,3-Dimethyl-1- (1- {2- [4- (2-methyl-1H-indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl) -butan-1-one

159. (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

160. 1,2,3,4-tetrahydro-naphthalen-2-yl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidine-1'- Yl)-] ethyl} -3,4-dihydro-1H-isoquinolin-2-yl) -methanone

161. (4-Methylsulfanyl-phenyl)-(1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro -1H-isoquinolin-2-yl) -methanone

162. 3,5,5-Trimethyl-1- (1- {2- [4- (2-methyl-1H-indol-3-yl) -piperidin-1-yl] -ethyl} -3,4 -Dihydro-1H-isoquinolin-2-yl) -hexan-1-one

163. 3-phenyl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro -1H-isoquinolin-2-yl) -propan-1-one

164. Furan-2-yl- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-iso Quinolin-2-yl) -Methanone

165. 2-benzyloxy-1- (1- {2- [4- (2-methyl-1H-indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro -1H-isoquinolin-2-yl) -ethanone

166. 1- (1- {2- [4- (4-Chloro-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H-isoquinolin-2-yl)- 2-phenoxy-ethanone

167. Quinoxalin-2-yl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4 -Dihydro-1H-isoquinolin-2-yl) -methanone

168. 2,2-Dimethyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H -Isoquinolin-2-yl) -propan-1-one

169. (2,2-Dichloro-cyclopropyl)-(1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl) -methanone

170. 4-methylsulfanyl-phenyl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3, 4-dihydro-1H-isoquinolin-2-yl) -methanone

171. (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

172. 1- (1- {2- [4- (4-isopropyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-isoquinolin-2-yl) -3,5,5-trimethyl-hexan-1-one

173. 2,2-Dichloro-cyclopropyl- (1- {2- [spiro (isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl) -methanone

174.N- (4-phenyl-1- {2- [2- (1,2,3,4-tetrahydro-naphthalene-2-carbonyl) -1,2,3,4-tetrahydro-isoquinoline -1-yl] -ethyl} -piperidin-4-yl) -acetamide

175. 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

176. N- (1- {2- [2- (3,3-dimethyl-butyryl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl- Piperidin-4-yl) -acetamide

177. 3-Chloro-2,2-dimethyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4- Dihydro-1H-isoquinolin-2-yl) -propan-1-one

178. Tetrahydro-pyran-4-yl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3, 4-dihydro-1H-isoquinolin-2-yl] -butan-1-one

The following compounds were prepared as enantiomers by Method B starting from enantiomer 2 of the corresponding amine of formula V. Analytical data is presented in Table 1.

compound

179. N- (4- (3-fluoro-phenyl) -1- {2- [2- (2-methoxy-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl ] -Ethyl} -piperidin-4-yl) acetamide (enantiomer)

180. N- (4- (3-fluoro-phenyl) -1- {2- [2- (2-methoxy-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl ] -Ethyl} -piperidin-4-yl) acetamide (enantiomer)

181. 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)

182. N- [1- {2- [2- (4-bromo-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Rho-phenyl) -piperidin-4-yl] -acetamide (enantiomer)

183. N- [1- {2- [2- (4-Fluoro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Rho-phenyl) -piperidin-4-yl] -acetamide (enantiomer)

184.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)

185. 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)

186.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)

187.N- [1- {2- [2- (2-bromo-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Rho-phenyl) -piperidin-4-yl] -acetamide (enantiomer)

188. N- (1- {2- [2- (4-Bromo-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperi Din-4-yl) acetamide (enantiomer)

189. N- (1- {2- [2- (2,4-Dichloro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-pi Ferridin-4-yl) acetamide (enantiomer)

190. 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)

191.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)

192.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)

193. N- [1- [2- (2-cyclopentanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl) -ethyl] -4- (3-fluoro-phenyl) -Piperidin-4-yl] -acetamide (enantiomer)

194. N- (1- {2- [2- (4-Chloro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine -4-yl) acetamide (enantiomer)

195. 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)

196.N- [1- {2- [2- (6-Fluoro-4H-benzo [1,3] dioxine-8-carbonyl) -1,2,3,4-tetrahydro-isoquinoline- 1-yl] -ethyl} -4- (3-fluoro-phenyl) -piperidin-4-yl] acetamide (enantiomer)

197. N- [1- {2- [2- (3-Bromo-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Rho-phenyl) -piperidin-4-yl] acetamide (enantiomer)

198. N- [1- {2- [2- (2-Fluoro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Rho-phenyl) -piperidin-4-yl] acetamide (enantiomer)

199. N- (1- {2- [2- (4-methyl-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine -4-yl) acetamide (enantiomer)

200. 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)

201.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)

202. N- (1- {2- [2- (3-chloro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine -4-yl) acetamide (enantiomer)

203. N- (1- {2- [2- (4-Fluoro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperi Din-4-yl) acetamide (enantiomer)

204. N- {1- [2- (2-cycloheptancarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl) -ethyl] -4-phenyl-piperidine-4- Il} -acetamide (enantiomer)

205. N- (1- {2- [2- (3-bromo-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperi Din-4-yl) acetamide (enantiomer)

206. 2-N- (4- (3-fluoro-phenyl) -1- {2- [2- (3-methoxy-benzoyl) -1,2,3,4-tetrahydro-isoquinoline-1 -Yl] -ethyl} -piperidin-4-yl) acetamide (enantiomer)

207.N- (4- (3-fluoro-phenyl) -1- {2- [2- (thiophen-3-carbonyl) -1,2,3,4-tetrahydro-isoquinoline-1- Yl] -ethyl} -piperidin-4-yl) acetamide (enantiomer)

208.N- (4- (3-fluoro-phenyl) -1- {2- [2- (4-pyrazol-1-yl-benzoyl) -1,2,3,4-tetrahydro-isoquinoline -1-yl] -ethyl} -piperidin-4-yl) acetamide (enantiomer)

209. N- (1- {2- [2- (naphthalene-1-carbonyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperi Din-4-yl) acetamide (enantiomer)

Pharmacological examination

The compounds of the present invention were tested by well known and reliable test methods. The test was as follows:

Of human NK2 receptors ¹²⁵ Inhibition of I-NKA Binding

Compounds of the present invention have been shown to strongly inhibit the binding of ¹²⁵ I-NKA to human NK2 receptors.

In this way, inhibition of ¹²⁵ I-NKA binding by the drug to the membrane of human cloned NK2 receptor expressed in CHO-cells is determined in vitro.

In summary, the affinity of the compounds was determined by their ability to repel ¹²⁵ I-NKA by incubating CHO membranes expressing hNK2 with compounds and radioligands for 60 minutes at room temperature. Incubation was terminated by rapid filtration through GF / C filters, and the filters were counted on the Wallac Trilux Scintillation Counter. Compound No. exemplified above. IC50 values for 1-209 were determined to be 200 nM or less. For most compounds, IC 50 values were 50 nM or less, and for large groups of compounds, IC 50 values were 10 nM or less.

Formulation example

Pharmaceutical formulations of the invention can be prepared by conventional methods in the art.

For example: tablets may be prepared by mixing conventional adjuvants and / or diluents with the active ingredient and then compressing the mixture in a conventional tablet making machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, rubber, and the like. Any other auxiliaries or additives commonly used for this purpose, such as colorants, flavors, preservatives, etc., may also be used as long as they are compatible with the active ingredient.

Injection solutions can be prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably in sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it in a suitable vial or ampule. Any suitable additive commonly used in the art may be added, such as isotonic agents, preservatives, antioxidants and the like.

Typical examples of methods for the formulation of the invention are as follows:

1) Tablets containing 5.0 mg of the compound of the invention calculated as free base:

compound1aor1b 5.0mg

Lactose 60mg

Corn Starch 30mg

Hydroxypropylcellulose 2.4mg

Microcrystalline Cellulose 19.2mg

Croscarmellose Sodium Type A 2.4mg

Magnesium Stearate 0.84mg

2) Tablets containing 0.5 mg of the compound of the invention, calculated as the free base

0.5 mg of compound 1a or 1b

Lactose 46.9mg

Cornstarch 23.5mg

Povidone 1.8mg

Microcrystalline Cellulose 14.4mg

Croscarmellose Sodium Type A 1.8mg

Magnesium Stearate 0.63mg

3) syrup containing per milliliter of:

25 mg of compound 1a or 1b

Sorbitol 500mg

Hydroxypropylcellulose 15mg

Glycerol 50mg

Methyl-paraben 1 mg

Propyl-paraben 0.1mg

Ethanol 0.005mL

Flavoring Agent 0.05mg

Saccharin Sodium 0.5mg

Add up to 1 mL of water

4) Injection solutions containing the following per milliliter:

0.5 mg of compound 1a or 1b

Sorbitol 5.1mg

Acetic acid 0.05mg

Saccharin Sodium 0.5mg

Add up to 1 mL of water

Claims (32)

3,4-dihydro-1H-isoquinolin-2-yl derivative of formula (I) or a pharmaceutically acceptable acid addition salt thereof: [In the meal, R^OneSilver group R¹¹CO-, R¹¹CS-, R¹¹SO₂-, R¹¹OCO-, R¹¹SCO- or R¹¹CO-CR¹²R¹³Or {in the formula, R¹¹Silver c_1-12Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8-Cycloalkyl-C_1-6-Alkyl, aryl, aryl-C_1-6-Alkyl, heteroaryl, heteroaryl-C_1-64H-benzo [1,3] dioxynyl, which may be substituted by alkyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphthalenyl, or halogen (C_1-6Alkyl, aryl, heteroaryl and C_3-8Each cycloalkyl group is independently unsubstituted, halogen, C_1-6Alkyl, C_1-6-Alkoxy, aryl-C_1-6Alkoxy, C_1-6-Substituted with one or more substituents selected from the group comprising alkylsulfanyl, aryl and aryloxy, wherein the aryl and aryloxy are independently unsubstituted or substituted with one or more halogen), R¹²And R¹³Is independently hydrogen or C_1-6-Alkyl}; R^OneSilver group R¹⁴R¹⁵NCO-, R¹⁴R¹⁵NCS-, where R is¹⁴And R¹⁵Is independently hydrogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8-Cycloalkyl-C_1-6-Alkyl, aryl or aryl-C_1-6-Alkyl or (C_1-6Alkyl, aryl and C_3-8Each cycloalkyl group is independently unsubstituted, halogen, C_1-6Alkyl and C_1-6-Substituted with one or more substituents selected from the group comprising alkoxy), R¹⁴And R¹⁵silver Together with the N-atom to which they are attached form a pyrrolidinyl, piperidinyl or perhydroazinylyl group; R ² is selected from hydrogen, trifluoromethyl and C _1-6 -alkyl; R ³ -R ⁶ , R ^7a , R ^7b , R ^8a and R ^8b are hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6- Alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, Independently selected from trifluoromethyl, trifluoromethylsulfonyl and C _1-6 -alkylsulfonyl; m is 2-6; R ⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclic aryl or heteroaryl, wherein benzyl, benzoyl, aryl or heteroaryl are each halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, C _{1- 6} -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) Substitution with one or more substituents selected from aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl Can be}; Q is C, N or CR ¹⁰ ; Wherein R ¹⁰ is hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _{3- 8} -cycloalkyl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6 -alkylcarbonyl, aminocarbonyl, C _{1- 6} -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluorine Rhomethyl, trifluoromethylsulfonyl, the group -NR ³⁰ COR ^{31 wherein} R ³⁰ is hydrogen or C _1-6 -alkyl and R ³¹ is C _1-6 -alkyl, the group -COOR ¹⁶ ( Wherein R ¹⁶ is hydrogen or C _1-6 -alkyl, or a group -CONR ¹⁷ R ¹⁸ (wherein R ¹⁷ and R ¹⁸ are independently selected from hydrogen and C _1-6 -alkyl, or R ¹⁷ and R ¹⁸ can form a piperidinyl, piperazinyl or morpholinyl, together with the nitrogen to which they are attached (the piperidinyl, piperazinyl and morpholinyl is Ring unsubstituted or C _1-6 - from substituted by alkyl)) selected}; Or R ⁹ and R ¹⁰ together with the carbon to which they are attached form a cyclic structure selected from the group comprising: Wherein Q 'is carbon shared with the piperidine ring such that the cyclic structure forms a spiro structure with the piperidine ring; X, Y, and Z are O; NR ¹⁹ ; CR ²³ R ²⁴ ; Independently selected from S (O) _n and a bond (R ¹⁹ is hydrogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-Ci_ ₆ -alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R ¹⁹ is a group R ²⁰ SO _2- , R ²⁰ OCO- or R ²⁰ SCO- or (R ²⁰ is C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _{1- 6} -alkyl or aryl, R ¹⁹ is a group R ²¹ R ²² NCO- or R ²¹ R ²² NCS- (R ²¹ and R ²² are independently hydrogen, C _1-6 -alkyl, C _2-6 -al Kenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, or aryl (the aryl is unsubstituted or C _1-6 -alkyl or substituted with one or more substituents selected from halogen); R ²¹ and R ²² are the blood with N- wonjagwa which they are attached pyrrolidinyl, piperidinyl, or tetrahydro-flops ah Jaffe To form a group); R ²³ and R ²⁴ is hydrogen, halogen, cyano, nitro, C _1-6 - alkyl, C _2-6 - alkenyl, C _2-6 - alkynyl, C _3-8 - cycloalkyl, Independently selected from C _3-8 -cycloalkyl-C _1-6 -alkyl, aryl, heteroaryl (the aryl is unsubstituted or C _1-6 -alkyl or halogen, amino, C _1-6 -alkyl Amino, groups NR ²⁵ R ²⁶ (R ²⁵ and R ²⁶ are C _1-6 -alkyl, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1- Independently selected from ₆ -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C _1-6 -alkylsulfonyl Or R ²⁵ and R ²⁶ are substituted with one or more substituents selected from which they form a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group together with the N-atom to which they are attached, R ²³ and R ²⁴ together is oxo; n is 0, 1 or 2; Provided that one or less of X, Y and Z may be a bond provided that two adjacent groups X, Y or Z cannot be selected from O and S at the same time; A ¹ , A ² , A ³ and A ⁴ are independently selected from N and CR ²⁷ (R ²⁷ is hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylamino Carbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, tri Fluoromethylsulfonyl C _1-6 -alkylsulfonyl amino or groups NR ²⁸ R ²⁹ (R ²⁸ and R ²⁹ are independently selected from hydrogen and C _1-6 -alkyl, or R ²⁸ and R ²⁹ are combined Together with the N-atom form a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group); Provided that only one of A ¹ , A ² , A ³ and A ⁴ may be N; The dotted line from Q is a bond when Q is C and not a bond when Q is CR ¹⁰ or N}]. The compound of claim 1, wherein Q is CR ¹⁰ and R ⁹ and R ¹⁰ together with the carbon to which they are attached form the following bicyclic structures: Wherein Q 'is carbon shared with the piperidine ring such that the bicyclic structure together with the piperidine ring forms a spiro structure; X, Y and Z are O; NR ¹⁹ ; Independently selected from CR ²³ R ²⁴ and S (O) _n and a bond and {R ¹⁹ is hydrogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _{3-8 -Cycloalkyl} , C _3-8 -cycloalkyl-C _1-6 -alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R ¹⁹ is a group R ²⁰ SO _2- , R ²⁰ OCO- or R ²⁰ SCO- (R ²⁰ is C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl -C _1-6 -alkyl or aryl) or R ¹⁹ is a group R ²¹ R ²² NCO-, R ²¹ R ²² NCS- (R ²¹ and R ²² are independently hydrogen, C _1-6 -alkyl, C _{2 -6} -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl or aryl (the aryl is unsubstituted or C _{1- 6-substituted} with one or more substituents selected from alkyl or halogen); R ²¹ and R ²² are the blood with the N- atom to which they are attached pyrrolidinyl, piperidinyl, or tetrahydro-flops ah Jaffe To form a group shown below); R ²³ and R ²⁴ are hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _{3-8 -Cycloalkyl} -C _1-6 -alkyl, aryl, heteroaryl (wherein aryl is unsubstituted or C _1-6 -alkyl or halogen, amino, C _1-6 -alkylamino, group NR ²⁵ R ²⁶ (R ²⁵ And R ²⁶ is C _1-6 -alkyl, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _{1 -6} -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl, and C _1-6 -alkylsulfonyl, or R ²⁵ and R ²⁶ are selected from Or substituted with one or more substituents selected from the group consisting of a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group together with the attached N-atom, or R ²³ and R ²⁴ are Together is oxo; n is 0, 1 or 2; Provided that at most one of X, Y and Z may be a bond provided that two adjacent groups X, Y or Z cannot be selected from O and S at the same time; A ¹ , A ² , A ³ and A ⁴ are N and CR ²⁷ {R ²⁷ is hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alky Nyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, groups NR ²⁸ R ²⁹ (R ²⁸ and R ²⁹ are independently from hydrogen and C _1-6 -alkyl. Or R ²⁸ and R ²⁹ together with the N- atom to which they are attached form a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group), C _1-6 -alkylcarbonyl, aminocarbon Carbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, di Fluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C _1-6 -alkylsulfonyl}; Provided that only one of A ¹ , A ² , A ³ and A ⁴ may be N]. The compound of claim 2, wherein X, Y and Z are selected from one of the following combinations: X is oxygen, Y is a bond, and Z is CR ²³ R ²⁴ ; X is CR ²³ R ²⁴ , Y is a bond, and Z is oxygen; X is NR ¹⁹ , Y is a bond, and Z is CR ²³ R ²⁴ ; X is CR ²³ R ²⁴ , Y is a bond, and Z is NR ¹⁹ ; X is CO, Y is a bond, and Z is NR ¹⁹ ; X is SO ₂ , Y is a bond, and Z is NR ¹⁹ ; X is SO, Y is a bond, and Z is NR ¹⁹ ; X is CR ²³ R ²⁴ , Y is a bond, and Z is S; X is CR ²³ R ²⁴ , Y is a bond, and Z is SO; X is CR ²³ R ²⁴ , Y is a bond, and Z is SO ₂ [wherein R ¹⁹ is hydrogen, acetyl or methylsulfonyl, and R ²³ and R ²⁴ are hydrogen, methyl, isobutyl, cyclohexyl and 4- Independently selected from fluorophenyl]. 3. A compound according to claim 2, wherein -XYZ- together form a group selected from: -O-CR ²³ R ^24- , -CR ²³ R ²⁴ -O-, -NR ¹⁹ -CR ²³ R ^24- , -CR ²³ R ²⁴ -NR ^19- , -CO-NR ^19- , -SO ₂ -NR ^19- , -SO-NR ^19- , -CR ²³ R ²⁴ -S-, -CR ²³ R ^24- SO-, -CR ²³ R ²⁴ -SO _2- [wherein R ¹⁹ is hydrogen, acetyl or methylsulfonyl, and R ²³ and R ²⁴ are from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl Independently selected]. 5. The compound of claim 2, wherein A ³ is N or CR ²⁷ [R ²⁷ is halogen, cyano, nitro, a group NR ²⁸ R ²⁹ (R ²⁸ and R ²⁹ are hydrogen and C _1-6- ). Independently selected from alkyl, or R ²⁸ and R ²⁹ together with the N-atom to which they are attached form a pyrrolidinyl, piperidinyl, perhydroazinyl or morpholinyl group), C _1-6 -alkylcar Carbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- (C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, hydroxy, trifluoromethyl, difluoromethyl, Fluoromethyl, trifluoromethylsulfonyl or C _1-6 -alkylsulfonyl. 6. The method of claim ² , wherein A ¹ , A ² , A ³ and A ⁴ are independently selected from CR ²⁷ wherein R ²⁷ is as defined above. 7. compound. The compound of claim 2, wherein said bicyclic structure is selected from the group comprising: [Wherein, R ^{19 '} is acetyl or methylsulfonyl, R ^23' is hydrogen or methyl, R ^{27 '} is hydrogen or fluoro, R ^27'' is hydrogen, fluoro, methyl or isopropyl, R ^{27 '''} is hydrogen, fluoro or trifluoromethyl. The compound of claim 1, wherein R ⁹ and R ¹⁰ together with the carbon to which they are attached form a cyclic structure selected from the group comprising: Wherein Q 'is carbon shared with the piperidine ring such that the cyclic structure forms a spiro structure with the piperidine ring. The compound of claim 1, wherein R ⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl or mono- or bicyclic aryl or heteroaryl [wherein each of benzyl, benzoyl, aryl or heteroaryl is halogen , Cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6- Alkyl, amino, C _1-6 -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- ( From C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl Optionally substituted with one or more substituents selected]. 10. The method of claim 9, R ⁹ is 2,3-dihydro-benzofuran-7-yl, benzyl or benzoyl, or [the benzyl or benzoyl is unsubstituted or substituted, substituted by at least one halogen in the phenyl group], R ⁹ is Mono- or bicyclic aryl or heteroaryl selected from the group comprising phenyl, indolyl, pyridyl, thiophenyl and benzisoxazolyl [each of the aryl or heteroaryl is halogen, cyano, nitro, C _1-6- Alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, amino, C _1-6 -alkylamino , di - (C _1-6 - alkyl) amino, C _1-6 - alkylcarbonyl, aminocarbonyl, C _1-6 - alkylamino-carbonyl, di - (C1 _-6 - alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 - alkylthio, hydroxy, at least one substitution is trifluoromethyl, difluoromethyl, methyl, selected from methyl and trifluoromethyl fluoro methylsulfonyl Compound, characterized in that may be substituted; a. 12. The compound of claim 10, wherein the mono- or bicyclic aryl or heteroaryl is phenyl, indol-3-yl and benzisoxazol-3-yl [the phenyl, indol-3-yl or benzisoxazol-3-yl is halogen , Cyano, nitro, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6- Alkyl, amino, C _1-6 -alkylamino, di- (C _1-6 -alkyl) amino, C _1-6 -alkylcarbonyl, aminocarbonyl, C _1-6 -alkylaminocarbonyl, di- ( From C _1-6 -alkyl) aminocarbonyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl Which may be substituted with one or more substituents selected from. 12. The compound of claim 11, wherein said optional substituent is selected from the group comprising halogen, phenyl and methyl. 13. A compound according to any one of claims 9 to 12, wherein Q is CR ¹⁰ [wherein R ¹⁰ is hydrogen, C _1-6 -alkylcarbonyl, hydroxy, -NR ³⁰ COR ³¹ group (wherein R ³⁰ Is hydrogen or C _1-6 -alkyl and R ³¹ is C _1-6 -alkyl), -COOR ¹⁶ groups (wherein R ¹⁶ is C _1-6 -alkyl), or -CONR ¹⁷ R ¹⁸ group { Wherein R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form piperidinyl, piperazinyl or morpholinyl (the piperidinyl, piperazinyl and morpholinyl are unsubstituted or C _{1- 6} -alkyl substituted). 14. A group according to claim 13, wherein R ¹⁰ is hydrogen, acetyl, hydroxy, a -NR ³⁰ COR ³¹ group, wherein R ³⁰ is hydrogen and R ³¹ is methyl, -COOR ¹⁶ group, wherein R ¹⁶ is ethyl Or -CONR ¹⁷ R ¹⁸ group wherein R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form piperidinyl or 4-methylpiperazinyl. 15. The compound of any of claims 1-14, wherein m is 2, 3 or 4. The compound of claim 15, wherein m is 2. The compound of any one of claims 1-16, wherein R ¹ is a group R ¹¹ CO—, R ¹¹ OCO— wherein R ¹¹ is C _3-6 -alkyl, C _3-8 -cycloalkyl, C _{3 -8} -cycloalkyl-Ci_ ₆ -alkyl, phenyl, phenyl-Ci_ ₆ -alkyl, pyridyl, furanyl, benzo [1,2,5] oxadiazolyl, quinoxalinyl, benzo [b] Thiophenyl or naphthalenyl {The above C _3-6 -alkyl, phenyl, pyridyl and furanyl groups are each independently unsubstituted or halogen, C _1-6 -alkyl, C _1-6 -alkoxy, phenyl and phenoxy Wherein said phenyl and phenoxy are independently substituted or substituted with one halogen) or substituted with one or more substituents selected from the group consisting of; Or R ¹ is a R ¹⁴ R ¹⁵ NCO- group wherein R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl, or aryl-C _1-6 -alkyl (wherein C _1-6- Alkyl and aryl groups are each independently unsubstituted or substituted with one substituent selected from the group comprising halogen and C _1-6 -alkoxy). 18. A compound according to any one of claims 1 to 17, wherein R ² is hydrogen. 19. A compound according to any one of claims 1 to 18, wherein R ³ is hydrogen. 20. The compound of any one of claims 1 to 19, wherein R ⁴ is hydrogen or methoxy. 21. A compound according to any one of claims 1 to 20, wherein R ⁵ is hydrogen or methoxy. 22. A compound according to any one of claims 1 to 21, wherein R ⁶ is hydrogen. 23. The compound of any of claims 1 to 22, wherein R ^7a and R ^7b are hydrogen. The compound of any one of claims 1-23, wherein R ^8a and R ^8b are hydrogen. The compound of claim 1, wherein 1- (1- {2- [4- (5-fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro -1H -isoquinolin-2-yl) -1- (4-fluoro-phenyl) methanone 1-cyclopentyl-1- (1- {2- [4- (-1H- indol-3-yl) 5-fluoro-piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-2-car Acid phenethyl-amide 1- (1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline- 2-yl) -1-phenylmethanone 1- (1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline- 2-yl) -1- (2-fluoro-phenyl) methanone 1- (1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline- 2-yl) -3-phenyl-propan-1-one 1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-2-car Acid (3-Chloro-propyl) amide 1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-2-car Acid (2-methoxy-phenyl) amide 1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-2-car Acid tert-butyl ester 3-chloro-1- (1- {2- [4- (5-fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H - isoquinolin-2-yl) -2,2-dimethyl-propan-1-one 1-cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro- 1H -isoquinolin-2-yl) methanone 1- [2- (4-Chloro-phenoxy) -pyridin-3-yl] -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperi Din-1'-yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-2 -Carboxylic acid tert-butyl ester 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-2-yl) -1-phenylmethanone 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-2-yl) -1-p-tolylmethanone 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-2-yl) -1- (2-methoxy-phenyl) methanone 1-cycloheptyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro- 1H -isoquinolin-2-yl) methanone 1- (2-fluoro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1- (2-Chloro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1- (4-fluoro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1- (4-Chloro-phenyl) -1- (1- {2- [6-fluorophospho [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-2 -Carboxylic acid phenethyl amide 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-2-yl) -1- (4-methoxy-phenyl) methanone 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-2-yl) -3-phenyl-propan-1-one 2-ethyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro -1H -isoquinolin-2-yl) -butan-1-one 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-2-yl) -1- (3-methoxy-phenyl) methanone 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-2-yl) -2-phenylethanone 3-cyclohexyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro- 1H -isoquinolin-2-yl) -propan-1-one 2- (4-fluoro-phenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) ethanone 1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-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'-piperidin-1'-yl] -ethyl} -3,4-di Hydro- 1H -isoquinolin-2-yl) methanone 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-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 '-Piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 2- (4-Chloro-phenyl) -1- (1- {2- [6-fluorophospho [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 3,4-dihydro- 1H -isoquinolin-2-yl) ethanone 1- (1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-2-yl) -2-methyl-propan-1-one 1- {2- [6-Fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H -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-fluoro Phenyl) -piperidin-4-yl] acetamide 1-cyclopentyl-1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl]]-ethyl}- 3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1-cycloheptyl-1- {1- [1-acetyl-spiro [2,3-dihydro- 1H - indol -3,4'-piperidin-1'-yl] ethyl] -3,4-di Hydro- 1H -isoquinolin-2-yl} methanone N- (1- {2- [2- (1-cycloheptyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenylpiperidine- 4-yl) acetamide 1-cycloheptyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone 1- (4-fluorophenyl) -1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -Ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1-cycloheptyl-1- (1- {2- [5-fluoro-1-methanesulfonyl-spiro [2,3-dihydro- 1H -indole-3,4'-piperidine-1'- Yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1- (1- {2- [2- (1-cycloheptyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine -4-yl) -1-piperidin-1-ylmethanone 1- (4-fluorophenyl) -1- (1- {2- [5-fluoro-1-methanesulfonyl-spiro [2,3-dihydro- 1H -indole-3,4'-piperi Din-1'-yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1-cycloheptyl-1- (1- {2- [4- (2-methyl- 1H-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 -isoquinoline 2-yl) methanone 1-cyclopentyl-1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3 , 4-dihydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone 1-cyclopentyl-1- {1- [spiro [2,3-dihydro- 1H - indol -3,4'-piperidin-1'-yl] ethyl] -3,4-dihydro- 1H- Isoquinolin-2-yl} methanone 1-cyclopentyl-1- (1- {2- [5-fluoro-1-methanesulfonyl-spiro [2,3-dihydro- 1H -indole-3,4'-piperidine-1'- Yl] -ethyl} -3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1- (4-fluorophenyl) -1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -Ethyl} -3,4-dihydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone 1- (2-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 3,4-dihydro- 1H -isoquinolin-2-yl) methanone 1-cycloheptyl-1- (1- {2- [spiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro- 1H- Isoquinolin-2-yl) methanone 1-cycloheptyl-1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3 , 4-dihydro-6,7-dimethoxy- 1H -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- [5-isopropylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro- 1H -isoquinolin-2-yl) methanone N- [1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Phenyl) -piperidin-4-yl] acetamide 1-cycloheptyl-1- {1- [2- (4-phenylpiperidin-1-yl) -ethyl] -3,4-dihydro-1 H -isoquinolin-2-yl} methanone 1-cycloheptyl-1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-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-1 H -isoquinoline-2 Methnon 1-cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone 1- (4-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 3,4-dihydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone 1- (1- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H- iso Quinolin-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-1 H -isoquinoline- 2-yl) methanone 8- {2- [2- (1-cycloheptyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -1-phenyl-1,3,8- Triaza-spiro [4.5] decane-4-one 1-cycloheptyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-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-yl] -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-piperidine -4-yl) -ethanone 1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone 1-cyclopentyl-1- (1- {2- [4- (2-methyl-1H-indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H -isoquinolin-2-yl) methanone 1- (1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine -4-yl) ethanone 1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro-6,7-dimethoxy- 1H -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-yl] -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-yl) -1 Cyclopentylmethanone 1- (4-Fluoro-phenyl) -1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-di Hydro- 1H -isoquinolin-2-yl) methanone 1- (4-fluorophenyl) -1- (1- {2- [pyro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4- Dihydro- 1H -isoquinolin-2-yl) methanone 1-cyclopentyl-1- (1- {2- [4-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro- 1H -isoquinolin-2-yl) methanone 1- (2-fluorophenyl) -1- (1- {2- [6-fluoro-3-methylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -Ethyl} -3,4-dihydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone N- [4- (3-Fluoro-phenyl) -1- (2- {2- [1- (4-fluoro-phenyl) -methanoyl] -1,2,3,4-tetrahydro-iso Quinolin-1-yl} -ethyl) -piperidin-4-yl] -acetamide 1- (2-fluorophenyl) -1- {1- [spiro [2,3-dihydro- 1H - indol -3,4'-piperidin-1'-yl] ethyl] -3,4- Dihydro- 1H -isoquinolin-2-yl} methanone 1-cycloheptyl-1- (1- {2- [5-fluoro-1-methanesulfonyl-spiro [2,3-dihydro- 1H -indole-3,4'-piperidine-1'- Il] -ethyl} -3,4-dihydro-6,7-dimethoxy- 1H -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- 1H -isoquinolin-2-yl} -1-cycloheptylmethanone 1- (2-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone 1- (1- {2-[(Chloro-trifluoromethyl-phenyl) -hydroxy-piperidin-1-yl] -ethyl} -6,7-dimethoxy-3,4-dihydro-1 H -isoquinolin-2-yl) -1-cycloheptylmethanone 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 1-cycloheptyl-1- (1- {2- [4- (2-isopropoxy-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H -isoquinoline 2-yl) methanone 1- (1- {2- [4- (7-chloro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-2 -Yl) -1-cyclopentylmethanone 1-cyclopentyl-1- (1- {2- [4- (2,3-dihydro-benzofuran-7-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro -1 H - isoquinolin-2-yl) methanone 1- (1- {2- [4- (2,3-Dihydro-benzofuran-7-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H -iso Quinolin-2-yl) -1- (4-fluoro-phenyl) methanone 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 1- (4-Fluoro-phenyl) -1- {1- [2- (4-phenyl-piperidin-1-yl) -ethyl] -3,4-dihydro- 1H -isoquinoline-2- Methanon 1- (1- {2- [4- (6-Chloro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-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- 1H - indol -3,4'-piperidin-1'-yl] ethyl] -3,4-dihydro-6, 7-dimethoxy- 1H -isoquinolin-2-yl} methanone N- (1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine -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'-piperidin-1'-yl] -ethyl} -3,4-dihydro-6, 7-dimethoxy- 1H -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- 1H -isoquinolin-2-yl) -1 -(4-fluoro-phenyl) methanone 1-cyclopentyl-1- (1- {2- [4- (4-isopropyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro- 1H -isoquinoline-2 Methnon 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-cyclopentyl-1- {1- [2- (4-phenyl-piperidin-1-yl) -ethyl] -3,4-dihydro-1 H -isoquinolin-2-yl} methanone 1- (2-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 3,4-dihydro-6,7-dimethoxy- 1H -isoquinolin-2-yl) methanone 1- (4-Fluoro-phenyl) -1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl]- Ethyl} -3,4-dihydro-1H-isoquinolin-2-yl) -methanone 1- (4-fluorophenyl) -1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-1H-isoquinolin-2-yl) methanone 3,3-dimethyl - [1 - {2- [spiro (5-fluoro-benzofuran -2 H -3,4'- piperidin-1'-yl)] ethyl} -3,4-dihydro -1 H-isoquinolin-2-yl] -butane-1-one Cyclohexyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H-iso Quinolin-2-yl] -Methanone Cyclohexyl- (1- {2- [spiro (5-methyl-isobenzofuran- 3H- 1,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1 H -isoquinolin-2-yl) -methanone Cyclohexyl- [1- {2- [spiro (benzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H-isoquinoline-2- Sun] -Methanone Cyclohexyl- (1- {2- [4- (2-methyl-1H-indol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H -isoquinoline 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-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H- Isoquinolin-2-yl) -butan-1-one Cyclohexyl- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H -isoquinoline-2- Sun) -Methanone Cyclohexyl- (1- {2- [4- (4-dimethylamino-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H -isoquinolin-2-yl) -Metanon 3-phenyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H- Isoquinolin-2-yl] -propanone (1- {2- [4- (4-chloro-3-trifluoromethyl-phenyl) -4-hydroxy-piperidin-1-yl] -ethyl} -6,7-dimethoxy-3, 4-dihydro-1 H -isoquinolin-2-yl) -cyclohexyl-methanone 2-phenoxy- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H -Isoquinolin-2-yl] -ethan-1-one Benzo [1,2,5] oxadiazol-5-yl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-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-1 H -isoquinolin-2-yl) -Metanon 2-propyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H- Isoquinolin-2-yl] -pentan-1-one 2,2-dimethyl-3-chlor- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4 -Dihydro-1H-isoquinolin-2-yl] -propan-1-one Cyclohexyl- (1- {2- [4- (2,3-dihydro-benzofuran-7-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H- Isoquinolin-2-yl) -methanone 3,3-dimethyl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro -1H-isoquinolin-2-yl) -butan-1-one Benzo [1,2,5] oxadiazol-5-yl- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3, 4-dihydro-1 H -isoquinolin-2-yl) -methanone 2-ethyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H -isoquinoline -2-yl) -butan-1-one 2-benzyloxy- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl) -ethan-1-one Benzo [1,2,5] oxadiazol-5-yl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)]- Ethyl} -3,4-dihydro-1H-isoquinolin-2-yl] -methanone (1- {2- [4- (4-Chloro-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H -isoquinolin-2-yl) -cyclohexyl- Metanon 1- (1- {2- [4- (4-chloro-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-isoquinolin-2-yl) -3, 3-dimethyl-butan-1-one 3,5,5-trimethyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl] -hexan-1-one 3,5,5-trimethyl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4- Dihydro-1H-isoquinolin-2-yl) -hexan-1-one 2-phenoxy- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -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-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H -Isoquinolin-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-1H-isoquinoline -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-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl] -propan-1-one 3-cyclohexyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H-isoquinoline -2-yl) -propan-1-one Furan-2-yl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro- 1H-isoquinolin-2-yl] -methanone N- (4-phenyl-1- {2- [2- (3,5,5-trimethyl-hexanol) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl}- Piperidin-4-yl) -acetamide Quinoxalin-2-yl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro -1H-isoquinolin-2-yl] -methanone 3-cyclohexyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H -Isoquinolin-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-1 H-isoquinoline- 2-yl) -pentan-1-one 2-ethyl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4-dihydro-1H- Isoquinolin-2-yl] -butan-1-one 3-phenyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1 H-isoquinoline- 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-naphthalen-2-yl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl) Ethyl] -3,4-dihydro-1 H-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-di Hydro-1H-isoquinolin-2-yl) -hexan-1-one 3-phenyl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-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-1 H-isoquinoline- 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-1H-isoquinolin-2-yl) -2- Phenoxy-Ethanone Quinoxalin-2-yl- (1- {2- [spiro (5-methyl-isobenzofuran-3H-1,4'-piperidin-1'-yl)-] ethyl} -3,4-di Hydro-1H-isoquinolin-2-yl) -methanone 2,2-dimethyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro-1H-iso Quinolin-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'-piperidin-1'-yl)] ethyl} -3,4-di Hydro-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-yl) -3 , 5,5-trimethyl-hexan-1-one 2,2-dichloro-cyclopropyl- (1- {2- [spiro (isobenzofuran-3H-1,4'-piperidin-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-isoquinoline-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-di Hydro-1H-isoquinolin-2-yl) -methanone N- (1- {2- [2- (3,3-Dimethyl-butyryl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperi Din-4-yl) -acetamide 3-chloro-2,2-dimethyl-1- (1- {2- [4- (3-trifluoromethyl-phenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro -1H-isoquinolin-2-yl) -propan-1-one Tetrahydro-pyran-4-yl- [1- {2- [spiro (5-fluoro-benzofuran-2H-3,4'-piperidin-1'-yl)-] ethyl} -3,4- Dihydro-1H-isoquinolin-2-yl] -butan-1-one 1- (1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -5-chloro-3,4-dihydro- 1H - isoquinolin-2-yl) -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- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro-3 , 4-dihydro- 1H -isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro -3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, N- [1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Phenyl) -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-phenylpiperidine- 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- 1H - indol -3,4'-piperidin-1'-yl] ethyl] -5-chloro-3 , 4-dihydro- 1H -isoquinolin-2-yl} methanone, 1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro- 1H - indol -3,4'-piperidin-1'-yl] ethyl]- 5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone, 1-cyclopentyl-1- {1- [1-acetyl-spiro [2,3-dihydro - 5-fluoro- 1H -indol-3,4'-piperidin-1'-yl] -ethyl] -5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone, 1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indole-3,4'-piperidine-1'- Il] -ethyl] -5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone, 1-cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -5-chloro-3,4-dihydro- 1H- Isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -5-chloro-3,4- Dihydro- 1H -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-yl) -1- (4-fluorophenyl) methanone, 1- (1- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) -piperidin-1-yl] -ethyl} -5-chloro-3,4-dihydro 1H -isoquinolin-2-yl) -1- (cyclopentyl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -5-chloro-3,4-dihydro- 1H -isoquinolin-2-yl) -methanone, 1- (4-fluorophenyl) -1-({2- [6-fluorophospho [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro -3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro -3,4-dihydro- 1H -isoquinolin-2-yl) -methanone, 1-cyclopentyl-1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5-chloro-3,4- Dihydro- 1H -isoquinolin-2-yl) methanone, 1- (1- {2- [4- (5-Fluoro- 1H-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- (-1H- indol-3-yl) 5-fluoro-piperidin-1-yl] -ethyl} -3,4-dihydro- 5-fluoro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-di Hydro - 5-fluoro- 1H -isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 3,4-dihydro - 5-fluoro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro - 5-fluoro- 1H -isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro - 5-fluoro- 1H -isoquinolin-2-yl) methanone, N- [1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Phenyl) -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-phenylpiperidine- 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- 1H - indol -3,4'-piperidin-1'-yl] ethyl] -3,4-di Hydro - 5-fluoro- 1H -isoquinolin-2-yl} methanone, 1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro- 1H - indol -3,4'-piperidin-1'-yl] ethyl]- 3,4-dihydro - 5-fluoro- 1H -isoquinolin-2-yl} methanone, 1-cyclopentyl-1- {1- [1-acetyl-spiro [2,3-dihydro - 5-fluoro- 1H -indol-3,4'-piperidin-1'-yl] -ethyl] -3,4-dihydro - 5-fluoro- 1H -isoquinolin-2-yl} methanone, 1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indole-3,4'-piperidine-1'- Yl] -ethyl] -3,4-dihydro - 5-fluoro- 1H -isoquinolin-2-yl} methanone, 1-cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 5-fluoro- 1H - isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 5 -Fluoro- 1H -isoquinolin-2-yl) methanone, 1- (1- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) -piperidin-1-yl] -ethyl} -3,4-dihydro - 5-fluoro Rho - 1H -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 Rho - 1H -isoquinolin-2-yl) -1- (cyclopentyl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -3,4-dihydro-5-fluoro- 1H -isoquinolin-2-yl) -methanone, 1- (4-fluorophenyl) -1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-5-fluoro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4 -Dihydro-5-fluoro- 1H -isoquinolin-2-yl) -methanone, 1-cyclopentyl-1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -3,4-dihydro-5 -Fluoro- 1H -isoquinolin-2-yl) methanone, 1- (1- {2- [4- (5-Fluoro- 1H-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- 1H-indol-3-yl ) -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'-piperidin-1'-yl] -ethyl} -5,6-dichloro -3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6 -Dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, N- [1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Phenyl) -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-phenylpiperidine- 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- 1H - indol -3,4'-piperidin-1'-yl] ethyl] -5,6-dichloro -3,4-dihydro- 1H -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 - 5-fluoro- 1H -indol-3,4'-piperidin-1'-yl] -ethyl] -5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone, 1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indole-3,4'-piperidine-1'- Il] -ethyl] -5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone, 1-cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) -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- 1H -isoquinolin-2-yl) 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- (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'-piperidin-1'-yl] -ethyl } -5,6-dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) -methanone, 1- (4-fluorophenyl) -1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-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'-piperidin-1'-yl] -ethyl} -5,6 -Dichloro-3,4-dihydro- 1H -isoquinolin-2-yl) -methanone, 1-cyclopentyl-1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6-dichloro-3, 4-dihydro- 1H -isoquinolin-2-yl) methanone, 1- (1- {2- [4- (5-Fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -5,6-difluoro-3,4- Dihydro- 1H -isoquinolin-2-yl) -1- (4-fluoro-phenyl) methanone, 1-cyclopentyl-1- (1- {2- [4- (5-fluoro- 1H-indol-3-yl ) -piperidin-1-yl] -ethyl} -5,6-difluoro -3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6-di Fluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [6-fluorospiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl}- 5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6 -Difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1- (4-fluorophenyl) -1- (1- {2- [6-trifluoromethylspiro [isobenzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl } -5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, N- [1- {2- [2- (1-cyclopentyl-methanoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4- (3-fluoro Phenyl) -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-phenylpiperidine- 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- 1H - indol -3,4'-piperidin-1'-yl] ethyl] -5,6-di Fluoro-3,4-dihydro- 1H -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-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone, 1-cyclopentyl-1- {1- [1-acetyl-spiro [2,3-dihydro - 5-fluoro- 1H -indol-3,4'-piperidin-1'-yl] -ethyl] -5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone, 1- (4-fluorophenyl) -1- {1- [1-acetyl-spiro [2,3-dihydro-5-fluoro- 1H -indole-3,4'-piperidine-1'- Il] -ethyl] -5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl} methanone, 1-cyclopentyl-1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -5,6-difluoro-3,4-di Hydro- 1H -isoquinolin-2-yl) methanone, 1- (4-Fluorophenyl) -1- (1- {2- [4- (3-trifluoromethylphenyl) -piperidin-1-yl] -ethyl} -5,6-difluoro- 3,4-dihydro- 1H -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'-piperidin-1'-yl] -ethyl } -5,6-difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) -methanone, 1- (4-fluorophenyl) -1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6 -Difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) methanone, 1-cyclopentyl-1- (1- {2- [5,6-difluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6 -Difluoro-3,4-dihydro- 1H -isoquinolin-2-yl) -methanone, and 1-cyclopentyl-1-({2- [6-fluorospiro [benzofuran-1 (3H), 4'-piperidin-1'-yl] -ethyl} -5,6-difluoro- 3,4-dihydro- 1H -isoquinolin-2-yl) methanone Is selected from the group comprising: or Formula V Wherein R ² to R ⁹ and Q are as defined for Formula (I)] Enantiomer 2 (enantiomer 2 of e.g. Characterized in that it is selected from the group comprising the following enantiomers prepared by acylation of the enantiomeric pair slowly by supercritical HPLC at 20 Mpa on a system comprising an OD column: N- (4- (3-fluoro-phenyl) -1- {2- [2- (2-methoxy-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl]- Ethyl} -piperidin-4-yl) acetamide (enantiomer), N- (4- (3-fluoro-phenyl) -1- {2- [2- (2-methoxy-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl]- Ethyl} -piperidin-4-yl) acetamide (enantiomer), 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-piperidine- 4-yl) acetamide (enantiomer), N- (1- {2- [2- (2,4-Dichloro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine -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-phenyl) -pi Ferridin-4-yl] -acetamide (enantiomer), N- (1- {2- [2- (4-chloro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine-4 -Yl) acetamide (enantiomer), N- [1- {2- [2- (benzo [b] thiophen-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-isoquinoline-1- Il] -ethyl} -4- (3-fluoro-phenyl) -piperidin-4-yl] acetamide (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-piperidine-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-piperidine-4 -Yl) acetamide (enantiomer), N- (1- {2- [2- (4-Fluoro-benzoyl) -1,2,3,4-tetrahydro-isoquinolin-1-yl] -ethyl} -4-phenyl-piperidine- 4-yl) acetamide (enantiomer), N- {1- [2- (2-cycloheptancarbonyl-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-piperidine- 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- (thiophen-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-isoquinoline-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-piperidine- 4-yl) acetamide (enantiomer). A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 25 together with one or more pharmaceutically acceptable carriers or diluents. Use of a compound according to any one of claims 1 to 25 for the manufacture of a pharmaceutical preparation for treating central nervous system disease. The method of claim 27, wherein the disease is depression, mood swings, bipolar disorder, mood modulation, mixed anxiety depression, general anxiety disorder, social anxiety disorder, panic anxiety disorder, late traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, Uses selected from the group comprising premenstrual discomfort disorders, psychosis and Huntington's disease, and Parkinson's dementia, dysregulation, pain, vomiting, migraine, epilepsy, obesity and cerebrovascular disease. 29. The method of claim 28, wherein the disease is depression, mood swings, bipolar disorder, mood modulation, mixed anxiety depression, general anxiety disorder, social anxiety disorder, panic anxiety disorder, late traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, Use selected from the group comprising premenstrual malaise disorder and psychosis. Use of a compound according to any one of claims 1 to 25 in the treatment of central nervous system diseases. 31. The method of claim 30, wherein the disease is depression, mood swings, bipolar disorder, mood modulation, mixed anxiety depression, general anxiety disorder, social anxiety disorder, panic anxiety disorder, late traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, Uses selected from the group comprising premenstrual discomfort disorders, psychosis and Huntington's disease, and Parkinson's dementia, dysregulation, pain, vomiting, migraine, epilepsy, obesity and cerebrovascular disease. The method of claim 31, wherein the disease is depression, mood swings, bipolar disorder, mood modulation, mixed anxiety depression, general anxiety disorder, social anxiety disorder, panic anxiety disorder, late traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, Use selected from the group comprising premenstrual malaise disorder and psychosis.