HK1118047A

HK1118047A - Tetrahydroisoquinoline compounds for treatment of cns disorders

Info

Publication number: HK1118047A
Application number: HK08108982.5A
Authority: HK
Inventors: Nicholas I. Carruthers; Leslie A. Gomez; Jill A. Jablonowski; John M. Keith; Michael A. Letavic; Kiev S. Ly; Jennifer M. B. Miller; Emily M. Stocking; Ronald L. Wolin
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2004-12-17
Filing date: 2005-12-15
Publication date: 2009-01-30

Description

Tetrahydroisoquinoline compounds for the treatment of central nervous system disorders

Technical Field

The present invention provides histamine H₃Receptor and 5-hydroxytryptamine transporter modulators. More specifically, the present invention provides tetrahydroisoquinoline compounds and methods of use thereof for the treatment of histamine H₃Receptor and 5-hydroxytryptamine transporter mediated diseases and conditions. With these activities, the compounds of the present invention have therapeutic utility in the treatment of depression and various related disorders.

Background

Depression is a chronic disease with an estimated lifetime incidence of 17%. The total annual cost of depression in the united states is estimated to be $440 billion. Depression is therefore a major health problem with major impact on the drug economy (Griffiths, r.i. et al, pharmacopoeicomics 1999, 15(5), 495-. Although the biochemical basis of depression has not been fully elucidated, it is a well-established hypothesis that depression occurs when monoaminergic neurotransmission in the brain is impaired. This theory is largely based on the following observations: compounds that improve noradrenergic and/or 5-hydroxytryptamine-ergic neurotransmission generally have beneficial effects on depression. Monoaminergic neurotransmission may be improved in several ways. The following two mechanisms can terminate the biological effects of norepinephrine: reuptake from the synaptic cleft into neurons by the norepinephrine transporter (NET) and degradation by monoamine oxidase (MAO). For 5-hydroxytryptamine, its availability in the synaptic cleft is also limited by re-uptake into neurons via the 5-hydroxytryptamine transporter (SERT).

Currently, clinical treatment of depression relies mainly on class 4 drugs: 1) MAO inhibitors; 2) tricyclic antidepressants(TCA); 3) a selective 5-hydroxytryptamine reuptake inhibitor (SSRI); and 4) reboxetine and venlafaxine. MAO-based drugs have long been used as second-line drugs because of their potentially dangerous side effects, and more recently, reversible MAO-A selective inhibitors with improved properties have been described (Bonnet, U.S. CNS Drug Rev.2002, 8(3), 283-308). TCAs, such as amitriptyline (amitriptiline), exhibit complex pharmacological activities. They inhibit the reuptake of norepinephrine and 5-hydroxytryptamine by their respective transporters, and are active against muscarinic and histamine H₁The receptor also has affinity. Thus, their efficacy in treating depression is a rival compared to its numerous unwanted side effects. SSRIs represent the largest, most successful class of antidepressants, with higher selectivity for SERT than NET, despite the differences in the exact affinity ratios between the drugs. The medicine is characterized in that the side effect is lighter than that of MAO inhibitor or TCA. Other Drugs such as reboxetine (which preferentially targets NET) and venlafaxine (which has dual activity for SERT and NET) have been described (Olver, j.s. et al, CNS Drugs 2001, 15(12), 941-954).

Although significant advances have been made in the treatment of depression, there remains an opportunity for improvement. The delay between the start of treatment and the improvement in subjective perception is a suitable example. In the Hamilton depression rating scale, most drugs take weeks to treat before they cause improvement, but during this time the patient may remain in serious mental distress. Currently available drugs have a limited response rate, and only about 30% of patients show clinical improvement in most clinical trials (Menza, M.A., et al, J.Clin.Psych.2000, 61(5), 378-381). Psychiatrists often need to evaluate several drugs for each patient in order to observe a satisfactory therapeutic response. Thus, there is a clear therapeutic need for drugs that have faster onset, fewer side effects, and higher response rates.

To understand the joint SERT/H₃The rationale for the antagonists, it is necessary to understand histamine H₃The physiology of the receptor. The receptor was in 1983 (Ar)ran, J. -M. et al, Nature (London)1983, 302(5911), 832-oza 837) are described as presynaptic, self-inhibitory receptors on histaminergic neurons with characteristic pharmacology. H₃Activation of the receptor has been shown to reduce the release of histamine from nerve endings and to inhibit the activity of histidine decarboxylase, the rate-limiting enzyme in histamine synthesis. To human H ₃The cloning and characterization of the receptor made possible the study of its pharmacology (Lovenberg, T.W. et al, Molec. Pharmacol.1999, 55(6), 1101- "1107). It is now known that H₃Receptors are expressed on a variety of neurons and, when activated, are capable of reducing the release of a variety of other neurotransmitters, including norepinephrine, dopamine and acetylcholine (Hill s.j. et al, pharmacol. rev.1997, 49(3), 253-. To carry out this discussion we will focus on its known effects on the release of neurotransmitters involved in depression (norepinephrine and 5-hydroxytryptamine). Although 5-hydroxytryptamine-competent cell bodies are found in the dorsal raphe nucleus, while histaminergic cells are located in the tuberomamillary nucleus of the hypothalamus, both systems have extensive projections throughout the brain. Both neurotransmitters are present in some areas, such as the suprachiasmatic nucleus (Laitinen, K.S.M. et al, Eur.J.Pharmacol.1995, 285(2), 159-164) and the striatum. Known as H₃Activation of the receptor results in a reduction in 5-hydroxytryptamine release, for example in rat cortical sections (Fink, K. et al, Nauyn-Schmiedeberg's Arch. Pharmacol.1990, 342(5), 513-. H ₃Functional antagonists of the receptor cause increased norepinephrine release in the central nervous system (mouse cortical section, Leurs, R. et al, J. Pharmacol. exp. Ther.1996, 276 (3)), 1009-, 1015; rat hippocampus, Alvez-Rodrigues, A. et al, Brain Res.1998, 788(1-2), 179- > 186) and peripheral nervous system (human cardiac nerve, Hatta, E. et al, J. Pharmacol. exp. Ther.1997, 283 (2)), 494- > 500; guinea pig enteric sympathetic nerve, Blandizzi, C. et al, Br. J. Pharmacol.2000, 129(7), 1387- > 1396). However, there is little evidence for H₃The receptor antagonist can singly enable the 5-hydroxytryptamine in vivoThe level increases to a level required for an antidepressant effect. Lack of H₃Microdialysis studies of the effect of antagonists on 5-hydroxytryptamine levels in the brain of living animals. Sporadic reports indicate that tiopronamide (an H)₃Receptor antagonists) may have antidepressant effects in forced swimming tests in mice or rats (Lamberti, C. et al, Br. J. Pharmacol.1998, 123(7), 1331-1336; Perez-Garcia, C. et al, Psychopharmacology 1999, 142(2), 215-.

It is desirable to combine H in one molecule₃Receptor blockade and SERT activity, such that these two mechanisms act synergistically to increase the concentration of 5-hydroxytryptamine in the synaptic cleft. At H ₃Antagonism at the receptor will increase the release of 5-hydroxytryptamine-containing vesicles into the synaptic cleft, accompanied by blockade of SERT which will decrease neuronal reuptake of these neurotransmitter molecules. Therefore, higher 5-hydroxytryptamine concentration can be achieved, and the curative effect is improved.

The most prominent autonomic symptom of depression (vegetitive symptomm) is disturbed sleep and daytime fatigue associated therewith. Polysomnography studies have shown severe disturbances in the sleep structure of depressed patients. Typical anomalies observed therein are: intermittent sleep, reduced slow wave sleep, shorter REM sleep latency, and increased intensity and duration of REM sleep (Riemann, d. et al, Neuropsychobiology 2002, 45 (supplement 1), 7-12). It is believed that the antidepressant efficacy includes inhibition of REM sleep. This is demonstrated by dramatic success in overnight deprivation (REM) of sleep (Riemann et al, 2002). Another non-drug treatment of depression, electroconvulsive therapy, also reduced REM sleep. Virtually all available antidepressants, regardless of their neurochemical mechanism of action, inhibit REM sleep, and nefazodone, a 5-HT inhibitor_2AAntagonists) are the exception (Sharpley, a.l., Cowen, p.j.biol.psych.1995, 37(2), 85-98). Antidepressants also act on slow wave sleep, although the manner is not well understood. H ₃Antagonists also have such REM sleep inhibitory properties, but histamine H₃One of the major biological effects of antagonists is to improve wakefulness. It is known to administer H₃Antagonists can reduce REM sleep and non-REM sleep in some animals. E.g. H₃The antagonist carboperamide induced the awakening of rats (Monti, J.M. et al, Neuropsychopharmacology 1996, 15(1), 31-35). Another H₃The antagonist tioplamide reduces both REM sleep and non-REM sleep in rats (Monti, J.M. et al, Eur.J.Pharmacol.1991, 205(3), 283-287) and cats (Lin, J. -S. et al, Brain Res.1990, 523(2), 325-330). It is interesting to note, though H₃Antagonists promote wakefulness, but they are much less potent than amphetamine derivatives. Therefore, they are considered mild stimulants. Disruptive sleep is associated with daytime fatigue. Indeed, fatigue and lethargy are prominent symptoms of depression and are of considerable interest in the use of stimulants to enhance antidepressant therapy (Menza et al, 2000). However, most available stimulants, such as amphetamine derivatives and methylphenidate, have a considerable risk of abuse and are not ideal therapeutic options. Modafinil, a mechanism agnostic wakefulness-promoting compound with low addictive potential, is commercially available for the treatment of narcolepsy. In a small percentage of patients, it is known that the addition of a low dose of modafinil to traditional antidepressant therapy results in a faster onset of action. Fatigue is particularly responsive to this therapy, but cognitive and body parts in the Hamilton depression rating scale are also improved (Menza et al, 2000). H ₃The behavioral characteristics of the antagonist (inhibiting sleep, but not stimulating motor activity and limiting addictive potential) are very similar to modafinil. Thus, in combination with H₃the/SERT modulating compounds will cause a reduction in fatigue symptoms during the first few weeks of treatment before the mood-enhancing effects of SERT modulators can be noticed.

Depression is also associated with a number of cognitive symptoms, such as memory decline and concentration difficulties. Is already known as H₃Antagonists can improve memory in a variety of memory tests, including the mouse elevated plus maze test (Miyazaki, S. et al, Life Sci.1995, 57(23), 2137-Avoidance test (Miyazaki, S. et al, meth.Find.Exp.Clin.Pharmacol.1995, 17 (10)), 653-. In addition, in spontaneously hypertensive rats (animal model for learning decline of attention deficit disorder), H₃Antagonists have been shown to improve memory (Fox, G.B., et al, Behav. brain Res.2002, 131(1-2), 151-161). Although no human studies are available, there is evidence that SERT/H is combined ₃Modulators would provide additional benefit in combating depression-related cognitive decline.

Having H₃Compounds for receptor activity and SERT activity have been disclosed in U.S. patent application No. 60/691,958 (6/17/2005) and U.S. patent application No. 60/692,003 (6/17/2005), both of which are incorporated herein by reference.

Various uses of tetrahydroisoquinoline compounds are described in the following documents: U.S. patent No. 4,113,869 (9/12 in 1978), european patent application No. EP1113007 (7/4 in 2001), and international patent application No. WO200132624 (5/10 in 2001).

In summary, H₃The combination of receptor antagonism with SERT activity will result in the production of drugs with improved antidepressant characteristics compared to SERT modulators alone. These drugs would be particularly effective in relieving symptoms of fatigue, disturbed sleep and memory loss associated with depression.

Summary of The Invention

The invention features methods of treating or preventing a neurological disease or Central Nervous System (CNS) disease in a mammal by administering a compound of the following formula (I):

Wherein

L is-O-, and n is 1 or 2; or L is-C ≡ C-or-CH₂CH₂-n is 0 or 1;

R¹is-H; or is-C_1-6Alkyl, -C_3-6Alkenyl, -C_3-6Alkynyl, -C_3-7Cycloalkyl, -C_1-6Alkyl radical C_3-7Cycloalkyl, -COOC_1-6Alkyl or-COObenzyl, each of which is optionally substituted by R^aMono-, di-or tri-substituted;

wherein R is^aSelected from-OH, -OC_1-6Alkyl, optionally substituted by-OC_1-4Alkyl or halogen substituted phenyl, -CN, -NO₂、-N(R^b)R^c、-C(O)N(R^b)R^c、-N(R^b)C(O)R^b、-N(R^b)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^b)R^c、-SCF₃Halogen, -CF₃、-OCF₃-COOH and-COOC_1-6An alkyl group;

wherein R is^bAnd R^cEach independently is-H or-C_1-6An alkyl group;

R²and R³Each independently selected from: -H;

A)-C_1-6alkyl, -C_3-6Alkenyl, -C_3-6Alkynyl, -C_3-7Cycloalkyl, -C_1-6Alkyl radical C_3-7Cycloalkyl, -CH (C)_3-8Cycloalkyl radicals₂-CH (phenyl)₂Benzyl and-C (O) OC_1-4Alkyl, wherein the alkyl, cycloalkyl or benzyl are each optionally substituted with: -OH, -OC_1-4Alkyl, -CN, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂Halogen, -CF₃、-OCF₃-COOH or-COOC_1-6An alkyl group;

B) phenyl or pyridyl optionally fused on two adjacent ring carbon atoms to a 3-or 4-membered hydrocarbon moiety to form a fused 5-or 6-membered aromatic ring, one carbon atom of said moiety being substituted with > O, > S, > NH, > N (C)_1-4Alkyl) or > NC (O) OC_1-4Alkyl, and up to one more carbon atom in the moiety is optionally replaced by-N ═ c;

C) A naphthyl group,

D) a 4-8 membered heterocyclic ring having as a point of attachment a carbon atom, having 1 or 2 ring heteroatoms selected from: > O, > S (O)_0-2、＞NH、＞N(C_1-4Alkyl) and > NC (O) OC_1-4Alkyl, and having 0 or 1 double bond; and

E) monocyclic aromatic hydrocarbon groups having 5 or 6 ring atoms, having carbon atoms as attachment points, having one carbon atom replaced with: > O, > S, > NH, > N (C)_1-4Alkyl) or > NC (O) OC_1-4Alkyl, up to one carbon atom being optionally replaced by-N ═ and optionally benzo-fused or pyridine-fused;

wherein each of said B) -E) is optionally mono-, di-or trisubstituted with a moiety selected from: -C_1-4Alkyl, -OH, -C_1-4Alkyl OH, -OC_1-6Alkyl, -CN, -NO₂、-N(R^d)R^e-C(O)N(R^d)R^e、-N(R^d)C(O)R^d、-N(R^d)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^d)R^e、-SCF₃Halogen, -CF₃、-OCF₃、-COOH、-COOC_1-6Alkyl, -OC (O) N (R)^d)R^eand-OC (O) OC^1-6An alkyl group;

wherein R is^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

alternatively, the first and second electrodes may be,

R²and R³May be taken together with the nitrogen atom to which they are attached to form a tetrahydro-pyrimidin-2-ylidene or a 4-8 membered heterocyclic ring having at least one carbon atom spaced from the attached nitrogen and selected from > O, > S (O)_0-2NH and > NR^fHas 0 or 1 double bond, has 0, 1 or 2 ring carbon atoms spaced from the connecting nitrogen by at least one carbon atom as carbonyl group, is optionally benzo-fused or pyridine-fused, optionally has one ring carbon atom forming a bridge, and has 0 to 5 ring carbon atom substituents R ^ff，

Wherein R is^fSelected from:

i) optionally substituted with R^zsubstituted-C_1-6Alkyl, -C_3-6Alkenyl, -C_3-6Alkynyl, -C (O) N (R)^g)R^h、-C(O)Rⁱ、-S(O)_0-2-C_1-6Alkyl and-COOC_1-6An alkyl group, a carboxyl group,

wherein R is^zIs fluorine, -CN, -OH, -OC_1-4Alkyl, -C_3-7Cycloalkyl or-CF₃；

Wherein R is^gAnd R^hEach independently is-H or-C_1-6An alkyl group; and

wherein R isⁱis-C_1-6Alkyl, -C_3-8Cycloalkyl, phenyl or a 5-or 6-membered aromatic heterocyclyl, wherein each of said alkyl, cycloalkyl, phenyl or heterocyclyl is optionally substituted by-C_1-4Alkyl, -OH, -OC_1-6Alkyl, -CF₃CN or halogen mono-, di-or tri-substituted;

ii)-(CH₂)_0-1-ring a, wherein ring a is phenyl or a 5-or 6-membered carbon-linked aromatic heterocyclyl, optionally substituted by R^aaSubstitution;

wherein R is^aais-OH, -C_1-6Alkyl, -OC_1-6Alkyl, phenyl, -CN, -NO₂、-N(R^g)R^h-C(O)N(R^g)R^h、-N(R^g)C(O)R^h、-N(R^h)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^g)R^h、-SCF₃Halogen, -CF₃、-OCF₃、-OCHF₂-COOH and-COOC_1-6An alkyl group; and

iii)-(CH₂)_0-1-ring B, wherein ring B is-C with one or two ring carbon atoms optionally replaced by > O or > NH_3-7Cycloalkyl and optionally substituted by-C_1-4Alkyl, fluoro, -CN, -OH, -OC_1-4Alkyl or-CF₃Substitution;

wherein R is^ffSelected from the group consisting of^zMono-or disubstituted-C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_3-7Cycloalkyl, -CH (phenyl)₂Halogen, -OH, -OC_1-6Alkyl, -OC_2-3Alkyl O-, -CN, -NO₂、-N(R^g)R^h、-C(O)N(R^g)R^h、-N(R^g)C(O)R^g、-N(R^g)SO₂C_1-6Alkyl, -C (O) R ⁱ、-S(O)_0-2-C_1-6Alkyl, -SO₂N(R^g)R^h、-SCF₃、-CF₃、-OCF₃-COOH and-COOC_1-6An alkyl group;

R⁴is-OH, -OC_1-6Alkyl, -CF₃、-C_1-6Alkyl or halogen; two R⁴The substituents may be taken together to form methylene or ethylene; or a R⁴And R²Combined together to form methylene, ethylene, propylene or-CH₂CH₂O-, wherein each of said groups is optionally substituted with: -OH, -OC_1-6Alkyl, -SC_1-6Alkyl, -CF₃、-C_1-6Alkyl, amino or halogen;

m is 0, 1 or 2;

R⁵is selected from-C_1-6Alkyl, -OH, -OC_1-6Alkyl, -SC_1-6Alkyl and halogen;

Ar¹is an aryl or heteroaryl ring selected from:

a) phenyl, which is optionally substituted by R^jMono-, di-or tri-substituted and optionally substituted on adjacent carbon atoms by-OC_1-4Alkylene O-disubstituted, optionally by fluorine, - (CH)₂)_2-3NH-、-(CH₂)_1-2NH(CH₂)-、-(CH₂)_2-3N(C_1-4Alkyl) -or- (CH₂)_1-2N(C_1-4Alkyl) (CH₂) -mono-or di-substitution;

wherein R is^jSelected from:

1)-OH、-C_1-6alkyl, -OC optionally mono-, di-or trisubstituted by halogen_1-6Alkyl, -C_2-6Alkenyl, -OC_3-6Alkenyl, optionally trimethylsilyl-substituted-C_2-6Alkynyl, -OC_3-6Alkynyl, -C_3-6Cycloalkyl, -OC_3-6Cycloalkyl, -CN, -NO₂、-N(R^k)R₁、-N(R^k)C(O)R¹、-N(R^k)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -C (O) N (R)^m)Rⁿ、-SO₂N(R^m)Rⁿ、-SCF₃Halogen, -CF₃、-COOH、-COOC_1-6Alkyl and-COOC_3-7A cycloalkyl group;

wherein R is^kAnd R¹Each independently is-H or-C_1-6An alkyl group;

wherein R is^mAnd RⁿEach independently is-H or-C _1-6Alkyl, or R^mAnd RⁿMay be taken together with the nitrogen atom to which they are attached to form a 4-8 membered heterocyclic ring having 1 or 2 ring heteroatoms selected from: > O, > S (O)_0-2NH and > NC_1-6Alkyl with 0 or 1 double bond, with 0 or 1 carbonyl;

2)-G-Ar²wherein G is a bond, -O-or-S-, Ar²Is phenyl or is a monocyclic aromatic hydrocarbon radical having 5 or 6 ring atoms, having one carbon atom replaced by: > O, > S, > NH or > N (C)_1-4Alkyl) and up to one further carbon atom is optionally replaced by-N ═ and the radicals are optionally substituted by R^pMono-, di-or tri-substituted;

wherein R is^pIs a substituent independently selected from: -OH, -C_1-6Alkyl, -OC_1-6Alkyl, phenyl, -CN, -NO₂、-N(R^q)R^r、-C(O)N(R^q)R^r、-N(R^q)C(O)R^r、-N(R^q)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^q)R^r、-SCF₃Halogen, -CF₃、-OCF₃、-OCHF₂-COOH and-COOC_1-6An alkyl group;

wherein R is^qAnd R^rEach independently selected from-H, -C_1-6Alkyl and-C_2-6An alkenyl group; and

3)4-8 membered saturated or partially saturated heterocycle having 1 or 2 members selected from > O, > S (O)_0-2NH and > NC_1-6A ring hetero atom of an alkyl group, and having 0 or 1 carbonyl group, said ring being optionally substituted by R^pMono-, di-or tri-substituted;

b) phenyl or pyridyl fused to a 3-membered hydrocarbon moiety on two adjacent ring carbon atoms to form a fused 5-membered aromatic ring, one carbon atom in said moiety being substituted by > O, > S, > NH or > N (C) _1-4Alkyl) and up to one further carbon atom in said moiety is optionally replaced by-N ═ and fused rings are optionally substituted by R^tMono-, di-or tri-substituted;

wherein R is^tIs a substituent independently selected from: -OH, -C_1-6Alkyl, -OC_1-6Alkyl, phenyl, -CN, -NO₂、-N(R^u)R^v、-C(O)N(R^u)R^v、-N(R^u)C(O)R^v、-N(R^u)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^u)R^v、-SCF₃Halogen, -CF₃、-OCF₃、-OCHF₂-COOH and-COOC_1-6An alkyl group;

wherein R is^uAnd R^vEach independently is-H or C_1-6An alkyl group;

c) a phenyl group fused on two adjacent ring atoms to a 4-membered hydrocarbon moiety to form a fused 6-membered aromatic ring, wherein 1 or 2 carbon atoms are replaced by-N ═ and the fused ring is optionally substituted by R^tMono-, di-or tri-substituted;

d) naphthyl, which is optionally substituted by R^tMono-, di-or tri-substituted;

e) a monocyclic aromatic hydrocarbon group having 5 ring atoms, having a carbon atom as a point of attachment, having one carbon atom replaced with: > O, > S, > NH or > N (C)_1-4Alkyl) up to one further carbon atom being optionally replaced by-N ═ optionally by R^jMono-or disubstituted and optionally benzo-or pyridine-fused at two adjacent carbon atoms, wherein the benzo-or pyridine-fused moiety is optionally substituted with R^tMono-, di-or tri-substituted; and

f) monocyclic aromatic hydrocarbon groups having 6 ring atoms, having carbon atoms as points of attachment, having 1 or 2 carbon atoms replaced by-N ═ optionally by R ^jMono-or disubstituted and optionally benzo-or pyridine-fused at two adjacent carbon atoms, wherein the benzo-or pyridine-fused moiety is optionally substituted with R^tMono-or di-substitution;

the precondition is that:

when n is 1, L is-O-, Ar is unsubstituted phenyl, and R is²And R³When both are methyl, then R⁴Is not-OH.

The isomeric forms of the compounds of formula (I) and their pharmaceutically acceptable salts, esters and amides are included in the present invention, and such isomeric forms as described herein refers to at least one such isomer. One of ordinary skill in the art will appreciate that the compounds of the present invention may exist, for example, as a single isomer, while other compounds may exist as mixtures of regioisomers (regioisomers).

The invention also features pharmaceutical compositions containing the compounds and the use of the compounds and compositions in the treatment or prevention of histamine H₃Methods for the treatment of disease states mediated by the receptor and the 5-hydroxytryptamine transporter.

The compounds of the present invention may be used as a combination therapy in combination with other therapeutic agents, including in combination with: h₁Receptor antagonists, H₂Receptor antagonists, H₃Receptor antagonists and neurotransmitter modulators, such as 5-hydroxytryptamine-norepinephrine reuptake inhibitors, selective 5-hydroxytryptamine reuptake inhibitors (SSRI), norepinephrine reuptake inhibitors, non-selective 5-hydroxytryptamine reuptake inhibitors (NSSRI), and modafinil.

Other features and advantages of the invention will be apparent from the following detailed description and examples, and from the appended claims.

Detailed Description

Particularly preferred compounds of the invention include compounds of formula (I) or enantiomers, diastereomers, hydrates, solvates or pharmaceutically acceptable salts, amides or esters thereof, wherein n, m, R^1-5And Ar¹Having any of the meanings defined above and equivalents thereof, or at least one of the following values and equivalents thereof. When applicable to any definition, claim or embodiment defined herein, such values may be used:

preferably, L is-O-, and n is 1.

Preferably, L is-C.ident.C-and n is 0.

Preferably L is-CH₂CH₂-, n is 0.

Preferably R¹is-C_1-4An alkyl group.

In a preferred embodiment, R¹Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, benzyl, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, -COOCH₃-COO-tert-butyl and-COObenzyl.

More preferably R¹Methyl, ethyl, propyl, tert-butyl, allyl, propargyl or benzyl.

Even more preferably R ¹Is hydrogen or methyl.

Preferably when R is²When it is methyl, R³Is not methyl.

Preferably R²And R³Is hydrogen, or is optionally substituted, and is independently selected from the group consisting of:

A) methyl, ethyl, propyl, isopropyl, sec-butyl, pentyl, hexyl, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, dicyclopropylmethyl, benzhydryl, benzyl, -C (O) O-tert-butyl,

B) phenyl, pyridyl, 4-, 5-, 6-or 7-benzoxazolyl, 4-, 5-, 6-or 7-benzothienyl, 4-, 5-, 6-or 7-benzofuranyl, 4-, 5-, 6-or 7-indolyl, 4-, 5-, 6-or 7-benzothiazolyl, 4-, 5-, 6-or 7-benzimidazolyl, 4-, 5-, 6-or 7-indazolyl, imidazo [1, 2-a ] pyridin-5, 6, 7 or 8-yl, pyrazolo [1, 5-a ] pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo [2, 3-b ] pyridine-4, 5, 6 or 7-yl, 5 or 6-yl, 1H-pyrrolo [3, 2-c ] pyridin-4, 6 or 7-yl, 1H-pyrrolo [2, 3-c ] pyridin-4, 5 or 7-yl, 1H-pyrrolo [3, 2-b ] pyridin-5, 6 or 7-yl,

C) a naphthyl group,

D) azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and

E) furyl, oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2-or 3-benzothienyl, 2-or 3-benzofuranyl, 2-or 3-indolyl, 2-benzothiazolyl, 2-benzimidazolyl and 3-indazolyl.

More preferably R²And R³Independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, sec-butyl, hydroxyethyl, 2-hydroxy-2-methylpropyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, dicyclopropylmethyl, pyrrolidinyl, piperidinyl, N-methylpiperidinyl, tetrahydropyranyl, 2-benzothiazolyl and methoxyethyl.

Even more preferably R²And R³Each independently hydrogen, ethyl, isopropyl, methoxyethyl, 2-benzothiazolyl, cyclopropyl, cyclobutyl, or cyclopentyl.

In a preferred embodiment, R²And R³Optionally substituted and taken together with the nitrogen atom to which it is attached to form a tetrahydro-pyrimidin-2-ylidene or a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, 1, 3-dihydro-isoindol-2-yl, 5, 6-dihydro-4H-pyrimidin-1-yl, and 1, 1-dioxo-1. lamda⁶-thiomorpholin-4-yl.

Preferably R^fOptionally substituted, and is methyl, ethyl, isopropyl, allyl, cyclopropyl, tert-butoxycarbonyl, tetrahydrofuryl methyl, [1, 3 ]]Dioxolane-ylmethyl, thiazolyl, thienyl, thienylmethyl, pyridyl, phenyl, acetyl, isobutyryl, cyclopropanecarbonyl, cyclobutanecarbonyl, pyridyl, pyri Pyridine-carbonyl, 1H-pyrrole-carbonyl and 1H-imidazole-carbonyl.

In an alternative embodiment, R²And R³Taken together with the nitrogen atom to which they are attached to form a 4-to 8-membered heterocyclic ring selected from piperidine, pyrrolidine and morpholine, said ring being substituted with 1 or 2 substituents R^ffAnd (4) substitution.

Preferably R^ffSelected from methyl, ethyl, isopropyl, butyl, hexyl, -CHF₂Benzhydryl, -CF₃Vinyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclobutylethyl, bromo, chloro, fluoro, iodo, -OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, isopropoxy, pentyloxy, -O (CH)₂)₂O-、-O(CH₂)₃O-, -CN, amino, methylamino, dimethylamino, diethylamino, diethylcarbamoyl, methylthio, methylsulfonyl, methanesulfonamido, -C (O) Rⁱ-COOH and ethoxycarbonyl.

More preferably R^ffSelected from methyl, fluoro, -OH, -CF₃Hydroxymethyl, hydroxyethyl, benzhydryl, dimethylamino, ethoxycarbonyl, cyano and-O (CH)₂)₂O-。

Preferably RⁱSelected from the group consisting of methyl, pyridyl, isopropyl, cyclobutyl, cyclopropyl, N-methylpyrrolyl and 1-methylimidazolyl.

More preferably R²And R³Combined with the nitrogen atom to which they are attached to form azetidinyl, 3-difluoroazetidinyl, 3-benzhydryl-azetidinyl, 2-methylpyrrolidyl, 3-hydroxypyrrolidinyl, 3-dimethylaminopyrrolidinyl, 2, 5-dimethylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3-difluoropyrrolidinyl, piperidinyl, 4-fluoropiperidinyl, 3-difluoropiperidinyl, 4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl, 4-trifluoromethylpiperidinyl, 1, 4-dioxa-8-aza-spiro [4.5 ]Decan-8-yl, 4-cyanopiperidinyl, 4-ethoxycarbonyl (carboet)hoxy) piperidyl group, 3-hydroxypiperidinyl group, 4-hydroxypiperidinyl group, 2-hydroxymethylpiperidyl group, 3-hydroxymethylpiperidyl group, 4-hydroxymethylpiperidyl group, 3-hydroxyethylpiperidyl group, 4-hydroxyethylpiperidyl group, morpholinyl group, 2-methylmorpholin-4-yl group, 3-hydroxymethylmorpholin-4-yl group, 2-hydroxymethylmorpholin-4-yl group, 4-methyl-piperazin-1-yl group, 4-ethyl-piperazin-1-yl group, 4-isopropyl-piperazin-yl group, 4-allyl-piperazin-1-yl group, 4-cyclopropyl-piperazin-1-yl group, 4- (2-hydroxyethyl) -piperazin-1-yl group, 2-hydroxymethylpiperidyl group, 3-hydroxymethylpiperidyl group, 4-, 4- (2-methoxyethyl) -piperazin-1-yl, 4- (tert-butoxycarbonyl) -piperazin-1-yl, 4- (tetrahydrofuran-2-ylmethyl) -piperazin-1-yl, 4- [1, 3]-dioxolan-2-ylmethyl-piperazin-1-yl, 4-thiazol-2-yl-piperazin-1-yl, 4- (2-thienyl) piperazinyl, 4-thiophen-2-ylmethyl-piperazin-1-yl, 4- (pyridin-4-yl-) -piperazin-1-yl, 4-phenyl-piperazin-1-yl, 4- (2-hydroxyphenyl) piperazinyl, 4- (4-trifluoromethyl-phenyl) -piperazin-1-yl, 4- (4-cyanophenyl) -piperazin-1-yl, 4-acetyl-piperazin-1-yl, 4-thiazo l-methyl-piperazin-1-yl, 4-thiazo-methyl-piperazin-1-yl, 4-, 4-isobutyryl-piperazin-1-yl, 4-cyclopropanecarbonyl-piperazin-1-yl, 4-cyclobutanecarbonyl-piperazin-1-yl, 4-pyridin-4-yl-piperazin-1-yl, 4- (pyridine-4-carbonyl) -piperazin-1-yl, 4- (1-methyl-1H-pyrrole-2-carbonyl) -piperazin-1-yl, 4- (1-methyl-1H-imidazole-4-carbonyl) -piperazin-1-yl, 1-dioxo-1. lambda.6-thiomorpholin-4-yl, 2, 6-dimethylmorpholin-4-yl, and 1, 3-dihydro-isoindol-2-yl, 5, 6-dihydro-4H-pyrimidin-1-yl.

Even more preferably R²And R³Taken together with the nitrogen atom to which they are attached to form piperidinyl, 4-fluoropiperidinyl, 4-difluoropiperidinyl, morpholinyl or 3-methylmorpholin-4-yl.

Preferably R⁴Is hydroxy, methoxy, ethoxy, isopropoxy, pentyloxy, -CF₃Methyl, ethyl, propyl, isobutyl, pentyl, chlorine or fluorine.

More preferably R⁴Is hydroxy, methyl, methoxy, fluoro or-CF₃。

Preferably two R⁴Taken together to form a methylene group.

Preferably R²And one R⁴Combined together to form methylene, ethylene or-CH₂CH₂O-。

Preferably m is 0 or 1.

Preferably R⁵Is methyl, ethyl, isopropyl, hexyl, hydroxyl, methoxy, ethoxy, isopropoxy, methylthio, bromo, chloro, fluoro or iodo.

More preferably R⁵Is methyl, hydroxy or fluorine.

Preferably Ar¹Is optionally substituted, and is selected from:

a) phenyl, 5-, 6-, 7-, 8-benzo-1, 4-dioxanyl, 4-, 5-, 6-, 7-benzo-1, 3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-isoindolinyl, 1, 2, 3, 4-tetrahydro-quinolin-4, 5, 6 or 7-yl, 1, 2, 3, 4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,

b)4-, 5-, 6-or 7-benzoxazolyl, 4-, 5-, 6-or 7-benzothienyl, 4-, 5-, 6-or 7-benzofuranyl, 4-, 5-, 6-or 7-indolyl, 4-, 5-, 6-or 7-benzothiazolyl, 4-, 5-, 6-or 7-benzimidazolyl, 4-, 5-, 6-or 7-indazolyl, imidazo [1, 2-a ] pyridin-5, 6, 7 or 8-yl, pyrazolo [1, 5-a ] pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo [2, 3-b ] pyridin-4, 5 or 6-yl, optionally substituted heteroaryl, 1H-pyrrolo [3, 2-c ] pyridin-4, 6 or 7-yl, 1H-pyrrolo [2, 3-c ] pyridin-4, 5 or 7-yl, 1H-pyrrolo [3, 2-b ] pyridin-5, 6 or 7-yl,

c)5-, 6-, 7-or 8-isoquinolinyl, 5-, 6-, 7-or 8-quinolyl, 5-, 6-, 7-or 8-quinoxalinyl, 5-, 6-, 7-or 8-quinazolinyl,

d) a naphthyl group,

e) furyl, oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2-or 3-benzothienyl, 2-or 3-benzofuranyl, 2-or 3-indolyl, 2-benzothiazolyl, 2-benzimidazolyl, 3-indazolyl, and

f) pyridyl, pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, 1-, 3-or 4-isoquinolinyl, 2-, 3-or 4-quinolyl, 2-or 3-quinoxalinyl, 2-or 4-quinazolinyl, [1, 5], [1, 6], [1, 7] or [1, 8] naphthyridin-2-, 3-or 4-yl, [2, 5], [2, 6], [2, 7], [2, 8] naphthyridin-1, 3-or 4-yl.

More preferably Ar¹Optionally substituted, and is selected from phenyl, pyridyl, pyrazinyl, thiazolyl, pyrazolyl, and thienyl.

Preferably G is a bond or-S-.

Preferably Ar²Selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or pyrazinyl.

Even more preferably Ar¹Selected from the group consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-ethoxyphenyl, 2, 4-dimethoxyphenyl, 2, 5-dimethoxyphenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethoxyphenyl, 3, 4, 5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methoxyphenyl, and the like, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3-trifluoromethoxyphenyl group, 4-difluoromethoxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 3-acetylphenyl group, 4-acetylphenyl group, 3, 4-difluorophenyl group, 3, 4-dichlorophenyl group, 2, 3-difluorophenyl group, 2, 3-dichlorophenyl group, 2, 4-difluorophenyl group, 2, 4-dichlorophenyl group, 2, 5-dichlorophenyl group, 3, 5-dichlorophenyl group, m,3-nitrophenyl, 4-nitrophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, 3-chloro-4-difluoromethoxyphenyl, 3-fluoro-4-chlorophenyl, 2-fluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, benzo [1, 3 ]Dioxol-4-or 5-yl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3, 4-dihydroxyphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-morpholin-4-yl-phenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, 4-trifluoromethylthiophenyl, thiophen-2-yl, thiophen-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chloro-5-pyridyl, 2-hydroxy-3-yl, 4-morpholin-4-yl-phenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, 4-, 2-dimethylamino-5-pyridinyl, 6-methoxy-pyridin-3-yl, 6-methylsulfanyl-pyridin-3-yl, 2-hydroxy-5-pyridinyl, 6-pyrazol-1-yl-pyridin-3-yl, 6-bromo-pyridin-3-yl, 6-ethynyl-pyridin-3-yl, 6-trimethylsilylethynyl-pyridin-3-yl, 6-thiophenyl-pyridin-3-yl, 6-imidazol-1-yl-pyridin-3-yl, 6- (1H-imidazol-2-ylsulfanyl) -pyridin-3-yl, optionally substituted phenyl and unsubstituted phenyl, 6- (pyrimidin-2-ylsulfanyl) -pyridin-3-yl, oxazol-5-yl, thiazol-2-yl, 2H-pyrazol-3-yl, pyrazin-2-yl, 1-naphthyl, 2-naphthyl, 4-imidazol-1-ylphenyl, 4-pyrazol-1-ylphenyl, 1H-indol-5-yl, 1H-benzimidazol-5-yl, benzo [ b [ -b]Thiophen-7-yl and 4-biphenyl.

In a specific embodiment, Ar¹Optionally substituted by halogen and is 4-methoxyphenyl, 4-methylthiophenyl or 4-chlorophenyl.

Preferably when (a) n is 1, (b) L is-O-, (c) Ar is unsubstituted phenyl or phenyl substituted with fluorine, chlorine, nitro, trifluoromethyl, methyl or methoxy, and (d) R²And R³When it is hydrogen, methyl or ethyl, then R⁴Is not-OH.

Or, when (a) n is 1, (b) L is-O-, (c) Ar is optionally substituted phenyl, and (d) R²And R³When it is hydrogen, methyl or ethyl, then R⁴Is not-OH.

Or, R⁴Is not-OH.

The compounds of the present invention also include compounds of the following formula (II) and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof:

wherein n, m, R¹、R⁵And Ar¹As defined for formula (I);

x is 0 or 1;

wherein n + x is 1 or 2;

R³is hydrogen or is selected from:

A)-C_1-6alkyl, -C_3-6Alkenyl, -C_3-6Alkynyl, -C_3-7Cycloalkyl, -C_1-6Alkyl radical C_3-7Cycloalkyl, -CH (C)_3-8Cycloalkyl radicals₂-CH (phenyl)₂Benzyl and-C (O) OC_1-4Alkyl, wherein the alkyl, cycloalkyl or benzyl are each optionally substituted with: -OH, -OC_1-4Alkyl, -CN, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂Halogen, -CF₃、-OCF₃-COOH or-COOC _1-6An alkyl group;

C) a naphthyl group,

D) a 4-8 membered heterocyclic ring having as a point of attachment a carbon atom, having 1 or 2 ring heteroatoms selected from: > O, > S (O))_0-2、＞NH、＞N(C_1-4Alkyl) and > NC (O) OC_1-4Alkyl, and having 0 or 1 double bond; and

wherein each of said B) -E) is optionally mono-, di-or trisubstituted with a moiety selected from: -C_1-4Alkyl, -OH, -C_1-4Alkyl OH, -OC_1-6Alkyl, -CN, -NO₂、-N(R^d)R^e-C(O)N(R^d)R^e、-N(R^d)C(O)R^d、-N(R^d)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^d)R^e、-SCF₃Halogen, -CF₃、-OCF₃、-COOH、-COOC_1-6Alkyl, -OC (O) N (R)^d)R^eand-OC (O) OC_1-6An alkyl group;

wherein R is ^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

-R²-R⁴is methylene, ethylene, propylene or-CH₂CH₂O-, wherein each of said groups is optionally substituted with: -OH, -OC_1-6Alkyl, -SC_1-6Alkyl, -CF₃、-C_1-6Alkyl, amino or halogen;

R⁴is-OH, -OC_1-6Alkyl, -CF₃、-C_1-6Alkyl or halogen.

For formula (II), preferably n is 2 and x is 0. More preferably, n is 1 and x is 0. Even more preferably n is 1 and x is 1.

It will be appreciated that certain compounds of the invention are chiral and/or have geometric isomeric centres, for example the E-isomer and the Z-isomer. The present invention includes all such optical isomers, including stereoisomers and racemic mixtures, diastereomers and geometric isomers, which possess the characteristic activity of the compounds of the present invention. The compounds of the invention may exist as single enantiomers, mixtures of enantiomers or racemic mixtures. In certain embodiments, the absolute configuration of a single enantiomer is unknown. In addition, certain compounds described herein may exist in solvated as well as unsolvated forms. It is to be understood that the invention includes all such solvated and unsolvated forms which possess the characteristic activity of the compounds of the invention.

The compounds of the invention may be modified to a form detectable by some analytical technique and these are also included within the scope of the invention. The compounds of the invention may be labelled with radioactive elements, e.g.¹²⁵I、¹⁸F、¹¹C、⁶⁴Cu, etc., for imaging or for radiotherapy of a patient. Examples of such compounds are isotopically labelled compounds, e.g.¹⁸An F-isotopically-labelled compound which is useful as a probe for detection and/or imaging techniques such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT). Preferably by¹⁸F or¹¹The C-labeled compound of the invention is used as a Positron Emission Tomography (PET) molecular probe for researching histamine H₃Receptor and 5-hydroxytryptamine transporter mediated diseases. Another example of such compounds are isotopically labeled compounds, such as deuterium and/or tritium labeled compounds, which can be used for reaction kinetic studies. Alternatively, the first and second electrodes may be,³h-or¹⁴The C-labelled compounds are useful in biodistribution studies. The compounds described herein can be reacted with a suitable functionalized radioactive agent using conventional chemistry to provide radiolabeled compounds.

Prodrugs of the compounds of the present invention are included within the scope of the present invention. In general, such prodrugs are functional derivatives of the compounds that are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term "administering" includes treating the various disorders described herein with a compound of formula (I) or formula (II) or a compound that is capable of being converted in vivo to a compound of formula (I) or (II) after administration to a patient. Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of produgs", h. In addition to salts, the present invention provides esters, amides, and other protected or derivatized forms of the compounds.

Preferred compounds are tetrahydroisoquinoline compounds and are selected from:

examples	Chemical name
examples	Chemical name	1	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
1A	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);	1
1A		1B	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);
2	1- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolineQuinoline-7-yloxy]-propyl } -piperazin-1-yl) -ethanone;	1B
2		3	diethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;
4	(4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperazin-1-yl) -pyridin-4-yl-methanone;	3
4		5	1- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperazin-1-yl) -2-methyl-propan-1-one;
6	cyclobutyl- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy) ]-propyl } -piperazin-1-yl) -methanone;	5
6		7	cyclopropyl- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperazin-1-yl) -methanone;
8	7- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	7
8		9	4- (4-methoxy-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline
10	(1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -pyrrolidin-3-yl) -dimethyl-amine;	9
10		11	7- [3- ((2R, 5R) -trans-dimethyl-pyrrolidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

12	4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -piperazine-1-carboxylic acid ethyl ester;
12		13	(4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperazin-1-yl) - (1-methyl-1H-pyrrol-2-yl) -methanone;
14	(4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperazin-1-yl) - (1-methyl-1H-imidazol-4-yl) -methanone;	13
14		15	(1, 3-dimethyl-tetrahydro-pyrimidin-2-ylidene) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;
16	7- [3- (1, 3-dihydro-isoindol-2-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	15
16		17	bis- (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;
18	7- [3- (5, 6-dihydro-4H-pyrimidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	17
18		19	benzothiazol-2-yl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -methyl-amine;
20	1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -piperidin-3-ol;	19
20		21	1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -piperidin-4-ol;
22	(1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperidin-4-yl) -methanol;	21
22		23	(1-{3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ]-propyl } -piperidin-3-yl) -methanol;
24	(1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperidin-2-yl) -methanol;	23
24		25	4- (4-methoxy-phenyl) -2-methyl-7- [3- (3-trifluoromethyl-piperidin-1-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;

26	2- (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperidin-4-yl) -ethanol;
26		27	7- [3- (1, 1-dioxo-1. lamda.6-thiomorpholin-4-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
28	4- (4-methoxy-phenyl) -2-methyl-7- [3- ((2S) -trifluoromethyl-pyrrolidin-1-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	27
28		29	7- [3- (3, 3-difluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
29A	7- [3- (3, 3-difluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);	29
29A		29B	7- [3- (3, 3-difluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);
30	(1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy) ]-propyl } -pyrrolidin- (2R) -yl) -methanol;	29B
30		31	1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } - (R) -pyrrolidin-3-ol;
32	7- [3- (2, 6-dimethyl-morpholin-4-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	31
32		33	1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -piperidine-4-carboxylic acid ethyl ester;
34	7- (3-azetidin-1-yl-propoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	33
34		35	4- (4-methoxy-phenyl) -2-methyl-7- [3- (2-methyl-pyrrolidin-1-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;
36	2- (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperidin-2-yl) -ethanol;	35
36		37	1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -piperidine-4-carbonitrile;

37A	1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -piperidine-4-carbonitrile (enantiomer 1);
37A		37B	1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ]-propyl } -piperidine-4-carbonitrile (enantiomer 2);
38	4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-trifluoromethyl-piperidin-1-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	37B
38		39	7- [3- (3-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
40	ethyl- (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;	39
40		41	7- [3- (1, 4-dioxa-8-aza-spiro [4.5 ]]Decan-8-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
42	1- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-3-piperidin-1-yl-propan-2-ol;	41
42		43	7- [ 2-fluoro-3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
44	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	43
44		45A	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);
45B	7- [3- (4-fluoro-piperidine)-1-yl) -propoxy]-4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);	45A
45B		46	4- (3-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
47	4- (4-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	46
47		48	4- (3-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

49	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
49		50	4- (4-difluoromethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
51	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methanesulfonyl-phenyl) -2-methyl-1,2, 3, 4-tetrahydro-isoquinoline;	50
51		52	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
53	4- (3-chloro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	52
53		54	4- (2, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
55	4- (2, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	54
55		56	4- (3, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
57	2-methyl-7- (3-piperidin-1-yl-propoxy) -4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;	56
57		58	4- (3, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
59	2-methyl-7- (3-piperidin-1-yl-propoxy) -4-pyridin-3-yl-1,2, 3, 4-tetrahydro-isoquinoline;	58
59		60	2-methyl-7- (3-piperidin-1-yl-propoxy) -4- (trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
61	4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (racemate);	60
61		62	4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

63	4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);
63		64	2-tert-butyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
65	2-benzyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	64
65		66	2-ethyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
67	4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -2-propyl-1, 2, 3, 4-tetrahydro-isoquinoline;	66
67		68	2-isopropyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
69	4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	68
69		70	3- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl]-propan-1-ol;
71	2- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl]-ethanol;	70
71		72	2- (2-fluoro-ethyl) -4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
73	2-cyclopropyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	72
73		74	4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
75	4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);	74
75		75A	4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

76	4- (3, 4-dichloro-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
76		77	4- (3, 4-dichloro-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
78	4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	77
78		79	4- (3-chloro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
80	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	79
80		81	4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
82	4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	81
82		83	7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
84	4- (4-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	83
84		85	4- (4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
86	7- (1-cyclopentyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	85
86		87	7- (1-ethyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
88	4- (3-chloro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	87
88		89	4- (3-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

90	4- (2-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
90		91	7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
92	4- (3-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	91
92		93	4- (3-methoxy)-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
94	7- (1-cyclopentyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	93
94		95	7- (1-ethyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
96	4- (3-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	95
96		97	4- (3-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
98	7- (1-isopropyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	97
98		99	7- (1-cyclobutyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
100	7- (1-ethyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	99
100		101	7- (1-cyclopentyl-piperazine)Pyridin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
102	4- (3-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	101
102		103	7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

104	7- (1-cyclobutyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
104		105	7- (1-ethyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
106	4- (3-chloro-4-methoxy-phenyl) -7- (1-cyclobutyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	105
106		107	4- (3-chloro-4-methoxy-phenyl) -7- (1-ethyl-piperidin-4-ylmethoxy) -2-methyl-1,2, 3, 4-tetrahydro-isoquinoline;
108	4- (3-chloro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	107
108		109	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
110	7- (1-isobutyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	109
110		111	7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (3-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
112	4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	111
112		113	7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (2-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
114	4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	113
114		115	4- (2-fluoro-4-methoxy)-phenyl) -7- (1-isobutyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
116	7- [1- (2-fluoro-ethyl) -piperidin-4-ylmethoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	115
116		117	7- (1-isopropyl-piperidin-4-yloxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

118	7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
118		119	4- (2-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
120	4- (3-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	119
120		121	4- (4-methoxy-phenyl) -2-methyl-7- [1- (tetrahydro-pyran-4-yl)-piperidin-4-yloxy]-1, 2, 3, 4-tetrahydro-isoquinoline;
122	2, 2, 2-trifluoro-1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl]-piperidin-1-yl } -ethanone;	121
122		123	4- (4-methoxy-phenyl) -2-methyl-7- [1- (2, 2, 2-trifluoro-ethyl) -piperidin-4-ylmethoxy-piperidine]-1, 2, 3, 4-tetrahydro-isoquinoline;
124	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4-phenyl-1, 2, 3, 4-tetrahydro-isoquinoline;	123
124		125	4- (2-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
126	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4-p-tolyl-1, 2, 3, 4-tetrahydro-isoquinoline;	125
126		127	2-benzyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
128	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (3-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	127
128		129	7- [3- (3, 3-difluoro-pyrrolidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
130	4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	129
130		131	bicyclopropylmethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;

132	4- (2-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
132		133	2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-4- (4-morpholin-4-yl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
134	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-morpholin-4-yl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	133
134		135	4- { 2-methyl-7- [3- (3S-methyl)Yl-morpholin-4-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -benzonitrile;
136	4- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -benzonitrile;	135
136		137	7- [3- (3-benzhydryl-azetidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
138	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	137
138		139	4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (racemate);
140	4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);	139
140		141	4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);
142	4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (racemate);	141
142		143	4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);
144	4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);	143
144		145	4- (4-ethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

146	2-Ethyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
146		147	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
148	4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	147
148		149	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
150	4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	149
150		151	4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
152	7- [1- (2-fluoro-ethyl) -piperidin-4-yloxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	151
152		153	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);
154	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);	153
154		155	4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);
156	4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);	155
156		157	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);
158	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);	157
158		159	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

160	4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
160		161	7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
163	4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	161
163		164	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methylsulfinyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
165	4- (4-methylsulfinyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	164
165		165A	4- (4-methylsulfinyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);
167	4- (4-methanesulfonyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	165A
167		168	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2, 6-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline;
169	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline;	168
169		170	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ol;
171	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-8-ol;	170
171		172	2, 8-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
173	2, 6-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	172
173		174	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinolin-8-ol;

175	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinolin-6-ol;
175		176	8-fluoro-2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
177	6-fluoro-2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	176
177		178	7- [1- (2-fluoro-ethyl) -piperidin-4-ylmethoxy]-2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
179	7- [1- (2-fluoro-ethyl) -piperidin-4-yloxy]-2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	178
179		180	4- (4-methoxy-phenyl) -7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;
181	4- (4-methylsulfinyl-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	180
181		182	7- [3- (3, 3-difluoro-azetidin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
183	(4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy) ]-propyl } -morpholin-3-yl) -methanol;	182
183		183A	(4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -morpholin-3S-yl) -methanol;
184	(4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -morpholin-2-yl) -methanol;	183A
184		185	{3- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } - (2H-pyrazol-3-yl) -amine;
186	4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	185
186		187	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (6-methylsulfanyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

188	(5- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -pyridin-2-yl) -dimethyl-amine;
188		189	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (6-trimethylsilylethynyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;
190	4- (6-ethynyl-piperidin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	189
190		191	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (6-thiophenyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;
192	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (6-imidazol-1-yl-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	191
192		193	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (6-methoxy-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
194	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (6-pyrazol-1-yl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;	193
194		195	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- [6- (1H-imidazol-2-ylsulfanyl) -pyridin-3-yl]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
196	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- [6- (pyrimidin-2-ylsulfanyl) -pyridin-3-yl]-1, 2, 3, 4-tetrahydro-isoquinoline;	195
196		197	4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-methyl-piperazin-1-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;
198	7- [3- (4-ethyl-piperazin-1-yl) -Propoxy group]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	197
198		199	7- [3- (4-isopropyl-piperazin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
200	4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-thiazol-2-yl-piperazin-1-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	199
200		201	4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-thiophen-2-ylmethyl-piperazin-1-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;

202	2- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperazin-1-yl) -ethanol;
202		203	2- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperazin-1-yl) -phenol;
204	4- (4-methoxy-phenyl) -2-methyl7- [3- (4-pyridin-4-yl-piperazin-1-yl) -propoxy-group]-1, 2, 3, 4-tetrahydro-isoquinoline;	203
204		205	4- (4-methoxy-phenyl) -2-methyl-7- {3- [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl]-propoxy } -1, 2, 3, 4-tetrahydro-isoquinoline;
206	7- [3- (4-allyl-piperazin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	205
206		207	7-[3-(4-[1，3]-dioxolan-2-ylmethyl-piperazin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
208	4- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy)]-propyl } -piperazin-1-yl) -benzonitrile;	207
208		209	7- {3- [4- (2-methoxy-ethyl) -piperazin-1-yl]-propoxy } -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
210	4- (4-methoxy-phenyl) -2-methyl-7- {3- [4- (tetrahydro-furan-2-ylmethyl) -piperazin-1-yl]-propoxy } -1, 2, 3, 4-tetrahydro-isoquinoline;	209
210		211	4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -piperazine-1-carboxylic acid tert-butyl ester;
212	7- [3- (4-cyclopropyl-piperazin-1-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	211
212		213	4- (4-bromo-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
214	4- (4-difluoromethoxy-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	213
214		215	2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

216	7- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
216		217	7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
218	2-methyl-7- (3-morpholin-4-yl-propoxy) -4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	217
218		219	2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ]-4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
220	4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	219
220		221	4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;
222	2-methyl-7- (3-piperidin-1-yl-propoxy) -4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	221
222		223	{3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy-methyl]-propyl } - (tetrahydro-pyran-4-yl) -amine;
224	cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } - (1-methyl-piperidin-4-yl) -amine;	223
224		225	(2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3,4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;
226	3- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propylamino } -propan-1-ol;	225
226		227	allyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;
228	isobutyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ]-propyl } -amine;	227
228		229	cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;

230	isopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;
230		231	{3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy-methyl]-propyl } -propyl-amine;
232	ethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;	231
232		233	isopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -methyl-amine;
234	cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -methyl-amine;	233
234		235	bicyclic propyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl } -amine;
236	7- (1-isopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	235
236		237	7- (1-cyclopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
238	7- (1-cyclobutyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	237
238		239	7- [1- (2-fluoro-ethyl)) -azetidin-3-ylmethoxy]-2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
240	4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	239
240		240A	4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);
240B	4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);	240A
240B		241	4- (3-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

242	{4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl]-piperidin-1-yl } -acetonitrile;
242		243	2-methyl-7- (1-methyl)-piperidin-4-yloxy) -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
244	2-methyl-4- (4-methylsulfanyl-phenyl) -7- [1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yloxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	243
244		245	{4- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-piperidin-1-yl } -acetonitrile;
246	2-methyl-4- (4-methylsulfanyl-phenyl) -7- [1- (tetrahydro-pyran-4-yl) -piperidin-4-yloxy]-1, 2, 3, 4-tetrahydro-isoquinoline;	245
246		247	7- (1-cyclopropyl-piperidin-4-yloxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
248	7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	247
248		249	7- (1-cyclopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
250	1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl]-piperidin-1-yl } -2-methyl-propan-2-ol;	249
250		251	4- (4-methoxy-phenyl) -2-methyl-7- (4-methyl-morpholin-2-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
252	4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2S-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	251
252		253	4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2R-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
254	7- (4-isopropyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	253
254		255	7- (4-isopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

256	7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
256		256A	7- (4-isopropyl-morpholine)lin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);
256B	7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);	256A
256B		257	7- (4-ethyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
258	7- [4- (2-fluoro-ethyl) -morpholin-2-ylmethoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	257
258		259	7- (4-cyclopropyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
260	7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	259
260		260A	7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);
260B	7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);	260A
260B		261	7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
261A	7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);	261
261A		261B	7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);
262	7- (4-isopropyl-morpholin-2-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	261B
262		263	7- (4-cyclopropyl-morpholin-2-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

264	2-methyl-4- (4-methylsulfanyl-phenyl) -7- (morpholin-2-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
264		265	4- (4-methoxy-phenyl) -2, 6-dimethyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
266	4- (4-methoxy-phenyl) -2, 6-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	265
266		267	4- (3-fluoro-4-methoxy-phenyl) -2, 6-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
268	4- (3-fluoro-4-methoxy-phenyl) -2, 8-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	267
268		269	4- (4-methoxy-phenyl) -2, 8-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;
270	2, 6-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;	269
270		271	7- (4-piperidin-1-yl-but-1-ynyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;
272	7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;	271
272		273	2-methyl-7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;
274	7- [4- (4, 4-difluoro-piperidin-1-yl) -but-1-ynyl]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	273
274		275	4- (4-methoxy-phenyl) -2-methyl-7- (4-piperidin-1-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
276	4- (4-methoxy-phenyl) -2-methyl-7- (4-morpholin-4-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	275
276		277	4- (4-methoxy-phenyl) -2-methyl-7- (4-thiomorpholin-4-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
278	7- [4- (4-isopropyl-piperazin-1-yl) -but-1-ynyl]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	277

279	4- (4-fluoro-phenyl) -2-methyl-7- (4-piperidin-1-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
279		280	7- [4- (4, 4-difluoro-piperidin-1-yl) -butyl]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;
281	4- (4-methoxy-phenyl) -2-methyl-7- (4-morpholin-4-yl-butyl) -1, 2, 3, 4-tetrahydro-isoquinoline;	280
281		282	4- (4-methoxy-phenyl) -2-methyl-7- (4-thiomorpholin-4-yl-butyl) -1, 2, 3, 4-tetrahydro-isoquinoline;
283	7- [4- (4-isopropyl-piperazin-1-yl) -butyl]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;	282

and salts thereof.

The features and advantages of the present invention will be readily apparent to those of ordinary skill in the art. Various modifications and adaptations of those conditions and uses will occur to those skilled in the art in light of the present disclosure (including the summary, detailed, background, examples, and claims). All publications described herein are incorporated by reference in their entirety. When chemical symbols are used, it is understood that they are read from left to right, otherwise their spatial orientation is meaningless.

The compounds described above may be prepared according to methods within the skill of the art and/or as described in the schemes and examples below. To obtain the various compounds herein, starting materials bearing the ultimately desired substituents may be employed, although with or without protection as desired in the reaction scheme. This can be achieved by conventional protecting groups such as those described in the following references: "Protective Groups in Organic Chemistry", master catalog J.F.W.McOmie, plenum Press, 1973; greene and P.G.M.Wuts, "Protective Groups in organic Synthesis", 3 rd edition, John Wiley & Sons, 1999. The protecting group may be removed in a convenient subsequent step using methods known in the art. Alternatively, at the position of the final desired substituent, an appropriate group may be used, which may be carried throughout the reaction scheme and substituted with the desired substituent as appropriate. Such compounds, precursors or prodrugs also fall within the scope of the invention. The reaction may be carried out at a temperature between the melting point and the reflux temperature of the solvent, preferably between 0 ℃ and the reflux temperature of the solvent.

Acronyms or acronyms

Term(s) for	Acronyms or abbreviations
Term(s) for	Acronyms or abbreviations	N-butanol	n-BuOH
1, 2-dichloroethane	DCE	N-butanol	n-BuOH
1, 2-dichloroethane	DCE	Methylene dichloride	DCM
Diisopropylethylamine	DIPEA	Methylene dichloride	DCM
Diisopropylethylamine	DIPEA	Ethylene glycol dimethyl ether	DME
N, N-dimethylformamide	DMF	Ethylene glycol dimethyl ether	DME
N, N-dimethylformamide	DMF	Ethyl acetate	EtOAc
Ethanol	EtOH	Ethyl acetate	EtOAc
Ethanol	EtOH	Methanol	MeOH
Triethylamine	TEA	Methanol	MeOH
Triethylamine	TEA	Tetrahydrofuran (THF)	THF

Tetrahydroisoquinoline compounds of formula (I) and (II) can be prepared by a variety of reaction schemes. Methods for synthesizing compounds of formula (I) and (II) are described in schemes A-C. One skilled in the art will recognize that the production of certain compounds by a certain procedure may be advantageous over the production of other compounds. Additional methods of use are described in U.S. patent application No. 60/691,958 (6/17/2005) and U.S. patent application No. 60/692,003 (6/17/2005).

Procedure A

For scheme a, reagents of formulae a1, a2, and a5 are commercially available or can be prepared by known methods. Following the Williamson ether synthesis scheme, a suitable base such as K is used₂CO₃、Na₂CO₃Or NaH, in a solvent such as acetonitrile, with or without KI or NaI catalysts, reacting the 3-hydroxybenzaldehyde derivative a1 with an alcohol a2 to produce ether A3. Alternatively, ethers of formula A3 were prepared under Mitsunobu conditions in which a2 contained a protected hydroxyl group instead of a bromo substituent. Reductive amination of the aldehyde function of compound A3 will give a compound of formula A4. The aldehyde may be treated with a suitable R1-containing amine with or without the addition of an activator such as a protonic acid or Lewis acid (Lewis acid) and the addition of a suitable reducing agent such as NaBH ₄、NaCNBH₃Or NaB (OAc)₃H. Preferred conditions include NaBH₄The methanol solution of (1). Alkylation of amine a4 with α -halo ketone a5 produces ketone a6, which is accomplished in the presence of a tertiary amine base such as TEA or DIPEA in a suitable solvent such as THF or DCM. Cyclization to produce tetrahydroisoquinoline A7 includes cyclization to produce tetrahydroisoquinolinium salts by exposure to a suitable protic or Lewis acid such as methanesulfonic acid (MSA), trifluoroacetic acid (TFA), AlCl₃、TiCl₄Or BF₃·OEt₂With or without a solvent such as DCM. Preferred conditions are pure MSA or a DCM solution of MSA. With standard reducing agents, e.g. NaCNBH₃The acid methanol medium of (2) can reduce the intermediate salt. Alternatively, previously known methods (including NaBH)₄) The ketones a6 are reduced to their corresponding alcohols. The intermediate alcohol was treated with MSA in DCM to afford cyclic compound A7. Finally, the pendant primary alcohol group in compound a7 was converted to the corresponding amine a9 by activation to yield a suitable leaving group (e.g., mesylate or bromide), which was then replaced with the appropriate amine A8. With a suitable base, e.g. Na₂CO₃The metathesis reaction is carried out in a polar solvent such as n-BuOH with or without KI or NaI catalyst. Alternatively, the aldehyde may be subjected to reductive amination by oxidation of the alcohol, Preparation of amine A9.

Process A1

For scheme A1, benzaldehyde A1 can also be alkylated with a suitable alcohol A10 under, for example, Mitsunobu conditions, where Q is-NR²R³Or a protected amino group or substituent. Ether A11 can be changed to Compound A12 as described in scheme A.

Procedure B

For scheme B, the ether of formula A3 can be first converted to the corresponding optionally protected amine B1 as described in scheme A. Benzaldehyde B1 is then converted to diamine B2 using the reductive amination scheme of scheme A. Alkylation as shown in scheme A leads to ketone B3, which is cyclized to form the compound of formula A12.

Procedure C

For scheme C, compounds of formula A12 can also be prepared using the Pictet-Spengler protocol. Intermediates of formula C1 can be prepared by a variety of methods including scheme a and scheme B. Aryl bromide C1, halogen-metal exchanged, is reacted with nitroalkene C2 to yield a compound of formula C3. The nitro group is reduced to the amine by methods well known to those skilled in the art and then alkylated or reductively aminated to give the amine C4. Reaction of amine C4 with a formaldehyde equivalent such as formaldehyde, formic acid or a formaldehyde equivalent under Pictet-Spengler conditions results in the formation of the tetrahydroisoquinoline series of compound a 12.

Procedure D

For scheme D, aryl bromides D1 can be obtained according to the procedures described in schemes A-C. In the presence of palladium catalysts such as PdCl₂(PPh₃)₂Or Pd (PPh)₃)₄Phosphine ligands such as PPh₃With optional addition of copper (I) iodide and diethylamine or the like, palladium is coupled with a suitable alkyne such as the functionalized alkyne D2 (optionally hydroxyl protected) or D3 in a solvent such as DMF or DME at a temperature between room temperature and the reflux temperature of the solvent, or using a high pressure reaction vessel. When alkynes D5 are formed, they can be converted to compounds of formula (I) according to scheme a. In the presence of palladium catalysts such as Pd/BaSO₄Or Pd (OH)₂Alkynes D5 or D6 may be hydrogenated in the presence of a solvent such as methanol or ethanol to produce alkanes D7 and D8. Alkane D7 can be converted to a compound of formula (I) according to scheme a.

Procedure E

Compounds of formula (I) can also be prepared according to scheme E. Aryl bromides E1 are commercially available or can be readily prepared by known methods, the aryl bromides E1 being alkylated by the nucleophilic aromatic substitution: by a) treating E1 with a strong base such as NaH or BuLi in a solvent such as THF at a temperature between 0 ℃ and the reflux temperature of the solvent; and b) with a suitable electrophilic Ar¹-F or Ar¹-Cl reagents such as 1-fluoro-4-nitro-benzene, 2-chloropyridine or 4-fluoropyridine. With a suitable reducing agent, e.g. hydrogen, and a catalyst LiAlH ₄Or NaBH₄(warp I)₂Or Raney nickelConversion) of nitrile E2 to amine E3 in a solvent such as THF at a temperature ranging from room temperature to the reflux temperature of the solvent. The amine E3 can be protected as carbamic acid C_1-4Alkyl esters, such as methyl carbamate (not shown), or they may be alkylated using a reductive amination scheme to give the amine E4. Amine E3, a carbamate-protected analog thereof, or amine E4 are all suitable reagents for Pictet-Spengler cyclization, which is accomplished according to the scheme depicted in scheme C. The cyclized product E5 can be converted to the compound of formula (I) using the methods described in the schemes above, particularly schemes A and D.

For each of the above schemes, when the group Q is-NR²R³Compounds A12, D6 and D8 all fall within the scope of formula (I). When the group Q is a protected amino group or a surrogate, it will be understood by those skilled in the art that Q may be converted to-NR by conventional deprotection methods, optionally by alkylation or reductive amination at any of several points in the synthetic procedure²R³。

The compounds prepared according to the above schemes may be obtained as single enantiomers, diastereomers or regioisomers, or as racemic mixtures or as mixtures of enantiomers, diastereomers or regioisomers. When a mixture of regioisomers or diastereomers is obtained, the isomers may be separated by conventional methods such as chromatography or crystallization. When a mixture of racemic (1: 1) and non-racemic (other than 1: 1) enantiomers is obtained, the single enantiomers can be separated by conventional separation methods known to those skilled in the art. Particularly useful separation methods may include chiral chromatography, recrystallization, formation of diastereomeric salts or derivatization into diastereomeric adducts followed by separation.

For therapeutic use, salts of the compounds of the present invention are pharmaceutically acceptable salts. However, non-pharmaceutically acceptable acid and base salts may also be used, for example, during the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

Pharmaceutically acceptable salts, esters and amides of the compounds of the invention are meant to be salts, esters and amides of the compounds of the invention which are apparent to the pharmaceutical chemist, i.e. they are non-toxic and have a beneficial effect on the pharmacokinetic properties of the compounds of the invention. These compounds with beneficial pharmacokinetic properties are obvious to the pharmaceutical chemist that they are non-toxic and that their pharmacokinetic properties provide adequate palatability, absorption, distribution, metabolism and excretion. Other factors that are more practical in nature and also important in the selection are raw material cost, ease of crystallization, yield of the resulting bulk drug (bulk drug), stability, hygroscopicity and flowability.

Examples of acids useful for preparing pharmaceutically acceptable salts include the following: acetic acid, 2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+) -camphoric acid, camphorsulfonic acid, (+) - (1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid (cyclamic acid), cyclohexanesulfamic acid (cyclamate acid), dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, alpha-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, formic acid, benzoic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric, Hydrochloric acid, hydroiodic acid, (+) -L-lactic acid, (±) -DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-) -L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

The compounds of the present invention containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable salt forms of the bases include, for example, ammonium salts; alkali metal salts and alkaline earth metal salts (e.g., lithium, sodium, potassium, magnesium and calcium salts, which may be prepared by treatment with, for example, magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide); and amine salts prepared with organic bases such as primary, secondary, tertiary aliphatic and aromatic amines such as L-arginine, benzphetamine, benzathine, choline, dinor, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylamine, 1, 2-ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amine, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol and tris). See, e.g., s.m. berge et al, "Pharmaceutical Salts", j.pharm. sci, 1977, 66: 1-19, which are incorporated herein by reference.

Pharmaceutically acceptable esters and amides are those which are pharmacologically effective, within a reasonable benefit/risk ratio, and which are adapted to contact the tissues of a patient without undue toxicity, irritation, or allergic response. Representative pharmaceutically acceptable amides of the invention include amides derived from: ammonia, C_1-6Alkyl primary amines and di (C)_1-6Alkyl) secondary amines. Secondary amines include 5-or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally 1-2 additional heteroatoms. Preferred amides are from ammonia, C_1-3Alkyl primary amines and di (C)_1-2Alkyl) amines.

Representative pharmaceutically acceptable esters of the invention include C_1-7Alkyl ester, C_5-7Cycloalkyl esters, phenyl esters, substituted phenyl esters and phenyl C_1-6An alkyl ester. Preferred esters include methyl esters. Further, examples of suitable esters include esters in which more than one carboxyl substituent is substituted with: p-methoxybenzyloxy-carbonylA group, 2, 4, 6-trimethylbenzyloxycarbonyl, 9-anthracenyloxycarbonyl, CH₃SCH₂COO-, tetrahydrofuran-2-yloxycarbonyl, tetrahydropyran-2-yloxy-carbonyl, furan-2-yloxycarbonyl, benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2, 2, 2-trichloroethoxy-carbonyl, 2, 2, 2-tribromoethoxycarbonyl, tert-butoxycarbonyl, tert-pentoxycarbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycarbonyl, 2-benzyloxyphenoxycarbonyl, 4-methylthiophenoxycarbonyl or tetrahydropyran-2-yloxycarbonyl.

The compound of the invention is histamine H₃Modulators of the receptor and 5-hydroxytryptamine transporter, such that said compounds are useful for the treatment of histamine H₃And 5-hydroxytryptamine mediated disease states. The compounds of the invention have a 5-hydroxytryptamine transporter and H₃Receptor modulating activity. As such modulators, the compounds may act as antagonists or agonists. Inverse agonists may also produce antagonist effects.

The compounds of the invention are useful in methods of treating or preventing the following neurological or CNS disorders: including disorders of sleep/wake and arousal/vigilance (e.g., insomnia, jet lag and disturbed sleep), Attention Deficit Hyperactivity Disorder (ADHD), attention deficit disorder, learning and memory disorders, learning impairment, memory loss, cognitive disorders, migraine, neuroinflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy with or without cataplexy, sleep/thought homeostatic disorder, idiopathic somnolence, Excessive Daytime Sleepiness (EDS), circadian rhythm disorder, sleep/fatigue disorder, fatigue, sleep apnea-related drowsiness, decreased sleep due to hormonal variations in the peri-menopause, Parkinson-related fatigue, MS-related fatigue, depression-related fatigue, chemotherapy-induced fatigue, Work-related fatigue, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, mania and depression. The method comprises the step of administering to a mammal suffering from the disease an effective amount of at least one compound of the present invention.

Specifically, histamine H₃Modulators of the receptor and 5-hydroxytryptamine transporter, the compounds of the present invention are useful for the treatment or prevention of depression, disturbed sleep, fatigue, lethargy, cognitive decline, memory loss, learning decline and attention deficit disorder.

The present invention also contemplates the treatment or prevention of histamine H with combination therapy₃A method of treating a disease or condition mediated by a receptor and a 5-hydroxytryptamine transporter, comprising administering at least one compound of the invention and one or more therapeutic agents. Suitable therapeutic agents include: h₁Receptor antagonists, H₂Receptor antagonists, H₃Receptor antagonists and neurotransmitter modulators, such as 5-hydroxytryptamine-norepinephrine reuptake inhibitors, selective 5-hydroxytryptamine reuptake inhibitors (SSRI), norepinephrine reuptake inhibitors, non-selective 5-hydroxytryptamine reuptake inhibitors (NSSRI), and modafinil. In a particular embodiment, the combination therapy comprises the administration of at least one compound of the invention and the administration of modafinil, for example, for the treatment of narcolepsy, Excessive Daytime Sleepiness (EDS), alzheimer's disease, depression, attention deficit disorder, MS-related fatigue, post-anesthesia weakness (post-anesthesia grogginess), cognitive decline, schizophrenia, spasticity with cerebral palsy, age-related memory decline, idiopathic somnolence, or jet-lag.

The compounds of the invention may be administered in the form of pharmaceutical compositions to treat patients suffering from H₃Patients (humans and other mammals) for diseases mediated by the receptor and the 5-hydroxytryptamine transporter. Accordingly, the invention features pharmaceutical compositions containing at least one compound of the invention and a pharmaceutically acceptable carrier. The compositions of the invention may also comprise at least one other therapeutic agent (e.g., a combination of differently formulated active agents in a combined preparation or combination therapy).

The invention also features methods of using or making or formulating the pharmaceutical compositions. The pharmaceutical compositions may be prepared using conventional pharmaceutical excipients and mixing techniques known to those skilled in the art of dosage form preparation. It is contemplated that the compounds of the present invention may be administered by oral, parenteral, rectal, topical or intraocular routes or by inhalation. The formulations may also be designed to release the active ingredient slowly. The formulations may be in the form of tablets, capsules, cachets, vials (tubes), powders, granules, lozenges, reconstituted powders, liquids, or suppositories. Preferably the compounds may be administered by intravenous infusion or topically, but more preferably by oral administration.

For oral administration, the compounds of the invention may be in the form of tablets or capsules or in the form of solutions, emulsions or suspensions. Tablets for oral use may contain the active ingredient in admixture with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like; typical liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone, sodium starch glycolate, microcrystalline cellulose and alginic acid are all suitable disintegrants. The binder may include starch and gelatin. The lubricant (if included) is typically magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be enteric-coated. Capsules for oral use include hard gelatin capsules wherein the active ingredient is mixed with a solid, semi-solid or liquid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water, an oil (e.g. peanut oil or olive oil), liquid paraffin, a mixture of mono-and di-glycerides of short chain fatty acids, polyethylene glycol 400 or propylene glycol.

The liquid for oral administration may be a suspension, solution, emulsion or syrup or may be a dry product which is reconstituted with water or other suitable vehicle just prior to use. Such liquid compositions may contain pharmaceutically acceptable excipients such as: suspending agents (e.g., sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, etc.); non-aqueous vehicles including oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol or water; preservatives (e.g., methyl paraben, propyl paraben, or sorbic acid); wetting agents, such as lecithin; if necessary, flavoring agent or coloring agent is also contained.

The compounds of the present invention may also be administered by non-oral routes. The compositions may be formulated as suppositories for rectal administration. For parenteral use (including intravenous, intramuscular, intraperitoneal or subcutaneous routes), the compounds of the invention are generally prepared as sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in a parenterally acceptable oil. Suitable aqueous vehicles include ringer's solution and isotonic sodium chloride. Such forms may be presented in unit dosage form (e.g., ampoules or disposable injection devices) or in multi-dose form (e.g., vials (tubes) from which appropriate doses may be drawn) or in solid form or in pre-concentrated form (which may be used to prepare preparations for injection). Another mode of administration of the compounds of the present invention may utilize a patch for transdermal administration. The compounds of the present invention may also be administered by inhalation via the nasal or oral route using a spray formulation comprised of the compound of the present invention and a suitable carrier.

Methods for determining the effective amount of a pharmaceutical composition or combination of the invention (whether formulated in the same composition or not) for therapeutic and prophylactic purposes are known in the art. The specific dosage level for any particular patient will depend upon a variety of factors including the severity of the condition to be treated, the route of administration and the weight of the patient. For therapeutic purposes, an "effective dose" or "effective amount" is intended to mean that the biological response in a tissue system, animal or human, is elicited by each active compound or drug, alone or in combination, as determined by a researcher, veterinarian, medical doctor or other clinicianOr the amount of drug response (including alleviation of symptoms of the disease being treated). For prophylactic purposes (i.e., to inhibit the onset or progression of a disease), "effective dose" or "effective amount" means that each active compound or drug alone or in combination with one another, as determined by a researcher, veterinarian, medical doctor or other clinician, inhibits the onset or progression of a disease in a patient by delaying the onset or progression of a disease caused at least in part by histamine H₃Modulation of the receptor and/or 5-hydroxytryptamine transporter. Thus, the present invention provides a combination of two or more agents, wherein, for example, (a) each agent is administered in an independent therapeutically or prophylactically effective amount; (b) at least one drug is administered in a subtherapeutic or subtherapeutic amount when administered alone, but in a therapeutic or prophylactic amount when administered in combination with a second or additional drug of the invention; or (c) both agents are administered in a subtherapeutic or subtherapeutic amount when administered separately, but are administered in a therapeutic or prophylactic amount when administered together. Combinations of more than three drugs are possible in a similar manner. Combination therapy methods include the simultaneous administration of a single formulation containing all of the active agents; administering more than one formulation substantially simultaneously; and administering two or more separately formulated active agents.

It is contemplated that the daily amount (whether administered as a single dose or in divided doses) will range from 0.01 to 1000 mg/day, more usually from 1 to 500 mg/day, and most usually from 10 to 200 mg/day. Typical doses, if expressed in doses per unit body weight, are between 0.0001mg/kg and 15mg/kg, especially between 0.01mg/kg and 7mg/kg, most especially between 0.15mg/kg and 2.5 mg/kg.

A preferred oral dosage range is about 0.05-200mg/kg, administered once daily, in 1-4 divided doses. Certain compounds of the invention may be administered orally in the range of about 0.05mg/kg to about 50mg/kg per day, others may be administered in the range of 0.05mg/kg to about 20mg/kg per day, and others may be administered in the range of 0.1mg/kg to about 10mg/kg per day. The infusion dose ranges from about 1-1000 μ g/kg/min of inhibitor, mixed with a pharmaceutically acceptable carrier, administered over a period ranging from several minutes to several days. For topical administration, the compounds of the present invention may be combined with a pharmaceutically acceptable carrier in a concentration of from about 0.1% to about 10% drug in a vehicle.

Examples

For the purpose of illustrating the invention, the following examples are included. These examples are not intended to limit the present invention. They are used only to suggest a method of practicing the invention. Those skilled in the art will find other ways of practicing the invention that will be apparent to them. However, these methods are considered to fall within the scope of the present invention.

When solutions or mixtures are "concentrated", they are usually concentrated under reduced pressure using a rotary evaporator.

Normal phase Flash Column Chromatography (FCC) is usually carried out on a RediSep ® silica gel column using 2MNH₃MeOH/DCM of (g/g) as eluent.

Preparative reverse phase High Performance Liquid Chromatography (HPLC) was performed using A Gilson ® instrument using YMC-Pack ODS-A, 5 μm, 75X 30mm column, flow rate 25 ml/min, detection at 220nm and 254nm, with A15% -99% acetonitrile/water/0.05% TFA gradient.

Analytical reverse phase HPLC is generally performed using the following instruments and conditions: 1) hewlett packard Series 1100 instrument, with an Agilent ZORBAX ® Bonus RP, 5 μm, 4.6X 250mm column, flow rate 1 ml/min, detection at 220nm and 254nm, gradient with 1% -99% acetonitrile/water/0.05% TFA; or 2) Hewlett Packard HPLC apparatus using an Agilent ZORBAX ® Eclipse XDB-C8, 5 μm, 4.6X 150mm column, flow rate 1 ml/min, detection at 220nm and 254nm, with a gradient of 1% -99% acetonitrile/water/0.05% TFA.

Chiral chromatography is generally performed in the following manner. Preparative Supercritical Fluid Chromatography (SFC) was performed using a thumb Technologies ® instrument using a Chiracel AD, 10 μm, 250X 20mm column, flow rate 37 g/min, detection at 220nm and 254nm, pressure 150 bar (bar), temperature 35 ℃, isocratic 30% isopropanol/70% CO ₂A mobile phase. Analytical SFC was generally performed using a Jasco ® instrument using a Chiracel AD, 10 μm, 250X 4.6mm column, flowThe speed is 1 g/min, the detection is carried out at 220nm and 254nm, the pressure is 150bar, the temperature is 35 ℃, the isocratic 30% isopropanol/70% CO₂A mobile phase. Chiral HPLC was performed using a Chiracel AD-H, 21X 250mm, 5. mu.M (Chiral technologies) column, flow rate 8 ml/min, eluent 0.2% Et₂NH/EtOH。

Mass spectra were acquired on Agilent series 1100MSD, using electrospray ionization (ESI), in the positive or negative mode shown. The calculated molecular weight corresponds to the exact molecular weight.

Merck silica gel 60F for thin layer chromatography₂₅₄2.5cm by 7.5cm 250 μm or 5.0cm by 10.0cm 250 μm. Preparative EMScience silica gel 60F for thin layer chromatography₂₅₄20cm by 20cm 0.5mm pre-coated plate (with 20cm by 4cm concentrated bands).

NMR spectra were taken on Bruker DPX400 (400MHz), DPX500 (500MHz), DRX600 (600MHz) spectrometers.¹The H NMR data format is as follows: chemical shifts in ppm (multiplicity, coupling constant j (hz), integral) at the magnetic field of the tetramethylsilane reference.

When a potential chiral center is represented by a solid bond (rather than a bold or dashed bond), the structure refers to a racemic mixture, a mixture of enantiomers, or the single enantiomer. When a single enantiomer is described at a chiral center without enantiomeric designation, it goes without saying that the absolute configuration of the single enantiomer is unclear.

Example 1 (racemate), 1A (enantiomer 1) and 1B (enantiomer 2): 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- (3-hydroxy-propoxy) -benzaldehyde. To 3-hydroxybenzaldehyde (40.0g, 328mmol), K₂CO₃(68.0g, 491mmol) and acetonitrile (650ml) 3-bromo-propan-1-ol (54.6g, 393mmol) was added and the mixture heated to reflux for 2 days. The mixture was allowed to cool to room temperature (rt), the white solid was removed by filtration and the filtrate was concentrated. The crude product was purified by FCC to give the desired product (53.4g, 90%, clear oil). Ms (esi): c₁₀H₁₂O₃Calculated value of molecular weight of (c): 180.2 of the total weight of the mixture; m/z found: 181[ M + H ]]⁺。

¹H NMR(CDCl₃)：9.95(s，1H)，7.46-7.41(m，2H)，7.39(s，1H)，7.18-7.15(m，1H)，4.17(t，J＝6.0，2H)，3.87-3.85(m，2H)，2.09-2.03(m，2H)，1.96-1.87(m，1H).

Step 2: 3- (3-methylaminomethyl-phenoxy) -propan-1-ol. To a solution of 3- (3-hydroxy-propoxy) -benzaldehyde (30.0g, 167mmol) and aqueous MeNH at 0 deg.C₂(40% wt, 27.2ml, 350mmol) of MeOH (330ml) was added NaBH in portions₄(12.0g, 316 mmol). The reaction mixture was stirred at 0 ℃ for 30 minutes. The ice-water bath was then removed and the reaction was stirred at room temperature overnight. The mixture was concentrated and the residue was stirred in 1N NaOH (300ml) for 2 h. The resulting product was extracted with DCM and the combined organic layers were washed with brine, over Na ₂SO₄Drying and concentration gave the product (32.5g, 100%, clear oil). Ms (esi): c₁₁H₁₇NO₂Calculated value of molecular weight of (c): 195.2, respectively; m/z found: 196.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.24-7.21(m，1H)，6.91-6.88(m，1H)，6.89(d，J＝7.5，1H)，6.80(dd，J＝8.1，2.1，1H)，4.12(t，J＝6.1，2H)，3.82(t，J＝5.9，2H)，3.74(s，2H)，2.44(s，3H)，2.07-2.00(m，2H).

And step 3: 2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino } -1- (4-methoxy-benzene) Alkyl) -ethanones. To a solution of 3- (3-methylaminomethyl-phenoxy) -propan-1-ol (43.5g, 166mmol) and DIPEA (32.5g, 250mmol) in THF (415ml) was added 2-bromo-4' -methoxyPhenyl-acetophenone (40.0g, 175 mmol). The mixture was stirred at room temperature for 45 minutes, then most of the THF was removed in vacuo. The mixture was diluted with water (200ml) and extracted with DCM. The combined organic layers were washed with brine, over Na₂SO₄Drying and concentration gave a pale yellow oil (62g) which was used without purification. Ms (esi): c₂₀H₂₅NO₄Calculated value of molecular weight of (c): 343.42, respectively; m/z found: 344.5[ M + H ]]⁺。

And 4, step 4: 7- (3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -2-methyl-isoquinolinium Salt (salt). 2- { [3- (3-hydroxy-propoxy) -benzyl at 60 deg.C]-methyl-amino } -1- (4-methoxy-phenyl) -ethanone (62g, 181mmol) was stirred in methanesulfonic acid (MSA, 60ml) overnight. The mixture was poured into cold 1N NaOH (500ml), basified with 6N NaOH and extracted with DCM (3 times). The combined organic layers were washed with brine, over Na ₂CO₃Drying and concentration gave the desired product (62.3g) which was used without further purification. Ms (esi): c₂₀H₂₂NO₃ ⁺Calculated value of molecular weight of (c): 324.39, respectively; m/z found: 324.5[ M + H]⁺。

And 5: 3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy Base of]-propan-1-ol. To a solution of 7- (3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -2-methyl-isoquinolinium salt (2.5g, 7.7mmol) in MeOH (100ml) was added NaCNBH in one portion₃(1.5g, 23.1 mmol). Bromocresol green (3mg, 0.004mmol) was added, followed by 1.25M HCl with methanol, until the color changed from orange-brown or green to yellow. The mixture was stirred for an additional 30 minutes, and periodically methanol in HCl was added to maintain the yellow color. The mixture was concentrated and the residue was diluted with water, basified with 1N NaOH and extracted with DCM (3 times). The combined organic layers were washed with brine, over Na₂CO₃Dried and concentrated. The crude product was purified by FCC to give the desired product (1.2g, 28%, orange semi-solid, over 3 steps). Ms (esi): c₂₀H₂₅NO₃Calculated value of molecular weight of (c): 327.42, respectively; m/z found: 328.4[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：7.17(d，J＝11.5，2H)，6.92(d，J＝11.5，2H)，6.85-6.72(m，3H)，4.67-4.58(m，2H)，4.54(br s，1H)，4.09(t，J＝5.3，2H)，3.80(s，3H)，3.83-3.76(m，1H)，3.71(t，J＝6.1，2H)，3.46(br s，1H)，3.07(s，3H)，1.97-1.92(m，2H).

Step 6: methanesulfonic acid 3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy]-propyl ester. Methanesulfonyl chloride (0.20g, 1.75mmol) was added dropwise to 3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy) at 0 deg.C ]-Propan-1-ol (0.52g, 1.59mmol) and TEA (0.24g, 2.38mmol) in DCM (8 ml). The mixture was warmed to room temperature and stirred for 20 minutes. The mixture was then diluted with DCM (30ml) and saturated NaHCO₃The aqueous solution (15ml), water (15ml) and brine (15ml) were washed over MgSO₄Dried and concentrated to give the crude product (0.60g, 93%). Ms (esi): c₁₈H₂₆N₂Calculated value of molecular weight of O: 405.51, respectively; m/z found: 406.4[ M + H]⁺。

Step 7: a mixture of 4-fluoropiperidine hydrochloride (128mg, 0.92mmol), sodium tert-butoxide (60mg0.62mmol) and n-BuOH (1ml) was added to methanesulfonic acid 3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propyl ester (250mg, 0.62mmol), Na₂CO₃(98mg, 0.92mmol), KI (5mg, 0.031mmol) and n-BuOH (1.2ml), and the resulting mixture was heated at 50-80 ℃ overnight. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The crude product was purified by FCC and then reverse phase chromatography to afford the desired product (98mg, 25%, TFA salt). Ms (esi): c₂₅H₃₃FN₂O₂Calculated value of molecular weight of (c): 412.54, respectively; m/z found: 413.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.19(d，J＝8.6，2H)，6.95(d，J＝8.5，2H)，6.86-6.75(m，3H)，5.04(d，J＝48, 1H), 4.71-4.56(m, 3H), 4.12(t, J ═ 4.9, 2H), 3.89-3.80(m, 1H), 3.81(s, 3H), 3.64-3.61(m, 2H), 3.50(br s, 1H), 3.42(t, J ═ 7.2, 2H), 3.29-3.20(m, 2H), 3.12(s, 3H), 3.36-3.31(m, 3H), 2.26-2.17(m, 3H) enantiomers were separated (SFC HPLC) yielding example 1A (first elution) and example 1B (second elution).

Following a similar procedure as described in example 1, the following examples 2-41 were prepared.

Example 2: 1- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -ethanone

Yield: 48.0mg (7%) as the free base. Ms (esi): c₂₆H₃₅N₃O₃Calculated value of molecular weight of (c): 437.27, respectively; m/z found: 438.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：4.09(d，J＝8.7，2H)，6.82(d，J＝8.7，2H)，6.77(d，8.5，1H)，6.64-6.56(m，2H)，4.17-4.14(m，1H)，3.98(t，J＝6.3，2H)，3.80(s，3H)，3.72-3.68(m，1H)，3.62(t，J＝4.9，1H)，3.58-3.54(m，1H)，3.46(t，J＝4.9，2H)，3.00-2.97(m，1H)，2.55-2.50(m，3H)，2.50-2.39(m，5H)，2.42(s，3H)，2.09(s，3H)，1.98-1.90(m，2H).

Example 3: diethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 275.0mg (30%, TFA)Salt). Ms (esi): c₂₄H₃₄N₂O₂Calculated value of molecular weight of (c): 382.26, respectively; m/z found: 383.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.20(d，J＝8.6，2H)，6.95(d，J＝8.5，2H)，6.88-6.75(m，3H)，3.72-4.48(m，3H)，4.16(t，J＝5.6，2H)，3.85-3.77(m，1H)，3.81(s，3H)，3.49-3.30(m，7H)，3.06(s，3H)，2.34-2.27(m，2H)，1.37(t，J＝7.3，6H).

Example 4: (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -pyridin-4-yl-methanone

Yield: 58.6mg (11%, TFA salt). Ms (esi): c₃₀H₃₆N₄O₃Calculated value of molecular weight of (c): 500.28, respectively; m/z found: 501.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.72-8.70(m，2H)，7.62-7.60(m，2H)，7.05(d，J＝8.7，2H)，6.80(d，J＝8.5，2H)，6.71-6.63(m，3H)，4.55-4.43(m，3H)，4.00(t，J＝5.6，2H)，3.81(br s，4H)，3.67(s，3H)，3.40-3.30(m，6H)，2.98(s，3H)，2.24-2.18(m，2H).

Example 5: 1- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -2-methyl-propan-1-one

Yield: 0.9mg (5%, TFA salt). Ms (esi): c₂₈H₃₉N₃O₃Calculated value of molecular weight of (c): 465.63, respectively; m/z found: 466.6[ M + H ]⁺。

¹H NMR (acetone-d)₆)：7.05(d，J＝8.4，2H)，6.81(d，J＝8.5，2H)，6.72-6.62(m，3H)，4.55-4.40(m，3H)，3.00(t，J＝5.0，2H)，3.71-3.65(m，1H)，3.63(s，3H)，3.38-3.27(m，1H)，3.29(t，J＝7.8，2H)，2.99(s，3H)，2.85-2.79(m，1H)，2.24-2.18(m，2H)，0.97-0.90(m，6H).

Example 6: cyclobutyl- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -methanone

Yield: 73.0mg (17%, TFA salt). Ms (esi): c₂₉H₃₉N₃O₃Calculated value of molecular weight of (c): 477.64, respectively; m/z found: 478.6[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.05(d，J＝8.6，2H)，6.81(d，J＝8.6，2H)，6.71-6.63(m，3H)，4.54-4.38(m，3H)，4.00(t，J＝4.6，2H)，3.71-3.62(m，1H)，3.63(s，3H)，3.34-3.26(m，5H)，2.95(s，3H)，2.21-2.13(m，4H)，2.05-2.00(m，2H)，1.93-1.81(m，1H)，1.67-1.64(m，1H).

Example 7: cyclopropyl- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -methanone

Yield: 87.4mg (20%, TFA salt). Ms (esi): c₂₈H₃₇N₃O₃Calculated value of molecular weight of (c): 477.64, respectively; m/z found: 478.6[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.05(d，J＝8.5，2H)，6.81(d，8.5，2H)，6.72-6.61(m，3H)，4.56-4.41(m，4H)，4.01(t，J＝5.2，2H)，3.72-3.53(m，2H)，3.67(s，3H)，3.42-3.30(m，2H)，3.30(t，J＝7.8，2H)，2.99(s，3H)，2.25-2.17(m，2H)，1.88-1.82(m，1H)，0.71-.069(m，2H)，0.65-0.61(m，2H).

Example 8: 7- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 79.8mg (20%, TFA salt). Ms (esi): c₂₅H₃₂F₂N₂O₂Calculated value of molecular weight of (c): 430.24, respectively; m/z found: 431.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.19(d，J＝8.6，2H)，6.95(d，J＝8.6，2H)，6.86-6.78(m，3H)，4.73-4.56(m，3H)，4.15(t，J＝5.3，2H)，3.85-3.77(m，2H)，3.81(s，3H)，3.50-3.43(m，3H)，3.43(br s，1H)，3.14(s，3H)，2.61-2.38(m，4H)，2.47-2.34(m，2H).

Example 9: 4- (4-methoxy-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 86.0mg (22%, TFA salt). Ms (esi): c₂₄H₃₂N₂O₃Is divided intoCalculated values of the sub-quantities: 396.2; m/z found: 397.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.06(d，J＝8.6，2H)，6.81(d，J＝8.6，2H)，6.72-6.63(m，3H)，4.57-4.36(m，3H)，4.00(t，J＝5.2，2H)，3.93-3.87(m，2H)，3.84-3.75(m，2H)，3.72-3.67(m，1H)，3.67(s，3H)，3.53-3.46(m，2H)，3.33(br s，1H)，3.27(t，J＝8.0，2H)，3.10-3.01(m，2H)，2.96(s，3H)，2.22-2.16(m，2H).

Example 10: (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -pyrrolidin-3-yl) -dimethyl-amine

Yield: 72.5mg (18%, TFA salt). Ms (esi): c₂₆H₃₇N₂O₂Calculated value of molecular weight of (c): 423.29, respectively; m/z found: 424.6[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.18(d，J＝8.6，2H)，6.93(d，J＝8.6，2H)，6.84-6.73(m，3H)，4.65-4.43(m，3H)，4.31(br s，1H)，4.13(t，J＝5.8，2H)，4.10(brs，1H)，4.01(br s，1H)，3.80(s，3H)，3.80-3.76(m，1H)，3.72(br s，2H)，3.54-3.51(m，2H)，3.44(br s，1H)，2.70(m，1H)，3.06(s，3H)，3.04(s，6H)，2.60-2.56(m，1H)，2.32-2.27(m，2H).

Example 11: 7- [3- ((2R, 5R) -trans-dimethyl-pyrrolidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 39.9mg (10%, TFA salt). Ms (esi): c₂₆H₃₆N₂O₂Calculated value of molecular weight of (c): 408.28, respectively; m/z found: 409.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.19(d，J＝8.6，2H)，6.93(d，J＝8.7，2H)，6.88-6.73(m，3H)，4.66-4.44(m，3H)，4.18-4.09(m，3H)，3.80(s，3H)，3.76(br s，1H)，3.68-3.57(m，1H)，3.45-3.39(m，2H)，3.20-3.14(m，1H)，3.06(s，3H)，2.41-2.32(m，3H)，2.28-2.22(m，1H)，1.92-1.84(m，1H)，1.80-1.72(m，1H)，1.51-1.47(m，4H)，1.35-1.32(m，2H).

Example 12: 4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazine-1-carboxylic acid ethyl ester

Yield: 60.8mg (12%, TFA salt). Ms (esi): c₂₇H₃₇N₃O₄Calculated value of molecular weight of (c): 467.28, respectively; m/z found: 468.6[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.06(d，J＝8.6，2H)，6.81(d，J＝8.6，2H)，6.72-6.63(m，3H)，4.57-4.34(m，3H)，4.01-3.96(m，4H)，3.71-3.69(m，1H)，3.67(s，3H)，3.36-3.27(m，5H)，2.96(s，3H)，2.22-2.19(m，2H)，1.09(t，J＝7.1，3H).

Example 13: (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) - (1-methyl-1H-pyrrol-2-yl) -methanone

Yield: 61.7mg (12%, TFA salt). Ms (esi): c₃₀H₃₈N₄O₃Calculated value of molecular weight of (c): 502.29, respectively; m/z found: 503.6[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.06(d，J＝8.6，2H)，6.81(d，J＝8.7，2H)，6.74-6.72(m，2H)，6.69-6.61(m，2H)，6.32-6.30(m，1H)，5.93-5.91(m，1H)，4.53-4.40(m，4H)，4.02-4.00(m，2H)，3.68(s，4H)，3.63(s，4H)，3.35-3.27(m，5H)，2.93(s，3H)，2.24-2.19(m，2H).

Example 14: (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) - (1-methyl-1H-imidazol-4-yl) -methanone

Yield: 17.0mg (3%, TFA salt). Ms (esi): c₂₉H₃₇N₅O₃Calculated value of molecular weight of (c): 503.29, respectively; m/z found: 504.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.94(br s，1H)，7.69(br s，1H)，7.05(d，J＝8.6，2H)，6.81(d，J＝8.4，2H)，6.76-6.61(m，3H)，4.52-4.41(m，3H)，4.01-3.99(m，2H)，3.77(s，3H)，3.73-3.71(m，1H)，3.67(s，4H)，3.53-3.07(m，10H)，2.95(s，3H)，2.25-2.20(m，2H).

Example 15: (1, 3-dimethyl-tetrahydro-pyrimidin-2-ylidene) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 2.1mg (0.5%, TFA salt). Ms (esi): c₂₆H₃₆N₄O₂Calculated value of molecular weight of (c): 436.28, respectively; m/z found: 437.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.18(d，J＝8.6，2H)，6.93(d，J＝8.7，2H)，6.81-6.76(m，3H)，4.65-4.41(m，3H)，4.13(t，J＝5.3，2H)，3.80(s，3H)，3.81(br s，1H)，3.45-3.38(m，7H)，3.26(s，1H)，3.05(s，3H)，2.95(s，3H)，2.48-2.45(m，1H)，2.34-2.27(m，2H)，2.07-2.02(m，3H).

Example 16: 7- [3- (1, 3-dihydro-isoindol-2-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 98mg (20%, TFA salt). Ms (esi): c₂₈H₃₂N₂O₂Calculated value of molecular weight of (c): 428.25, respectively; m/z found: 429.5[ M + H]⁺。

¹HNMR (acetone-d)₆)：7.33-7.23(m，4H)，7.06(d，J＝8.2，2H)，6.81(d，J＝8.2，2H)，6.75-6.62(m，3H)，4.94(br s，2H)，4.71-4.39(m，5H)，4.08-4.00(m，2H)，3.72-3.66(m，1H)，6.68(s，3H)，3.35(br s，1H)，3.00(s，3H)，2.32-2.24(m，2H)，1.83-1.80(m，2H).

Example 17: bis- (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 41.1mg (8%, TFA salt). Ms (esi): c₂₆H₃₈N₂O₄Calculated value of molecular weight of (c): 442.28, respectively; m/z found: 443.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.06(d，J＝8.5，2H)，6.81(d，J＝8.6，2H)，6.74-6.63(m，3H)，4.59-4.31(m，3H)，4.04(t，J＝5.0，2H)，3.73-3.70(m，4H)，3.68(s，4H)，3.48-3.44(m，6H)，3.35(br s，1H)，3.21(s，6H)，2.93(s，3H)，2.25-2.19(m，2H).

Example 18: 7- [3- (5, 6-dihydro-4H-pyrimidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 3.8mg (1%, TFA salt). Ms (esi): c ₂₄H₃₁N₃O₂Calculated value of molecular weight of (c): 393.24, respectively; m/z found: 394.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.11-8.08(m，1H)，7.07(d，J＝8.6，2H)，6.81(d，J＝8.7，2H)，6.76-6.60(m，3H)，4.54-4.39(m，3H)，4.07-4.03(m，2H)，3.72-3.63(m，3H)，3.68(s，3H)，3.52-3.49(m，2H)，3.40-3.30(m，3H)，2.91(s，3H)，2.13-2.09(m，2H)，2.02-1.98(m，2H).

Example 19: benzothiazol-2-yl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl ] -methyl-amine

Yield: 3.2mg (1%, TFA salt). Ms (esi): c₂₈H₃₁N₃O₂Calculated value of molecular weight of S: 473.21, respectively; m/z found: 474.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.85(d，J＝8.1，1H)，7.53(d，J＝8.2，1H)，7.43(t，J＝7.4，1H)，7.28(t，J＝7.5，1H)，7.06(d，J＝8.6，2H)，6.77(d，J＝8.0，2H)，6.72-6.58(m，3H)，4.58-4.46(m，4H)，4.35(br s，1H)，4.08(t，J＝5.3，2H)，(m，1H)，3.68(s，3H)，3.68-3.60(m，1H)，3.31(br s，1H)，3.06(s，2H)，2.93(s，3H)，2.25-2.18(m，2H).

Example 20: 1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-3-ol

Yield: 65.0mg (15%) as a TFA salt and a mixture of diastereomers. Ms (esi): c₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.06(d，J＝8.6，2H)，6.81(d，J＝8.5，2H)，6.75-6.63(m，3H)，4.57-4.35(m，3H)，4.14(br s，0.5H)，4.06-3.98(m，2H)，3.97-3.87(m，0.5H)，3.68(s，3H)，3.69-3.63(m，1H)，3.61-3.58(m，1H)，3.52-3.43(m，1H)，3.40-3.22(m，3H)，3.19-3.14(m，0.5H)，3.05-2.96(m，0.5H)，2.95-2.93(m，3H)，2.79-2.73(m，0.5H)，2.60-2.53(m，0.5H)，2.25-2.14(m，3H)，1.83-1.59(m，3H)，1.33-1.25(m，0.5H).

Example 21: 1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-4-ol

Yield: 36.0mg (13%, TFA salt). Ms (esi): c₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.19(d，J＝8.6，2H)，6.93(d，J＝8.6，2H)，6.85-6.76(m，3H)，4.72-4.46(m，4H)，4.12-4.11(m，3H)，3.89-3.84(m，1H)，3.80(s，3H)，3.68-3.66(m，1H)，3.48-3.44(m，2H)，3.34-3.29(m，3H)，3.04(s，4H)，2.36-2.28(m，2H)，2.17-2.09(m，2H)，1.93-1.87(m，2H).

Example 22: (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-4-yl) -methanol

Yield: 10.0mg (13%, TFA salt). Ms (esi): c₂₆H₃₆N₂O₃Calculated value of molecular weight of (c): 424.27, respectively; m/z found: 425.5[ M + H ]⁺。

¹H NMR (acetone-d)₆)：7.19(d，J＝8.6，2H)，6.94(d，J＝8.6，2H)，6.85-6.75(m，3H)，4.66-4.45(m，3H)，4.13-4.10(m，2H)，3.80(s，3H)，3.82-3.78(m，1H)，3.75-3.68(m，2H)，3.48-3。43(m，4H)，3.38-3.34(m，2H)，3.06(s，3H)，3.05-2.94(m，2H)，2.34-2.30(m，2H)，2.01-1.96(m，2H)，1.33-1.28(m，1H)，1.76-1.63(m，2H).

Example 23: (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-3-yl) -methanol

Yield: 110.0mg (20%, TFA salt). Ms (esi): c₂₆H₃₆N₂O₃Calculated value of molecular weight of (c): 424.27, respectively; m/z found: 425.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.07(d，J＝8.6，2H)，6.82(d，J＝8.6，2H)，6.74-6.63(m，3H)，4.57-4.36(m，4H)，4.04-4.00(m，2H)，3.69-3.62(m，1H)，3.69(s，3H)，3.60-3.55(m，2H)，3.48-3.45(m，1H)，3.35-3.31(m，2H)，3.25-3.20(m，2H)，2.96(s，3H)，2.82-2.73(m，1H)，2.67-2.58(m，1H)，2.24-2.19(m，2H)，，2.11-2.02(m，1H)；1.85-1.82(m，2H)，1.72-1.69(m，1H)，1.22-1.87(m，1H).

Example 24: (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-2-yl) -methanol

Yield: 46.5mg (8%, TFA salt). Ms (esi): c₂₆H₃₆N₂O₃Calculated value of molecular weight of (c): 424.27, respectively; m/z found: 425.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.17(d，J＝8.5，2H)，6.92(d，J＝8.5，2H)，6.80-6.71(m，3H)，4.67-4.47(m，3H)，4.16-4.11(m，2H)，4.05-3.99(m，1H)，3.79(s，3H)，3.83-3.75(m，2H)，3.68-3.62(m，2H)，3.53-3.33(m，3H)，3.15-3.21(m，1H)，3.06(s，3H)，2.41-2.32(m，2H)，2.07-2.00(m，1H)，1.93-1.78(m，5H)，1.65-1.54(m，1H).

Example 25: 4- (4-methoxy-phenyl) -2-methyl-7- [3- (3-trifluoromethyl-piperidin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 104.0mg (18%, TFA salt). Ms (esi): c₂₆H₃₃F₃N₂O₂Calculated value of molecular weight of (c): 462.25, respectively; m/z found: 463.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.12(d，J＝8.6，2H)，6.88(d，J＝8.6，2H)，6.79-6.68(m，3H)，4.63-4.43(m，3H)，4.13-4.05(m，2H)，3.79-3.74(m，2H)，3.74(s，3H)，3.70-3.66(m，1H)，3.51-3.34(m，3H)，3.15-3.07(m，1H)，3.07-2.97(m，2H)，2.99(s，3H)，2.34-2.25(m，2H)，2.10-2.04(m，1H)，1.89-1.94(m，2H)，1.61-1.50(m，1H).

Example 26: 2- (1- {3- [4- [ 4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-4-yl) -ethanol

The TFA salt was isolated. Ms (esi): c₂₇H₃₈N₂O₃Calculated value of molecular weight of (c): 438.29, respectively; m/z found: 439.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.12(d，J＝8.5，2H)，6.87(d，J＝8.5，2H)，6.79-6.67(m，3H)，4.60-4.36(m，4H)，4.07-4.03(m，2H)，3.77-3.69(m，1H)，3.74(s，3H)，3.61-3.55(m，2H)，3.50(t，J＝4.2，2H)，3.41-3.34(m，2H)，3.27-3.23(m，2H)，2.99(s，3H)，2.95-2.76(m，2H)，2.26-2.17(m，1H)，1.99-1.85(m，2H)，1.75-1.69(m，1H)，1.64-1.56(m，2H)，1.44-1.39(m，2H).

Example 27: 7- [3- (1, 1-dioxo-1. lamda.) -1 ⁶-thiomorpholin-4-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 69.0mg (12%, TFA salt). Ms (esi): c₂₄H₃₂N₂O₄Calculated value of molecular weight of S: 444.21, respectively; m/z found: 445.5[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：7.15(d，J＝8.7，2H)，6.90(d，J＝8.6，2H)，6.82-6.70(m，3H)，4.63-4.51(m，3H)，4.10(t，J＝4.9，2H)，3.81-3.74(m，1H)，3.77(s，3H)，3.65-3.62(m，4H)，3.47-3.40(m，5H)，3.29(t，J＝7.6，2H)，3.06(s，3H)，2.24-2.18(m，2H).

Example 28: 4- (4-methoxy-phenyl) -2-methyl-7- [3- ((2S) -trifluoromethyl-pyrrolidin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 2.5mg (0.5%, TFA salt). Ms (esi): c₂₅H₃₁F₃N₂O₂Calculated value of molecular weight of (c): 448.23, respectively; m/z found: 449.5[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：7.15(d，J＝8.6，2H)，6.90(d，J＝8.4，2H)，6.81-6.70(m，3H)，4.78-4.57(m，4H)，4.03(t，J＝6.1，2H)，3.86-3.82(m，1H)，3.77(s，3H)，3.46(br s，1H)，3.41-3.30(m，1H)，3.36-3.19(m，1H)，3.10-3.04(m，1H)，3.10(s，3H)，2.82-2.71(m，1H)，2.51-2.42(m，1H)，1.96-1.91(m，2H)，1.90-1.72(m，3H).

Example 29 (racemate), 29A (enantiomer 1) and 29B (enantiomer 2): 7- [3- (3, 3-difluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 59.0mg (11%, TFA salt). Ms (esi): c₂₅H₃₂F₂N₂O₂Calculated value of molecular weight of (c): 430.24, respectively; m/z found: 431.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.16(d，J＝8.6，2H)，6.92(d，J＝8.5，2H)，6.82-6.71(m，3H)，4.67-4.58(m，3H)，4.10(t，J＝5.4，2H)，3.84-3.75(m，1H)，3.78(s，3H)，3.66(t，J＝10.9，2H)，3.46-3.36(m，5H)，3.08(s，3H)，2.37-2.28(m，2H)，2.23-2.11(m，2H)，2.11-2.07(m，2H).

The enantiomers were separated (SFC HPLC) to give example 29A (first elution) and example 29B (second elution).

Example 30: (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -pyrrolidin- (2R) -yl) -methanol

Yield: 68.0mg (12%, TFA salt). Ms (esi): c ₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.5[M+H]⁺。

¹H NMR (acetone-d)⁶)：7.19(d，J＝8.6，2H)，6.94(d，J＝8.5，2H)，6.86-6.77(m，3H)，4.79-4.53(m，5H)，4.16-4.11(m，2H)，3.91-3.69(m，9H)，3.48-3.37(m，2H)，3.34-3.29(m，1H)，3.09(s，3H)，2.39-2.24(m，3H)，2.12-2.05(m，1H)，1.96-1.89(m，1H).

Example 31: 1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (R) -pyrrolidin-3-ol

Yield: 56.0mg (10%, TFA salt). Ms (esi): c₂₄H₃₂N₂O₃Calculated value of molecular weight of (c): 396.24, respectively; m/z found: 397.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.18(d，J＝8.6，2H)，6.93(d，J＝8.6，2H)，6.85-6.75(m，3H)，4.64-4.51(m，4H)，4.35(br s，2H)，3.96-3.84(m，1H)，3.84-3.72(m，2H)，4.04(s，3H)，3.70-3.55(m，3H)，3.52-3.38(m，3H)，3.34-3.23(m，2H)，3.26(s，3H)，2.33-2.26(m，2H).

Example 32: 7- [3- (2, 6-dimethyl-morpholin-4-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 118.0mg (21%, TFA salt). Ms (esi): c₂₆H₃₆N₂O₃Calculated value of molecular weight of (c): 424.27, respectively; m/z found: 425.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.19(d，J＝8.6，2H)，6.95(d，J＝8.6，2H)，6.85-6.75(m，3H)，4.76-4.51(m，3H)，4.14-4.11(m，2H)，4.06-3.99(m，2H)，3.85-3.77(m，1H)，3.81(s，3H)，3.60(d，J＝11.8，2H)，3.52-3.44(m，1H)，3.40-3.36(m，2H)，3.10(s，3H)，2.70(t，J＝11.5，2H)，2.37-2.31(m，2H)，1.25-1.18(d，J＝6.3，6H).

Example 33: 1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidine-4-carboxylic acid ethyl ester

Yield: 56.0mg (9%, TFA salt). Ms (esi): c₂₈H₃₈N₂O₄Calculated value of molecular weight of (c): 466.28, respectively; m/z found: 467.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.19(d，J＝8.5，2H)，6.95(d，J＝8.4，2H)，6.86-6.75(m，3H)，4.68-4.54(m，3H)，4.20-4.12(m，4H)，3.87-3.74(m，5H)，3.75-3.61(m，1H)，3.52-3.43(m，1H)，3.38-3.31(m，2H)，3.14-3.06(m，5H)，2.73(m，1H)，2.36-2.30(m，2H)，2.24-2.16(m，3H)，2.10-2.02(m，1H)，1.26-1.18(m，3H).

Example 34: 7- (3-azetidin-1-yl-propoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 2.0mg (0.4%, TFA salt). Ms (esi): c₂₃H₃₀N₂O₂Calculated value of molecular weight of (c): 366.23; m/z found: 367.5[ M + H ]⁺。

¹H NMR (acetone-d)₆)：7.16(d，J＝8.5，2H)，6.90(d，J＝8.6，2H)，6.81-6.72(m，3H)，4.58-4.34(m，3H)，4.32-4.24(m，2H)，4.10-4.01(m，5H)，3.81(s，3H)，3.81-3.72(m，1H)，3.41-3.32(m，3H)，2.95(s，3H)，2.60-2.55(m，1H)，2.36(br s，1H)，2.09-2.03(m，1H).

Example 35: 4- (4-methoxy-phenyl) -2-methyl-7- [3- (2-methyl-pyrrolidin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 78.0mg (25%, TFA salt). Ms (esi): c₂₅H₃₄N₂O₂Calculated value of molecular weight of (c): 394.26, respectively; m/z found: 395.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.16(d，J＝8.6，2H)，6.91(d，J＝8.5，2H)，6.83-6.70(m，3H)，4.65-4.45(m，4H)，4.78-4.10(m，2H)，3.92-3.88(m，1H)，3.80-3.73(m，1H)，3.77(s，3H)，3.63-3.57(m，1H)，3.53-3.39(m，2H)，3.22-3.18(m，2H)，3.07(s，3H)，2.32-2.27(m，3H)，2.09-2.03(m，2H)，1.83-1.73(m，1H)，1.49-1.46(m，2H).

Example 36: 2- (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-2-yl) -ethanol

The TFA salt was isolated. Ms (esi): c₂₇H₃₈N₂O₃Molecular weight of (2)Calculating the value: 438.29, respectively; m/z found: 439.6[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.17(d，J＝8.7，2H)，6.88(d，J＝8.7，2H)，6.81-6.72(m，3H)，4.66-4.51(m，3H)，4.16-4.08(m，2H)，3.83-3.73(m，3H)，3.78(s，3H)，3.69-3.61(m，2H)，3.49-3.31(m，4H)，3.16(br s，1H)，3.06(s，3H)，2.33-2.28(m，2H)，2.22-2.12(m，1H)，2.07-2.03(m，1H)，1.93-178(m，5H)，1.65-1.58(m，1H).

Example 37 (racemate), 37A (enantiomer 1) and 37B (enantiomer 2): 1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidine-4-carbonitrile

Yield: 75.2mg (14%, TFA salt). Ms (esi): c₂₆H₃₃N₃O₂Calculated value of molecular weight of (c): 419.26, respectively; m/z found: 420.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.18(d，J＝8.6，2H)，6.93(d，J＝8.6，2H)，6.84-6.71(m，3H)，4.66-4.50(m，3H)，4.14-4.08(m，2H)，3.84-3.65(m，3H)，3.80(s，3H)，3.45-3.36(m，4H)，3.21-3.11(m，2H)，3.07(s，3H)，2.39-2.18(m，6H).

The enantiomers were separated (SFC HPLC) to give example 37A (first elution) and example 37B (second elution).

Example 38: 4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-trifluoromethyl-piperidin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 56.2mg (9%, TFA salt). Ms (esi): c ₂₆H₃₃F₃N₂O₂Calculated value of molecular weight of (c): 462.25, respectively; m/z found: 463.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.18(d，J＝8.6，2H)，6.93(d，J＝8.7，2H)，6.84-6.71(m，3H)，4.63-4.43(m，3H)，4.14-4.09(m，2H)，3.84-3.76(m，3H)，3.80(s，3H)，3.45-3.39(m，1H)，3.38-3.32(m，2H)，3.14-3.08(m，2H)，3.08(s，3H)，2.69-2.65(m，1H)，2.34-2.29(m，2H)，2.16-2.06(m，4H).

Example 39: 7- [3- (3-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 77.4mg (14%, TFA salt). Ms (esi): c₂₅H₃₃FN₂O₂Calculated value of molecular weight of (c): 412.25, respectively; m/z found: 413.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.18(d，J＝8.6，2H)，6.94(d，J＝8.6，2H)，6.84-6.71(m，3H)，5.11(brs，1H)，4.63-4.51(m，3H)，4.13(t，J＝4.3，2H)，3.93(brs，1H)，3.84-3.76(m，2H)，3.80(s，3H)，3.50-3.41(m，4H)，3.22-3.14(m，1H)，3.12(s，3H)，2.35-2.30(m，2H)，2.29-2.12(m，2H)，1.92-1.82(m，2H).

Example 40: ethyl- (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 49.7mg (9%, TFA salt). Ms (esi): c₂₅H₃₆N₂O₃Calculated value of molecular weight of (c): 412.27, respectively; m/z found: 413.5[ M + H]⁺。

¹H NMR (acetone-d)⁶)：7.18(d，J＝8.6，2H)，6.94(d，J＝8.6，2H)，6.86-6.71(m，3H)，4.67-4.51(m，3H)，4.14(t，J＝5.1，2H)，3.83(t，J＝4.8，2H)，3.76(s，4H)，3.52-3.39(m，7H)，3.34(s，3H)，3.06(s，3H)，2.33-2.28(m，2H)，1.37(t，J＝7.3，3H).

Example 41: 7- [3- (1, 4-dioxa-8-aza-spiro [4.5] dec-8-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 61.2mg (10%, TFA salt). Ms (esi): c₂₇H₃₆N₂O₄Calculated value of molecular weight of (c): 452.27, respectively; m/z found: 453.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.16(d，J＝8.6，2H)，6.91(d，J＝8.5，2H)，6.87-6.70(m，3H)，4.67-4.51(m，3H)，4.09（t，J＝2.8，2H)，4.01-3.91(m，1H)，3.97(s，3H)，3.82-3.74(m，1H)，3.77(s，3H)，3.68-3.63(m，2H)，3.50-3.35(m，3H)，3.19-3.12(m，2H)，3.06(s，3H)，2.32-2.26(m，2H)，2.19-2.13(m，2H)，1.91-1.85(m，2H).

Example 42: 1- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -3-piperidin-1-yl-propan-2-ol

Step 1: 3-Oxiranylmethoxy-benzaldehydes. To 3-hydroxybenzaldehyde (10.0g, 81.9mmol) and K ₂CO₃Epichlorohydrin (15.2g, 163.8mmol) was added to a mixture of (17.0g, 123.0mmol) acetonitrile (235ml) and the mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc, washed with 1N NaOH and brine, and dried (MgSO 4)₄) And concentrated. The crude product was purified by FCC (EtOAc/hexanes) to give the desired product (8.49g, 58%, clear oil).

¹H NMR(CDCl₃)：9.98(s，1H)，7.50-7.44(m，2H)，7.41-7.40(m，1H)，7.24-7.21(m，1H)，4.33(dd，J＝11.0，2.8，1H)，4.00-3.97(m，1H)，3.40-3.37(m，1H)，2.94-2.93(m，1H)，2.79-2.78(m，1H).

Step 2: 3- (2-hydroxy-3-piperidin-1-yl-propoxy) -benzaldehyde. A mixture of 3-oxacyclopropylmethoxy-benzaldehyde (0.59g, 3.31mmol) and piperidine (0.34ml, 3.48mmol) in EtOH (10ml) was heated at reflux overnight. The reaction mixture was allowed to cool to room temperature and then concentrated. The crude product was purified by FCC (MeOH/DCM) to give the desired product (0.63g, 72%, yellow oil). Ms (esi): c₁₅H₂₁NO₃Calculated value of molecular weight of (c): 263.15, respectively; m/z found: 264.4[ M + H]⁺。

¹H NMR(CDCl₃)：9.98(s，1H)，7.48-7.41(m，3H)，7.23-7.21(m，1H)，4.13-4.08(m，1H)，4.06-4.00(m，2H)，2.76-2.57(m，2H)，2.53-2.45(m，2H)，2.42-2.31(m，2H)，1.64-1.57(m，4H)，1.49-1.45(m，2H).

And step 3: 1- (3-methylaminomethyl-phenoxy) -3-piperidin-1-yl-propan-2-ol. Prepared in analogy to 3- (3-methylaminomethyl-phenoxy) -propan-1-ol to give the desired product (0.59g, 89%, clear oil). Ms (esi): c₁₆H₂₆N₂O₂Calculated value of molecular weight of (c): 278.20, respectively; m/z found: 279.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.22(t，J＝7.8，1H)，6.91-6.88(m，2H)，6.83-6.80(m，1H)，4.09-4.05(m，1H)，3.98-3.97(m，2H)，3.72(s，2H)，2.65-2.56(m，2H)，2.51-2.45(m，2H)，2.45(s，3H)，2.42-2.32(m，2H)，1.65-1.54(m，5H)，1.48-1.43(m，2H).

And 4, step 4: 2- { [3- (2-hydroxy-3-piperidin-1-yl-propoxy) -benzyl ]-methyl-amino } -1- (4-methoxy-phenyl) -ethanones. According to analogy to 2- { [3- (3-hydroxy-propoxy) -benzyl]Preparation of (E) -methyl-amino } -1- (4-methoxy-phenyl) -ethanone to give the desired product (0.83g, > 100% crude, yellow oil) which was used without purification. Ms (esi): c₂₅H₃₄N₂O₄Calculated value of molecular weight of (c): 426.25, respectively; m/z found: 427.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.97(d，J＝6.9，2H)，7.21(t，J＝7.6，1H)，6.93-6.88(m，4H)，6.84-6.82(m，1H)，4.11-4.07(m，1H)，3.95-3.93(m，2H)，3.89-3.84(m，1H)，3.86(s，3H)，3.61(s，2H)，3.57(s，2H)，2.65-2.60(m，2H)，2.52-2.46(m，2H)，2.34(s，3H)，2.04(s，1H)，1.64-1.58(m，4H)，1.48-1.45(m，2H).

And 5: 7- (2-hydroxy-3-piperidin-1-yl-propoxy) -4- (4-methoxy-phenyl) -2-methyl Yl-isoquinolinium salts. Prepared in analogy to 7- (3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -2-methyl-isoquinolinium salt to give the desired product (0.67g, crude 86%, yellow oil) which was used without purification. Ms (esi): c₂₅H₃₁N₂O₃Calculated value of molecular weight of (c): 407.23, respectively; m/z found: 407.5[ M]⁺。

Step 6:according to the method, the compound is similar to the 3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquineQuinoline-7-yloxy]-propan-1-ol to give the desired product (61.5mg, 12%, TFA salt). Ms (esi): c₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.19(d，J＝8.5，2H)，6.95(d，J＝8.4，2H)，6.83-6.76(m，3H)，4.58-4.56(m，2H)，4.56-4.51(m，2H)，4.10-4.06(m，1H)，4.02-3.99(m，1H)，3.85-3.82(m，1H)，3.81(s，3H)，3.77-3.74(m，2H)，3.52-3.44(m，2H)，3.37-3.32(m，1H)，3.15-3.06(m，2H)，3.10(s，3H)，1.98-1.90(m，4H)，1.85-1.82(m，1H)，1.57-1.53(m，1H).

Example 43: 7- [ 2-fluoro-3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- (3-benzyloxy-2-hydroxy-propoxy) -benzaldehyde. Adding 3-hydroxybenzaldehyde (1.12g, 9.14mmol) and K₂CO₃A mixture of (1.30g, 9.14mmol) and 2-benzyloxymethyl-ethylene oxide (1.00g, 6.09mmol) in acetonitrile (25ml) was heated under reflux overnight. The mixture was cooled to room temperature and filtered to remove the white solid. The filtrate was concentrated, diluted with EtOAc, washed with 1N NaOH (2 times) and brine, and dried (MgSO 4)₄) And concentrated. The crude product was purified by FCC to give the desired product (1.22g, 70%, clear oil). Ms (esi): c₁₇H₁₈O₄Calculated value of molecular weight of (c): 286.12, respectively; m/z found: 287.0[ M + H]⁺。

¹H NMR(CDCl₃)：9.97(s，1H)，7.49-7.43(m，2H)，7.40-7.39(m，1H)，7.37-7.29(m，5H)，7.20-7.18(m，1H)，4.59(s，2H)，4.23-4.22(m，1H)，4.13-4.09(m，2H)，3.70-3.63(m，2H)，2.55(d，J＝5.0，1H).

Step 2: 3- (3-benzyloxy-2-fluoro-propoxy) -benzaldehyde. A mixture of 3- (3-benzyloxy-2-hydroxy-propoxy) -benzaldehyde (250mg, 0.87mmol), perfluorobutanesulfonyl fluoride (0.31ml, 1.75mmol), triethylamine trihydrofluoride salt (0.28ml, 1.75mmol), TEA (0.73ml, 5.24mmol) and THF (2.5 ml). The mixture was stirred at room temperature overnight, diluted with EtOAc, and washed with water (2X), saturated NaHCO₃The aqueous solution and brine were washed and dried (MgSO)₄) And concentrated to give the desired product (0.22g, 88%, light yellow oil). Gcms (ei): c₁₇H₁₇FO₃Calculated value of molecular weight of (c): 288.12, respectively; m/z found: 288.0[ M ] ]⁺。

¹H NMR(CDCl₃)：9.95(s，1H)，7.50-7.44(m，2H)，7.40-7.39(m，1H)，7.37-7.28(m，5H)，7.21-7.19(m，1H)，5.07-4.93(m，1H)，4.61(s，2H)，4.30-4.27(m，1H)，4.26-4.23(m，1H)，3.81(d，J＝4.5，1H)，3.76(d，J＝4.8，1H).

And step 3: [3- (3-benzyloxy-2-fluoro-propoxy) -benzyl]-methyl-amine. A clear oil (0.20g, 87%) was obtained in analogy to the procedure for 3- (3-methylaminomethyl-phenoxy) -propan-1-ol to give the desired product. Ms (esi): c₁₈H₂₂FNO₂Calculated value of molecular weight of (c): 303.16, respectively; m/z found: 304.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.36-7.32(m，4H)，7.31-7.28(m，1H)，7.23(t，J＝7.9，1H)，6.92-6.89(m，2H)，6.81-6.79(m，1H)，5.04-4.91(m，1H)，4.60(s，2H)，4.20(dd，J＝20.9，5.4，2H)，3.79(dd，J＝21.9，4.6，2H)，3.72(s，2H)，2.45(s，3H)，1.41-1.33(br s，1H).

And 4, step 4: 2-fluoro-3- (3-methylaminomethyl-phenoxy) -propan-1-ol. [3- (3-benzyloxy-2-fluoro-propoxy) -benzyl purged with nitrogen]To a solution of-methyl-amine (0.16g, 0.53mmol) in EtOAc (1mL) was added 10% Pd/C (160mg, 0.18 mmol). The mixture is in H₂Stirred overnight under atmosphere and then filtered through celite. The filtrate was concentrated and purified by FCC (MeOH/DCM) to give a yellow oil (24.0mg, 21%). Ms (esi): c₁₁H₁₆FNO₂Calculated value of molecular weight of (c): 213.12, respectively; m/z found: 214.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.23(t，J＝7.8，1H)，6.94-6.88(m，2H)，6.83-6.80(m，1H)，4.91-4.81(m，1H)，4.19(dd，J＝20.9，4.9，2H)，3.90-3.84(m，2H)，3.72(s，2H)，2.43(s，3H).

And 5: 2- { [3- (2-fluoro-3-hydroxy-propoxy) -benzyl]-methyl-amino } -1- (4-methoxy-acid) Phenyl-ethanones. According to analogy to 2- { [3- (3-hydroxy-propoxy) -benzyl]The procedure of (4-methoxy-phenyl) -ethanone-methyl-amino } -1- (4-methoxy-phenyl) -ethanone gave the desired product (0.41g, > 100% crude, yellow oil) which was used without further purification. Ms (esi): c₂₇H₃₀FNO₄Calculated value of molecular weight of (c): 361.17, respectively; m/z found: 362.4[ M + H ]⁺。

Step 6: 7- (2-fluoro-3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -2-methyl-isoquinoline Quinolinium salts. The desired product (0.39g, 100% crude) was obtained in analogy to the procedure for 7- (3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -2-methyl-isoquinolinium salt and was used without further purification. Ms (esi): c₂₅H₃₀FN₂O₂ ⁺Calculated value of molecular weight of (c): 342.15, respectively; m/z found: 342.5[ M ]]⁺。

Step 7: according to the formula]-propan-1-ol to give the desired product (70.0mg, 12%). Ms (esi): c₂₅H₃₂F₂N₂O₂Calculated value of molecular weight of (c): 430.24, respectively; m/z found: 431.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.12(d，J＝8.7，2H)，8.7，2H)，6.76-6.68(m，3H)，4.99-4.89(m，1H)，4.68-4.55(m，1H)，4.23-4.08(m，3H)，3.76(s，3H)，3.58(s，2H)，2.87-2.84(m，1H)，2.82(s，2H)，2.78(br s，1H)，2.76-2.74(m，1H)，2.72-2.65(m，2H)，2.52-2.44(m，3H)，2.33(s，3H)，1.93-1.85(m，2H)，1.78-1.70(m，2H).

Following a similar procedure as used in example 1, the following examples 44-56 were prepared.

Example 44 (racemate), 45A (enantiomer 1) and 45B (enantiomer 2): 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino } -1- (3-methoxy-benzene) Alkyl) -ethanones. Yield (5.12mmol scale): 2.11g (> 100%) of crude product. Ms (esi): c₂₀H₂₅NO₄Calculated value of molecular weight of (c): 343.2, respectively; m/z found: 344.5[ M + H ] ]⁺。

Step 2: 7- (3-hydroxy-propoxy) -4- (3-methoxy-phenyl) -2-methyl-isoquinolinium Salt (salt). Yield (5.12mmol scale): 1.82g (97%) of crude product. Ms (esi): c₂₀H₂₂NO₃ ⁺Calculated value of molecular weight of (c): 324.2, respectively; m/z found: 324.4[ M ]]⁺。

And step 3: 3- [4- (3-methoxy-phenyl) -2-methyl-1.2.3, 4-tetrahydro-isoquinolin-7-yloxy Base of]-propan-1-ol. Yield (5.06mmol scale): after FCC, purification by reverse phase HPLC was carried out, yielding 0.78g (47%). The compound was characterized as a TFA salt. Ms (esi): c₂₀H₂₃NO₃Calculated value of molecular weight of (c): 327.2; m/z found: 328.5[ M + H ]]⁺。

¹H NMR(MeOH-d₄)：7.29-7.26(m，1H)，6.88-6.87(m，1H)，6.81(br s，5H)，4.91(s，3H)，4.58-4.50(m，3H)，4.09-4.05(m，2H)，3.79-3.71(m，1H)，3.75(s，3H)，3.72(t，J＝6.3，2H)，3.45(br s，1H)，3.05(br s，3H)，1.99-1.92(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy]-propyl ester. Yield (2.11mmol scale): 925.4mg (> 100%) of crude product. Ms (esi): c₂₁H₂₇NO₅Calculated value of molecular weight of S: 405.2; m/z found: 406.4[ M + H]⁺。

And 5: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (3-methoxy-phenyl) -2-methyl -1, 2, 3, 4-tetrahydro-isoquinoline. Yield (2.11mmol scale): after HPLC purification 378.7mg (28%). The compound was characterized as a TFA salt. Ms (esi): c₂₅H₃₃FN₂O₂Calculated value of molecular weight of (c): 412.2, respectively; m/z found: 413.5[ M + H]⁺。

¹H NMR(MeOH-d₄)：7.29-7.26(m，1H)，6.91-6.79(m，6H)，4.97(s，4H)，4.56-4.50(m，3H)，4.09(t，J＝5.4，2H)，3.79(br s，1H)，3.76(s，3H)，3.54(d，J＝11.6，2H)，3.36-3.33(m，2H)，3.26-3.21(m，2H)，3.06(br s，3H)，2.28-2.08(m，6H).

Separation of the enantiomers (SFC HPLC) gave 45A (first elution of enantiomer) and 45B (second elution of enantiomer).

Example 46: 4- (3-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 1- (3-chloro-phenyl) -2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino- Ethanones. Yield (5.12mmol scale): 2.23g (> 100%) of crude product. Ms (esi): c₁₉H₂₂ClNO₃Calculated value of molecular weight of (c): 347.1; m/z found: 348.4[ M + H]⁺。

Step 2: 4- (3-chloro-phenyl) -7- (3-hydroxy-propoxy) -2-methyl-isoquinolinium salt.Yield (5.12mmol scale): 1.90g (> 100%) of crude product. Ms (esi): c₁₉H₁₉ClNO₂ ⁺Calculated value of molecular weight of (c): 328.1; m/z found: 328.4[ M ]]⁺。

And step 3: 3- [4- (3-chloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]- Propan-1-ol. Yield (5.12mmol scale): 0.45g (26%) was purified by HPLC and characterized as TFA salt. Ms (esi): c₁₉H₂₂ClNO₂Calculated value of molecular weight of (c): 331.1, respectively; m/z found: 332.4[ M + H]⁺。

¹H NMR(MeOH-d₄)：7.38-7.32(m，2H)，7.26(brs，1H)，7.19(br d，J＝6.5，1H)，6.88-6.72(m，3H)，4.89(s，3.5H)，4.58-4.45(m，4H)，4.11-4.06(m，2H)，3.85-3.77(m，1H)，3.72(t，J＝6.5，2H)，3.46(br s，1H)，3.05(s，3H)，1.99-1.92(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (3-chloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline-7- Radical oxy radical]-propyl ester. Yield (1.08mmol scale): 498.7mg (> 100%) of crude product. Ms (esi): c₂₀H₂₄ClNO₄Calculated value of molecular weight of S: 409.1, respectively; m/z found: 410.4[ M + H]⁺。

And 5: 4- (3-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ]-2-methyl- 1, 2, 3, 4-tetrahydro-isoquinolines. Yield (1.08mmol scale): after HPLC purificationThe TFA salt was isolated as 163.5mg (23%). Ms (esi): c₂₄H₃₀ClFN₂Calculated value of molecular weight of O: 416.2; m/z found: 417.4[ M + H]⁺。

¹H NMR(MeOH-d₄)：7.40-7.29(m，2H)，7.26(brs，1H)，7.19(d，J＝6.4，1H)，6.85(brs，2H)，6.78(brs，1H)，5.00(s，3H)，4.93-4.75(m，1H)，4.59-4.56(m，3H)，4.10(t，J＝5.4，2H)，3.81(brs，1H)，3.70-3.66(brm，1H)，3.55(d，J＝12.0，2H)，3.46(brs，1H)，3.35(t，J＝7.8，2H)，3.27-3.22(m，2H)，3.22-3.11(m，1H)，3.06(s，3H)，2.29-1.92(m，6H).

Example 47: 4- (4-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 1- (4-chloro-phenyl) -2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino- Ethanones. Yield (5.12mmol scale): 2.26g (> 100%) of crude product. Ms (esi): c₁₉H₂₂ClNO₃Calculated value of molecular weight of (c): 347.1; m/z found: 348.4[ M + H]⁺。

Step 2: 4- (4-chloro-phenyl) -7- (3-hydroxy-propoxy) -2-methyl-isoquinolinium salts. Yield (5.12mmol scale): 2.06g (> 100%) of crude product. Ms (esi): c₁₉H₁₉ClNO₂ ⁺Calculated value of molecular weight of (c): 328.1; m/z found: 328.3[ M ]]⁺。

And step 3: 3- [4- (4-chloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]- Propan-1-ol. Yield (5.12mmol scale): 584.3mg (34%), which was characterized as a TFA salt after HPLC purification. Ms (esi): c₁₉H₂₂ClNO₂Of (a) a moleculeCalculating a value: 331.1, respectively; m/z found: 332.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.23(d，J＝8.3，2H)，7.08(d，J＝8.4，2H)，6.65-6.58(m，2H)，6.52(br s，1H)，4.80(br s，1.5H)，4.50-4.47(m，1H)，4.41(t，J＝6.3，2H)，3.93-3.83(m，2H)，3.67-3.59(m，1H)，3.51(t，J＝6.2，2H)，3.28(br s，1H)，2.86(s，3H)，1.84-1.81(m，1H)，1.74-1.68(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (4-chloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline-7- Radical oxy radical]-propyl ester. Yield (1.36mmol scale): 601.9mg (> 100%) of crude product. Ms (esi): c₂₀H₂₄ClNO₄Calculated value of molecular weight of S: 409.1, respectively; m/z found: 410.3[ M + H]⁺。

And 5: 4- (4-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl- 1, 2, 3, 4-tetrahydro-isoquinolines. Yield (1.36mmol scale): 8.7mg (1%, characterized as TFA salt after HPLC purification). Ms (esi): c₂₄H₃₀ClFN₂Calculated value of molecular weight of O: 416.2; m/z found: 417.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.41(d，J＝8.5，2H)，7.30(d，J＝8.5，2H)，6.86-6.82(m，2H)，6.76(br s，1H)，4.73-4.70(m，1H)，4.13(t，J＝5.0，2H)，3.89(br s 1H)，3.61(brd，J＝10.5，2H)，3.53(br s，1H)，3.40(t，J＝7.0，2H)，3.26-3.16(br m，2H)，3.10(s，3H)，2.33(br s，3H)，2.25-2.10(m，2H).

Example 48: 4- (3-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 1- (3-fluoro-phenyl) -2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino- Ethanones. Yield (4.19mmol scale): 1.56g (> 100%) of crude product. Ms (esi): c₁₉H₂₂FNO₃Calculated value of molecular weight of (c): 331.2; m/z found: 332.4[ M + H]⁺。

Step 2: 4- (3-fluoro-phenyl) -7- (3-hydroxy-propoxy) -2-methyl-isoquinolinium salts. Yield (4.19mmol scale): 1.43g (94%) of the crude product. Ms (esi): c₁₉H₁₉FNO₂ ⁺Calculated value of molecular weight of (c): 312.1; m/z found: 312.3[ M ]]⁺。

And step 3: 3- [4- (3-fluoro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]- Propan-1-ol. Yield (4.19mmol scale): 348.3mg (25%); characterized as TFA salt. Ms (esi): c ₁₉H₂₂FNO₂Calculated value of molecular weight of (c): 315.2; m/z found: 316.4[ M + H]⁺。

¹HNMR (acetone-d)₆)：7.23-7.19(m，1H)，6.93(d，J＝7.6，1H)，6.89-6.82(m，2H)，6.65-6.59(m，2H)，6.54(br s，1H)，4.52-4.49(m，1H)，4.40(t，J＝6.3，2H)，4.36(br s，1H)，3.95-3.83(m，2H)，3.63(br s，1H)，3.48(t，J＝6.1，2H)，3.30(br s，1H)，2.85(s，3H)，1.85-1.81(m，3H)，1.75-1.69(m，2H)，1.21-1.14(m，1H).

And 4, step 4: methanesulfonic acid 3- [4- (3-fluoro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline-7- Radical oxy radical]-propyl ester. Yield (0.859mmol scale): 364.8mg (> 100%) of crude product. Ms (esi): c₂₀H₂₄FNO₄Calculated value of molecular weight of S: 393.1, respectively; m/z found: 394.4[ M + H]⁺。

And 5: 4- (3-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl- 1, 2, 3, 4-tetrahydro-iso-Quinolines. Yield (0.859mmol scale): 2.8mg (0.5%, TFA salt). Ms (esi): c₂₄H₃₀F₂N₂Calculated value of molecular weight of O: 400.2; m/z found: 401.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.45-7.40(m，1H)，7.15(d，J＝7.5，1H)，7.11-7.04(m，2H)，6.86-6.75(m，3H)，4.74-4.71(m，1H)，4.56(br s，2H)，4.12-4.10(m，2H)，3.83(br s，1H)，3.58(br s，2H)，3.49(br s，2H)，3.36(t，J＝8.0，2H)，3.21(br s，2H)，3.04(s，3H)，2.33-2.26(m，4H)，2.17-2.12(m，2H).

Example 49: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino } -1- (4-trifluoromethoxy) ester Phenyl-ethanones. Yield (5.12mmol scale): 2.37g (> 100%) of crude product. Ms (esi): c₂₀H₂₂F₃NO₄Calculated value of molecular weight of (c): 397.2; m/z found: 398.4[ M + H]⁺。

Step 2: 7- (3-hydroxy-propoxy) -2-methyl-4- (4-trifluoromethoxy-phenyl) -isoquinoline Quinolinium salts. Yield (5.12mmol scale): 2.06g (94%) of the crude product. Ms (esi): c ₂₀H₁₉F₃NO₃ ⁺Calculated value of molecular weight of (c): 378.1, respectively; m/z found: 378.3[ M ]]⁺。

And step 3: 3- [ 2-methyl-4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline-7- Radical oxy radical]-propan-1-ol. Yield (5.12mmol scale): 1.19mg (59%) of it is characterized as TFA salt. Ms (esi): c₂₀H₂₂F₃NO₃Calculated value of molecular weight of (c): 381.2, respectively; m/z found: 382.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.21-7.19(m，2H)，7.12(d，J＝8.2，2H)，6.65-6.58(m，2H)，6.51(br d，J＝7.8，1H)，4.56-4.52(m，1H)，4.42-4.30(m，1H)，3.88-3.85(m，2H)，3.66-3.62(m，2H)，3.48(t，J＝6.0，2H)，3.28(br s，1H)，2.84(s，3H)，1.85-1.81(m，2H)，1.74-1.69(m，2H).

And 4, step 4: methanesulfonic acid 3- [ 2-methyl-4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-iso Quinolin-7-yloxy]-propyl ester. Yield (2.82mmol scale): 1.50g (> 100%) of crude product.

And 5: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-trifluoromethoxy- Phenyl) -1, 2, 3, 4-tetrahydro-isoquinolines. Yield (2.82mmol scale): 333.4mg (17%, TFA salt). Ms (esi): c₂₄H₃₀F₂N₂Calculated value of molecular weight of O: 400.2; m/z found: 401.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.41(d，J＝8.5，2H)，7.33(d，J＝7.5，2H)，6.87-6.76(m，3H)，5.03(br d，J＝48，1H)，4.78-4.75(m，1H)，4.65(br s，2H)，4.12(br s，2H)，3.93-3.90(m，1H)，3.77(br s，1H)，3.63(br d，J＝11.0，2H)，3.43(br s，2H)，3.31-3.21(m，2H)，3.13(s，3H)，2.47-2.25(m，3H)，2.24-2.10(m，2H).

Example 50: 4- (4-difluoromethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 1- (4-difluoromethoxy-phenyl) -2- { [3- (3-hydroxy-propoxy) -benzyl]-first of all Amino-ethanones. Yield: (5.12mmol scale): 2.21g (> 100%) of crude product. Ms (esi): c ₂₀H₂₃F₂NO₄Calculated value of molecular weight of (c): 379.2; m/z found: 380.4[ M + H]⁺。

Step 2: 4- (4-difluoromethoxy-phenyl) -7- (3-hydroxy-propoxy) -2-methyl-isoquinoline Quinolinium salts. Yield (5.12mmol scale): 1.63g (78%) of the crude product. Ms (esi): c₂₀H₂₀F₂NO₃ ⁺Calculated value of molecular weight of (c): 360.1; m/z found: 360.4[ M ]]⁺。

And step 3: 3- [4- (4-difluoromethoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline-7- Radical oxy radical]-propan-1-ol. Yield (4.12mmol scale): 1.00g (67%) was characterized as TFA salt. Ms (esi): c₂₀H₂₃F₂NO₃Calculated value of molecular weight of (c): 363.2, respectively; m/z found: 364.4[ M + H]⁺。

¹H NMR(MeOH-d₄)：7.28(d，J＝7.0，2H)，7.15(d，J＝8.5，2H)，6.97-6.68(t，J＝74，1H)，6.86-6.70(m，3H)，4.99(brs，2H)，4.61-4.55(m，3H)，4.06(t，J＝6.0，2H)，3.79(br s，1H)，3.72(t，J＝6.5，2H)，3.44(br s，1H)，3.06(s，3H)，1.98-1.93(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (4-difluoromethoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-iso Quinolin-7-yloxy]-propyl ester. Yield (0.660mmol scale): 357.8mg (> 100%) of crude product. Ms (esi): c₂₁H₂₅F₂NO₅Calculated value of molecular weight of S: 441.1; m/z found: 442.4[ M + H]⁺。

And 5: 4- (4-difluoromethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2- The methyl groups of the 1, 2, 3,4-tetrahydro-isoquinolines. Yield (0.660mmol scale): 202.8mg (44%, TFA salt). Ms (esi): c₂₅H₃₁F₃N₂O₂Calculated value of molecular weight of (c): 448.2, respectively; m/z found: 449.5[ M + H ]]⁺。

¹H NMR(MeOH-d₄)：7.21(d，J＝7.5，2H)，7.08(d，J＝8.5，2H)，6.78(brs，2H)，6.76(t，J＝74，1H)，6.72(br s，1H)，5.00-4.80(br m，3H)，4.54-4.51(m，3H)，4.04(t，J＝5.5，2H)，3.77-3.70(br m，1H)，3.64-3.61(br m，1H)，3.49(d，J＝12.0，2H)，3.39(br s，1H)，3.31-3.27(m，3H)，3.21-3.16(m，1H)，3.00(s，3H)，2.20-2.14(m，6H).

Example 51: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methanesulfonyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino } -1- (4-methanesulfonyl- Phenyl) -ethanones. Yield (3.60mmol scale): 1.73g (> 100%) of crude product. Ms (esi): c₂₀H₂₅NO₅Calculated value of molecular weight of S: 391.2; m/z found: 392.4[ M + H]⁺。

Step 2: 7- (3-hydroxy-propoxy) -4- (4-methanesulfonyl-phenyl) -2-methyl-isoquinoline Onium salts. Yield (3.60mmol scale): 1.45g (99%) of the crude product. Ms (esi): c₂₀H₂₂NO₄S⁺Calculated value of molecular weight of (c): 372.4, respectively; m/z found: 372.4[ M ]]⁺。

And step 3: 3- [4- (4-methanesulfonyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl Oxy radical]-propan-1-ol. Yield (3.60mmol scale): 810.8mg (60%), itCharacterized as TFA salt. Ms (esi): c₂₀H₂₅NO₄Calculated value of molecular weight of S: 375.2, respectively; m/z found: 376.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.73(d，J＝8.1，2H)，7.34(d，J＝8.3，2H)，6.67-6.59(m，2H)，6.51(br s，1H)，5.25(br s，2H)，4.65-4.62(m，1H)，4.40(t，J＝6.3，2H)，3.87(t，J＝6.1，2H)，3.72-3.68(m，1H)，3.48(t，J＝6.1，2H)，3.35(brs，1H)，2.90(s，3H)，2.88(s，3H)，1.82-1.81(m，1H)，1.74-1.69(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (4-methanesulfonyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline Quinoline-7-yloxy]-propyl ester. Yield (1.98mmol scale): 762.7mg (> 100%) of crude product.

And 5: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (4-methanesulfonyl-phenyl) -2-methyl 1, 2, 3, 4-tetrahydro-isoquinolines. Yield (1.98mmol scale): 127.5mg (9%, TFA salt). Ms (esi): c ₂₅H₃₃FN₂O₃Calculated value of molecular weight of S: 460.2, respectively; m/z found: 461.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.95(d，J＝8.5，2H)，7.55(d，J＝8.0，2H)，6.88(brs，1H)，6.83(br d，J＝8.0，1H)，8.74(br s，1H)，5.03(br d，J＝48，1H)，4.88-4.84(m，1H)，4.64(br s，2H)，4.12(t，J＝5.5，2H)，3.94-3.91(m，1H)，3.61(br d，J＝10.5，2H)，3.40(t，J＝7.0，2H)，3.30-3.17(m，3H)，3.13(s，3H)，3.09(s，3H)，2.36-2.26(m，3H)，2.24-2.10(m，3H).

Example 52: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino } -1- (4-methylsulfanyl-benzene Alkyl) -ethanones. Yield (5.12mmol scale): 2.37g (> 100%) of crude product. Ms (esi): c₂₀H₂₅NO₃Calculated value of molecular weight of S: 359.2, respectively; m/z found: 360.4[ M + H]⁺。

Step 2: 7- (3-hydroxy-propoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -isoquinolinium Salt (salt). Yield (5.12mmol scale): 2.07g (98%) of crude product. Ms (esi): c₂₀H₂₂NO₂S⁺Calculated value of molecular weight of (c): 340.1 of the total weight of the mixture; m/z found: 340.4[ M ]]⁺。

And step 3: 3- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy Base of]-propan-1-ol. Yield (5.12mmol scale): 352.4mg (14%) which was characterized as a TFA salt. Ms (esi): c₂₀H₂₅NO₂Calculated value of molecular weight of S: 343.2, respectively; m/z found: 344.4[ M + H ]]⁺。

¹H NMR(MeOH-d₄)：7.25(d，J＝8.0，2H)，7.15(br d，J＝6.0，2H)，6.81(br s，2H)，6.78(br s，1H)，4.90(s，3H)，4.58-4.49(m，3H)，4.06(t，J＝6.0，2H)，3.77(br s，1H)，3.72(t，J＝6.5，2H)，3.41(br s，1H)，3.05(s，3H)，2.45(s，3H)，1.99-1.94(m，2H).

And 4, step 4: methanesulfonic acid 3- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy]-propyl ester. Yield (0.563mmol scale): 305.1mg (> 100%) of crude product. Ms (esi): c₂₁H₂₇NO₄S₂Calculated value of molecular weight of (c): 421.1, respectively; m/z found: 422.4[ M + H ]⁺。

And 5: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-4- (4-methylthio) methanePhenyl radical 1, 2, 3, 4-tetrahydro-isoquinolines. Yield (0.563mmol scale): 145.9mg (39%, TFA salt). Ms (esi): c₂₅H₃₃FN₂Calculated molecular weight of OS: 428.2; m/z found: 429.5[ M + H]⁺。

¹H NMR(MeOH-d₄): 7.25(d, J ═ 8.5, 2H), 7.15(br d, J ═ 7.0, 2H), 6.83(br s, 2H), 6.79(br s, 1H), 4.92(s, 3H), 4.54-4.49(m, 3H), 4.09(t, J ═ 5.5, 2H), 3.77(br s, 1H), 3.68(br d, not split), 3.54(d, J ═ 11.0, 2H), 3.42(br s, 1H), 3.36-3.33(m, 2H), 3.24(t, J ═ 12.5, 2H), 3.13-3.00(m, 1H), 3.05(s, 3H), 2.45(s, 3H), 2.31-2.14(m, 5H), 2.13-3.00 (m, 1H).

Example 53: 4- (3-chloro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 1- (3-chloro-4-methoxy-phenyl) -2- { [3- (3-hydroxy-propoxy) -benzyl]-first of all Amino-ethanones. Yield (3.61mmol scale): 2.10g (> 100%) of crude product. Ms (esi): c₂₀H₂₄ClNO₄Calculated value of molecular weight of (c): 377.1; m/z found: 378.4[ M + H]⁺。

Step 2: 4- (3-chloro-4-methoxy-phenyl) -7- (3-hydroxy-propoxy) -2-methyl-isoquinoline Quinolinium salts. Yield (3.61mmol scale): 1.84g (> 100%) of crude product. Ms (esi): c₂₀H₂₁ClNO₃ ⁺Calculated value of molecular weight of (c): 358.1; m/z found: 358.4[ M ]]⁺。

And step 3: 3- [4- (3-chloro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline-7- Oxygen baseBase of]-propan-1-ol. Yield (3.61mmol scale): 352.5mg (21%, TFA salt). Ms (esi): c₂₀H₂₄ClNO₃Calculated value of molecular weight of (c): 361.1, respectively; m/z found: 362.4[ M + H]⁺。

¹H NMR(MeOH-d₄)：7.24(br s，1H)，7.16(br s，1H)，7.04(d，J＝8.5，1H)，6.81(br s，3H)，4.96(br s，2.5H)，4.57-4.48(m，3H)，4.06(t，J＝6.5，2H)，3.85(s，3H)，3.80(br s，1H)，3.72(t，J＝6.0，2H)，3.41(br s 1H)，3.04(s，3H)，1.97-1.93(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (3-chloro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro- Isoquinolin-7-yloxy group]-propyl ester. Yield (0.663mmol scale): 344.6mg (> 100%) of crude product. Ms (esi): c₂₁H₂₆ClNO₅Calculated value of molecular weight of S: 439.1, respectively; m/z found: 440.4[ M + H ]]⁺。

And 5: 4- (3-chloro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2- Methyl-1, 2, 3, 4-tetrahydro-isoquinolines. Yield (0.663mmol scale): 205.9mg (46%, TFA salt). Ms (esi): c₂₅H₃₂ClFN₂O₂Calculated value of molecular weight of (c): 446.2; m/z found: 447.5[ M + H]⁺。

¹H NMR(MeOH-d₄)：7.22(br s，1H)，7.16(d，J＝7.5，1H)，7.04(d，J＝8.5，1H)，6.84-6.77(m，3H)，5.27(s，6H)，5.02-4.74(m，1H)，4.57-4.48(m，3H)，4.09(br s，2H)，3.96(s，1H)，3.86(s，3H)，3.80-3.77(m，1H)，3.70-3.65(m，1H)，3.54(d，J＝12.0，2H)，3.43-3.33(m，4H)，3.26-3.20(m，2H)，3.15-3.10(m，1H)，3.05(s，3H)，2.31-1.97(m，8H).

Example 54: 4- (2, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 1- (2, 4-dichloro-phenyl) -2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-ammonia Alkyl-ethanone. Yield (7.02mmol scale): 3.15g (> 100%) of crude product. Ms (esi): c₁₉H₂₁Cl₂NO₃Calculated value of molecular weight of (c): 381.1, respectively; m/z found: 382.3[ M + H]⁺，384.3[M+H]⁺。

Step 2: 4- (2, 4-dichloro-phenyl) -7- (3-hydroxy-propoxy) -2-methyl-isoquinolinium Salt (salt). Yield (7.02mmol scale): 2.78g (99%) of the crude product. Ms (esi): c₁₉H₁₈Cl₂NO₂ ⁺Calculated value of molecular weight of (c): 362.1; m/z found: 362.3[ M ]]⁺364.3[M]⁺。

And step 3: 3- [4- (2, 4-dichloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy-methyl-amino Base of]-propan-1-ol. Yield (6.97mmol scale): 1.537g (46%, TFA salt). Ms (esi): c₁₉H₂₁Cl₂NO₂Calculated value of molecular weight of (c): 365.1, respectively; m/z found: 366.3[ M + H]⁺，368.3[M+H]⁺。

¹H NMR(MeOH-d₄)：7.56(d，J＝2.0，1H)，7.32(d，J＝8.0，1H)，7.13(brs，1H)，6.87-6.80(m，2H)，6.75(br s，1H)，5.06(br s，1H)，4.89(s，3H)，4.58-4.46(m，2H)，4.08(t，J＝6.5，2H)，3.84-3.81(m，1H)，3.72(t，J＝6.5，2H)，3.52(br s，1H)，3.08(s，3H)，1.99-1.94(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (2, 4-dichloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy]-propyl ester. Yield (3.02mmol scale): 1.62g (> 100%) of crude product. Ms (esi): c₂₀H₂₃Cl₂NO₄Calculated value of molecular weight of S: 443.1; m/z found: 443.3[ M + H]⁺，445.3[M+H]⁺。

And 5: 4- (2, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl- 1, 2, 3, 4-tetrahydro-isoquinolines. Yield (3.02mmol scale): 1.13g (55%, TFA salt). Ms (esi): c₂₄H₂₉Cl₂FN₂Calculated value of molecular weight of O: 450.2 of the total weight of the mixture; m/z found: 451.4[ M + H ]⁺，453.4[M+H]⁺。

¹H NMR(MeOH-d₄)：7.53(d，J＝2.0，1H)，7.29(br s，1H)，7.16(brs，1H)，6.86(br s，2H)，6.74(br s，1H)，5.09(s，3H)，5.02-4.75(m，1H)，4.57(br s，2H)，4.11(t，J＝5.5，2H)，3.84-3.80(m，1H)，3.69(br d，J＝10.0，1H)，3.55(d，J＝11.0，2H)，3.36(t，J＝8.0，2H)，3.27-3.21(m，2H)，3.17-3.03(m，1H)，3.08(s，3H)，2.34-2.96(m，6H).

Example 55: 4- (2, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 1- (2, 5-dichloro-phenyl) -2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-ammonia Alkyl-ethanone. Yield (5.12mmol scale): 3.10g (> 100%) of crude product. Ms (esi): c₁₉H₂₁Cl₂NO₃Calculated value of molecular weight of (c): 381.1, respectively; m/z found: 382.4[ M + H]⁺，384.4[M+H]⁺。

Step 2: 4- (2, 5-dichloro-phenyl) -7- (3-hydroxy-propoxy) -2-methyl-isoquinolinium Salt (salt). Yield (5.12mmol scale): 2.22g (> 100%) of crude product. Ms (esi): c₁₉H₁₈Cl₂NO₂ ⁺Calculated value of molecular weight of (c): 362.1; m/z found: 362.3[ M ]]⁺364.3[M]⁺。

And step 3: 3- [4- (2, 5-dichloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy-methyl-amino Base of]-propan-1-ol. Yield (5.12mmol scale): 1.12g (42%, TFA salt). Ms (esi): c₁₉H₂₁Cl₂NO₂Calculated value of molecular weight of (c): 365.1, respectively; m/z found: 366.4[ M + H]⁺，368.4[M+H]⁺。

¹H NMR(MeOH-d₄)：7.49(d，J＝8.5，1H)，7.36-7.34(m，1H)，7.15(br s，1H)，6.89-6.81(m，2H)，6.77(br s，1H)，5.07(br s，1H)，4.88(s，2.5H)，4.56-4.55(m，2H)，4.09(t，J＝6.0，2H)，3.85-3.82(m，1H)，3.72(t，J＝6.5，2H)，3.55(br s，1H)，3.08(s，3H)，2.00-1.95(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (2, 5-dichloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy]-propyl ester. Yield (2.08mmol scale): 1.24g (> 100%) of crude product. Ms (esi): c₂₀H₂₃Cl₂NO₄Calculated value of molecular weight of S: 443.1; m/z found: 443.3.

and 5: 4- (2, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ]-2-methyl- 1, 2, 3, 4-tetrahydro-isoquinolines. Yield (2.08mmol scale): 895.5mg (64%, TFA salt). Ms (esi): c₂₄H₂₉Cl₂FN₂Calculated value of molecular weight of O: 450.2 of the total weight of the mixture; m/z found: 451.4[ M + H]⁺，453.4[M+H]⁺。

¹H NMR(MeOH-d₄)：7.47(d，J＝8.5，1H)，7.33-7.31(m，1H)，7.17(br s，1H)，6.87(br s，2H)，6.77(br s，1H)，5.06(s，3H)，5.02-4.75(m，1H)，4.58(br s，1H)，4.11(t，J＝5.0，2H)，3.85-3.81(m，1H)，3.69(br d，J＝10.0，1H)，3.56(d，J＝11.5，2H)，3.36(t，J＝8.0，2H)，3.27-3.22(m，2H)，3.16-3.02(m，1H)，3.08(s，3H)，2.40-1.95(m，6H).

Example 56: 4- (3, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 1- (3, 5-dichloro-phenyl) -2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-ammonia Alkyl-ethanone. Yield (5.12mmol scale): 2.31g (> 100%) of crude product. Ms (esi): c₁₉H₂₁Cl₂NO₃Calculated value of molecular weight of (c): 381.1, respectively; m/z found: 382.3[ M + H]⁺，384.3[M+H]⁺。

Step 2: 4- (3, 5-dichloro-phenyl) -7- (3-hydroxy-propoxy) -2-methyl-isoquinolinium Salt (salt). Yield (5.12mmol scale): 2.10g (> 100%) of crude product. Ms (esi): c₁₉H₁₈Cl₂NO₂ ⁺Calculated value of molecular weight of (c): 362.1; m/z found: 362.3[ M ]]⁺364.3[M]⁺。

And step 3: 3- [4- (3, 5-dichloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy-methyl-amino Base of]-propan-1-ol. Yield (5.12mmol scale): 708.5mg (27%, TFA salt). Ms (esi): c₁₉H₂₁Cl₂NO₂Calculated value of molecular weight of (c): 365.1, respectively; m/z found: 364.4[ M + H]⁺，366.4[M+H]⁺。

¹H NMR(MeOH-d₄)：7.38-7.24(m，2H)，7.14(d，J＝8.0，1H)，6.96-6.67(m，3H)，4.99(br s，2H)，4.60-4.55(m，3H)，4.09-4.05(m，2H)，3.83-3.73(m，1H)，3.74-3.71(m，2H)，3.44(brs，1H)，3.06(s，3H)，1.98-1.94(m，2H).

And 4, step 4: methanesulfonic acid 3- [4- (3, 5-dichloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy ]-propyl ester. Yield (1.20mmol scale): 646.9mg (> 100%) of crude product. Ms (esi): c₂₀H₂₃Cl₂NO₄Calculated value of molecular weight of S: 443.1; m/z found: 442.4[ M + H]⁺，444.4[M+H]⁺。

And 5: 4- (3, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl- 1, 2, 3, 4-tetrahydro-isoquinolines. Yield (1.20mmol scale): 175.5mg (21%, TFA salt). Ms (esi): c₂₄H₂₉Cl₂FN₂Calculated value of molecular weight of O: 450.2 of the total weight of the mixture; m/z found: 451.4[ M + H]⁺，453.4[M+H]⁺。

¹H NMR(MeOH-d₄)：7.33(s，1H)，7.18(s，2H)，6.84-6.76(m，3H)，4.97-4.85(m，4H)，4.57-4.50(m，3H)，4.06(t，J＝5.5，2H)，3.79-3.75(m，1H)，3.62-3.42(m，3H)，3.31-3.28(m，4H)，3.25-3.14(m，2H)，3.00(s，3H)，2.20-1.94(m，7H).

Example 57: 2-methyl-7- (3-piperidin-1-yl-propoxy) -4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 2- [ (3-methoxy-benzyl) -methyl-amino]-1-thiophen-3-yl-ethanones. A solution of (3-methoxy-benzyl) -methyl-amine (0.590g, 3.93mmol) and TEA (1.1ml) in DCM (5ml) was treated with 2-bromo-1-thiophen-3-yl-ethanone (1.11g, 5.11 mmol). After 16 h at 23 ℃ the mixture was poured into water and extracted with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated to give the desired product (1.149g, crude product)＞100％)。

¹H NMR(CDCl₃)：8.24(dd，J＝2.9，1.2，1H)，7.57(dd，J＝5.1，1.2，1H)，7.28(dd，J＝5.1，2.9，1H)，7.26-7.21(m，1H)，6.94-6.90(m，2H)，6.83-6.79(m，1H)，3.79(s，3H)，3.65(s，2H)，3.64(s，2H)，2.37(s，3H).

Step 2: 7-methoxy-2-methyl-4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline. Reacting 2- [ (3-methoxy-benzyl) -methyl-amino]-1-thiophen-3-yl-ethanone (1.14g, 4.14mmol) was diluted with MSA (3 ml). The mixture was stirred at 23 ℃ for 2 hours and then saturated NaHCO was poured in ₃In aqueous solution, extract with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated with MeOH (5ml) and excess NaCNBH₃And (6) processing. A few crystals of bromocresol green were added and the pH of the mixture was adjusted to about 4-5 with HCl (1.25M MeOH). The mixture was stirred at 23 ℃ for 16 h and extracted with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. FCC gave 7-methoxy-2-methyl-4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline (0.412g, 38%).

¹H NMR(CDCl₃)：7.23(dd，J＝5.1，3.1，1H)，7.03(ddd，J＝2.9，1.4，0.4，1H)，6.90(dd，J＝5.1，1.4，1H)，6.87(dd，J＝8.0，0.4，1H)，6.66(dd，J＝8.4，2.7，1H)，6.59(d，J＝2.7，1H)，4.32(dd，J＝8.0，6.3，1H)，3.77(s，3H)，3.68(d，J＝14.9，1H)，3.58(d，J＝14.9，1H)，2.97(ddd，J＝11.5，5.5，1.4，1H)，2.60(dd，J＝11.3，8.2，1H)，2.43(s，3H).

And step 3: 2-methyl-4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinolin-7-ol. To a solution of 7-methoxy-2-methyl-4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline (0.278g, 1.07mmol) in DCM (3ml) at 0 deg.C was added BBr₃(1.0M DCM, 2.0 ml). After 1 hour at 0 ℃ saturated NaHCO was added₃Aqueous solution, the organics were dissolved in DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. By FCCThe desired compound (0.042g, 16%) was obtained.

¹H NMR(DMSO-d₆)：9.17(s，1H)，7.40(dd，J＝4.9，2.9，1H)，7.19(dd，J＝2.9，1.2，1H)，6.94(dd，J＝4.9，1.2，1H)，6.67(d，J＝8.0，1H)，6.49(dd，J＝8.2，2.3，1H)，6.46(d，J＝2.5，1H)，4.17(dd，J＝6.8，6.1，1H)，3.50(d，J＝15.5，1H)，3.45(d，J＝15.5，1H)，2.78(dd，J＝15.5，5.5，1H)，2.56(dd，J＝11.3，7.2，1H)，2.30(s，3H).

Step 4: to a solution of 2-methyl-4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinolin-7-ol (0.0498g, 0.203mmol) in THF (2ml) was added NaH (60% oil dispersion, 0.029g, 0.728mmol) and 1-bromo-3-chloropropane (0.075 ml). After 1 hour, the resulting mixture was treated with additional NaH (0.050g) and 1-bromo-3-chloropropane (0.10ml), and the mixture was heated to 50 ℃ for 18 hours. The mixture was then cooled and saturated NaHCO ₃Dilute the aqueous solution and extract with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. FCC gave 7- (3-chloro-propoxy) -2-methyl-4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline (0.0188g), doped in small amounts with 2-methyl-4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinolin-7-ol. The crude product can be used for the next reaction. A solution of 7- (3-chloro-propoxy) -2-methyl-4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline (0.0188g, 0.058mmol) in n-butanol (2ml) was dissolved with Na₂CO₃(0.0306g), piperidine (0.5ml) and KI (. about.0.005 g). The resulting mixture was heated at 55 ℃ for 18 hours, cooled and saturated NaHCO₃Dilute the aqueous solution and extract with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. FCC gave the desired compound (0.020g, 92%). Ms (esi): c₂₂H₃₀N₂Calculated molecular weight of OS: 370.55, respectively; m/z found: 371.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.23(dd，J＝5.1，3.1，1H)，7.03(dd，2.9，1.0，1H)，6.89(dd，J＝2.9，1.0，1H)，6.84(d，J＝8.6，1H)，6.65(dd，J＝8.6，2.7，1H)，6.59(d，J＝2.7，1H)，4.13(dd，J＝7.8，5.9，1H)，3.97(d，J＝6.5，1H)，3.95(d，J＝6.5，1H)，3.67(d，J＝14.9，1H)，3.57(d，J＝15.1，1H)，2.96(ddd，11.3，5.5，1.2，1H)，2.59(dd，J＝11.5，8.4，1H)，2.48-2.32(m，9H)，2.01-1.91(m，2H)，1.63-1.54(m，4H)，1.48-1.40(m，2H).

Example 58: 4- (3, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

The preparation is carried out analogously to that used in example 1.

Step 1: 3- [4- (3, 4-dichloro-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy-methyl-amino Base of]-propan-1-ol。MS(ESI)：C₁₉H₂₁Cl₂NO₂Calculated value of molecular weight of (c): 365.09, respectively; m/z found: 366.3[ M + H ]⁺。

¹H NMR(CDCl₃)：7.34(d，J＝8.2，1H)，7.29(d，J＝2.0，1H)，7.03(dd，J＝8.2，2.2，1H)，6.75(d，J＝8.4，1H)，6.67(dd，J＝8.4，2.5，1H)，6.63(d，J＝2.5，1H)，4.16-4.07(m，3H)，3.87(d，J＝5.9，1H)，3.85(d，J＝5.9，1H)，3.62(s，2H)，2.93(dd，J＝11.3，5.3，1H)，2.54(dd，J＝11.5，7.4，1H)，2.40(s，3H)，2.07-2.00(m，2H).

Step 2：MS(ESI)：C₂₄H₂₉Cl₂FN₂Calculated value of molecular weight of O: 450.16, respectively; m/z found: 451.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.33(d，J＝8.3，1H)，7.29(d，J＝2.3，1H)，7.03(dd，J＝8.3，2.0，1H)，6.75(d，J＝8.6，1H)，6.66(dd，J＝8.6，2.8，1H)，6.61(d，J＝2.8，1H)，4.78-4.58(m，1H)，4.13(dd，J＝7.1，5.6，1H)，3.99(d，J＝6.3，1H)，3.97(d，J＝6.3，1H)，3.62(s，2H)，2.93(dd，J＝11.4，5.3，1H)，2.65-2.48(m，5H)，2.40(s，3H)，2.41-2.35(m，2H)，2.00-1.83(m，6H).

Example 59: 2-methyl-7- (3-piperidin-1-yl-propoxy) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 7-methoxy-2-methyl-4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline。

Synthesis of 3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy-in analogy]-propan-1-ol. Ms (esi): c₁₆H₁₈N₂Calculated value of molecular weight of O: 254.14, respectively; m/z found: 255.4[ M + H]⁺。

¹H NMR(CDCl₃)：8.78-8.74(m，2H)，7.98(d，J＝7.6，1H)，7.66(m，1H)，6.86(dd，J＝8.6，2.5，1H)，6.79(d，J＝8.6，1H)，6.72(d，J＝2.5，1H)，4.94-4.81(m，1H)，4.46(br s，2H)，3.88-3.70(m，4H)，3.01(s，3H).

Step 2: 2-methyl-4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinolin-ol. To a solution of 7-methoxy-2-methyl-4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline (99mg, 0.39mmol) in DCM (4.0ml) was added BBr₃(0.78ml, 0.78 mmol). The mixture was heated to reflux overnight. Then adding BBr₃(1 eq.) the mixture was heated under reflux for an additional 4 hours. The mixture was then poured into water over 2N Na₂CO₃Neutralized, extracted with DCM and dried (Na)₂SO₄) And concentrated to give the crude product. By FCCPurification gave the desired product (48mg, 48%). Ms (esi): c₁₅H₁₆N₂Calculated value of molecular weight of O: 240.13, respectively; m/z found: 241.4[ M + H]⁺。

¹H NMR(CDCl₃)：8.38(dd，J＝4.9，1.6，2H)，7.64-7.59(m，1H)，7.36-7.31(m，1H)，6.63-6.53(m，3H)，4.29-4.22(m，1H)，3.69-3.56(m，2H)，3.06-2.97(m，1H)，2.55(dd，J＝11.5，8.4，1H)，2.40(s，3H).

And step 3: 7- (3-chloro-propoxy-2-methyl-4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline . In a sealed pressure tube, 2-methyl-4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinolin-7-ol (40mg, 0.17mmol), 1-bromo-3-chloropropane (53mg, 0.34mmol), K₂CO₃A mixture of (116mg, 0.84mmol) and acetone was heated to 100 ℃. After 3 hours, the mixture was cooled to room temperature, diluted with water and extracted with DCM (3 times). The combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated to give the crude product as a brown residue. Purification by FCC gave the desired product (18mg, 33%).

Step 4: 7- (3-chloro-propoxy-2-methyl-4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline (18mg, 0.06mmol), piperidine (7.2mg, 0.09mmol), Na₂CO₃A solution of (9.0mg, 0.09mmol) and KI (0.5mg, 0.003mmol) in n-butanol was heated at 80 ℃ and stirred overnight. The mixture was concentrated, and the residue was purified by reverse phase column chromatography to give the desired compound (2.5mg, 12%, TFA salt). Ms (esi): c₂₃H₃₁N₃Calculated value of molecular weight of O: 365.25; m/z found: 366.5[ M + H]⁺。

¹H NMR(CDCl₃)：8.44(d，J＝1.9，1H)，8.40(dd，J＝4.7，1.6，1H)，7.41-7.38(m，1H)，7.14-7.10(m，1H)，6.68(d，J＝8.5，1H)，6.57-6.52(m，2H)，4.14-4.10(m，1H)，4.06-3.99(m，1H)，3.96(t，J＝5.7，2H)，3.58(d，J＝3.6，2H)，2.91-2.86(m，1H)，2.75-2.71(m，1H)，2.56-2.48(m，2H)，2.34(s，3H)，1.61-1.36(br m，6H)，1.29-1.10(m，10H)，0.84-0.80(m，4H).

Example 60: 2-methyl-7- (3-piperidin-1-yl-propoxy) -4- (trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- (3-piperidin-1-yl-propoxy) -benzaldehyde. Prepared in analogy to the procedure used for 3- (3-hydroxy-propoxy) -benzaldehyde, replacing 3-bromo-propan-1-ol with 1- (3-hydroxypropyl) piperidine.

Step 2: methyl- [3- (3-piperidin-1-yl-propoxy) -benzyl]-amines. Prepared in analogy to the procedure used for 3- (3-methylaminomethyl-phenoxy) -propan-1-ol.

And step 3: 1- (4-methoxy-phenyl) -2- { methyl- [3- (3-piperidin-1-yl-propoxy) -benzyl Base of]-amino } -ethanone. Reacting methyl- [3- (3-piperidin-1-yl-propoxy) -benzyl]A solution of amine (150mg, 0.57mmol), 2-bromo-1- (4-trifluoromethyl-phenyl) -ethanone (168mg, 0.63mmol) and TEA (80. mu.l, 0.57mmol) in DCM (5.7ml) was stirred at room temperature overnight, diluted with water and extracted with DCM (3 times). The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and concentrated to give the crude product. Purification by FCC gave the desired compound (84%).

And 4, step 4: 1- (4-methoxy-phenyl) -2- { methyl- [3- (3-piperidin-1-yl-propoxy) -benzyl Base of]-amino } -ethanol. To a solution of 1- (4-methoxy-phenyl) -2- { methyl- [3- (3-piperidin-1-yl-propoxy) -benzyl]-amino } -ethanone (216mg, 0.48mmol) in MeOH (4.8ml) at 0 deg.C and NaBH was added₄(37mg, 0.96 mmol). The mixture was allowed to warm to room temperature and stirred at room temperature overnight. The mixture was diluted with water and extracted with DCM (3X 50 ml). The organic layers were combined, washed with brine and dried Dry (Na)₂SO₄) And concentrated to give the crude product. Purification by FCC gave the desired compound (87%).

Step 5: 1- (4-methoxy-phenyl) -2- { methyl- [3- (3-piperidin-1-yl-propoxy) -benzyl]-amino } -ethanol (146mg, 0.32mmol) of MSA mixture was heated to 65 ℃ overnight. The mixture was cooled to room temperature, slowly neutralized with 2N NaOH and basified. The mixture was diluted with water and extracted with DCM (3X 25 ml). The combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated to give a crude oil. Purification on an Isco using a 35g Biotage column yielded the desired compound (22%). Ms (esi): c₂₅H₃₁F₃N₂Calculated value of molecular weight of O: 432.24, respectively; m/z found: 433.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.45(d，J＝8.0，2H)，7.23(d，J＝8.8，2H)，6.65(d，J＝8.4，1H)，6.58(d，J＝2.5，1H)，6.57-6.54(m，2H)，4.17(t，J＝6.5，1H)，3.91(t，J＝6.3，2H)，3.57(s，2H)，2.89(dd，J＝11.5，5.5，1H)，2.53-2.35(m，8H)，2.33(s，3H)，1.98-1.89(m，2H)，1.61-1.52(m，4H)，1.43-1.34(m，2H).

Example 61 (racemate), 62 (enantiomer 1) and 63 (enantiomer 2): 4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 2- { methyl- [3- (3-piperidin-1-yl-propoxy) -benzyl]-amino } -1- (4-trifluoro-l) Methyl-phenyl) -ethanones. According to analogy to 2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino } -1- (4-methoxy-phenyl) -ethanone.

Step 2: 2- { methyl- [3- (3-piperidin-1-yl-Propoxy) -benzyl]-amino } - (4-trifluoromethyl) Phenyl-ethanol. Preparation was carried out in analogy to the preparation of example 60.

Step 3: preparation was carried out in analogy to the preparation of example 60 to give the desired product as racemic mixture. Ms (esi): c₂₅H₃₄N₂O₂Calculated value of molecular weight of (c): 394.26, respectively; m/z found: 395.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.08-6.92(m，2H)，6.84-6.72(m，2H)，7.76-6.48(m，3H)，4.66-4.43(m，2H)，4.17-3.91(m，4H)，3.73(s，3H)，3.63-3.51(m，2H)，3.20-3.05(m，2H)，2.90(s，3H)，2.66-2.52(m，2H)，2.25-2.09(m，2H)，1.99-1.71(m，6H)，1.42-1.28(m，1H).

The two enantiomers, examples 62 and 63, were separated by chiral HPLC. R_T(62): 12.9 minutes. R_T(63): 14.8 minutes.

Example 64: 2-tert-butyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- [3- (tert-butylamino-methyl) -phenoxy]-propan-1-ol. To a solution of 3- (3-hydroxy-propoxy) -benzaldehyde (1.0 eq), tert-butylamine (1.1 eq) and acetic acid (1.0 eq) in anhydrous DCE (0.5M) was added NaB (OAc) in portions₃H (1.5 equiv.). The resulting mixture was stirred at room temperature overnight. The mixture was treated with 1N NaOH (200ml), stirred for 30 min and extracted with DCM (3 times). The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. The product was obtained by FCC (2.75g, 70%). Ms (esi): c₁₄H₂₃NO₂Calculated value of molecular weight of (c): 237.17, respectively; m/z found: 238.4[ M + H ]]⁺。

¹H NMR(CDCl₃): 7.21(t, J ═ 7.7, 1H), 6.91-6.89(m, 2H), 6.76(dd, J ═ 8.3, 2.2, 1H), 4.09(t, J ═ 6.1, 2H), 3.78(t, J ═ 6.0, 2H), 3.68(s, 2H), 1.99(m, 2H), 1.17(s, 9H), steps 2-5 were performed in a manner similar to that described in example 1.

Step 2: 2- { tert-butyl- [3- (3-hydroxy-propoxy) -benzyl]-amino } -1- (4-methoxy- Phenyl) -ethanones. Yield (11.8mmol scale): 5.33g (> 100%) of crude product. Ms (esi): c₂₃H₃₁NO₄Calculated value of molecular weight of (c): 385.23, respectively; m/z found: 386.5[ M + H]⁺。

And step 3: 2-tert-butyl-7- (3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -isoquinoline Onium salts. Yield (13.8mmol scale): 3.33g of crude product. Ms (esi): c₂₃H₂₈NO₃ ⁺Calculated value of molecular weight of (c): 366.5, respectively; m/z found: 366.5[ M ]]⁺。

And 4, step 4: 3- [ 2-tert-butyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yl Oxy radical]-propan-1-ol. Yield (9.08mmol scale): 3.2g of crude product, which can be used directly in the next step. Ms (esi): c₂₃H₃₁NO₃Calculated value of molecular weight of (c): 369.23, respectively; m/z found: 370.5[ M + H]⁺。

And 5: methanesulfonic acid 3- [ 2-tert-butyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline Quinoline-7-yloxy]-propyl ester. Yield (0.51mmol scale): 0.28g (> 100%). Ms (esi): c₂₄H₃₃NO₅Calculated value of molecular weight of S: 447.21, respectively; m/z found: 448.5[ M + H]⁺。

Step 6: yield (0.62mmol scale): 33mg (8%, two steps, TFA salt). Ms (esi): c₂₈H₄₀N₂O₂Calculated value of molecular weight of (c): 436.31, respectively;m/z found: 437.5[ M + H ]⁺。

¹H NMR(CDCl₃)：7.15-7.13(m，2H)，6.90-6.88(m，2H)，6.76-6.74(m，1H)，6.68-6.65(m，2H)，4.77-4.70(m，2H)，4.20-4.18(m，1H)，4.05-4.04(m，2H)，3.81(s，3H)，3.74-3.71(m，1H)，3.67-3.60(m，2H)，3.16(m，2H)，2.85(t，J＝11.9，1H)，2.64(m，2H)，2.24-2.23(m，2H)，2.04-1.97(m，2H)，1.89-1.87(m，3H)，1.53(s，9H)，1.45-1.37(m，1H).

Example 65: 2-benzyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Preparation was carried out in analogy to the procedure used in example 64.

Step 1: 3- [3- (benzylamino-methyl) -phenoxy]-propan-1-ol. Yield (16.6mmol scale): 2.5g (55%). Ms (esi): c₁₇H₂₁NO₂Calculated value of molecular weight of (c): 271.16, respectively; m/z found: 272.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.34-7.31(m，4H)，7.27-7.21(m，2H)，6.92-6.91(m，2H)，6.81-6.79(m，1H)，4.12(t，J＝5.9，2H)，3.85(t，J＝5.88，2H)，3.80(s，2H)，3.77(s，2H)，2.03(m，2H).

Step 2: 2- { benzyl- [3- (3-hydroxy-propoxy) -benzyl]-amino } -1- (4-methoxy-benzene) Alkyl) -ethanones. Yield (9.32mmol scale): 4.18g (> 100%) of crude product. Ms (esi): c₂₆H₂₉NO₄Calculated value of molecular weight of (c): 419.21, respectively; m/z found: 420.5[ M + H]⁺。

And step 3: 2-benzyl-7- (3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -isoquinolinium salts Salt (salt). Yield (9.32mmol scale): 3.70g of crude product. Ms (esi): c₂₆H₂₆NO₃ ⁺Calculated value of molecular weight of (c): 400.49, respectively; m/z found: 400.4[ M ]]⁺。

And 4, step 4: 3- [ 2-benzyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy Base of]-propan-1-ol。8.96g(36％)。MS(ESI)：C₂₆H₂₉NO₃Calculated value of molecular weight of (c): 403.51, respectively; m/z found: 404.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.45(s，5H)，7.05-7.03(m，2H)，6.85(d，J＝8.5，2H)，6.75(s，2H)，6.60(s，1H)，4.54(s，2H)，4.40-4.31(m，2H)，4.06(m，3H)，3.81-3.79(m，6H)，3.08(s，1H)，2.01-1.99(m，2H).

And 5: methanesulfonic acid 3- [ 2-benzyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy]-propyl ester. Yield (7.06mmol scale): 3.87g (> 100%). Ms (esi): c ₂₇H₃₁NO₅Calculated value of molecular weight of S: 481.60, respectively; m/z found: 482.4[ M + H]⁺。

Step 6: yield: FCC and reverse phase HPLC gave 119mg (31%, two steps) of the TFA salt. Ms (esi): c₃₁H₃₈N₂O₂Calculated value of molecular weight of (c): 470.29, respectively; m/z found: 471.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.44-7.43(m；5H)，7.04-7.02(m，2H)，6.84(d，J＝8.4，2H)，6.76(s，1H)，6.68(s，1H)，6.54(s，1H)，4.51(s，1H)，4.34(q，J＝12.9，2H)，4.16(s，1H)，3.98(s，2H)，3.78(s，3H)，3.75(s，1H)，3.61(s，2H)，3.15(s，2H)，2.97(s，1H)，2.62-2.61(m，3H)，2.22(s，2H)，2.00-1.97(m，2H)，1.87-1.85(m，3H)，1.44-1.39(m，1H).

Example 66: 2-ethyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- [4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propane- 1-alcohols. To the reaction vessel is charged with 3- [ 2-benzyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]A250 ml Parr reaction flask of a solution of propan-1-ol (3.79g, 9.39mmol) in anhydrous EtOH (0.4M) was charged with Pd/C (10% wt, 4.25 g). The resulting mixture is in H₂The mixture was stirred at room temperature under an atmosphere (50psi) for 20 hours. The mixture was filtered and the filtrate was concentrated. Purification by FCC gave the desired product (2.17g, 73%). Ms (esi): c₁₉H₂₃NO₃Calculated value of molecular weight of (c): 313.17, respectively; m/z found: 314.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.03-7.01(m，2H)，6.86-6.84(m，2H)，6.79-6.71(m，2H)，6.62(m，1H)，4.31-4.28(m，3H)，4.05-4.02(m，2H)，3.81-3.80(m，5H)，3.63-3.61(m，1H)，3.20-3.18(m，1H)，2.00-1.98(m，2H).

Step 2: 3- [ 2-ethyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy Base of]-propan-1-ol. To 3- [4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy group]To a solution of propan-1-ol (330mg, 1.05mmol) in anhydrous DCE (0.5M) were added anhydrous acetaldehyde (1.1 equiv.), acetic acid (1.0 equiv.), and NaB (OAc) ₃H (1.5 equiv.). The resulting solution was stirred at room temperature overnight. The mixture was diluted with 1N NaOH (10ml) and extracted with DCM (3 times). The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. Purification by FCC and reverse phase HPLC gave the desired product (54mg, 15%, TFA salt). Ms (esi): c₂₁H₂₇NO₃Calculated value of molecular weight of (c): 341.20, respectively; m/z found: 342.5[M+H]⁺。

¹H NMR(CDCl₃)：7.12-7.04(m，2H)，6.91-6.89(m，2H)，6.80-6.74(m，2H)，6.66-6.63(m，1H)，4.63-4.54(m，2H)，4.12-4.06(m，3H)，3.83-3.81(m，5H)，3.25-2.90(m，5H)，2.02-2.01(m，2H)，1.45-1.43(m，3H).

And step 3: methanesulfonic acid 3- [ 2-ethyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy]-propyl ester. According to the method, the starting material is analogous to methanesulfonic acid 3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]Propyl ester on a 0.158mmol scale, 111mg (> 100%) of the desired product are obtained. Ms (esi): c₂₂H₂₉NO₅Calculated value of molecular weight of S: 419.54, respectively; m/z found: 420.4[ M + H]⁺。

Step 4: the desired product (40mg, 40%, two steps, TFA salt) was obtained in analogy to the procedure described for 2-benzyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline, on the 0.26mmol scale. Ms (esi): c₂₆H₃₆N₂O₂Calculated value of molecular weight of (c): 408.58, respectively; m/z found: 409.5[ M + H]⁺。

¹HNMR(CDCl₃)：7.11-7.06(m，2H)，6.88-6.87(m，2H)，6.79-6.77(m，1H)，6.70-6.68(m，1H)，6.63(m，1H)，4.68-4.61(m，1H)，4.23-4.02(m，4H)，3.81-3.78(m，4H)，3.63(m，2H)，3.28-3.26(m，2H)，3.18(m，2H)，2.96-2.91(m，1H)，2.65-2.63(m，2H)，2.24(m，2H)，2.05-1.87(m，5H)，1.45-1.43(m，4H).

Example 67: 4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -2-propyl-1, 2, 3, 4-tetrahydro-isoquinoline

Prepared in analogy to the procedure used for 2-ethyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline.

Step 1: 3- [4- (4-methoxy-phenyl) -2-propyl-1, 2, 3, 4-tetrahydro-isoquinolin-yloxy-phenyl Base of]-propan-1-ol. Yield (1.05mmol scale): 212mg (57%, free base). Ms (esi): c₂₂H₂₉NO₃Calculated value of molecular weight of (c): 355.47, respectively; m/z found: 356.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.11-7.05(m，2H)，6.87(d，J＝8.5，2H)，6.80-6.76(m，2H)，6.74-6.65(m，1H)，4.72-4.61(m，2H)，4.15-4.06(m，3H)，3.85-3.77(m，5H)，3.14-3.11(m，2H)，2.95-2.90(m，1H)，2.03-2.02(m，2H)，1.90-1.86(m，2H)，1.03-1.00(m，3H).

Step 2: methanesulfonic acid 3- [4- (4-methoxy-phenyl) -2-propyl-1, 2, 3, 4-tetrahydro-isoquinoline -7-yloxy]-propyl ester. Yield (0.42mmol scale): 260mg (> 100%) of the crude product. Ms (esi): c₂₃H₃₁NO₅Calculated value of molecular weight of S: 433.56, respectively; m/z found: 434.4[ M + H]⁺。

Step 3: yield (0.42mmol scale): 82mg (30%, two-step, TFA salt). Ms (esi): c₂₇H₃₈N₂O₂Calculated value of molecular weight of (c): 422.60, respectively; m/z found: 423.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.11-7.06(m，2H)，6.87(d，J＝8.5，2H)，6.79-6.78(m，1H)，6.70-6.81(m，1H)，6.61(s，1H)，4.69-4.61(m，1H)，4.11-4.02(m，3H)，3.81-3.75(m，4H)，3.67-3.65(m，3H)，3.14-3.11(m，4H)，2.96-2.91(m，1H)，2.65-2.63(m，2H)，2.25(s，2H)，2.04-1.97(m，2H)，1.89-1.87(m，5H)，1，46-1.41(m，1H)，1.02(t，J＝7.4，3H).

Example 68: 2-isopropyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- [ 2-isopropyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yl Oxy radical]-propan-1-ol. Yield (1.05mmol scale): 239mg (64%) of the crude product as free base. Ms (esi): c₂₂H₂₉NO₃Calculated value of molecular weight of (c): 355.47, respectively; m/z found: 356.5[ M + H]⁺。

Step 2: methanesulfonic acid 3- [ 2-isopropyl-4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline Quinoline-7-yloxy]-propyl ester. Yield (0.59mmol scale): 292mg (> 100%) of crude product. Ms (esi): c₂₃H₃₁NO₅Calculated value of molecular weight of S: 433.56, respectively; m/z found: 434.4[ M + H]⁺。

Step 3: yield (0.59mmol scale): 119mg (31%, two steps, TFA salt). Ms (esi): c₂₇H₃₈N₂O₂Calculated value of molecular weight of (c): 422.60, respectively; m/z found: 423.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.82-7.80(m，2H)，7.58(d，J＝8.4，2H)，7.48-7.47(m，1H).7.39-7.35(m，2H)，5.38-5.36(m，1H)，5.23-5.20(m，1H)，4.97-4.94(m，1H)，4.73-4.72(m，2H)，4.51(s，3H)，4.56-4.43(m，1H)，4.34-4.32(m，3H)，3.91-3.81(m，2H)，3.69-3.64(m，1H)，3.44-3.31(m，2H)，2.95-2.80(m，2H)，2.75-2.51(m，5H)，2.14-2.12(m，6H).

Example 69: 4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Prepared as described in example 66, step 1, from 2-benzyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline to give 1.72g (46%) of a TFA salt on a 6.05mmol scale. Ms (esi): c₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.52, respectively; m/z found: 381.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.01(d，J＝8.7，2H)，6.84(d，J＝8.7，2H)，6.76(d，J＝8.7，1H)，6.67-6.65(m，1H)，6.60-6.59(m，1H)，4.37-4.29(m，3H)，3.99-3.97(m，2H)，3.78(s，3H)，3.63-3.58(m，3H)，3.19-3.16(m，3H)，2.70-2.68(m，2H)，2.21-2.16(m，2H)，1.91-1.84(m，5H)，1.43-1.41(m，1H).

Example 70: 3- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl ] -propan-1-ol

To a solution of 4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (90mg, 0.236mmol) in anhydrous DMF (0.3M) was added K ₂CO₃(1.5 equiv.) and 3-bromo-propan-1-ol (1.05 equiv.). The resulting mixture was heated at 50 ℃ overnight. After cooling to room temperature, the mixture was diluted with EtOAc and washed with brine. The combined organic layers were washed with Na₂SO₄Dried and concentrated. Purification by FCC and reverse phase HPLC afforded the desired product (19.1)mg, 3%, TFA salt). Ms (esi): c₂₇H₃₈N₂O₃Calculated value of molecular weight of (c): 438.6, respectively; m/z found: 439.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09-7.05(m，2H)，6.87(d，J＝8.6，2H)，6.80-6.75(m，1H)，6.72-6.70(m，1H)，6.64(s，1H)，4.04(s，2H)，3.82-3.80(m，6H)，3.66-3.65(m，2H)，3.40-3.36(m，2H)，3.25-3.15(m，2H)，2.9-2.87(m，2H)，2.78-2.65(m，4H)，2.25-2.23(m，2H)，2.08-1.88(m，8H)，1.45-1.40(m，2H).

Example 71: 2- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl ] -ethanol

Step 1: 2- [2- (tert-butyl-dimethyl-silyloxy) -ethyl]-4- (4-methoxy-) Phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline. According to analogy to 3- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl]-propan-1-ol was prepared as described to give the product (74mg, 58%) on a 0.23mmol scale. Ms (esi): c₃₂H₅₀N₂O₃Calculated molecular weight of Si: 538.8, respectively; m/z found: 539.6[ M + H]⁺。

Step 2: to 2- [2- (tert-butyl-dimethyl-silyloxy) -ethyl]To a solution of (E) -4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (0.102mmol, 55mg) in dry THF (5ml) was added tetrabutylammonium fluoride (TBAF, 1M THF, 2 ml). The resulting solution was stirred at room temperature for 2 hours. The solution was concentrated and purified by FCC and reverse phase HPLC to give the desired product (35mg, 53%). Ms (esi): c ₂₆H₃₆N₂O₃Calculated value of molecular weight of (c): 424.58(ii) a m/z found: 425.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.06(d，J＝8.5，2H)，6.86(d，J＝8.7，2H)，6.85-6.63(m，3H)，4.85-4.21(m，4H)，4.13-4.01(m，4H)，3.83-3.75(m，4H)，3.63-3.61(m，2H)，3.35-3.21(m，2H)，3.20-3.16(m，2H)，2.70-2.64(m，2H)，2.25-2.21(m，2H)，2.00-1.86(m，5H)，1.45-1.40(m，1H).

Example 72: 2- (2-fluoro-ethyl) -4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

According to analogy to 3- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl]-propan-1-ol was prepared as described to give 166mg (38%) of the product as the TFA salt on a 0.44mmol scale. Ms (esi): c₂₆H₃₅FN₂O₂Calculated value of molecular weight of (c): 426.57, respectively; m/z found: 427.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.08(d，J＝8.5，2H)，6.88(d，J＝8.6，2H)，6.84-6.82(m，1H)，6.73-6.71(m，1H)，6.62-6.61(m，1H)，5.00-4.99(m，1H)，4.91-4.88(m，1H)，4.61-4.51(m，2H)，4.05-4.03(m，2H)，3.86-3.83(m，1H)，3.81(s，3H)，3.67-3.66(m，2H)，3.62-3.60(m，1H)，3.56-3.55(m，1H)，3.21-3.19(m，3H)，2.67-2.65(m，2H)，2.26-2.23(m，2H)，2.05-1.88(m，6H)，1.43-1.41(m，1H).

Example 73: 2-cyclopropyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (60mg, 0.157mmol), acetic acid (1.57mmol), molecular sieve (3 Å) and [ (1-ethoxycyclopropyl) oxy]Trimethylsilyl (0.96mmol) in MeOH (0.2M) with NaCNBH₃(0.71mmol) and the resulting mixture stirred at room temperature for 3 hours. The mixture was heated at 50 ℃ for 2 hours, then cooled to room temperature and stirred for 2 hours. The mixture was diluted with EtOAc and washed with brine. The combined organic phases are passed over Na₂SO₄Dried and concentrated. Purification by FCC and reverse phase HPLC gave the product (15mg, 15%, TFA salt). Ms (esi): c ₂₇H₃₆N₂O₂Calculated value of molecular weight of (c): 420.59, respectively; m/z found: 421.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.17-7.15(m，2H)，6.91-6.89(m，2H)，6.82(s，1H)，6.75-6.70(m，2H)，4.53-4.44(m，3H)，4.10-4.07(m，2H)，3.77(s，3H)，3.69-3.61(m，1H)，3.59-3.56(m，2H)，3.41-3.36(m，2H)，3.28-3.25(m，3H)，3.19-3.18(m，2H)，2.95-2.91(m，2H)，2.75-2.71(m，1H)，1.95-1.77(m，2H)，1.52-1.44(m，1H)，1.30-1.27(m，3H)，0.86-0.76(m，2H).

Examples 74 and 75: 4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Prepared in analogy to the procedure used for 2-benzyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline.

Step 1: 3- {3- [ (1-phenyl-ethylamino) -methyl]-phenoxy } -propan-1-ol. Yield (27.7mmol scale): 7.73g (96%) by FCC (FCC)EtOAc/hexanes). Ms (esi): c₁₈H₂₃NO₂Calculated value of molecular weight of (c): 285.2, respectively; m/z found: 286.4[ M + H]⁺。

¹H NMR(MeOH-d₄)：7.32-7.16(m，5H)，6.83-6.78(m，3H)，4.91(s，2H)，4.03(t，J＝7.8，2H)，3.80-3.71(m，3H)，3.57-3.47(m，2H)，1.99-1.91(m，2H)，1.37-1.35(d，J＝8.3，3H).

Step 2: 2- { [3- (3-hydroxy-propoxy) -benzyl]- (1-phenyl-ethyl) -amino } - (4-methyl) Oxy-phenyl) -ethanones. Yield (3.50mmol scale): FCC (EtOAc/hexanes) afforded 673.3mg (45%). Ms (esi): c₂₇H₃₁NO₄Calculated value of molecular weight of (c): 433.2, respectively; m/z found: 434.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.84-7.82(m，2H)，7.47(d，J＝7.4，2H)，7.34(t，J＝7.5，2H)，7.25-7.22(m，1H)，7.16(t，J＝7.9，1H)，6.95-6.88(m，4H)，6.77-6.75(m，1H)，4.16-4.11(m，1H)，4.02(t，J＝6.3，2H)，3.96(d，J＝16.4，1H)，3.84(s，3H)，3.78(d，J＝16.4，1H)，3.73(t，J＝6.2，2H)，3.69-3.60(m，3H)，1.97-1.92(m，2H)，1.41(d，J＝6.8，3H).

And step 3: 7- (3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -2- (1-phenyl-ethyl) -iso-propyl ester Quinolinium salts. Yield (3.50mmol scale): 1.64g (89%) of crude product. Ms (esi): c₂₇H₂₈NO₃ ⁺Calculated value of molecular weight of (c): 414.2; m/z found: 414.5[ M ]]⁺。

And 4, step 4: 3- [4- (4-methoxy-phenyl) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline Quinoline-7-yloxy]-propan-1-ol. Yield (3.50mmol scale): FCC (EtOAc/hexanes) provided 210.3mg (11%) of the desired product as a 1: 1 diastereomeric mixture. Ms (esi): c₂₇H₃₁NO₃Calculated value of molecular weight of (c): 417.2; m/z found:418.5[M+H]⁺。

and 5: methanesulfonic acid 3- [4- (4-methoxy-phenyl) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrakis Hydro-isoquinolin-7-yloxy]-propyl ester. The reaction was carried out on a 0.328mmol scale to give the crude product which was used directly in the next step.

Step 6: yield (0.328mmol scale): FCC gave 86.8mg (54%) of a 1: 1 mixture of diastereomers. Ms (esi): c₃₁H₃₈N₂O₃Calculated value of molecular weight of (c): 486.29, respectively; m/z found: 487.5[ M + H ]]⁺。

By manual HPLC (Chiralpak AD-H column, 5. mu.M, 97% hexane/IPA in 0.2% Et₂NH modification) the isomers are separated.

First eluting isomer (example 74): ms (esi): c₃₁H₃₈N₂O₃Calculated value of molecular weight of (c): 486.29, respectively; m/z found: 487.5[ M + H ]]⁺。

¹H NMR(MeOH-d₄)：7.23-7.17(m，5H)，6.97(d，J＝8.6，2H)，6.80-6.78(m，2H)，6.69(d，J＝8.5，1H)，6.63-6.60(m，1H)，6.57(d，J＝2.3，1H)，4.85(s，2H)，4.09-4.06(br m，1H)，3.94(t，J＝6.1，2H)，3.75(s，3H)，3.73-3.61(m，6H)，3.56-3.52(m，1H)，3.05-3.02(m，1H)，2.52-2.43(m，7H)，1.95-1.89(m，2H)，1.40(d，J＝6.7，3H).

Second elution of isomer (example 75): ms (esi): c₃₁H₃₈N₂O₃Calculated value of molecular weight of (c): 486.29, respectively; m/z found: 487.5[ M + H ]]⁺。

¹H NMR(MeOH-d₄)：7.31-7.27(m，4H)，7.23-7.21(m，1H)，6.96(d，J＝8.6，2H)，6.80-6.77(m，2H)，6.67-6.60(m，3H)，4.85(s，3H)，4.04-4.01(m，1H)，3.98-3.94(m，3H)，3.73(s，3H)，3.69-3.67(m，4H)，3.60-3.54(m，2H)，3.04-3.01(m，1H)，2.53-2.47(m，6H)，2.37-2.32(m，1h)，1.96-1.91(m，2H)，1.44(d，J＝6.7，3H).

Following a procedure similar to that used in example 1, the following examples 76-77 were prepared.

Example 76: 4- (3, 4-dichloro-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₄H₃₀Cl₂N₂Calculated value of molecular weight of O: 432.2; m/z found: 433.4, 435.4[ M + H ]]⁺。

¹H NMR(MeOH-d₄)：7.55(d，J＝8.1，1H)，7.44-7.38(m，1H)，7.18(br d，J＝8.6，1H)，6.93-6.80(m，3H)，4.61-4.49(m，3H)，4.10(dd，J＝5.8，5.3，2H)，3.87-3.80(m，1H)，3.63-3.50(m，3H)，3.16-3.11(m，1H)，3.06(s，3H)，2.96(dt，J＝12.8，2.8，2H)，2.28-2.18(m，2H)，2.02-1.93(m，2H)，1.90-1.68(m，4H)，1.59-1.47(m，1H).

Example 77: 4- (3, 4-dichloro-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₃H₂₈Cl₂N₂O₂Calculated value of molecular weight of (c): 434.15, respectively; m/z found: 435.4, 437.4[ M + H [ ]]⁺。

¹H NMR(MeOH-d₄)：7.55(d，J＝8.1，1H)，7.45-7.39(m，1H)，7.19(br dd，J＝8.4，2.0，1H)，6.93-6.80(m，3H)，4.61-4.49(m，3H)，4.12(dd，J＝5.6，5.6，3H)，4.09-4.02(m，1H)，3.89-3.72(m，3H)，3.60-3.45(m，3H)，3.38(dd，J＝8.1，7.8，2H)，3.26-3.12(m，2H)，3.06(s，3H)，2.30-2.21(m，2H).

Example 78: 4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 4- (3-formyl-phenoxymethyl) -piperidine-1-carboxylic acid tert-butyl ester. A solution of 3-hydroxybenzaldehyde (2.45g, 20.1mmol) in DCM (500ml) was treated with 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (4.45g, 20.7mmol), PPh₃(5.45g, 20.6mmol) and diethyl azodicarboxylate (DEAD; 3.15ml, 20.0 mmol). The resulting mixture was stirred at 23 ℃ for 16 hours. Evaporation of the solvent and passage through FCC (EtOAc/hexane) gave the desired product (4.27g, 67%).

¹H NMR(CDCl₃)：9.98(s，1H)，7.47-7.42(m，3H)，7.20-7.14(m，1H)，4.26-4.11(m，2H)，3.87(d，J＝3.6，2H)，2.84-2.69(m，2H)，2.03-1.93(m，1H)，1.83(d，J＝12.6，2H)，1.47(s，9H)，1.34-1.23(m，2H).

Step 2: 4- (3-methylaminomethyl-phenoxymethyl) -piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4- (3-formyl-phenoxymethyl) -piperidine-1-carboxylic acid tert-butyl ester (5.95g, 18.6mmol) in MeOH (100ml) was added MeNH₂(4ml, 40% solution in water) and the mixture was stirred at 23 ℃ for 1 hour. The mixture was cooled to 0 ℃ and NaBH was added in 4 portions ₄(1.34g, 35.8 mmol). After 3 days at 23 ℃, the mixture was concentrated, diluted with 1M NaOH and stirred for 1 hour. The mixture was extracted with EtOAc and dried (Na)₂SO₄) And concentrated to give the desired compound (5.83g, 94%).

Step 3: to a solution of 4- (3-methylaminomethyl-phenoxymethyl) -piperidine-1-carboxylic acid tert-butyl ester (1.5g, 4.49mmol) in THF (35ml) were added DIPEA (2.4ml) and 2-bromo-1- (4-methoxy-phenyl) -ethanone (1.05g, 4.59 mmol). The mixture was stirred at 23 ℃ for 15 hours. The mixture was saturated NaHCO₃Dilute the aqueous solution, extract with DCM and dry (Na)₂SO₄) And concentrated. The residue was diluted with MSA (10ml) and stirred at 23 ℃ for 3 h. DCM was then added and 1M aqueous KOH was added. The mixture was extracted with DCM and dried (Na)₂SO₄) And concentrated. The residue was treated in analogy to 7- (3-hydroxy-propoxy) -4- (4-methoxy-phenyl) -2-methyl-isoquinolinium salt to give the desired compound (0.452g, 27%). Ms (esi): c₂₃H₃₀N₂O₂Calculated value of molecular weight of (c): 366.23, respectively; m/z found: 367.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.8，2H)，6.83(d，J＝8.8，2H)，6.77(d，J＝8.6，1H)，6.65-6.57(m，2H)，4.15(dd，J＝8.5，5.7，1H)，3.79(s，3H)，3.77-3.67(m，3H)，3.56(d，J＝15，1H)，3.20-3.15(m，2H)，3.00-2.95(m，1H)，2.68(ddd，J＝12.5，12.0，2.5，2H)，2.49(dd，J＝11.3，8.9，1H)，2.41(s，3H)，1.89-1.78(m，2H).

The following examples 79-82 were prepared in a similar manner to that used for example 78.

Example 79: 4- (3-chloro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (3.32mmol scale): 0.583g (44%). Ms (esi): c₂₃H₂₉ClN₂O₂Calculated value of molecular weight of (c): 400.94, respectively; m/z found: 401.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.20(d，J＝2.0，1H)，7.04(dd，J＝8.2，2.3，1H)，6.84(d，J＝8.3，1H)，6.76(d，J＝8.6，2.6，1H)，6.59(d，J＝2.5，1H)，4.11(dd，J＝7.9，5.6，1H)，3.88(s，3H)，3.75(d，J＝6.3，2H)，3.66(d，J＝14.8，1H)，3.58(d，J＝14.9，1H)，3.15-3.09(m，2H)，2.95(dd，J＝11.6，5.5，1H)，2.65(ddd，J＝12.1，11.8，3.6，2H)，2.51(dd，J＝11.3，8.4，1H)，2.41(s，3H)，1.96-1.77(m，3H)，1.33-1.20(m，2H).

Example 80: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (3.47mmol scale): 0.552g (42%). Ms (esi): c₂₃H₃₀N₂O₂Calculated value of molecular weight of S: 382.56, respectively; m/z found: 383.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.4，1H)，7.11(d，J＝8.3，1H)，6.76(d，J＝8.3，1H)，6.65-6.57(m，2H)，4.16(dd，J＝7.7，6.0，1H)，3.74(d，J＝6.4，2H)，3.69(d，J＝14.6，1H)，3.58(d，J＝14.8，1H)，3.16-3.08(m2H)，2.97(ddd，11.4，5.5，1.0，1H)，2.64(ddd，12.1，12.1，2.5，2H)，2.55-2.47(m，1H)，2.47(s，3H)，2.41(s，3H)，1.96-1.77(m，3H)，1.32-1.19(m，2H).

Example 81: 4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (3.05mmol scale): 0.379g (32%). Ms (esi): c₂₃H₂₉FN₂O₂Calculated value of molecular weight of (c): 384.22, respectively; m/z found: 385.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.94(m，3H)，6.77(d，J＝8.6，1H)，6.64(dd，J＝8.7，2.8，1H)，6.59(d，J＝2.7，1H)，4.12(dd，J＝7.4，6.0，1H)，3.87(s，3H)，3.75(d，J＝6.6，2H)，3.66(d，J＝14.9，1H)，3.58(d，J＝14.9，1H)，3.15-3.08(m，2H)，2.95(ddd，J＝11.3，4.5，1.0，1H)，2.65(ddd，J＝12.4，12.1，2.6，2H)，2.52(dd，J＝11.3，8.1，1H)，2.41(s，3H)，1.95-1.78(m，3H)，1.33-1.20(m，2H).

Example 82: 4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (3.20mmol scale): 0.492g (40%). Ms (esi): c₂₃H₂₉FN₂O₂Calculated value of molecular weight of (c): 384.49, respectively; m/z found: 385.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.93(dd，J＝8.5，8.3，1H)，6.79(d，J＝8.6，1H)，6.68-6.55(m，4H)，4.80(dd，J＝6.4，6.2，1H)，3.77(s，3H)，3.75(d，J＝6.3，2H)，3.62(dd，J＝13.4，11.4，2H)，3.17-3.09(m，2H)，2.92(dd，J＝11.3，5.5，1H)，2.70-2.55(m，3H)，2.40(s，3H)，1.97-1.77(m 3H)，1.34-1.21(m，2H).

Example 83: 7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

A solution of 4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (0.100g, 0.273mmol) in DCM (5ml) was treated with acetone (0.1ml), acetic acid (0.030ml) and NaB (OAc) ₃H (0.081g, 0.382 mmol). After 15 hours, 1M NaOH was added and the reaction was stirred for 0.5 hours. The mixture was extracted with DCM and the organic layer was dried (Na)₂SO₄) And concentrated to give a residue which was further purified by FCC to give 7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (9.1mg, 8%).

Following a procedure similar to that used in example 83, the following examples 84-121 were prepared, unless otherwise noted.

Example 84: 4- (4-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.280mmol scale): 5mg (5%). Ms (esi): c₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.25, respectively; m/z found: 381.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.6，2H)，6.83(d，J＝8.8，2H)，6.76(d，J＝8.1，1H)，6.62(dd，J＝8.3，2.5，1H)＜6.58(d，J＝-2.3，1H)，4.19-4.13(m，1H)，3.79(s，3H)，3.76(d，J＝6.3，2H)，3.71(d，J＝15.2，1H)，3.56(d，J＝14.9，1H)，2.98(ddd，J＝11.1，5.3，1.0，1H)，2.92-2.85(m，1H)，2.49(dd，J＝11.3，8.8，1H)，2.41(s，3H)，2.28(s，3H)，1.96(ddd，J＝14.4，11.9，2.0，1H)，1.88-1.73(m，3H)，1.46-1.35(m，3H).

Example 85: 4- (4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.293mmol scale): 34.2mg (29%). Ms (esi): c₂₆H₃₆N₂O₂Calculated value of molecular weight of (c): 408.28, respectively; m/z found: 409.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.6，2H)，6.82(d，J＝8.8，2H)，6.76(d，J＝8.6，1H)，6.62(dd，J＝8.3，2.5，1H)，6.58(d，J＝2.5，1H)，4.15(dd，J＝8.3，5.6，1H)，3.80-3.73(m，5H)，3.70(d，J＝14.9，1H)，3.56(d，J＝14.9，1H)，3.02-2.92(m，3H)，2.49(dd，J＝11.4，8.8，1H)，2.41(s，3H)，2.33-2.25(m，2H)，1.94，(ddd，J＝13.4，11.3，1.8，2H)，1.86-1.74(m，3H)，1.57-1.47(m，2H)，1.46-1.37(m，2H)，0.90(t，J＝7.3，3H).

Example 86: 7- (1-cyclopentyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.293mmol scale): 7.7mg (6%). Ms (esi): c₂₈H₃₈N₂O₂Calculated value of molecular weight of (c): 434.29, respectively; m/z found: 435.5[ M + H ]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.8，2H)，6.82(d，J＝8.8，2H)，6.76(d，J＝8.6，1H)，6.62(dd，J＝8.3，2.5，1H)，6.58(d，J＝2.5，1H)，4.15(dd，J＝8.3，5.3，1H)，3.79(s，3H)，3.75(d，J＝6.1，1H)，3.70(d，J＝14.9，1H)，3.56(d，J＝14.9，1H)，3.10-3.02(m，2H)，2.98(ddd，J＝11.4，5.6，1.0，1H)，2.52-2.42(m，2H)，2.41(s，3H)，1.99-1.34(m，15H).

Example 87: 7- (1-Ethyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.293mmol scale): 7.1mg (6%). Ms (esi): c₂₅H₃₄N₂O₂Calculated value of molecular weight of (c): 394.26, respectively; m/z found: 395.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.8，2H)，6.82(d，J＝8.8，2H)，6.76(d，J＝8.6，1H)，6.62(dd，J＝8.6，2.8，1H)，6.59(d，J＝2.5，1H)，4.15(dd，J＝8.6，5.8，1H)，3.79(s，3H)，3.76(d，J＝6.3，2H)，3.70(d，J＝14.9，1H)，3.56(d，J＝14.9，1H)，3.02-2.94(m，3H)，2.49(dd，J＝11.3，8.8，1H)，2.43-2.37(m，5H)，1.97-1.80(m，5H)，1.47-1.37(m，2H)，1.10(t，J＝7.3，3H).

Example 88: 4- (3-chloro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.293mmol scale): 57.3mg (44%).

¹H NMR(CDCl₃)：7.20(d，J＝2.1，1H)，7.03(dd，J＝8.5，2.2，1H)，6.84(d，J＝8.2，1H)，6.76(d，J＝8.4，1H)，6.64(dd，J＝8.6，2.5，1H)，6.59(d J＝2.6，1H)，4.11(dd，J＝6.9，6.4，1H)，3.88(s，3H)，3.76(d，J＝6.3，2H)，3.67(d，J＝14.5，1H)，3.58(d，J＝15.0，1H)，2.98-2.89(m，3H)，2.76-2.68(m，1H)，2.50(dd，J＝11.4，8.3，1H)，2.41(s，3H)，2.19-2.11(m，2H)，1.89-1.70(m，3H)，1.43-1.33(m，2H)，1.05(d，J＝6.6，6H).

Example 89: 4- (3-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.318mmol scale): 68.2mg (50%). Ms (esi): c₂₆H₃₅FN₂O₂Calculated value of molecular weight of (c): 426.57, respectively; m/z found: 427.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.95-6.82(m，3H)，6.76(d，J＝8.7，1H)，6.64(dd，J＝8.6，2.8，1H)，6.59(d，J＝2.5，1H)，4.12(dd，J＝7.1，6.2，1H)，3.87(s，3H)，3.75(d，J＝6.6，2H)，3.65(d，J＝14.9，1H)，3.58(d J＝14.6，1H)，3.02-2.88(m，3H)，2.71(m，1H)，2.51(dd，J＝11.4，8.1，1H)，2.40(s，3H)，2.19-2.10(m，2H)，1.96-1.80(m，3H)，1.45-1.30(m，2H)，1.05(d，J＝6.6，6H).

Example 90: 4- (2-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.372mmol scale): 79.3mg (50%). Ms (esi): c₂₆H₃₅FN₂O₂Calculated value of molecular weight of (c): 426.27, respectively; m/z found: 427.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.92(t，J＝8.6，1H)，6.79(d，J＝8.7，1H)，6.66-6.54(m，4H)，4.48(dd，J＝6.4，6.2，1H)，3.79-3.73(m，5H)，3.63(d，J＝13.1，1H)，3.60(d，J＝13.1，1H)，2.96-2.88(m，3H)，2.71(h，J＝6.5，1H)，2.58(dd，J＝11.3，7.5，1H)，2.40(s，3H)，2.20-2.10(m，2H)，1.96-1.72(m，3H)，1.42-1.32(m，2H)，1.05(d，J＝6.6，6H).

Example 91: 7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.245mmol scale): 51.2mg (51%). Ms (esi): c₂₆H₃₆N₂O₂Calculated value of molecular weight of (c): 408.28, respectively; m/z found: 409.5[ M + H ]⁺。

¹H NMR(CDCl₃)：7.22-7.15(m，1H)，6.80-6.73(m，4H)，6.62(dd，J＝8.3，2.5，1H)，6.59(d，J＝2.5，1H)，4.18(dd，J＝6.8，5.6，1H)，3.77(s，3H)，3.75(d，J＝6.6，2H)，3.71(d，J＝14.9，1H)，3.56(d，J＝15.1，1H)，3.01(ddd，11.4，5.6，1.3，1H)，2.95-2.89(m，2H)，2.71(h，J＝6.6，1H)，2.53(dd，J＝11.6，8.8，1H)，2.41(s，3H)，2.14(ddd，J＝14.1，11.8，1.8，2H)，1.89-1.81(m，1H)，1.81-1.71(m，1H)，1.43-1.31(m，3H)，1.05(d，J＝6.6，6H).

Example 92: 4- (3-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.283mmol scale): 0.030g (28%). Ms (esi): c₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.25, respectively; m/z found: 381.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.20-7.17(m，1H)，6.80-6.72(m，4H)，6.62(dd，J＝8.6，2.8，1H)，6.58(d，J＝2.5，1H)，4.17(dd，J＝8.3，5.8，1H)，3.76(m，5H)，3.70(d，J＝14.9，1H)，3.54(d，J＝15.2，1H)，3.00(ddd，J＝11.9，5.8，1.3，1H)，2.92-2.85(m，2H)，2.53(dd，J＝11.6，8.8，1H)，2.41(s，3H)，d.28(s，3H)，1.95(ddd，J＝14.1，11.9，2.3，2H)，1.87-1.71(m，3H)，1.47-1.36(m，2H).

Example 93: 4- (3-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.273mmol scale): 14.6mg (13%). Ms (esi): c₂₆H₃₆N₂O₂Calculated value of molecular weight of (c): 408.28, respectively; m/z found: 409.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.20(dd，J＝7.6，7.3，1H)，6.80-6.73(m，4H)，6.62(dd，J＝8.3，2.5，1H)，6.59(d，J＝2.5，1H)，4.18(dd，J＝8.1，6.1，1H)，3.77(s，3H)，3.77-3.73(m，2H)，3.71(d，J＝14.9，1H)，3.56(d，J＝15.2，1H)，3.04-2.94(m，3H)，2.53(dd，J＝11.4，8.8，1H)，2.41(s，3H)，2.32-2.25(m，2H)，1.99-1.74(m，5H)，1.58-1.47(m，2H)，1.46-1.37(m，2H)，0.90(t，J＝7.3，3H).

Example 94: 7- (1-cyclopentyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.273mmol scale): 32.8mg (28%). Ms (esi): c₂₈H₃₈N₂O₂Calculated value of molecular weight of (c): 434.29, respectively; m/z found: 435.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.20(dd，J＝7.8，7.8，1H)，6.80-6.73(m，4H)，6.63(dd，J＝8.3，2.5，1H)，6.58(d，J＝2.5，1H)，4.18(dd，J＝8.3，6.1，1H)，3.77(s，3H)，3.77-3.73(m，2H)，3.70(d，J＝14.9，1H)，3.56(d，J＝15.2，1H)，3.11-3.04(m，2H)，3.01(ddd，J＝11.6，5.6，1.3，1H)，2.53(dd，J＝11.4，8.8，1H)，2.50-2.44(m，1H)，2.41(s，3H)，2.00-1.36(m，16H).

Example 95: 7- (1-Ethyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.273mmol scale): 16.8mg (16%).

¹H NMR(CDCl₃)：7.20(dd，J＝7.8，7.8，1H)，6.81-6.72(m，4H)，6.62(dd，J＝8.6，2.8，1H)，6.59(d，J＝2.5.1H)，4.18(dd，J＝8.3，5.8，1H)，3.79-3.74(m，5H)，3.70(d，J＝14.9，1H)，3.57(d，J＝15.7，1H)，3.04-2.96(m，3H)，2.53(dd，J＝11.4，8.8，1H)，2.45-2.37(m，5H)，1.98-1.75(m，5H)，1.47-1.37(m，2.H)，1.10(t，J＝7.1，3H).

Example 96: 4- (3-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared in analogy to the procedure used for example 78.

MS(ESI)：C₂₂H₂₈N₂O₂Calculated value of molecular weight of (c): 352.22, respectively; m/z found: 353.5[ M + H ] ]⁺。

¹H NMR(CDCl₃)：7.16-7.11(m，1H)，6.73-6.66(m，4H)，6.59-6.53(m，2H)，4.3-4.2(m.1H)4.10(dd，J＝5.7，8.4，1H)，3.70(s，3H)，3.62(d，J＝14.9，1H)，3.49(d，J＝14.9，1H)，3.12-3.01(m，2H)，2.97-2.89(m，1H)，2.91-2.60(m，2H)，2.46(dd，J＝11.4，8.8，1H)，2.34(s，3H)，1.99-1.88(m，2H)，1.65-1.51(m，2H).

Example 97: 4- (3-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₃H₃₀N₂O₂Calculated value of molecular weight of (c): 366.23, respectively; m/z found: 367.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.20(t，J＝9.7，1H)，6.81-6.73(m，4H)，6.65-6.58(m，2H)，4.38(br s，1H)，4.20-4.14(m，1H)，3.76(s，3H)，3.71-3.67(d，J＝14.8，1H)，3.59-3.53(d，J＝14.8，1H)，3.04-2.98(m，1H)，2.87-2.78(m，2H)，2.67-2.49(m，3H)，2.46(s，3H)，2.45(s，3H)，2.24-2.10(m，2H)，1.98-1.85(m，2H)，1.70-1.54(m，1H)，1.35-1.61(m，6H)，0.92-0.75(m，2H).

Example 98: 7- (1-isopropyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₄N₂O₂Calculated value of molecular weight of (c): 394.26, respectively; m/z found: 395.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.27-7.21(m，1H)，6.84-6.77(m，4H)，6.70-6.63(m，2H)，4.35-4.25(m，1H)，4.24-4.17(m，1H)，3.81(s，3H)，3.73(d，J＝14.9，1H)，3.59(d，J＝14.9，1H)，3.08-3.01(m，1H)，2.89-2.76(m，3H)，2.57(dt，J＝11.5，8.8，1H)，2.50-2.40(m，5H)，2.12-2.00(m，2H)，1.91-1.79(m，2H)，1.11(d，J＝6.65，6H).

Example 99: 7- (1-cyclobutyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₆H₃₄N₂O₂Calculated value of molecular weight of (c): 406.26, respectively; m/z found: 407.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.23-7.17(m，1H)，6.81-6.71(m，4H)，6.65-6.57(m，2H)，4.40-4.27(m，1H)，4.20-4.13(m，1H)，3.76(s，3H)，3.69(d，J＝14.8，1H)，3.55(d，J＝14.8，1H)，3.03-2.97(m，1H)，2.92-2.77(m，1H)，2.74-2.60(m，2H)，2.57-2.50(m，1H)，2.43-2.39(m，4H)，2.18-1.99(m，6H)，1.81-1.72(m，2H)，1.72-1.59(m，1H)，1.38-1.17(m，1H).

Example 100: 7- (1-ethyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.25, respectively; m/z found: 381.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.22-7.18(m，1H)，6.81-6.72(m，4H)，6.65-6.58(m，2H)，4.51-4.35(br m，1H)，4.19-1.12(m，1H)，3.76(s，3H)，3.69(d，J＝14.8，1H)，3.55(d，J＝14.8，1H)，3.04-2.98(m，1H)，2.95-2.86(m，1H)，2.80-2.68(m，2H)，2.53(dd，J＝11.5，8.8，1H)，2.42(s，3H)，2.36-2.23(m，2H)，2.04-1.93(m，2H)，1.33-1.22(m，3H).

Example 101: 7- (1-cyclopentyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₇H₃₆N₂O₂Calculated value of molecular weight of (c): 420.28, respectively; m/z found: 421.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.22-7.17(m，1H)，6.81-6.71(m，4H)，6.64-6.57(m，2H)，4.44-4.34(brm，1H)，1.20-4.13(m，1H)，3.76(s，3H)，3.69(d，J＝14.8，1H)，3.55(d，J＝14.8，1H)，3.04-2.96(m，1H)，2.96-2.86(m，2H)，2.56-2.50(m，2H)，2.53(dd，J＝11.5，8.8，1H)，2.41(s，3H)，2.33-2.16(m，2H)，2.02-1.87(m，4H)，1.83-1.64(m，4H)，1.63-1.49(m，2H)，1.35-1.18(m，1H).

Example 102: 4- (3-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline

¹H NMR(CDCl₃)：7.22-7.18(m，1H)，7.80-6.73(m，4H)，6.65-6.59(m，2H)，4.33-4.24(br m，1H)，4.20-4.14(m，1H)，3.77(s，3H)，3.69(d，J＝14.8，1H)，3.69(d，J＝14.8，1H)，3.04-2.97(m，1H)，2.82-2.72(br m，2H)，2.53(dd，J＝11.5，8.8)，2.41(s，3H)，3.86-2.30(m，4H)，2.08-1.97(m，2H)，1.90-7.77(m，2H)，1.62-1.49(m，2H)，0.91(t，J＝7.4，3H).

Example 103: 7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₆H₃₆N₂O₂Calculated value of molecular weight of (c): 424.25, respectively; m/z found: 425.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.21-7.16(m，2H)，7.12-7.08(m，2H)，6.75(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.7，1H)，6.60-6.59(m，1H)，4.18-4.12(m，1H)，3.78-3.73(m，2H)，3.68(d，J＝14.8，1H)，3.58(d，J ＝14.8，1H)，3.02-2.87(m，3H，2.74-2.67(m，1H)，2.55-2.48(m，1H)，2.43(s，3H)，2.40(s，3H)，2.18-2.16(m，1H)，2.15-2.10(m，1H)，1.65-1.20(m，5H)，1.45-1.31(m，2H)，1.31(m，1H)，1.05(d，J＝6.6，4H).

Example 104: 7- (1-cyclobutyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₇H₃₆N₂O₂Calculated value of molecular weight of (c): 436.25, respectively; m/z found: 437.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.20-7.16(m，2H)，7.12-7.08(m，2H)，6.75(d，J＝8.5，1H)，6.12(dd，J＝8.5，2.5，1H)，6.59-6.57(m，1H)，4.17-4.13(m，1H)，3.75(d，J＝6.3，2H)，3.68(d，J＝14.8，1H)，3.57(d，J＝14.8，1H)，2.99-2.94(m，1H)，2.94-2.88(m，2H)，2.72-2.64(m，1H)，2.54-2.47(m，1H)，2.46(s，3H)，2.40(s，3H)，2.08-1.99(m，2H)，1.93-1.59(m，10H)，1.43-1.32(m，2H).

Example 105: 7- (1-Ethyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₅N₂O₂Calculated value of molecular weight of (c): 410.24, respectively; m/z found: 411.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.21-7.15(m，2H)，7.13-7.07(m，2H)，6.75(d，J＝8.5，1H)，6.62(dd，J＝8.5，2.5，1H)，6.60-6.57(m，1H)，4.18-4.12(m，1H)，3.75(d，J＝6.1，2H)，3.68(d，J＝14.8，1H)，3.57(d，J＝14.8，1H)，3.01-2.93(m，3H)，2.54-2.47(m，1H)，2.46(s，3H)，2.44-2.42(m，4H)，2.17(s，2H)，1.96-1.73(m，5H)，1.46-1.34(m，2H)，1.13-1.06(m，3H).

Example 106: 4- (3-chloro-4-methoxy-phenyl) -7- (1-cyclobutyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₇H₃₅ClN₂O₂Calculated value of molecular weight of (c): 454.24, respectively; m/z found: 455.5[ M + H]⁺。

¹HNMR(CDCl₃)：7.19(d，J＝2.2，1H)，7.03(dd，J＝8.5，2.2，1H)，6.83(d，J＝8.5，1H)，6.75(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.7，1H)，6.60-6.57(m，1H)，4.14-4.08(m，1H)，3.87(s，3H)，3.76(d，J＝6.0，2H)，3.65(d，J＝14.8，1H)，3.58(d，J＝14.8，1H)，2.98-2.87(m，3H)，2.74-2.63(m，1H)，2.50(dd，J＝11.5，8.2，1H)，2.40(s，3H)，2.09-1.99(m，2H)，1.96-1.57(m，10H)，1.45-1.31(m，2H).

Example 107: 4- (3-chloro-4-methoxy-phenyl) -7- (1-ethyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₃ClN₂O₂Calculated value of molecular weight of (c): 428.22, respectively; m/z found: 429.5[ M + H]⁺。

¹HNMR(CDCl₃)：7.19(d，J＝1.9，1H)，7.03(dd，J＝8.2，2.2，1H)，6.83(d，J＝8.5，1H)，6.76(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.5，1H)，6.60-6.57(m，1H)，4.14-4.08(m，1H)，3.87(s，3H)，3.76(d，J＝6.3，2H)，3.66(d，J＝14.8，1H)，3.58(d，J＝14.8，1H)，3.04-2.90(m，3H)，2.53-2.46(m，1H)，2.45-2.37(m，5H)，1.98-1.88(m，2H)，1.88-1.71(m，4H)，1.47-1.34(m，2H)，1.12-1.06(m，3H).

Example 108: 4- (3-chloro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₆H₃₅ClN₂O₂Calculated value of molecular weight of (c): 442.24; m/z found: 443.5[ M + H]⁺。

¹HNMR(CDCl₃)：7.20(d，J＝2.2，1H)，7.03(dd，J＝8.5，2.2，1H)，6.84(d，J＝8.5，1H)，6.76(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.5，1H)，6.60-6.57(m，1H)，4.14-4.08(m，1H)，3.87(s，3H)，3.76(d，J＝6.3，2H)，3.66(d，J＝14.8，1H)，3.58(d，J＝14.8，1H)，3.01-2.91(m，3H)，2.50(dd，J＝11.2，8.2，1H)，2.40(s，3H)，2.46-2.34(m，2H)，2.00-1.89(m，2H)，1.87-1.72(m，3H)，1.64-1.47(m，5H)，1.46-1.33(m，2H)，0.90(t，J＝7.4，3H).

Example 109: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₆H₃₆N₂Calculated molecular weight of OS: 424.25, respectively; m/z found: 425.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.22-7.15(m，2H)，7.14-1.07(m，2H)，6.76(d，J＝8.6，1H)，6.62(d，J＝2.7H，1H)，6.60-6.57(m，1H)，4.16(dd，J＝8.0，5.9，1H)，3.76(d，J＝6.3，2H)，3.68(d，J＝14.9，1H)，3.57(d，J＝14.9，1H)，3.01-2.92(m，3H)，2.56-2.44(m，4H)，2.41(s，3H)，2.34-2.24(m，2H)，2.01-1.89(m.2H)，1.85-1.76(m，4H)，1.60-1.48(m，2H)，1.47-1.30(m，2H)，0.90(t，J＝7.4，3H).

Example 110: 7- (1-isobutyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₇H₃₈N₂O₂Calculated value of molecular weight of (c): 422.29, respectively; m/z found: 423.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.15-6.97(m，2H)，6.95-6.83(m，2H)，6.83-6.66(m，2H)，6.67-6.51(m，1H)，4.91-4.45(m，1H)，4.41-3.98(m，1H)，3.98-3.62(m，8H)，3.62-3.34(m，1H)，3.23-2.91(m，4H)，2.91-2.80(m，2H)，2.78-2.58(m，2H)，2.29-1.75(m，6H)，1.12-0.97(m，6H).

Example 111: 7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (3-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₇H₃₅FN₂O₂Calculated value of molecular weight of (c): 438.27, respectively; m/z found: 439.5[ M + H]⁺。

¹HNMR(CDCl₃)：7.11-6.52(m，6H)，1.95-1.43(m，2H)，4.43-4.11(m，1H)，3.99-3.65(m，6H)，3.65-3.44(m，2H)，3.43-3.24(m，1H)，3.19-2.83(m，4H)，2.67-2.33(m，4H)，2.33-2.14(m，2H)，2.11-1.94(m，3H)，1.94-1.58(m，4H).

Example 112: 4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₆H₃₅FN₂O₂Calculated value of molecular weight of (c): 426.27, respectively; m/z found: 427.5[ M + H]⁺。

¹HNMR(CDCl₃)：7.13-6.56(m，6H)，4.74-4.47(m，2H)，4.39-4.07(m，1H)，3.97-3.58(m，8H)，3.16-2.88(m，6H)，2.83-2.57(m，2H)，2.19-1.94(m，3H)，1.93-1.66(m，4H)，1.04-0.90(m，3H).

Example 113: 7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (2-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

¹HNMR(CDCl₃)：7.16-6.51(m，6H)，4.92-4.81(m，2H)，4.35-3.99(m，1H)，3.88-3.45(m，8H)，3.45-3.12(m，2H)，3.00(s，3H)，2.63-2.33(m，4H)，2.31-2.15(m，2H)，2.13-1.93(m，3H)，1.93-1.61(m，4H).

Example 114: 4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₆H₃₆FN₂O₂Calculated value of molecular weight of (c): 426.27, respectively; m/z found: 427.5[ M + H]⁺。

¹HNMR(CDCl₃)：7.16-6.87(m，1H)，6.85-6.54(m，5H)，4.96-4.55(m，2H)，4.29-3.88(m，1H)，3.88-3.48(m，8H)，3.45-3.11(m，1H)，3.11-2.89(m，5H)，2.86-2.63(m，2H)，2.13-1.93(m，3H)，1.93-1.68(m，4H)，1.06-0.92(m，3H).

Example 115: 4- (2-fluoro-4-methoxy-phenyl) -7- (1-isobutyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₇H₃₇FN₂O₂Calculated value of molecular weight of (c): 440.28, respectively; m/z found: 441.5[M+H]⁺。

¹HNMR(CDCl₃)：7.14-6.89(m，1H)，6.85-6.53(m，5H)，4.92-4.53(m，1H)，4.26-4.01(m，1H)，3.98-3.37(m，8H)，3.33-3.10(m，1H)，3.10-2.92(m，3H)，2.92-2.81(m，2H)，2.81-2.65(m，2H)，2.26-1.69(m，6H)，1.03(d，J＝6.5，6H).

Example 116: 7- [1- (2-fluoro-ethyl) -piperidin-4-ylmethoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₃FN₂O₂Calculated value of molecular weight of (c): 412.25, respectively; m/z found: 413.4[ M + H]⁺。

¹HNMR(CDCl₃)：7.16-6.97(m，2H)，6.94-6.67(m，4H)，6.67-6.55(m，1H)，4.97-4.87(m，1H)，4.87-4.75(m，1H)，4.74-4.50(m，1H)，4.23-4.01(m，1H)，7.07-3.90(m，7H)，3.59-3.23(m，3H)，3.13-2.93(m，4H)，2.92-2.75(m，2H)，2.31-1.70(m，5H).

Example 117: 7- (1-isopropyl-piperidin-4-yloxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.16mmol scale): 43mg (69%). Ms (esi): c₂₅H₃₄N₂O₂Calculated value of molecular weight of (c): 394.3, respectively; m/z found: 395.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.7，2H)，6.82(d，J＝8.7，2H)，6.76(d，J＝8.3，1H)，8.63(dd，J＝8.4，2.6，1H)，6.61(d，J＝2.3，1H)，4.26-4.20(m，1H)，4.15(dd，J＝8.5，5.7，1H)，3.78(s，3H)，3.70(d，J＝14.8，1H)，3.55(d，J＝14.8，1H)，2.99-2.96(m，1H)，2.80-2.70(m，3H)，2.49(dd，J＝11.4，8.8，1H)，2.40(s，3H)，2.40-2.32(m，2H)，2.04-1.95(m，2H)，1.83-1.74(m，2H)，1.05(d，J＝6.6，6H).

Example 118: 7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.43mmol scale): 94mg (53%). Ms (esi): c₂₅H₃₄N₂Calculated molecular weight of OS: 410.2; m/z found: 411.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.17(d，J＝8.3，2H)，7.10(d，J＝8.3，2H)，6.74(d，J＝8.4，1H)，6.63(dd，J＝8.4，2.6，1H)，6.60(d，J＝2.4，1H)，4.26-4.20(m，1H)，4.14(dd，J＝7.8，6.0，1H)，3.66(d，J＝14.8，1H)，3.56(d，J＝14.8，1H)，2.97-2.94(m，1H)，2.79-2.70(m，3H)，2.50(dd，J＝11.4，8.5，1H)，2.44(s，3H)，2.39(s，3H)，2.39-2.34(m，2H)，2.00-1.92(m，2H)，1.83-1.75(m，2H)，1.04(d，J＝6.6，6H).

Example 119: 4- (2-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.43mmol scale): 87mg(50％)。MS(ESI)：C₂₅H₃₃FN₂O₂Calculated value of molecular weight of (c): 412.3, respectively; m/z found: 413.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.93(dd，J＝8.7，8.7，1H)，6.78(d，J＝8.5，1H)，6.66(dd，J＝8.5，2.5，1H)，6.62-6.59(m，2H)，6.57(dd，J＝8.5，2.7，1H)，4.47(dd，J＝6.3，6.3，1H)，4.26-4.22(m，1H)，3.76(s，3H)，3.60(brs，2H)，2.92(m，1H)，2.80-2.72(m，3H)，2.58(dd，J＝11.3，7.5，1H)，2.42(s，3H)，2.42-2.36(m，2H)，2.04-1.92(m，2H)，1.85-1.75(m，2H)，1.06(d，J＝6.6，6H).

Example 120: 4- (3-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.38mmol scale): 129mg (82%). Ms (esi): c ₂₅H₃₃FN₂O₂Calculated value of molecular weight of (c): 412.3, respectively; m/z found: 413.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.91-6.83(m，3H)，6.75(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.5，1H)，6.60(d，J＝2.5，1H)，4.25-4.20(m，1H)，4.09(dd，J＝6.8，6.8，1H)，3.83(s，3H)，3.62(d，J＝14.9，1H)，3.56(d，J＝14.9，1H)，2.92(dd，J＝11.4，5.5，1H)，2.78-2.69(m，3H)，2.50(dd，J＝11.4，8.0，1H)，2.38(s，3H)，2.38-2.33(m，2H)，2.02-1.92(m，2H)，1.81-175(m，2H)，1.06(d，J＝6.6，6H).

Example 121: 4- (4-methoxy-phenyl) -2-methyl-7- [1- (tetrahydro-pyran-4-yl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.15mmol scale): 41mg (64%). Ms (esi): c₂₇H₃₆N₂O₃Calculated value of molecular weight of (c): 436.3, respectively; m/z found: 437.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.6，2H)，6.82(d，J＝8.7，2H)，6.76(d，J＝8.4，1H)，6.63(dd，J＝8.5，2.5，1H)，6.60(d，J＝2.2，1H)，4.27-4.23(m，1H)，4.17-4.12(m，1H)，4.02(dd，J＝11.0，4.0，2H)，3.80(s，3H)，3.69(d，J＝14.8，1H)，3.55(d，J＝14.8，1H)，3.40-3.35(m，2H)，2.97(dd J＝11.5，5.5，1H)，2.86-2.77(m，2H)，2.51-2.41(m，4H)，2.40(s，3H)，2.03-1.94(m，2H)，1.83-1.71(m，4H)，1.63(dd J＝12.0，4.3，1H)，1.58(dd J＝12.1，4.2，1H).

Example 122: 2, 2, 2-trifluoro-1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -ethanone

A solution of 4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (0.117g, 0.319mmol) in DCM (3ml) was treated with trifluoroacetic anhydride (0.25 ml). The mixture was aged for 1 hour and then concentrated. FCC gave the title compound (0.119g, 81%). Ms (esi): c₂₅H₂₉F₃N₂O₃Calculated value of molecular weight of (c): 462.21, respectively; m/z found: 463.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.6，2H)，6.83(d，J＝8.8，2H)，6.78(d，J＝8.1，1H)，6.61(dd，J＝8.6，2.8，1H)，6.58(d，J＝2.5，1H)，4.63-4.56(m，1H)，4.18-4.04(m，2H)，3.83-3.75(m，2H)，3.79(s，3H)，3.70(d，J＝14.4，1H)，3.56(d，J＝14.9，1H)，3.17(ddd，J＝13.7，13.3，2.5，1H)，2.99(ddd，J＝11.6，5.5，1.3，1H)，2.81(ddd，J＝12.8，12.6，2.0，1H)，2.49(dd，J＝11.4，8.8.1H)，2.41(s，3H)，2.16-1.92(m，3H)，1.45-1.32(m，2H).

Example 123: 4- (4-methoxy-phenyl) -2-methyl-7- [1- (2, 2, 2-trifluoro-ethyl) -piperidin-4-ylmethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline

2, 2, 2-trifluoro-1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl]-piperidin-1-yl } -ethanone (0.102g, 0.221mmol) in THF (5ml) was dissolved with LiAlH ₄(1M in THF, 1 ml). The mixture was stirred at 23 ℃ for 1 hour and then at 58 ℃ for 18 hours. After the mixture was cooled, saturated NH was added₄Dilute with aqueous Cl, dilute with 1M NaOH, and extract with DCM. The organic layer was concentrated. The desired product was obtained by FCC (0.0515g, 52%). Ms (esi): c₂₅H₃₁F₃N₂O₂Calculated value of molecular weight of (c): 448.23, respectively; m/z found: 449.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.8，2H)，6.83(d，J＝8.8，2H)，6.77(d，J＝8.6，1H)，6.61(dd，J＝8.6，2.8，1H)，6.58(d，J＝2.5，1H)，4.19-4.12(m，1H)，3.79(s，3H)，3.75(d，6.1，2H)，3.70(d，J＝14.7，1H)，3.56(d，J＝14.9，1H)，3.04(m，5H)，2.49(dd，11.4，8，8，1H)，2.41(s，3H)，2.41-2.33(m，2H)，1.85-1.74(m，3H)，1.49-1.39(m，2H).

Following a procedure analogous to that used for 2-benzyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydroisoquinoline, the following example 124-127 was prepared.

Example 124: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4-phenyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.672mmol scale): 22mg (5%, two steps, TFA salt). Ms (esi): c₂₄H₃₁FN₂Calculated value of molecular weight of O: 382.51, respectively; m/z found: 383.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.27-7.14(m，5H)，6.73-6.59(m，3H)，5.05-4.76(m，1H)，4.55-4.31(m，3H)，4.00-3.97(m，2H)，3.71-3.66(m，1H)，3.44-3.32(m，3H)，3.25-3.21(m，2H)，3.10-3.07(m，2H)，2.92(s，3H)，2.22-2.00(m，6H).

Example 125: 4- (2-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (1.9mmol scale): 434mg (36%, two steps, TFA salt). Ms (esi): c₂₄H₃₀F₂N₂Calculated value of molecular weight of O: 400.5; m/z found: 401.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.46-7.15(m，4H)，6.88-6.75(m，3H)，4.98-4.94(m，2H)，4.74-4.53(m，2H)，4.15-4.12(m，2H)，3.92-3.88(m，1H)，3.85-3.72(m，1H)，3.63-3.61(m，2H)，3.42-3.93(m，2H)，3.26-3.22(m，2H)，3.14(s，3H)，2.33-2.07(m，6H).

Example 126: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4-p-tolyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield (1.15mmol scale): 88mg (12%, two steps, TFA salt). Ms (esi): c₂₅H₃₃FN₂Calculated value of molecular weight of O: 396.54, respectively; m/z found: 397.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.16-7.15(m，2H)，7.06-7.04(m，2H)，6.89-6.67(m，2H)，6.61(s，1H)，5.05-4.93(m，1H)，4.77-4.55(m，2H)，4.24-4.02(m，3H)，3.83-3.68(m，1H)3.56-3.53(m，3H)3.24-3.21(m，2H)，3.08-3.02(m，2H)，2.96(s，3H)，2.44-2.14(m，9H).

Example 127: 2-benzyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.43mmol scale): 50mg (21%, two steps, TFA salt). Ms (esi): c₃₁H₃₇N₂O₂Calculated value of molecular weight of (c): 488.64 of the total weight of the product; m/z found: 489.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.44(s，5H)，7.04-7.03(m，2H)，6.86-6.84(m，2H)，6.77-6.69(m，2H)，6.56(s，1H)，5.03-4.93(m，1H)，4.52-4.36(m，4H)，4.14-3.83(m，3H)，3.79-3.64(m，4H)，3.55-3.53(m，2H)，3.23-3.21(m，2H)，3.07-3.03(m，2H)，2.92-2.85(m，1H)，3.38-2.00(m，6H).

Example 128-145 below was prepared in a similar manner to that used in example 1, except as otherwise noted.

Example 128: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (3-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.856mmol scale): 0.184g (46%). Ms (esi): c₂₅H₃₀F₄N₂O₂Calculated value of molecular weight of (c): 466.22, respectively; m/z found: 467.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.33-7.27(m，1H)，7.14-7.04(m，3H)，6.75(d，J＝8.6，1H)，6.65(dd，J＝8.4，2.5，1H)，6.61(d，J＝2.5，1H)，4.77-4.58(m，1H)，4.20(dd，J＝7.4，5.7，1H)，3.98(t，J＝6.5，2H)，3.67(d，J＝14.9，1H)，3.60(d，J＝15.3，1H)，2.98(m，1H)，2.65-2.48(m，5H)，2.43-2.33(m，5H)，1.99-1.83(m，6H).

Example 129: 7- [3- (3, 3-difluoro-pyrrolidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 135.0mg (14%, TFA salt). Ms (esi): c₂₄H₃₀F₂N₂O₂Calculated value of molecular weight of (c): 416.23, respectively; m/z found: 417.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.16(d，J＝8.7，2H)，6.92(d，J＝8.6，2H)，6.83-6.73(m，3H)，4.66-4.49(m，3H)，4.10(t，J＝5.9，2H)，3.97(t，J＝12.0，2H)，3.81-3.75(m，3H)，3.78(s，3H)，3.57-3.43(m，3H)，3.08(s，3H)，2.73-2.65(m，2H)，2.30-2.25(m，2H).

Example 130: 4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 88.0mg (9%, TFA salt). Ms (esi): c₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.16(d，J＝8.7，2H)，6.92(d，J ＝8.6，2H)，6.84-6.73(m，3H)，4.65-4.50(m，3H)，4.13(brs，2H)，4.02-3.91(m，3H)，3.84-3.77(m，2H)，3.78(s，3H)，3.72-3.59(m，2H)，3.51-3.34(m，15H)，3.33-3.20(m，2H)，3.19-3.17(m，1H)，3.08(s，3H)，2.34-2.23(m，2H)，1.47-1.42(m，1H)，1.38-1.35(m，2H).

Example 131: bicyclopropylmethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 87.0mg (9%, TFA salt). Ms (esi): c₂₇H₃₆N₂O₂Calculated value of molecular weight of (c): 420.28, respectively; m/z found: 421.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.17(d，J＝8.5，2H)，6.92(d，J＝8.5，2H)，6.84-6.72(m，3H)，4.77-4.53(m，4H)，4.15-4.13(m，2H)，3.82-3.74(m，1H)，3.78(s，3H)，3.53-3.41(m，3H)，3.06(s，3H)，2.32-2.27(m，2H)，2.25-2.18(m，1H)，1.26-1.23(m，2H)，0.67-0.61(m，4H)，0.56-0.53(m，2H)，0.48-0.46(m，2H).

Example 132: 4- (2-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Preparation according to example 1 gave 245mg (32%, TFA salt). Ms (esi): c₂₄H₃₀ClFN₂Calculated value of molecular weight of O: 416.20, respectively; m/z found: 417.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.50-7.48(m，1H)，7.36-7.29(m，2H)，7.19(br s，1H)，6.86(brs，1H)，6.83-6.80(m，1H)，6.72-6.69(m，1H)，5.17(br s，1H)，4.98(d，J＝47.9，1H)，4.65-4.55(m，2H)，4.11(t，J＝5.8，2H)，3.86-3.82(m，1H)，3.75-3.70(m，1H)，3.64-3.57(m，2H)，3.38-3.35(m，2H)，3.23-3.18(m，2H)，3.10(s，3H)，2.33-2.04(m，6H).

Example 133: 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-morpholin-4-yl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 31.9mg (6%, TFA salt). Ms (esi): c₂₈H₃₉N₃O₃Calculated value of molecular weight of (c): 465.30, respectively; m/z found: 466.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.13(s，J＝8.7，2H)，7.04(d，J＝8.8，2H)，6.83-6.68(m，3H)，4.62-4.69(m，1H)，4.59-4.55(m，2H)，4.16-4.09(m，2H)，4.03-4.91(m，3H)，4.87-4.84(m，2H)，3.77(t，J＝4.7，4H)，3.71-3.63(m，2H)，3.50-3.32(m，3H)，3.28-3.19(m，1H)，3.16(t，J＝4.9，4H)，3.13(s，3H)，2.38-2.26(m，2H)，1.50-1.46(m，1H)，1.39-1.37(m，2H).

Example 134: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-morpholin-4-yl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 155.6mg (29%, TFA salt). Ms (esi): c ₂₈H₃₈FN₃O₂Calculated value of molecular weight of (c): 467.29, respectively; m/z found: 468.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.13(d，J＝8.6，2H)，7.00(d，J＝8.3，2H)，6.85-6.72(m，3H)，5.02(d，J＝47.7，1H)，4.72-4.60(m，1H)，4.58-4.54(m，2H)，4.14-4.05(m，2H)，3.90-3.76(m，5H)，3.63-3.60(m，2H)，3.47-3.39(m，3H)，3.31-3.19(m，2H)，3.18-3.15(m，4H)，3.11(s，3H)，2.38-2.28(m，3H)，2.20-2.07(m，3H).

Example 135: 4- { 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -benzonitrile

Yield: 45.0mg (7%, TFA salt). Ms (esi): c₂₅H₃₁N₃O₂Calculated value of molecular weight of (c): 405.24, respectively; m/z found: 406.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.80(d，J＝8.2，2H)，7.50(d，J＝8.3，2H)，3.89(br s，1H)，6.85-6.82(m，1H)，6.75-6.72(m，1H)，4.85-4.81(m，1H)，4.62(br s，2H)，4.20-4.09(m，2H)，4.02-3.89(m，4H)，3.72-3.56(m，4H)，3.46-3.27(m，3H)，3.09(s，3H)，2.36-2.24(m，2H)，1.46-1.35(m，3H).

Example 136: 4- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -benzonitrile

Yield: 121.0mg (19%, TFA salt). Ms (esi): c₂₅H₃₀FN₃Calculated value of molecular weight of O: 407.24, respectively; m/z found: 408.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.80(d，J＝8.1，2H)，7.50(d，J＝8.2，2H)，6.87(s，1H)，6.84-6.80(m，1H)，6.75-6.71(m，1H)，5.02(d，J＝47.8，1H)，4.84-4.80(m，1H)，4.63-4.52(m，2H)，4.16-4.11(m，2H)，3.92-3.88(m，1H)，3.78-3.71(m，1H)，3.61-3.55(m，2H)，3.40-3.36(m，2H)，3.24-3.19(m，2H)，3.07(s，3H)，2.36-2.02(m，6H).

Example 137: 7- [3- (3-benzhydryl-azetidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

The title compound can be prepared by the methods described in the above examples.

Example 137A: 7- (1-benzhydryl-azetidin-3-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 6.1mg (0.2%, TFA salt). Ms (esi): c₃₄H₃₆N₂O₂Calculated value of molecular weight of (c): 504.28; m/z found: 505.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.70(d，J＝8.6，4H)，7.45-7.32(m，6H)，7.17(d，J＝8.5，2H)，6.93(d，J＝8.5，4H)，6.83-6.76(m，1H)，5.77(br s，1H)，4.68-4.47(m，3H)，4.44-4.31(m，2H)，4.29-4.16(m，3H)，4.12-4.03(m，2H)，3.79(s，3H)，3.48-3.39(m，2H)，3.06(s，3H).

Example 138: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (0.466mmol scale): 0.110g (57%). Ms (esi): c₂₄H₃₂N₂O₂Calculated value of molecular weight of S: 412.22, respectively; m/z found: 413.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.3，2H)，7.10(d，J＝8.3，2H)，6.76(d，J＝8.6，1H)，6.66-6.59(m，2H)，4.16(dd，J＝8.6，6.3，1H)，4.00-3.95(m，2H)，3.76-3.65(m，5H)，3.58(d，J＝15.2，1H)，2.97(ddd，J＝11.6，5.6，1.0，1H)，2.55-2.45(m，10H)，2.41(s，3H)，1.98-1.91(m，2H).

Example 139 (racemate), 140 (enantiomer 1) and 141 (enantiomer 2): 4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- [4- (2-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy]-propan-1-ol. Yield (5.94mmol scale): 0.98g (48%). Ms (esi): c₂₀H₂₄FNO₃Calculated value of molecular weight of (c): 345.2, respectively; m/z found: 346.4[ M + H]⁺。

¹H NMR(CDCl₃)：6.92(dd，J＝8.5，8.5，1H)，6.80(d，J＝8.5，1H)，6.67(dd，J＝8.5，2.7，1H)，6.63-6.57(m，3H)，4.48(dd，J＝6.5，6.5，1H)，4.09(t，J＝5.9，2H)，3.85(t，J＝5.9，2H)，3.77(s，3H)，3.62(s，2H)，2.93(dd，J＝11.4，5.5，1H)，2.58(dd，J＝11.4，7.7，1H)，2.40(s，3H)，2.02(m，2H)，1.75(brs，1H).

Step 2: yield (1.52mmol scale): 242mg (37%, enantiomeric mixture).

MS(ESI)：C₂₅H₃₂F₂N₂O₂Calculated value of molecular weight of (c): 430.2; m/z found: 431.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.92(dd，J＝8.6，8.6，1H)，6.79(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.6，1H)，6.62-6.59(m，2H)，6.57(dd，J＝8.5，2.6，1H)，4.74-4.60(m，1H)，4.47(dd，J＝6.4，6.4，1H)，3.97(t，J＝6.3，2H)，3.76(s，3H)，3.61(br s，2H)，2.92(dd，J＝11.4，5.5，1H)，2.65-2.60(m，3H)，2.52(t，J＝7.2，2H)，2.40(s，3H)，2.38-2.65(m，2H)，1.98-1.83(m，6H).

The enantiomers were separated (SFC HPLC) to give example 140 (first elution) and example 141 (second elution).

Example 142 (racemate), 143 (enantiomer 1) and 144 (enantiomer 2): 4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- [4- (3-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline-7- Radical oxy radical]-propan-1-ol.

Yield (9.12mmol scale): 1.55g (49%). Ms (esi): c ₂₀H₂₄FNO₃Calculated value of molecular weight of (c): 345.2, respectively; m/z found: 346.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.91-6.85(m，3H)，6.78(d，J＝8.5，1H)，6.66(dd，J＝8.5，2.6，1H)，6.61(d，J＝2.6，1H)，4.14-4.11(m，1H)，4.09(t，J＝5.9，2H)，3.87(s，3H)，3.85(t，J＝5.9，2H)，3.65(d，J＝14.9，1H)，3.58(d，J＝14.9，1H)，2.97-2.93(m，1H)，2.50(dd，J＝11.4，8.2，1H)，2.40(s，3H)，2.02(quint，J＝5.9，2H)，1.66(brs，1H).

Step 2: yield (1.40mmol scale): 351mg (58%) as a mixture of enantiomers. Ms (esi): c₂₅H₃₂F₂N₂O₂Calculated value of molecular weight of (c): 430.2; m/z found: 431.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.94(d，J＝8.8，1H)，6.88(d，J＝2.2，1H)，6.86(dd，J＝8.5，8.5，1H)，6.76(d，J＝8.5，1H)，6.64(dd，J＝8.5，2.5，1H)，6.59(d，J＝2.3，1H)，4.76-4.59(m，1H)，4.11(dd，J＝6.7，6.7，1H)，3.97(t，J＝6.3，2H)3.84(s，3H)，3.64(d，J＝14.9，1H)，3.58(d，J＝14.9，1H)，2.94(dd，J＝11.5，5.5，1H)，2.67-2.56(m，2H)，2.54(t，J＝7.3，2H)，2.51(dd，J＝11.4，8.1，1H)，2.49-2.40(m，2H)，2.39(s，3H)，1.99-1.83(m，6H).

The enantiomers were separated (SFC HPLC) to give example 143 (first elution) and example 144 (second elution).

Example 145: 4- (4-ethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3- [4- (4-ethoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy Base of]-propan-1-ol. Yield (4.76mmol scale): 0.15g (9%). Ms (esi): c₂₁H₂₇NO₃Calculated value of molecular weight of (c): 341.2, respectively; m/z found: 342.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.07(d，J＝8.6，2H)，6.81(d，J＝8.6，2H)，6.77(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.5，1H)，6.60(d，J＝2.5，1H)，4.16(dd，J＝8.9，5.8，1H)，4.04(t，J＝6.0，2H)，4.00(q，J＝7.0，2H)，3.80(t，J＝5.9，2H)，3.71(d，J＝14.9，2H)，3.54(d，J＝14.8，2H)，3.01-2.98(m，1H)，2.48(dd，J＝11.4，9.2，1H)，2.41(s，3H)，2.04-1.96(m，3H)，1.40(t，J＝7.0，1H).

Step 2: yield (0.28mmol scale): 64.2mg (53%). Ms (esi): c₂₆H₃₅FN₂O₂Calculated value of molecular weight of (c): 426.3 of the total weight of the mixture; m/z found: 427.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.07(d，J＝8.7，2H)，6.81(d，J＝8.7，2H)，6.77(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.6，1H)，6.59(d，J＝2.5，1H)，4.75-4.58(m，1H)，4.15(dd，J＝8.6，5.9，1H)，4.01(q，J＝7.0，2H)3.96(t，J＝6.3，2H)，3.70(d，J＝14.81，1H)，2.98(m，1H)，2.65-2.54(m，2H)，2.52-2.48(m，3H)，2.41(s，3H)，2.41-2.29(m，2H)，1.99-1.81(m，6H)1.40(t，J＝7.0，3H).

Example 146: 2-ethyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Preparation was carried out in analogy to 2-ethyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline to give the desired product (74mg, 0.11mmol) as the TFA salt (0.54mmol scale; 27%, two steps). Ms (esi): c ₂₆H₃₅FN₂O₂Calculated value of molecular weight of (c): 426.57, respectively; m/z found: 427.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09-7.03(m，2H)，6.88-6.86(m，2H)，6.79-6.63(m，3H)，5.02-4.93(m，1H)，4.80-4.56(m，2H)，4.24-4.02(m，3H)，3.80-3.76(m，4H)，3.65-3.61(m，1H)，3.56-3.52(m，2H)，3.28-3.23(m，4H)，3.08-2.93(m，3H)，2.36-2.20(m，6H)，1.44-1.39(m，3H).

Example 147: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

On a 0.046mmol scale, as per example 66 step 1From 2-benzyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy]Preparation of (E) -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline was started to give 10.2mg (35%) of the desired product as a TFA salt. Ms (esi): c₂₄H₃₁FN₂O₂Calculated value of molecular weight of (c): 398.51, respectively; m/z found: 399.5[ M + H]⁺。

¹HNMR(CDCl₃)：7.05-7.03(m，2H)，6.88-6.83(m，3H)，6.74-6.73(m，1H)，6.67-6.66(m，1H)，5.13-4.93(m，1H)，4.44-4.29(m，3H)，4.08-4.06(m，2H)，3.80(s，3H)，3.72-3.65(m，1H)，3.60-3.58(m，2H)，3.28-3.27(m，3H)，3.15-3.05(m，2H)，2.51-2.20(m，7H).

The following example 148-151 was prepared in a manner similar to that used in example 78.

Example 148: 4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (4.06mmol scale): 0.88g (58%). Ms (esi): c₂₂H₂₈N₂O₂Calculated value of molecular weight of (c): 352.2, respectively; m/z found: 353.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.6，2H)，6.82(d，J＝8.6，2H)，6.76(d，J＝8.4，1H)，6，63(dd，J＝8.4，2.5，1H)，6.61(d，J＝2.5，1H)，4.34-4.26(m，1H)，4.14(dd，J＝8.3，5.9，1H)，3.78(s，3H)，3.69(d，J＝14.8，1H)，3.55(d，J＝14.8，1H)，3.14-3.08(m，2H)，2.97(dd，J＝11.4，5.6，1H)，2.73-2.68(ddd，J＝12.5，9.4，3.1，2H)，2.49(dd，J＝11.4，8.8，1H)，2.40(s，3H)，2.32(br s，1H)，2.00-1.87(m，4H)，1.67-1.58(m，2H).

Example 149: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (1.38mmol scale): 0.178g (35%). Ms (esi): c₂₂H₂₈N₂Calculated molecular weight of OS: 368.2, respectively; m/z found: 369.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.15(d，J＝8.4，2H)，7.08(d，J＝8.5，2H)，6.73(d，J＝8.2，1H)，6.62-6.59(m，2H)，4.35-4.27(m，1H)，4.13(dd，J＝7.8，6.0，1H)，3.65(d，J＝14.9，1H)，3.54(d，J＝14.9，1H)，3.13-3.01(m，3H)，2.94(dd，J＝11.4，5.6，1H)，2.72(ddd，J＝12.3，8.7，3.2，2H)，2.28(dd，J＝11.4，8.5，1H)，2.43(s，3H)，2.38(s，3H)，2.00-1.96(m，2H)，1.69-1.61(m，2H).

Example 150: 4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (1.12mmol scale): 0.170g (41%). Ms (esi): c₂₂H₂₇FN₂O₂Calculated value of molecular weight of (c): 370.2 of the total weight of the mixture; m/z found: 371.4[ M + H]⁺。

¹H NMR(CDCl₃)：6.93(dd，J＝8.7，8.7，1H)，6.78(d，J＝8.5，1H)，6.65(dd，J＝8.5，2.6，1H)，6.62-6.54(m，3H)，4.47(dd，J＝6.3，6.3，1H)，4.26-4.22(m，1H)，3.76(s，3H)，3.60(brs，2H)，3.16-3.10(m，2H)，2.91(dd，J＝11.3，5.5，1H)，2.73(ddd，J＝12.4，9.1，3.1，2H)，2.58(dd，J＝11.3，7.6，1H)，2.41(br s，1H)，2.39(s，3H)，2.03-1.97(m，2H)，1.70-1.61(m，2H).

Example 151: 4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield (1.19mmol scale): 0.157g (40%). Ms (esi): c₂₂H₂₇FN₂O₂Calculated value of molecular weight of (c): 370.2 of the total weight of the mixture; m/z found: 371.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.90-6.82(m，3H)，6.74(d，J＝8.5，1H)，6.63(dd，J＝8.5，2.6，1H)，6.59(d，J＝2.4，1H)，4.32-4.27(m，1H)，4.09(dd，J＝6.9，6.9，1H)，3.83(s，3H)，3.62(d，J＝14.9，1H)，3.55(d，J＝14.9，1H)，3.13-3.08(m，2H)，2.92(dd，J＝11.3，5.6，1H)，2.70(ddd，J＝12.4，9.2，3.1，2H)，2.49(dd，J＝11.4，8.1，1H)，2.38(s，3H)，2.30(br s，1H)，2.00-1.95(m，2H)，1.67-1.58(m，2H).

Example 152: 7- [1- (2-fluoro-ethyl) -piperidin-4-yloxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

To 4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline (0.064g, 0.18mmol), K₂CO₃To a mixture of (0.038g, 0.27mmol) and DMF (1ml) was added 1-bromo-2-fluoroethane (14. mu.l, 0.19mmol) and the resulting mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and diluted with brineExtracted with EtOAc (3 times). The combined organic layers were dried (Na)₂SO₄) And concentrating. The crude product was purified by FCC to give the desired product (36.3mg, 50%). Ms (esi): c₂₄H₃₁FN₂O₂Calculated value of molecular weight of (c): 398.2; m/z found: 399.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.7，2H)，6.83(d，J＝8.7，2H)，6.76(d，J＝8.4，1H)，6.63(dd，J＝8.5，2.5，1H)，6.60(d，J＝2.2，1H)，4.62(t，J＝4.9，1H)，4.52(t，J＝4.9，1H)，4.30-4.25(m，1H)，4.16-4.14(m，1H)，3.79(s，3H)，3.69(d，J＝14.8，1H)，3.55(d，J＝14.8，1H)，2.99-2.96(m，1H)，2.84-2.80(m，2H)，2.74(t，J＝4.9，1H)，2.69(t，J＝4.9，1H)，2.49(dd，J＝11.4，8.8，1H)，2.46-2.39(m，2H)，2.41(s，3H)，2.01-1.96(m，2H)，1.88-1.80(m，2H).

Examples 153 (enantiomer 1) and 154 (enantiomer 2): 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

The enantiomer was isolated from the racemic product (example 51) (SFC HPLC) to afford example 153 (first elution) and example 154 (second elution). Each compound was diluted with DCM, treated with 1.25M HCl/MeOH, and then concentrated to give the HCl salt, which was then assayed and biologically tested.

Example 153: [ alpha ] to]₅₈₉13.89(c 9.36mg/ml, MeOH). Example 154: [ alpha ] to]₅₈₉＝+12.51(c 9.27mg/ml，MeOH)。

The compounds of example 155 to example 158 were obtained as described in examples 153 and 154.

Examples 155 (enantiomer 1) and 156 (enantiomer 2): 4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

The enantiomer was obtained from the racemic product of example 130 by SFC HPLC to afford example 155 (first elution) and example 156 (second elution). Each compound was treated with 1.25M HCl/MeOH and then concentrated to give the HCl salt, which was then assayed and biologically tested.

Examples 157 (enantiomer 1) and 158 (enantiomer 2): 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

The enantiomer was obtained from the racemic product of example 138 by SFC HPLC to give example 157 (first elution) and example 158 (second elution). Each compound was diluted with DCM, treated with 1.25M HCl/MeOH, and then concentrated to give the HCl salt, which was then assayed and biologically tested.

Example 157(HCl salt): [ alpha ] to]₅₈₉+9.89(c 10.8mg/ml, MeOH); mp: 251 ℃ and 255 ℃ (decomposition).

The compounds of example 159-171 can be prepared as described in the previous examples.

Example 159: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Example 160: 4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Example 161: 7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Example 163: 4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Example 164: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methylsulfinyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Example 165: 4- (4-methylsulfinyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Example 165A: 4- (4-methylsulfinyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1)

A solution of 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2) (example 158; 33mg, 0.068mmol) and isopropyl 2-iodoacyl-benzoate (IBX; 13.2mg, 0.0408mmol) in DMF (0.85ml) is heated at 120 ℃ for 1 h and then stirred at room temperature overnight. Additional IBX (10mg, 0.031) was added and the mixture was heated at 120 ℃ for 2 hours. After cooling to room temperature, the mixture was diluted with water and saturated NaHCO ₃The aqueous solution was basified and extracted with DCM (3 times). The combined organic layers were dried (Na)₂SO₄) And concentrated to give 12.5mg (43%) of the desired product. Ms (esi): c₂₄H₃₂N₂O₃Calculated value of molecular weight of S: 428.21, respectively; m/z found: 429.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.56(d，J＝8.2，2H)，7.34(d，J＝7.9，2H)，6.73(d，J＝8.3，1H)，6.67-6.60(m，2H)，3.99(t，J＝6.2，1H)，3.80-3.66(m，6H)，3.06-3.00(m，1H)，2.72(s，3H)，2.65-2.50(m，8H)，2.45(s，4H)，2.02-1.95(m，2H).

Example 167: 4- (4-methanesulfonyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Example 168: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2, 6-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline

Example 169: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline

Example 170: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ol

Example 171: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-8-ol

Example 172: 2, 8-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared in analogy to the procedure described for example 1. Yield: 27.6mg (17%. 3 steps). Ms (esi): c₂₅H₃₄N₂O₂Calculated value of molecular weight of S: 426.23, respectively; m/z found: 427.3[ M + H ]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.4，2H)，7.10(d，J＝8.3，2H)，6.67-6.60(m，2H)，4.20-4.15(m，1H)，3.97(t，J＝6.3，2H)，3.74-3.65(m，5H)，3.47(d，J＝15.3，1H)，2.96-2.90(m，1H)，2.56-2.50(m，3H)，2.50-2.44(m，10H)，2.12(s，3H)，2.00-1.93(m，2H).

Example 173: 2, 6-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared in analogy to the procedure described for example 1. Yield: 35mg (7%). Ms (esi): c₂₅H₃₄N₂O₂Calculated value of molecular weight of S: 426.23, respectively; m/z found: 427.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.19(d，J＝8.4，2H)，7.11(d，J＝8.3，2H)，6.61(s，1H)，6.51(s，1H)，4.14-4.08(m，1H)，4.00(t，J＝6.2，2H)，3.75-3.70(m，4H)，3.68-3.54(m，2H)，2.79-2.91(m，1H)，2.56-2.45(m，8H)，2.40(s，3H)，2.05(s，3H)，2.02-1.94(m，2H)，1.56(s，2H).

The compounds of examples 174-177, 180-181, 183 and 185 were prepared according to the methods described in the previous examples.

Example 174: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinolin-8-ol

Example 175: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinolin-6-ol

Example 176: 8-fluoro-2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Example 177: 6-fluoro-2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Example 178: 7- [1- (2-fluoro-ethyl) -piperidin-4-ylmethoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared in analogy to the procedure used for example 83. Yield: 11mg (6%). Ms (esi): c ₂₅H₃₃FN₂Calculated molecular weight of OS: 428.23, respectively; m/z found: 429.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.23(d，J＝8.3，2H)，7.14-7.02(m，2H)，6.88-6.70(m，2H)，6.66-6.58(m，1H)，4.96-4.92(m，1H)，4.84-4.80(m，1H)，4.71-4.58(m，1H)，4.13-4.04(m，1H)，3.88-3.74(m，4H)，3.57-3.44(m，1H)，3.45-3.40(m，1H)，3.39-3.33(m，1H)，3.04-2.98(m，1H)，2.97(s，3H)，2.87-2.75(m，2H)，2.49(s，3H)，2.12-1.98(m，3H)，1.98-1.82(m，3H).

Example 179: 7- [1- (2-fluoro-ethyl) -piperidin-4-yloxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared in analogy to the procedure used for example 152. Yield: 79mg (40%). Ms (esi): c₂₄H₃₁FN₂Calculated molecular weight of OS: 414.21, respectively; m/z found: 415.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.3，2H)，7.11(d，J＝8.3，2H)，6.75(d，J＝8.5，1H)，6.65-6.61(m，2H)，4.62(t，J＝4.8，1H)，4.54(t，J＝4.8，1H)，4.30-4.25(m，1H)，4.17-4.14(m，1H)，3.68(d，J＝14.8，1H)，3.57(d，J＝14.8，1H)，2.99-2.95(m，1H)，2.82-2.76(m，2H)，2.74(t，J＝4.8，1H)，2.70(t，J＝4.8，1H)，2.53-2.48(m，1H)，2.46(s，3H)，2.40(s，3H)，2.43-2.38(m，1H)，2.02-1.96(m，3H)，1.87-1.80(m，2H).

Example 180: 4- (4-methoxy-phenyl) -7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Example 181: 4- (4-methylsulfinyl-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Example 182: 7- [3- (3, 3-difluoro-azetidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared in analogy to the procedure described for example 1. Yield: 120mg (13%, TFA salt). Ms (esi): c₂₃H₂₈F₂N₂O₂Calculated value of molecular weight of (c): 402.21, respectively; m/z found: 403.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.17(d，J＝8.6，2H)，6.92(d，J＝8.7，2H)，6.84-6.73(m，3H)，4.77(t，J＝11.4，4H)，4.58-4.44(m，3H)，4.12(t，J＝6.0，2H)，3.82-3.74(m，1H)，3.78(s，3H)，3.60(t，J＝7.4，2H)，3.50-3.42(m，1H)，3.06(s，3H)，2.19-2.14(m，2H).

Example 183: (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-3-yl) -methanol

Example 183A: (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-3S-yl) -methanol

The title compound was prepared from (S) -morpholin-3-yl-methanol and the product obtained was a mixture of diastereomers. Yield: 103mg (11%, TFA salt). Ms (esi): c₂₅H₃₄N₂O₄Calculated value of molecular weight of (c): 426.25, respectively; m/z found: 427.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.17(d，J＝8.6，2H)，6.92(d，J＝8.6，2H)，6.85-6.73(m，3H)，4.64-4.45(m，3H)，4.18-4.06(m，2H)，4.05-4.01(m，4H)，3.94-3.89(m，3H)，3.82-3.74(m，2H)，3.78(s，3H)，3.67-3.59(m，1H)，3.52-3.44(m，3H)，3.39-3.30(m，1H)，3.06(s，3H)，2.37-2.30(m，2H).

Example 184: (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-2-yl) -methanol

Yield: 145mg (16%, TFA salt). Ms (esi): c₂₅H₃₄N₂O₄Calculated value of molecular weight of (c): 426.25, respectively; m/z found: 427.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.16(d，J＝8.6，2H)，6.92(d，J＝8.5，2H)，6.80-6.75(m，3H)，4.66-4.48(m，3H)，4.13-4.05(m，3H)，3.99-3.92(m，2H)，3.82-3.74(m，1H)，3.78(s，3H)，3.66-3.56(m，4H)，3.49-3.38(m，3H)，3.11-3.03(m，1H)，3.07(s，1H)，2.98-2.94(m，1H)，2.34-2.29(m，2H).

Example 185: {3- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (2H-pyrazol-3-yl) -amine

Example 186: 4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

The preparation is carried out analogously to example 1. Yield: 75.0mg (20%, TFA salt). Ms (esi): c₂₃H₂₉BrFN₃Calculated value of molecular weight of O: 461.15, respectively; m/z found: 462.4, 464.4[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：8.35(s，1H)，7.59(s，1H)，6.91-6.80(m，3H)，5.03(d，J＝47.7，1H)，4.80-4.76(m，1H)，4.55(bs，2H)，4.13(t，5.6，2H)，3.92-3.90(m，1H)，3.68-3.71(m，1H)，3.51-3.61(m，2H)，3.37-3.41(m，2H)，3.20-3.25(m，3H)，3.09(s，3H)，2.30-2.34(m，4H)，2.09-2.20(m，3H).

Example 187: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-methylsulfanyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline

Reacting 4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ]A solution of-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (250mg, 0.54mmol) and MeSNa (42.0mg, 0.59mmol) in DMF (2ml) was heated at 80 ℃ for 3 hours and then cooled to room temperature. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried (MgSO)₄) And concentrating. The crude product was purified by reverse phase chromatography, treated with MeOH-HCl to give 27mg (9%, HCl salt). Ms (esi): c₂₄H₃₂FN₃Calculated molecular weight of OS: 429.23, respectively; m/z found: 430.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.39-8.30(m，1H)，7.48-7.44(m，1H)，7.26(d，J＝8.3，1H)，6.87-6.79(m，3H)，5.03(d，J＝47.7，1H)，4.73-4.50(m，3H)，4.14-4.12(m，2H)，3.95-3.90(m，1H)，3.76-3.74(m，1H)，3.50-3.63(m，3H)，3.44-3.41(m，2H)，3.28-3.16(m，2H)，3.11(s，3H)，2.53(s，3H)，2.33-2.21(m，4H)，2.20-2.13(m，3H).

Example 188: (5- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -pyridin-2-yl) -dimethyl-amine

Reacting 4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]A solution of-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (250mg, 0.54mmol) and diethanolamine (0.13ml, 1.35mmol) in DMF (0.5ml) was heated at 120 ℃ for 4 days. The mixture was then diluted with water and extracted with EtOAc and DCM. The combined organic layers were dried (MgSO)₄) And concentrating. The residue was diluted with MeOH (4ml) and NaCNBH₃(2 spoons) and bromocresol green (spatula tip). After 5 min, MeOH-HCl was added until discoloration. Additional MeOH-HCl was added as necessary to maintain the color change. After 5 min, the mixture was diluted with water, basified with 1N NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, over MgSO ₄Dried and concentrated. Purification by reverse phase HPLC gave 6.0mg (3%) of the product. Ms (esi): c₂₅H₃₅FN₄Calculated value of molecular weight of O: 426.28, respectively; m/z found: 4274[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：7.99(d，J＝2.5，1H)，7.26(dd，J＝8.8，2.4，1H)，6.76-6.74(m，1H)，6.66-6.64(m，2H)，6.49(d，J＝8.8，1H)，4.63-4.52(m，1H)，3.99(t，J＝6.4，3H)，3.60-3.50(m，2H)，3.01(s，6H)，2.59-2.52(m，3H)，2.52-2.41(m，4H)，2.32(s，5H)，1.91-1.85(m，5H)，1.75-1.68(m，3H).

Example 189: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-trimethylsilylethynyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline

Reacting 4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (250mg, 0.54mmol), (Ph)₃P)₂PdCl₂(9.0mg, 0.0135mmol), CuI (3mg, 0.0135mmol) and iPr₂A mixture of NH (0.9ml) was warmed to 30 ℃ and treated with (trimethylsilyl) acetylene (0.083ml, 0.59 mmol). After 4 hours, the mixture was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried (MgSO)₄) And concentrated (180mg, 69%). The crude product was used in the next step without purification. Ms (esi): c₂₈H₃₈FN₃Calculated molecular weight of OSi: 479.28, respectively; m/z found: 480.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.51(s，1H)，7.65(dd，J＝20.7，2.3，1H)，7.50(d，J＝8.0，1H)，6.87-6.82(m，2H)，6.76-6.74(m，1H)，5.14-4.98(m，1H)，4.81-4.77(m，1H)，4.63-4.59(m，3H)，4.13-4.11(m，2H)，3.91-3.87(m，1H)，3.80-3.71(m，1H)，3.59-3.52(m，3H)，3.38-3.35(m，2H)，3.21-3.17(m，2H)，3.06(s，3H)，2.32-2.25(m，4H)，2.25-2.19(m，2H)，0.24(s，9H).

Example 190: 4- (6-ethynyl-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

To (5- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy group]To a solution of-2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -pyridin-2-yl) -dimethyl-amine (150mg, 0.31mmol) in 2: 1 MeOH/DCM (1ml) was added KOH (35mg, 0.62 mmol). The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried (MgSO) ₄) And concentrated. Purification by reverse phase chromatography gave 69mg (55%, TFA salt). Ms (esi): c₂₅H₃₀FN₃Calculated value of molecular weight of O: 407.24, respectively; m/z found: 408.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.48(s，1H)，7.68(dd，J＝8.0，2.1，1H)，7.57(d，J＝9.7，1H)，6.88-6.52(m，4H)，5.03(d，J＝47.2，1H)，4.82-4.79(m，1H)，4.68-4.58(m，2H)，4.14-4.12(m，2H)，4.08-4.03(m，1H)，3.79-3.72(m，1H)，3.61-3.54(m，2H)，3.43-3.32(m，2H)，3.24-3.18(m，3H)，3.07-3.02(m，4H)，2.38-2.25(m，5H)，2.22-2.10(m，3H).

Example 191: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-thiophenyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline

As for 7- [3- (4-fluoro-piperidin-1-yl) -propoxy]Preparation of (E) -2-methyl-4- (6-methylsulfanyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline by the method described above to give 118mg (30%, TFA salt). Ms (esi): c₂₉H₃₄FN₃Calculated molecular weight of OS: 491.24, respectively; m/z found: 492.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.34(s，1H)，7.61-7.58(m，2H)，7.48-7.43(m，4H)，6.91(d，J＝8.3，1H)，6.85-6.79(m，3H)，5.03(d，J＝47.7，1H)，4.71-4.57(m，3H)，4.12(t，J＝5.6，2H)，3.91-3.88(m，1H)，3.76-3.55(m，3H)，3.40(t，J＝7.5，2H)，3.29-3.17(m，2H)，3.09(s，3H)，2.34-2.25(m，3H)，2.23-2.11(m，3H).

Example 192: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (6-imidazol-1-yl-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

In a sealed pressure tube, 4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (250mg, 0.54mmol), CuO (4.0mg, 0.054mmol), K₂CO₃A mixture of (112mg, 0.81mmol), imidazole (110mg, 1.62mmol) and pyridine (0.5ml) was heated under reflux for 18 hours and then cooled to room temperature. The mixture was filtered and concentrated, and the residue was purified by reverse phase chromatography to give 124mg (29%, TFA salt). Ms (esi): c ₂₆H₃₂FN₅Calculated value of molecular weight of O: 449.26, respectively; m/z found: 450.4[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：10.15(br s，1H)，9.54(s，1H)，8.51(s，1H)，8.33(s，1H)，8.01(d，J＝8.5，1H)，7.92(d，J＝7.6，1H)，7.70(br s，1H)，6.86-6.78(m，2H)，6.71(br s，1H)，5.03-4.85(m，1H)，4.75-4.67(m，2H)，4.53-4.39(m，2H)，4.05-4.00(m，2H)，3.61(br s，1H)，3.64-3.52(m，1H)，3.45-3.42(m，1H)，3.25-3.20(m，2H)，3.16-3.02(m，2H)，2.95(s，3H)，2.21-1.83(m，7H).

Example 193: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (6-methoxy-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Reacting 4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]A mixture of-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (250mg, 0.54mmol), NaOMe (204mg, 3.78mmol) and DMSO (0.7ml) was heated at 140 ℃ for 3 days. Purification by reverse phase chromatography gave 18mg (8%) of product. Ms (esi): c₂₄H₃₂FN₃O₂Calculated value of molecular weight of (c): : 413.25, respectively; m/z found: 414.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.03(d，J＝2.3，1H)，7.46(dd，J＝2.5，8.5，1H)，6.75(d，J＝9.4，1H)，6.67-6.62(m，3H)，4.66-4.54(m，1H)，4.09(t，J＝5.5，1H)，3.99(t，J＝6.4，2H)，3.83(s，3H)，3.64(d，J＝14.9，1H)，3.48(d，J＝14.9，1H)，2.82-2.79(m，2H)，2.59-2.56(m，3H)，2.45(t，J＝7.0，2H)，2.32(s，3H)，2.32-2.28(m，2H)，1.91-1.86(m，4H)，1.74-1.72(m，2H).

Example 194: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-pyrazol-1-yl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline

According to 7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- (6-imidazol-1-yl-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline prepared as described to give 120mg (28%, TFA salt). Ms (esi): c₂₆H₃₂FN₅Calculated value of molecular weight of O: 449.26, respectively; m/z found: 450.4[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：8.59(s，1H)，8.41(s，1H)，7.94-7.90(m，1H)，7.81(s，1H)，7.75-7.73(m，1H)，6.86-6.80(m，2H)，6.75-6.71(m，1H)，6.58-6.55(m，1H)，4.98(d，J＝47.2，1H)，4.73-7.50(m，3H)，4.02-4.00(m，2H)，3.93-3.43(m，9H)，3.29-3.22(m，2H)，3.14-2.90(m，4H)，2.24-2.20(m，1H)，2.11-1.83(m，5H).

Example 195: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- [6- (1H-imidazol-2-ylsulfanyl) -pyridin-3-yl ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Reacting 4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (200mg, 0.43mmol), 2-mercaptoimidazole (130mg, 1.30mmol), K₂CO₃A mixture of (179mg, 1.30mmol) and DMA (0.5ml) was heated at 135 ℃ for 18 hours. After cooling to room temperature, the mixture was diluted with DCM, filtered and concentrated. Purification by reverse phase chromatography gave 35mg (10%, TFA salt). Ms (esi): c₂₆H₃₂FN₅Calculated molecular weight of OS: 481.23, respectively; m/z found: 482.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.35-8.34(m，1H)，7.64(s，2H)，7.60(dd，J＝2.3，8.3，1H)，7.31(d，J＝8.3，1H)，6.86-6.77(m，3H)，5.07-4.93(m，1H)，4.77-4.73(m，1H)，4.62-4.55(m，2H)，4.11(t，J＝6.0，2H)，3.90-3.86(m，1H)，3.61-3.55(m，3H)，3.39-3.29(m，2H)，3.23-3.18(m，2H)，3.06(s，3H)，2.34-2.13(m，7H).

Example 196: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- [6- (pyrimidin-2-ylsulfanyl) -pyridin-3-yl ] -1, 2, 3, 4-tetrahydro-isoquinoline

According to 7- [3- (4-fluoro-piperidin-1-yl) -propoxy]-4- [6- (1H-imidazol-2-ylsulfanyl) -pyridin-3-yl]-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (35mg, 22%). Ms (esi): c₂₇H₃₂FN₅Calculated molecular weight of OS: 493.23, respectively; m/z found: 494.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.58-8.55(m，2H)，8.48(d，J＝2.1，1H)，7.75(d，J＝8.1，1H)，7.64(d，J＝8.3，2.4，1H)，6.74-6.64(m，2H)，4.70-4.51(m.1H)，4.24-4.16(m，1H)，4.00(t，J＝6.4，2H)，3.75(d，J＝15.0，1H)，3.45(d，J＝15.0，1H)，2.87-2.76(m，2H)，2.78-2.66(m，1H)，2.63-2.50(m，2H)，2.46(t，J＝7.0，2H)，2.33(s，3H)，2.31-2.23(m，2H)，1.94-1.79(m，4H)，1.79-1.65(m，2H).

Example 197-236 was prepared in a manner similar to that described in example 1.

Example 197: 4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 31mg (12%). Ms (esi): c ₂₅H₃₅N₃O₂Calculated value of molecular weight of (c): 409.27, respectively; m/z found: 410.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.10(d，J＝8.7，2H)，6.81(d，J＝8.7，2H)，6.70(d，J＝8.2，1H)，6.66-6.62(m，2H)，4.10-4.06(m，1H)，3.98(t，J＝6.4，2H)，3.76(s，3H)，3.56(s，2H)，2.87-2.84(m，1H)，2.51-2.48(m，1H)，2.50-2.21(m，8H)，2.44(t，J＝7.0，2H)，2.32(s，3H)，2.16(s，3H)，1.91-1.87(m，2H).

Example 198: 7- [3- (4-ethyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 85mg (28%, HCl salt). Ms (esi): c₂₆H₃₇N₃O₂Calculated value of molecular weight of (c): 423.29, respectively; m/z found: 424.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.11(d，J＝8.7，2H)，6.81(d，J＝8.7，2H)，6.71(d，J＝8.2，1H)，6.64-6.61(m，2H)，4.08-4.05(m，1H)，3.99(t，J＝6.4，1H)，3.74(s，3H)，2.85-2.82(m，1H)，2.50-2.27(m，16H)，1.90-1.83(m，2H)，0.99(t，J＝7.2，3H).

Example 199: 7- [3- (4-isopropyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 54mg (17%, HCl salt). Ms (esi): c₂₇H₃₉N₃O₂Calculated value of molecular weight of (c): 437.30, respectively; m/z found: 438.5[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.10(d，J＝8.6，2H)，6.81(d，J＝8.7，2H)，6.71(d，J＝8.3，1H)，6.64-6.61(m，2H)，4.08-4.05(m，1H)，3.99(t，J＝6.4，2H)，3.74(s，3H)，3.55(s，.2H)，2.85-2.82(m，1H)，2.59-2.54(m，1H)，2.50-2.34(m，10H，2.31(s，3H)，1.90-1.84(m，2H)，0.96(d，J＝6.5，6H).

Example 200: 4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-thiazol-2-yl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 44mg (15%). Ms (esi): c₂₇H₃₄N₄O₂Calculated value of molecular weight of S: 478.24, respectively; m/z found: 479.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.13-7.10(m，3H)，6.81(d，J＝8.7，2H)，6.72-6.69(m，2H)，6.66-6.63(m，2H)，4.08-4.05(m，1H)，4.04(t，J＝6.4，2H)，3.74(s，3H)，3.55(s，2H)，3.44-3.42(m，4H)，2.86-2.82(m，1H)，2.80-2.76(m，1H)，2.56-2.47(m，6H)，2.31(s，3H)，1.95-1.93(m，2H).

Example 201: 4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-thiophen-2-ylmethyl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 56mg (18%). Ms (esi): c₂₉H₃₇N₃O₂Calculated value of molecular weight of S: 491.26, respectively; m/z found: 479.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.32-7.30(m，1H)，7.10(d，J＝8.7，2H)，6.93-6.91(m，2H)，6.81(d，J＝8.7，2H)，6.70(d，J＝8.2，1H)，6.64-6.61(m，2H)，4.08-4.05(m，1H)，3.99(t，J＝6.4，1H)，3.74(s，3H)，3.66(s，2H)，3.55(s，2H)，2.85-2.81(m，1H)，2.50-2.40(m，10H)，2.31(s，3H)，.1.90-1.85(m，2H).

Example 202: 2- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -ethanol

Yield: 48mg (18%). Ms (esi): c₂₆H₃₇N₃O₃Calculated value of molecular weight of (c): 439.28, respectively; m/z found: 440.4[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：7.11(d，J＝8.7.2H)，6.81(d，J＝8.7，2H)，6.71(d，J＝8.2，1H)，6.64-6.61(m，2H)，4.08-4.05(m，1H)，3.99(t，J＝6.4，2H)，3.74(s，3H)，3.55-3.51(m，4H)，3.29(br s，1H)，2.85-2.82(m，1H)，2.54-2.31(m，3H)，2.31(s，3H)，1.90-1.85(m，2H).

Example 203: 2- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -phenol

Yield: 94mg (31%). Ms (esi): c₃₀H₃₇N₃O₃Calculated value of molecular weight of (c): 487.28, respectively; m/z found: 488.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.13-7.08(m，3H)，6.96-6.93(m，1H)，6.85-6.77(m，4H)，6.73-6.70(m，1H)，6.67-6.64(m，2H)，4.09-4.06(t，J＝6.4，2H)，3.74(s，3H)，3.59(s，2H)，2.90(t，J＝4.7，4H)，2.86-2.83(m，1H)，2.63-2.57(m，4H)，2.53(t，J＝7.0，2H)，2.51-2.47(m，1H)，2.31(s，3H)，1.96-1.91(m，2H).

Example 204: 4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-pyridin-4-yl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 44mg (13%, HCl salt). Ms (esi): c₂₉H₃₆N₄O₂Calculated value of molecular weight of (c): 472.28, respectively; m/z found: 473.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：8.19-8.16(m，2H)，7.11(d，J＝8.7，2H)，6.81(d，J＝8.6，2H)，6.77-6.70(m，3H)，6.65-6.63(m，2H)，4.08-4.05(m，1H)，4.03(t，J＝6.3，2H)，3.74(s，3H)，3.55(s，2H)，3.55-3.27(m，4H)，2.85-2.81(m，1H)，2.55-2.44(m，7H)，2.31(s，3H)，1.96-1.91(m，2H).

Example 205: 4- (4-methoxy-phenyl) -2-methyl-7- {3- [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl ] -propoxy } -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 89mg (27%). Ms (esi): c₃₁H₃₆F₃N₃O₂Calculated value of molecular weight of (c): 539.28, respectively; m/z found: 540.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.49(d，J＝8.9，2H)，7.11(d，J＝8.6，2H)，7.05(d，J＝8.9，2H)，6.81(d，J＝8.6，2H)，6.71(d，J＝8.2，1H)，6.66-6.64(m，2H)，4.08-4.06(m，1H)，4.03(t，J＝6.4，2H)，3.74(s，3H)，3.55(s，2H)，3.31-3.29(m，4H)，2.85-2.81(m，1H)，2.58-2.55(m，4H)，2.53(t，J＝7.0，2H)，2.50-2.47(m，1H)，2.31(s，3H)，1.97-1.92(m，2H).

Example 206: 7- [3- (4-allyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 97mg (36%).

¹H NMR (acetone-d)₆)：7.10(d，J＝8.6，2H)，6.81(d，J＝8.6，2H)，6.71(d，J＝8.2，1H)，6.64-6.61(m，2H)，5.83-5.75(m，1H)，5.169-5.12(m，1H)，5.07-5.04(m，1H)，4.08-4.05(m，1H)，3.98(t，J＝6.4，2H)，2.85-2.81(m，1H)，2.52-2.25(m，14H)，1.90-1.85(m，2H).

Example 207: 7- [3- (4- [1, 3] -dioxolan-2-ylmethyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 60mg (20%). Ms (esi): c₂₈H₃₉N₃O₄Calculated value of molecular weight of (c): 481.29, respectively; m/z found: 482.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.11(d，J＝8.6，2H)，6.81(d，J＝8.7，2H)，6.71(d，J＝8.2，1H)，6.65-6.62(m，2H)，4.88(t，J＝4.3，1H)，4.08-4.05(m，1H)，3.98(t，J＝6.4，2H)，3.89-3.84(m，2H)，3.78-3.75(m，2H)，3.74(s，3H)，3.55(s，2H)，2.85-2.82(m，1H)，2.58-2.35(m，13H)，2.31(s，3H)，1.90-1.84(m，2H).

Example 208: 4- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -benzonitrile

Yield: 104mg (34%, TFA salt). Ms (esi): c₃₁H₃₆N₄O₂Calculated value of molecular weight of (c): 496.28, respectively; m/z found: 497.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.51(d，J＝9.1，2H)，6.81(d，J＝8.7，2H)，6.71(d，J＝8.2，1H)，6.65-6.63(m，2H)，4.08-4.05(m，1H)，4.03(t，J＝6.3，2H)，3.74(s，3H)，3.55(s，2H)，3.36-3.34(m，4H)，2.85-2.81(m，1H)，2.57-2.47(m，7H)，2.31(s，3H)，1.97-1.91(m，2H).

Example 209: 7- {3- [4- (2-methoxy-ethyl) -piperazin-1-yl ] -propoxy } -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 71mg (25%, TFA salt). Ms (esi): c₂₇H₃₉N₃O₃Calculated value of molecular weight of (c): 453.30, respectively; m/z found: 454.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.11(d，J＝8.7，2H)，6.81(d，J＝8.7，2H)，6.70(d，J＝8.2，1H)，6.65-6.62(m，2H)，4.08-4.05(m，1H)，3.98(t，J＝6.4，2H)，3.75(s，3H)，3.55(s，2H)，3.43(t，J＝6.0，2H)，3.24(s，3H)，2.85-2.81(m，2H)，2.50-2.31(m，12H)，2.27(s，3H)，1.90-1.84(m，2H).

Example 210: 4- (4-methoxy-phenyl) -2-methyl-7- {3- [4- (tetrahydro-furan-2-ylmethyl) -piperazin-1-yl ] -propoxy } -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 129mg (43%, TFA salt). Ms (esi): c₂₉H₄₁N₃O₃Calculated value of molecular weight of (c): 479.31, respectively; m/z found: 480.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.10(d，J＝8.7，2H)，6.81(d，J＝8.7，2H)，6.71(d，J＝8.2，1H)，6.65-6.62(m，2H)，4.08-4.05(m，1H)，3.98(t，J＝6.4，2H)，3.94-3.87(m，1H)，3.75-3.72(m，4H)，3.62-3.59(m，1H)，3.55(s，2H)，2.85-2.82(m，1H)，2.55-2.32(m，13H)，2.31(s，3H)，1.95-1.85(m，3H)，1.81-1.72(m，2H)，1.54-1.46(m，1H).

Example 211: 4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazine-1-carboxylic acid tert-butyl ester

Yield: 80mg (26%, TFA salt). Ms (esi): c ₂₉H₄₁N₃O₄Calculated value of molecular weight of (c): 495.31, respectively; m/z found: 496.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.11(d，J＝8.7，2H)，6.81(d，J＝8.7，2H)，6.71(d，J＝8.2，1H)，6.64-6.62(m，2H)，4.08-4.05(m，1H)，4.00(t，J＝6.4，2H)，3.74(s，3H)，3.55(s，2H)，3.39-3.34(m，4H)，2.85-2.82(m，1H)，2.50-2.45(m，3H)，2.35-2.33(m，4H)，2.31(s，3H)，1.93-1.87(m，2H)，1.41(s，9H).

Example 212: 7- [3- (4-cyclopropyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 15mg (6%, TFA salt). Ms (esl): c₂₇H₃₇N₃O₂Calculated value of molecular weight of (c): 435.29, respectively; m/z found: 436.4[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.11(d，J＝8.7，2H)，6.81(d，J＝8.7，2H)，6.71(d，J＝8.2，1H)，6.65-6.62(m，2H)，4.08-4.05(m，1H)，3.99(t，J＝6.4，2H)，3.74(s，3H)，3.55(s，2H)，2.85-2.82(m，2H)，2.58-2.30(m，13H)，1.89-1.84(m，2H)，1.56-1.53(m，1H)，0.37-0.35(m，2H)，0.27-0.25(m，2H).

Example 213: 4- (4-bromo-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 2.56g (31%, TFA salt). Ms (esi): c₂₄H₃₀BrFN₂Calculated value of molecular weight of O: 460.15, respectively; m/z found: 461.4, 463.4[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：7.55(d，J＝8.2，2H)，7.23(d，J＝8.4，2H)，6.89-6.70(m，3H)，5.03(d，J＝47.6，1H)，4.72-4.54(m，3H)，4.16-4.08(m，2H)，3.93-3.86(m，1H)，3.84-3.47(m，3H)，3.42-3.38(m，2H)，3.30-3.18(m，2H)，3.07(s，3H)，2.37-2.28(m，3H)，2.25-2.13(m，3H).

Example 214: 4- (4-difluoromethoxy-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 1.63g (95%). Ms (esi): c₂₄H₃₀F₂N₂O₃Calculated value of molecular weight of (c): 432.22, respectively; m/z found: 433.4[ M + H ]]⁺。

¹H NMR (acetone-d)₆)：7.28(d，J＝8.6，2H)，7.09(d，J＝8.6，2H)，6.75(d，J＝8.3，1H)，6.70-6.66(m，2H)，4.17(t，J＝5.8，1H)，4.03(t，J＝6.4，2H)，3.66-3.57(m，4H)，3.55-3.51(m，2H)，2.88-2.82(m，1H)，2.75-2.72(m，2H)，2.61-2.56(m，1H)，2.48(t，J＝7.0，2H)，2.42-2.36(m，3H)，2.34(s，3H)，1.95-1.89(m，2H).

Example 215: 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 30.1mg (4%). Ms (esi): c₂₅H₃₄N₂O₂Calculated value of molecular weight of S: 426.23, respectively; m/z found: 427.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.3，2H)，7.10(d，J＝8.3，2H)，6.76(d，J＝8.5，1H)，6.65-6.59(m，2H)，4.19-4.13(m，1H)，4.00-3.95(m，2H)，3.83-3.78(m，1H)，3.72-3.55(m，4H)，3.27-3.21(m，1H)，3.01-2.88(m，2H)，2.77(dt，J＝2.6，11.8，1H)，2.54-2.30(m，9H)，1.98-1.75(m，3H)，0.97(d，J＝6.3，3H).

Example 216: 7- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 330.7mg (37%). Ms (esi): c₂₅H₃₂F₂N₂Calculated molecular weight of OS: 446.22, respectively; m/z found: 447.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.19(d，J＝8.4，2H)，7.10(d，J＝8.3，2H)，6.76(d，J＝8.5，1H)，6.65-6.59(m，2H)，4.19-4.13(m，1H)，3.98(t，J＝6.3，2H)，3.69(d，J＝14.9，1H)，3.58(d，J＝14.9，1H)，3.01-2.94(m，1H)，2.60-2.48(m，7H)，2.47(s，3H)，2.41(s，3H)，2.05-1.90(m，6H).

Example 217: 7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 115mg (19%). Ms (esi): c₂₅H₃₀F₄N₂Calculated molecular weight of OS: 482.20, respectively; m/z found: 483.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.53(d，J＝8.2，2H)，7.23(d，J＝8.2，2H)，6.73(d，J＝8.5，1H)，6.66-6.60(m，2H)，4.73-4.58(m，1H)，4.21(t，J＝6.5，1H)，3.97(t，J＝6.3，2H)，3.62(s，2H)，2.97-2.92(m，1H)，2.63-2.52(m，3H)，2.50(t，J＝7.2，2H)，2.38(s，3H)，2.40-2.34(m，2H)，1.97-1.82(m，6H).

Example 218: 2-methyl-7- (3-morpholin-4-yl-propoxy) -4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 341mg (58%). Ms (esi): c₂₄H₂₉F₃N₂O₂Calculated value of molecular weight of S: 466.19, respectively; m/z found: 467.4[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.51(d，J＝8.1，2H)，7.21(d，J＝8.2，2H)，6.71(d，J＝8.5，1H)，6.65-6.59(m，2H)，6.40(t，J＝6.4，1H)，3.96(t，J＝6.3，2H)，3.68(t，J＝4.6，4H)，3.60(s，2H)，2.95-2.90(m，1H)，2.57-2.51(m，1H)，2.48(t，J＝7.1，2H)，2.45-2.40(m，4H)，2.37(s，3H)，1.95-1.89(m，2H).

Example 219: 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 154mg (25%). Ms (esi): c₂₅H₃₁F₃N₂O₂Calculated value of molecular weight of S: 480.21, respectively; m/z found: 481.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.54(d，J＝8.1，2H)，7.23(d，J＝8.2，2H)，6.73(d，J＝8.5，1H)，6.66-6.60(m，2H)，4.21(t，J＝6.5，1H)，3.98-3.94(m，2H)，3.81-3.76(m，1H)，3.67-3.60(m，4H)，3.25-3.20(m，1H)，2.97-2.88(m，2H)，2.77-2.73(m，1H)，2.58-2.53(m，1H)，2.45-2.30(m，6H)，1.96-1.85(m，2H)，0.96(d，J＝6.3，3H).

Example 220: 4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 10.2mg (2%). Ms (esi): c₂₅H₃₃FN₂O₃Calculated value of molecular weight of (c): 428.25, respectively; m/z found: 429.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.3，1H)，7.02(dd，J＝12.8，2.2，1H)，6.97(d，J＝2.6，1H)，6.95-6.92(m，1H)，6.85(d，J＝8.6，1H)，6.79(dd，J＝8.3，2.7，1H)，5.63(s，1H)，5.13(s，1H)，4.05(t，J＝6.0，2H)，3.87(s，3H)，3.81(dt，J＝11.2，2.8，1H)，3.69-3.64(m，2H)，3.43(s，2H)，3.27-3.22(m，1H)，2.98-2.91(m，1H)，2.87(dt，J＝11.7，2.6，1H)，2.47-2.32(m，3H)，2.25(s，3H)，2.08(s，1H)，2.00-1.90(m，2H)，0.98(d.J＝3.6.3H).

Example 221: 4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₃FN₂O₃Calculated value of molecular weight of (c): 428.25, respectively; m/z found: 429.4[ M + H]⁺。

¹HNMR(CDCl₃)：6.92-6.84(m，3H)，6.77(d，J＝8.5，1H)，6.64(dd，J＝2.6，8.5，1H)，6.60(d，J＝2.5，1H)，4.12(t，J＝6.8，1H)，3.97(td，J＝6.1，1.8，2H)，3.86(s，3H)，3.80(dt，J＝11.2，2.8，1H)，3.68-3.55(m，3H)，3.26-3.21(m，1H)，2.97-2.89(m，2H)，2.76(dt，J＝11.8，2.7，1H)，2.54-2.48(m，1H)，2.47-2.31(m，6H)，1.98-1.84(m，2H)，1.80-1.70(m，1H)，0.97(d，J＝6.3，3H).

Example 222: 2-methyl-7- (3-piperidin-1-yl-propoxy) -4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 20.7mg (84%). Ms (esi): c₂₅H₃₁F₃N₂O₂Calculated value of molecular weight of (c): 448.23, respectively; m/z found: 450.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.27-7.68(s，1H)，7.32-7.24(m，5H)，6.62-6.57(s，1H)，4.74-4.67(m，1H)，4.66-4.54(m，1H)，4.38(t，J＝5.4，2H)，4.36-4.24(m，1H)，3.81-3.74(m，1H)，3.68(t，J＝11.1，2H)，3.30-3.11(m，3H)，3.02(s，3H)，2.75-2.61(m，2H)，2.29-2.20(m，2H)，2.08-1.86(m，5H)，1.50-1.38(m，1H).

Example 223: {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (tetrahydro-pyran-4-yl) -amine

Yield: 28mg (21%). Ms (esi): c₂₅H₃₄N₂O₃Is divided intoCalculated values of the sub-quantities: 410.26, respectively; m/z found: 411.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.6，2H)，6.83(d，J＝8.6，2H)，6.77(d，J＝8.5，1H)，6.77(m.2H)，4.19-4.13(m，1H)，4.03-3.94(m，4H)，3.79(s，3H)，3.70(d，J＝14.9，1H)，3.56(d，J＝14.8，1H)，3.44-3.35(m，2H)，3.02-2.95(m，1H)，2.83(t，J＝6.9，2H)，2.72-2.63(m，1H)，2.53-2.46(m，1H)，2.41(s，3H)，1.98-1.90(m，2H)，1.87-1.74(m，3H)，1.46-1.36(m，2H).

Example 224: cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (1-methyl-piperidin-4-yl) -amine

Yield: 5mg (5%). Ms (esi): c₂₉H₄₁N₃O₂Calculated value of molecular weight of (c): 463.32, respectively; m/z found: 464.5[ M + H ]]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.6，2H)，6.83(d，J＝8.7，2H)，6.76(d，J＝8.3，1H)，6.64-6.57(m，2H)，4.18-4.13(m，1H)，3.92(t，J＝6.3，2H)，3.79(s，3H)，3.70(d，J＝14.8，1H)，3.56(d，J＝14.9，1H)，3.02-2.96(m，1H)，2.93-2.86(m，2H)，2.81(t，J＝7.0，2H)，2.60-2.45(m，2H)，2.41(s，3H)，2.26(s，3H)，1.96-1.85(m，4H)，1.76-1.62(m，6H)，0.50-0.45(m，2H)，0.40-0.35(m，2H).

Example 225: (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 301.8mg (86%). Ms (esi): c₂₃H₃₂N₂O₃Calculated value of molecular weight of (c): 384.24, respectively; m/z found: 385.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.6，2H)，6.82(d，J＝7.8，2H)，6.76(d，J＝8.4，1H)，6.65-6.59(m，2H)，4.00(t，J＝6.2，2H)，2.79-3.75(m，3H)，3.70(d，J＝14.9，1H)，3.55(d，J＝14.9，1H)，3.50(t，J＝4.8，2H)，3.36-3.34(m，4H)，3.01-2.95(m，1H)，2.81-2.76(m，4H)，2.52-2.46(m，1H)，2.42-2.37(m，3H)，1.99-1.91(m，2H).

Example 226: 3- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propylamino } -propan-1-ol

Yield: 178mg (51%). MS, (ESI): c₂₃H₃₂N₂O₃Calculated value of molecular weight of (c): 384.24, respectively; m/z found: 385.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.4，2H)，6.82(d，J＝8.0，2H)，6.77(d，J＝8.4，1H)，6.65-6.58(m，2H)，4.19-4.13(m，1H)，3.99(t，J＝6.1，2H)，3.81-3.76(m，5H)，3.71(d，J＝14.9，1H)，3.56(d，J＝14.9，1H)，3.44-3.42(m，1H)，3.02-2.92(m，2H)，2.90-2.84(m，2H)，2.82-2.77(m，2H)，2.52-2.45(m，1H)，2.41(s，3H)，1.98-1.90(m，2H)，1.73-1.65(m，2H).

Example 227: allyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 152.3mg (45%). Ms (esi): c₂₃H₃₀N₂O₂Calculated value of molecular weight of (c): 366.23, respectively; m/z found: 367.5[ M + H]⁺。

¹H NMR(CDCl₃): 7.09(d, J ═ 8.7, 2H), 6.82(d, J ═ 8.7, 2H), 6.76(d, J ═ 8.5, 1H), 6.65-6.58(m, 2H), 5.96-5.85(m, 1H), 5.21-5.14(m, 1H), 5.11-5.06(m, 1H), 4.18-4.13(m, 1H), 4.00(t, J ═ 6.2, 2H), 3.77(s, 3H), 3.69(d, J ═ 14.8, 1H), 3.55(d, J ═ 14.8, 1H), 3.27-3.24(m, 2H), 3.00-2.94(m, 1H), 2.79(t, J ═ 6.9, 2H), 2.46(m, 2H), 2.95(m, 2H), 6.46 (s, 6H), and 5.6.6.6H).

Example 228: isobutyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 238.5mg (68%). Ms (esi): c₂₄H₃₄N₂O₂Calculated value of molecular weight of (c): 382.26, respectively; m/z found: 383.4[ M + H]⁺。

¹H NMR(CDCl₃): 7.09(d, J ═ 8.7, 2H), 6.82(d, J ═ 8.7, 2H), 6.77(d, J ═ 8.5, 1H), 6.65 to 6.58(m, 2H), 4.18 to 4.12(m, 1H), 4.00(t, J ═ 6.2, 2H), 3.78(s, 3H), 3.70(d, J ═ 14.8, 1H), 3.56(d, J ═ 14.9, 1H), 3.01 to 2.95(m, 1H), 2.77(t, J ═ 6.9, 2H), 2.52 to 2.46(m, 1H), 2.43 to 2.40(m, 5H), 1.95 (quintuple, J ═ 6.6, 2H), 1.80 to 1.70(m, 1H), 6.6, 6H).

Example 229: cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 193.8mg (58%). Ms (esi): c₂₃H₃₀N₂O₂Calculated value of molecular weight of (c): 366.23, respectively; m/z found: 367.5[ M + H]⁺。

¹H NMR(CDCl₃): 7.09(d, J ═ 8.7, 2H), 6.82(d, J ═ 8.7, 2H), 6.77(d, J ═ 8.5, 1H), 6.66-6.59(m, 2H), 4.18-4.13(m, 1H), 3.99(t, J ═ 6.2, 2H), 3.78(s, 3H), 3.79-3.76(m, 1H), 3.70(d, J ═ 14.8, 1H), 3.56(d, J ═ 14.9, 1H), 3.01-2.95(m, 1H), 2.88(t, J ═ 7.0, 2H), 2.52-2.46(m, 1H), 2.41(s, 3H), 2.16-2.10(m, 1H), 1.95 (t, J ═ 7.0, 2H), 2.45-2.34 (m, 1H), 2.41 (m, 1H), 2.6, 0, 6.45-2H).

Example 230: isopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 112.5mg (33%). Ms (esi): c₂₃H₃₂N₂O₂Calculated value of molecular weight of (c): 368.25, respectively; m/z found: 369.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.7，2H)，6.82(d，J＝8.6，2H)，6.77(d，J＝8.5，1H)，6.65-6.58(m，2H)，4.18-4.12(m，1H)，4.00(t，J＝6.1，2H)，3.78(s，3H)，3.70(d，J＝14.9，1H)，3.56(d，J＝14.9，1H)，3.01-2.95(m，1H)2.84-2.74(m, 3H), 2.52-2.46(m, 1H), 2.41(s, 3H), 1.94 (quintuple, J ═ 6.7, 2H), 1.06(d, J ═ 6.2.6H).

Example 231: {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -propyl-amine

Yield: 235.4mg (70%). Ms (esi): c₂₃H₃₂N₂O₂Calculated value of molecular weight of (c): 368.25, respectively; m/z found: 369.5[ M + H]⁺。

¹H NMR(CDCl₃): 7.09(d, J ═ 8.6, 2H), 6.82(d, J ═ 8.6, 2H), 6.77(d, J ═ 8.5, 1H), 6.65 to 6.54(m, 2H), 4.18 to 4.12(m, 1H), 4.00(t, J ═ 6.2, 2H), 3.78(s, 3H), 3.70(d, J ═ 14.9, 1H), 3.56(d.J ═ 14.8, 1H), 3.01 to 2.95(m, 1H), 2.78(t, J ═ 7.0, 2H), 2.58(t, J ═ 7.2, 2H), 2.52 to 2.46(m, 1H), 2.41(s, 3H), 1.95 (quintuple, 6, 2H), 2.92 (t, 2H), 3.52 (m, 3H).

Example 232: ethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 7.7mg (4%). Ms (esi): c₂₂H₃₀N₂O₂Calculated value of molecular weight of (c): 354.23, respectively; m/z found: 355.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.7，2H)，6.83(d，J＝8.7，2H)，6.77(d，J＝8.4，1H)，6.66-6.59(m，2H)，4.18-4.13(m, 1H), 4.01(t, J ═ 6.2, 2H), 3.79(s, 3H), 3.70(d, J ═ 14.9, 1H), 3.56(d, J ═ 14.8, 1H), 3.01-2.95(m, 1H), 2.80(t, J ═ 7.0, 2H), 2.68(q, J ═ 7.2, 2H), 2.52-2.46(m, 1H), 2.41(s, 3H), 1.98 (quintuple, J ═ 6.4, 2H), 1.12(t, J ═ 7, 1, 3H),

example 233: isopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -methyl-amine

Yield: 15mg (7%). Ms (esi): c₂₄H₃₄N₂O₂Calculated value of molecular weight of (c): 382.26, respectively; m/z found: 383.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.7，2H)，6.82(d，J＝8.7，2H)，6.76(d，J＝8.5，1H)，6.66-6.59(m，2H)，4.18-4.13(m，1H)，3.97(t，J＝6.3，2H)，3.78(s，3H)，3.70(d，J＝14.8，1H)，3.56(d，J＝14.8，1H)，3.01-2.95(m，1H)，2.86-2.78(m，1H)，2.55-2.46(m，3H)，2.41(s，3H)，2.21(s，3H)，1.94-1.86(m，2H)，0.99(d，J＝6.6，6H).

Example 234: cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -methyl-amine

Yield: 25.2mg (40%, TFA salt). Ms (esi): c₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.25, respectively; m/z found: 381.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.17-6.99(m，2H)，6.93-6.69(m，4H)，6.63(br s，1H)，4.92-4.54(m，2H)，4.17-3.99(m，3H)，3.86-3.69(m，4H)，3.60-3.21(m，2H)，3.06-2.88(m，6H)，2.75-2.20(m，4H)，1.53-1.15.(m，2H)，0.92(br s，2H).

Example 235: bicyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine

Yield: 35.4mg (32%, TFA salt). Ms (esi): c₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.25, respectively; m/z found: 381.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.14-7.04(m，2H)，6.92-6.70(m，4H)，.664(br s，1H)，4.73-4.54(m，1H)，4.18-4.00(m，3H)，3.84-3.73(m，4H)，3.59-3.32(m，3H)，3.10-2.92(m，4H)，2.62-2.53(m，2H)，2.46-2.28(m，2H)，1.40-1.28(m，4H)，0.97-0.81(m，4H).

Example 236: 7- (1-isopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester. To a solution of azetidine-1, 3-dicarboxylic acid mono-tert-butyl ester (0.50g, 2.48mmol) and TEA (0.30ml, 2.98mmol) in THF (25ml) at 0 deg.C was added isobutyl chloroformate (0.39ml, 2.98 mmol). The mixture was stirred at room temperature for 1 hour, filtered and concentrated to about half volume. Cooling the resulting solution to 0 deg.CUsing NaBH₄(188mg, 4.96mmol) and water (12 ml). After 2 hours, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with EtOAc, washed with water and brine, over MgSO ₄Drying and concentration gave 310mg (67%) of the crude product, which was used without further purification. Ms (esi): c₉H₁₇NO₃Calculated value of molecular weight of (c): 187.12, respectively; m/z found: 210.4[ M + Na ]]⁺。

¹H NMR(CDCl₃)：3.98(t，J＝8.6，2H)，3.76-3.73(m，2H)，3.68-3.66(m，2H)，2.70-2.66(m，1H)，2.03-1.99(m，1H)，1.42(s，9H).

Step 2: 3- (3-formyl-phenoxymethyl) -azetidine-1-carboxylic acid tert-butyl ester. 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (3.35g, 18.96mmol), 3-hydroxybenzaldehyde (3.47g, 28.44mmol), DEAD (4.95g, 28.44mmol), resin bound PPh₃A mixture of (9.50g, 28.44mmol) and DCM (95ml) was shaken on a shaker for 5 days. The mixture was filtered and the filtrate was concentrated. The residue was purified by FCC to give 1.35g (24%) of product.

¹H NMR(CDCl₃)：9.96(s，1H)，7.47-7.42(m，2H)，7.38-7.36(m，1H)，7.18-7.16(m，1H)，4.14(d，J＝6.6，2H)，4.10(t，J＝8.6，2H)，3.81-3.78(m，2H)，3.00-2.97(m，1H)，1.44(s，9H).

And step 3: 3- (3-methylaminomethyl-phenoxymethyl) -azetidine-1-carboxylic acid tert-butyl ester Esters. The preparation was carried out as described in example 1, step 2. Yield: 2.33g (83%). Ms (esi): c₁₇H₂₆N₂O₃Calculated value of molecular weight of (c): 306.19, respectively; m/z found: 307.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.23(t，J＝7.8，1H)，6.91-6.87(m，2H)，6.78-6.76(m，1H)，4.08-4.03(m，4H)，3.79-3.75(m，2H)，3.67(s，2H)，2.95-2.92(m，1H)，2.44(s，3H)，1.43(s，9H).

And 4, step 4: 3- [3- ({ methyl- [2- (4-methylsulfanyl-phenyl) -2-oxo-ethyl]-amino } -methyl Radical) -phenoxymethyl]-azetidine-1-carboxylic acid tert-butyl ester. The preparation was carried out as described in example 1, step 3. Ms (esi): c₂₆H₃₄N₂O₄Calculated value of molecular weight of S: 470.22, respectively; m/z found: 471.5[ M + H]⁺。

And 5: 7- (1-isopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylthio) methane Phenyl-isoquinolinium salts. The preparation was carried out as described in example 1, step 4. Yield: 1.3g (48%, 2 steps).

Step 6: the title compound was prepared according to the procedure described in example 1, step 5, the reaction being carried out in the presence of acetone. Yield: 210mg (9%, TFA salt). Ms (esi): c₂₄H₃₂N₂Calculated molecular weight of OS: 396.22, respectively; m/z found: 397.3[ M + H]⁺。

¹H NMR (acetone-d)₆)：7.24(d，J＝8.3，2H)，7.14(d，J＝8.2，2H)，6.86-6.79(m，2H)，6.67(d，J＝8.1，1H)，4.45-4.29(m，3H)，4.25-4.20(m，1H)，4.19-4.02(m，4H)，3.92-3.82(m，2H)，3.65-3.56(m，1H)，3.17-3.06(m，1H)，3.02-2.92(m，1H)，2.85(br s，3H)，2.45(s，3H)，1.11(d，J＝6.3，6H).

Example 237: 7- (1-cyclopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 2-bromo-1- (4-methylthio-phenyl) -ethanone. 1- (4-methylthio-phenyl) -ethanone (200.3g, 1.205mmol) cooled in a water bath in MeOH (720mL) was dissolved over 1 h via addition funnelAdding Br dropwise into the solution₂(61.5ml, 1.20 mmol). After the addition was complete, water was added and the mixture was stirred vigorously. Vacuum filtration afforded the desired product (285.5g, 97%) as a solid. Ms (esi): c₉H₉Molecular weight calculation for BrOS: 243.96, respectively; m/z found: 245.2, 247.2[ M + H]⁺。

¹HNMR (acetone-d)₆)：7.98(d，J＝8.7，2H)，7.40(d，J＝8.7，2H)，4.72(s，2H)，2.59(s，3H).

Step 2: 2-methylamino-1- (4-methylsulfanyl-phenyl) -ethanol. To EtOH (400ml) and 40% MeNH₂To a solution of aqueous solution (63.5ml, 816mmol) was slowly added 2-bromo-1- (4-methylsulfanyl-phenyl) -ethanone (10.08g, 40.79mmol) with vigorous stirring for 20 min. Adding NaBH in portions ₄(4.764g, 122.4 mmol). After 18 hours, the mixture was concentrated and purified by FCC to give the desired product (6.34g, 78%). Ms (esi): c₁₀H₁₅Calculated molecular weight of NOS: 197.09, respectively; m/z found: 198.1[ M + H]⁺。

¹H NMR(MeOD)：7.31(d，J＝8.2，2H)，7.26(d，J＝8.4，2H)，4.76-4.72(m，1H)，2.76-2.72(m，1H)，2.70-2.65(m，1H)，2.47(s，3H)，2.41(s，3H).

And step 3: 3- ({ [ 2-hydroxy-2- (4-methylsulfanyl-phenyl) -ethyl]-methyl-amino } -methyl) -substituted benzene Phenol and its preparation. To a mixture of 2-methylamino-1- (4-methylsulfanyl-phenyl) -ethanol (3.40g, 17.2mmol), 3-hydroxy-benzaldehyde (2.81g, 22.4mmol), acetic acid (0.99ml, 17mmol) and THF (50ml) at 0 deg.C was added NaB (OAc)₃H (8.57g, 43.1mmol), and the mixture was stirred at room temperature for 3 days. The mixture was concentrated and the residue was dissolved in 1N NaOH and extracted with DCM. The combined organic layers were dried (Na)₂SO₄) And concentrating. Purification by FCC gave the desired product (3.51g, 78%, crystalline solid). Ms (esi): c₁₇H₂₁NO₂Calculated value of molecular weight of S: 303.13, respectively; m/z found: 304.3[ M + H]⁺。

¹H NMR(MeOD)：7.24(d，J＝8.2，2H)，7.20(d，J＝8.3，2H)，7.13(t，J＝7.8，1H)，6.80(s，1H)，6.77(d，J＝7.4，1H)，6.72-6.71(m，1H)，4.78-4.74(m，1H)，3.56(d，J＝13.0，1H)，3.48(d，J＝13.0，1H)，2.66-2.61(m，1H)，2.51-2.47(m，1H)，2.41(s，3H)，2.28(s，3H).

And 4, step 4: 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-ol. Preparation was carried out in a similar manner to example 1, steps 4 and 5, heating at 50 ℃ to give the desired product (3.08g, 67%). Ms (esi): c₁₇H₁₉Calculated molecular weight of NOS: 285.12, respectively; m/z found: 286.3[ M + H]⁺。

¹H NMR(MeOD)：7.21(d，J＝6.9，2H)，7.10(d，J＝7.1，2H)，6.63(d，J＝9.1，1H)，6.58-6.54(m，2H)，4.24-4.18(m，1H)，3.82(d，J＝14.9，1H)，3.61(d，J＝14.9，1H)，3.15-3.10(m，1H)，2.57(t，J＝11.1，1H)，2.48(s，3H)，2.46(s，3H).

And 5: 3- (toluene-4-sulfonyloxymethyl) -azetidine-1-carboxylic acid tert-butyl ester . To a solution of 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (250mg, 1.3mmol) in pyridine (2.2ml) at 0 deg.C was added p-toluenesulfonyl chloride (380mg, 2.0 mmol). After 18 hours, the mixture was poured into Et₂O and 2N HCl. The mixture was re-used with Et₂O washes (3 times), the combined organic layers were washed with brine and dried (MgSO)₄) And concentrated. The crude product was purified by FCC (EtOAc/hexanes) to give 240mg (55%, yellow solid).

¹H NMR(CDCl₃)：7.78(d，J＝8.3，2H)，7.35(d，J＝8.0，2H)，4.12(d，J＝6.9，2H)，3.95(t，J＝8.6，2H)，3.59-3.54(m，2H)，2.86-2.77(m，1H)，2.45(s，3H)，1.40(s，9H).

Step 6: 3- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy Radical methyl]-nitrogenHeterocyclobutane-1-carboxylic acid tert-butyl ester. 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-ol (260mg, 0.91mmol), 3- (toluene-4-sulfonyloxymethyl) -azetidine-1-carboxylic acid tert-butyl ester (373mg, 1.09mmol), Cs₂CO₃A mixture of (889mg, 2.73mmol) and DMSO (9ml) was heated at 50 ℃ for 4 hours. The mixture was cooled to room temperature and poured into Et₂And (4) in O. The organic layer was washed with 1N NaOH and brine, MgSO₄Dried and concentrated. The crude product was purified by FCC to give 350mg (85%) of product. Ms (esi): c₂₆H₃₄N₂O₃Calculated value of molecular weight of S: 454.23, respectively; m/z found: 455.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.3，2H)，7.09(d，J＝8.3，2H)，6.76(d，J＝8.5，1H)，6.64-6.58(m，2H)，4.17-4.13(m，1H)，4.07-4.02(m，4H)，3.78-3.74(m，2H)，3.68(d，J＝14.9.1H)，3.57(d，J＝14.9，2.99-2.87(m，2H)，2.53-2.47(m，1H)，2.46(s，3H)，2.40(s，3H)，1.43(s，9H).

And 7: 7- (azetidin-3-ylmethoxy) -2-methyl-4- (4-methylthio-phenyl) - 1, 2, 3, 4-tetrahydro-isoquinolines. To 3- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl]To a solution of tert-butyl (150mg, 0.33mmol) of azetidine-1-carboxylate in DCM (2ml) was added TFA (0.5 ml). After 18 h, the mixture was concentrated and the residue was diluted with MeOH (8ml) and treated with Dowex 550A (OH) anion exchange resin. After 1.5 hours, the mixture was filtered and the filtrate was concentrated to give 125mg (100%) of product. Ms (esi): c₂₁H₂₆N₂Calculated molecular weight of OS: 354.52, respectively; m/z found: 355.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.17(d，J＝8.3，2H)，7.09(d，J＝8.3，2H)，6.77(d，J＝8.0，1H)，6.66-6.63(m，2H)，4.18-4.13(m，1H)，4.08-4.03(m，4H)，3.93-3.90(m，2H)，3.69(d，J＝14.9，1H)，3.58(d，J＝15.0，1H)，3.30-3.21(m，1H)，2.99-2.95(m，1H)，2.52-2.48(m，1H)，2.46(s，3H)，2.40(s，3H).

Step 8: to a solution of 7- (azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (40mg, 0.11mmol) in MeOH (1.1ml) was added acetic acid (0.06ml, 1.1mmol), 4 Å powdered molecular sieves (. about.25 mg), 1-ethoxycyclopropyltrimethylsilane (0.12ml, 0.66mmol) and NaCNBH₃(31mg, 0.50 mmol). After 18 hours at 50 ℃, the mixture was diluted with DCM, washed with 1N NaOH and brine, over MgSO₄Dried and concentrated. The crude product was purified by reverse phase chromatography to give 15.2mg (35%) of product. Ms (esi): c₂₄H₃₀N₂Calculated molecular weight of OS: 394.21, respectively; m/z found: 395.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.17(d，J＝8.3，2H)，7.09(d，J＝8.3，2H)，6.75(d，J＝8.3，1H)，6.64-5.59(m，2H)，4.17-4.13(m，1H)，4.02(d，J＝6.5，2H)，3.68(d，J＝14.8，1H)，3.57(d，J＝14.9，1H)，3.53-3.49(m，2H)，3.20-3.16(m，2H)，2.99-2.94(m，2H)，3.20-3.16(m，2H)，2.99-2.94(m，1H)，2.90-2.84(m，1H)，2.52-2.47(m，1H)，2.46(s，3H)，2.40(s，3H)，1.89-1.85(m，1H)，0.39-0.32(m，4H).

Example 238: 7- (1-cyclobutyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

To a solution of 7- (azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (40mg, 0.11mmol) and cyclobutanone (9.0. mu.l, 0.13mmol) in THF (0.6ml) at 0 deg.C was added NaB (OAc)₃H (35mg, 0.17mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with 1N NaOH and brine,drying (MgSO)₄) And concentrated. The residue was purified by reverse phase chromatography to give 10.1mg (22%) of product. Ms (esi): c₂₅H₃₂N₂Calculated molecular weight of OS: 408.22, respectively; m/z found: 409.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.3，2H)，7.09(d，J＝8.3，2H)，6.77(d，J＝8.5，1H)，6.59-6.64(m，2H)，4.18-4.13(m，1H)，4.00(d，J＝5.4，2H)，3.78-3.65(m，3H)，3.57(d，J＝14.9，3.40(br s，3H)，3.12-3.02(m，1H)，2.99-2.95(m，1H)，2.54-2.47(m，1H)，2.46(s，3H)，2.41(s，3H)，2.10-1.97(m，4H)，1.87-1.77(m，1H)，1.75-1.68(m，1H).

Example 239: 7- [1- (2-fluoro-ethyl) -azetidin-3-ylmethoxy]-2-methyl-4- (4-methyl) Thio-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolines

7- (azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (40mg, 0.11mmol), 1-bromo-2-fluoroethane (10. mu.l, 0.13mmol) and K₂CO₃A mixture of (46mg, 0.33mmol) acetonitrile (1ml) was heated at 50 ℃ overnight. The mixture was filtered and concentrated, and the residue was purified by reverse phase chromatography to give 12.0mg (27%) of the product. Ms (esi): c₂₃H₂₉FN₂Calculated molecular weight of OS: 400.20, respectively; m/z found: 401.4[ M + H]⁺。

¹HNMR(CDCl₃)：7.18(d，J＝8.3，2H)，7.09(d，J＝8.3，2H)，6.77(d，J＝8.5，1H)，6.65-6.60(m，2H)，4.57-4.54(m，1H)，4.48-4.44(m，1H)，4.21-4.16(m，1H)，4.03(d，J＝5.9，2H)，3.78-3.60(m，4H)，3.42-3.30(m，2H)，3.06-3.00(m，2H)，2.96-2.85(m，2H)，2.58-2.52(m，1H)，2.48-2.43(m，6H).

Example 240 (mixture), 240A (diastereomer 1) and 240B (diastereomer 2): 4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

To a solution of 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-ol (100mg, 0.37mmol) in DCM (4ml) was added 2- (1-methyl-pyrrolidin-2-yl) -ethanol (47mg, 0.38mmol), PPh₃(102mg, 0.39mmol) and DEAD (64mg, 0.37 mmol). After 3 days, the mixture was concentrated and the residue was purified by FCC to give 60mg (43%) of example 240 as a mixture of diastereomers. Ms (esi): c₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.25, respectively; m/z found: 381.4[ M + H]⁺. The diastereomer was separated (SFC HPLC) to give example 240A (first elution) and example 240B (second elution).

Ms (ESI) example 240 a: c₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.25, respectively; m/z found: 381.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.7，2H)，6.83(d，J＝8.7，2H)，6.77(d，J＝8.5，1H)，6.65-6.58(m，2H)，4.19-4.13(m，1H)，4.09-4.02(m，1H)，4.00-3.91(m，1H)，3.79(s，3H)，3.71(d，J＝14.9，1H)，3.56(d，J＝14.8，1H)，3.32-3.25(m，1H)，3.02-2.96(m，1H)，2.60-2.49(m，2H)，2.47(s，3H)，2.42(s，3H)，2.37-2.22(m，2H)，2.13-2.04(m，1H)，1.96-1.74(m，3H)，1.73-1.62(m，1H).

Ms (ESI) example 240 b: c₂₄H₃₂N₂O₂Calculated value of molecular weight of (c): 380.25, respectively; m/z found: 381.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.16-7.04(m，2H)，6.91-6.72(m，3H)，6.67-6.54(m，2H)，4.25-4.10(m，2H)，4.05-3.89(m，1H)，3.79(s，3H)，3.75-3.64(m，1H)，3.62-3.50(m，1H)，3.12-3.93(m，2H)，2.75-2.47(m，2H)，2.41(s，3H)，2.37-2.27(m，4H)，2.25-1.44(m，8H).

Example 241: 4- (3-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Preparation was carried out in analogy to the preparation described in example 78 to yield 950mg (57%) of product. Ms (esi): c₂₃H₃₀N₂O₂Calculated value of molecular weight of (c): 366.23, respectively; m/z found: 367.5[ M + H]⁺。

The compounds of example 242-250 were prepared in analogy to the procedure described in example 83.

Example 242: {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -acetonitrile

Yield: 11mg (4%, TFA salt). Ms (esi): c₂₄H₂₉N₃O₂Calculated value of molecular weight of (c): 391.23, respectively; m/z found: 392.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.13-7.01(m，2H)，6.87(d，J＝8.5，2H)，6.85-6.81(m，1H)，6.80-6.74(m，1H)，6.72-6.93(m，1H)，5.10-4.75(m，1H)，4.73-4.65(m，1H)，4.64-4.56(m，2H)，4.47-4.42(m，1H)，4.13-4.04(m，1H)，3.80(s，3H)，3.80-3.74(m，2H)，3.08-3.02(m，2H)，2.99(s，3H)，2.90-2.84(m，2H)，2.15-2.07(m，2H)，2.05-1.95(m，3H).

Example 243: 2-methyl-7- (1-methyl-piperidin-4-yloxy) -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 23.7mg (50%). Ms (esi): c₂₃H₃₀N₂Calculated molecular weight of OS: 382.21, respectively; m/z found: 383.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.19(d，J＝8.3，2H)，7.11(d，J＝8.0，2H)，6.76(d，J＝8.5，1H)，6.65-6.60(m，2H)，4.16(t，J＝7.9，1H)，3.68(d，J＝14.9，1H)，3.57(d，J＝14.9，1H)，3.00-2.96(m，1H)，2.74(s，3H)，2.41(s，3H)，2.31(s，3H)，2.10-1.95(m，2H)，1.86-1.70(m，6H).

Example 244: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- [1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 44mg (33%). Ms (esi): c₂₅H₃₁F₃N₂Calculated molecular weight of OS: 464.21, respectively; m/z found: 465.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.2，2H)，7.11(d，J＝8.2，2H)，6.76(d，J＝8.4，1H)，6.65-6.60(m，2H)，4.31-4.26(m，1H)，4.17-4.14(m，1H)，3.68(d，J＝14.8，1H)，3.57(d，J＝14.8，1H)，3.00-2.95(m，1H)，2.75-2.70(m，2H)，2.64-2.60(m，2H)，2.53-2.54(m，1H)，2.47(s，3H)，2.41(s，3H)，2.37-2.29(m，4H)，2.00-1.94(m，2H)，1.85-1.79(m，2H).

Example 245: {4- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -piperidin-1-yl } -acetonitrile.

Yield: 61mg (65%). Ms (esi): c₂₄H₂₉N₃Calculated molecular weight of OS: 407.20, respectively; m/z found: 408.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.19(d，J＝8.2，2H)，7.11(d，J＝8.2，2H)，6.76(d，J＝8.4，1H)，6.65-6.61(m，2H)，4.33-4.28(m，1H)，4.16(t，J＝7.3，1H)，3.68(d，J＝14.9，1H)，3.57(d，J＝14.9，1H)，3.54(s，2H)，3.00-2.95(m，1H)，2.84-2.79(m，2H)，2.55-2.49(m，3H)，2.47(s，3H)，2.41(s，3H)，2.04-1.98(m，2H)，1.89-1.83(m，2H).

Example 246: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- [1- (tetrahydro-pyran-4-yl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 35mg (32%). Ms (esi): c₂₇H₃₆N₂O₂Calculated value of molecular weight of S: 452.25, respectively; m/z found: 453.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.3，2H)，7.11(d，J＝8.3，2H)，6.75(d，J＝8.5，1H)，6.65-6.60(m，2H)，4.29-4.24(m，1H)，4.17-4.13(m，1H)，4.03(dd，J＝11.1，4.2，2H)，3.68(d，J＝14.9，1H)，3.57(d，J＝14.8，1H)，3.41-3.35(m，2H)，2.99-2.95(m，1H)，2.85-2.80(m，2H)，2.53-2.48(m，1H)，2.47(s，3H)，2.45-2.41(m，2H)，2.41(s，3H)，2.01-1.95(m，3H)，1.84-1.74(m，4H)，1.65-1.56(m，2H).

Example 247: 7- (1-cyclopropyl-piperidin-4-yloxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 25mg (28%). Ms (esi): c₂₅H₃₂N₂Calculated molecular weight of OS: 408.22, respectively; m/z found: 409.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.18(d，J＝8.3，2H)，7.11(d，J＝8.3，2H)，6.75(d，J＝8.4，1H)，6.66-6.61(m，2H)，4.29-4.24(m，1H)，4.17-4.14(m，1H)，3.68(d，J＝14.8，1H)，3.57(d，J＝14.8，1H)，3.00-2.95(m，1H)，2.93-2.86(m，2H)，2.53-2.49(m，2H)，2.64(s，3H)，2.41(s，3H)，2.02-1.90(m，3H)，1.80-1.72(m，2H)，1.64-1.60(m，1H)，0.48-0.40(m，4H).

Example 248: 7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 28.2mg (21%). Ms (esi): c₂₇H₃₆N₂O₂Calculated value of molecular weight of (c): 420.28, respectively; m/z found: 421.5[ M + H]⁺。

Example 249: 7- (1-cyclopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 330mg (71%). Ms (esi): c₂₆H₃₄N₂O₂Calculated value of molecular weight of (c): 406.26, respectively; m/z found: 407.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.7，2H)，6.82(d，J＝8.7，2H)，6.76(d，J＝8.5，1H)，6.64-6.57(m，2H)，4.18-4.13(m，1H)，3.79(s，3H)，3.76-3.67(m，2H)，3.59-3.53(m，1H)，3.11-3.04(m，2H)，3.01-2.95(m，1H)，2.52-2.46(m，1H)，2.41(s，3H)，2.23-2.15(m，2H)，1.85-1.74(m，4H)，1.61-1.54(m，1H)，1.38-1.25(m，2H)，0.47-0.40(m，4H).

Example 250: 1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -2-methyl-propan-2-ol

Yield: 13mg (7%, TFA salt). Ms (esi): c₂₇H₃₈N₂O₃Calculated value of molecular weight of (c): 438.29, respectively; m/z found: 439.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.22-7.06(m，2H)，6.98-6.69(m，5H)，4.64-4.38(m，2H)，4.01-3.68(m，7H)，3.53-2.93(m，9H)，2.27-1.95(m，3H)，1.92-1.74(m，2H)，1.35(br s，7H).

Example 251: 4- (4-methoxy-phenyl) -2-methyl-7- (4-methyl-morpholin-2-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: 2- [4- (4-methoxy-phenyl) -2-methyl-1.2, 3, 4-tetrahydro-isoquinolin-7-yloxy Radical methyl]-morpholine-4-carboxylic acid tert-butyl ester. To a solution of 4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-ol (680.0mg, 2.52mmol) in DCM (25ml) was added tert-butyl 2-hydroxymethyl-morpholine-4-carboxylate (564mg, 2.60mmol), PPh ₃(690mg, 2.63mmol) and DEAD (439mg, 2.52 mmol). After 3 days, the mixture was concentrated. Purification by FCC gave 550mg (47%) of the product as a mixture of diastereomers. Ms (esi): c₂₇H₃₆N₂O₅Calculated value of molecular weight of (c): 468.26, respectively; m/z found: 469.4[ M + H]⁺。

Step 2: 4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2-ylmethoxy) -1, 2, 3, 4- Tetrahydro-isoquinolines. Prepared as described in example 237, step 7 to give 550mg (47%) of the product as a mixture of diastereomers. Ms (esi): c₂₂H₂₈N₂O₃Calculated value of molecular weight of (c): 368.21, respectively; m/z found: 369.4[ M + H]⁺。

Step 3: prepared as described for 7- (1-cyclobutyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline to give 14mg (20%) of the product as a mixture of diastereomers. Ms (esi): c₂₃H₃₀N₂O₃Calculated value of molecular weight of (c): 382.23, respectively; m/z found: 383.4[ M + H]⁺。

Example 252: 4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2S-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared in analogy to the procedure described in example 251, steps 1 and 2, using (S) -2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester. Yield: 271.6mg (82%). Ms (esi): c ₂₂H₂₈N₂O₃Calculated value of molecular weight of (c): 368.21, respectively; m/z found: 369.4[ M + H]⁺。

Example 253: 4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2R-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared in analogy to the procedure described for example 251, using (R) -2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester. Yield: 302mg (100%). Ms (esi): c₂₂H₂₈N₂O₃Calculated value of molecular weight of (c): 368.21, respectively; m/z found: 369.3[ M + H]⁺。

The compound of example 254-270 was prepared in analogy to the procedure described in example 251.

Example 254: 7- (4-isopropyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 20mg (25%). Ms (esi): c₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.5[ M + H]⁺。

Example 255: 7- (4-isopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 30mg (31%) as a diastereomer mixture. Ms (esi): c₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.4[ M + H]⁺。

Example 256 (mixture), 256A (diastereomer 1) and 256B (diastereomer 2): 7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.4[ M + H]⁺. Separation of diastereomers by SFC HPLC gave example 256A (first elution) and example 256B (second elution).

Example 257: 7- (4-Ethyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 40mg (52%) as a diastereomer mixture. Ms (esi): c₂₄H₃₂N₂O₃Calculated value of molecular weight of (c): 396.24, respectively; m/z found: 397.4[ M + H]⁺。

Example 258: 7- [4- (2-fluoro-ethyl) -morpholin-2-ylmethoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 71mg (60%) as a diastereomer mixture. Ms (esi): c₂₄H₃₁FN₂O₃Calculated value of molecular weight of (c): 414.23, respectively; m/z found: 415.4[ M + H]⁺。

Example 259: 7- (4-cyclopropyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 63mg (53%) as a diastereomer mixture. Ms (esi): c₂₅H₃₂N₂O₃Calculated value of molecular weight of (c): 408.24, respectively; m/z found: 409.4[ M + H]⁺。

Example 260 (mixture), 260A (diastereomer 1) and 260B (diastereomer 2): 7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Example 260. Yield: 65mg (33%) as a diastereomer mixture. Ms (esi): c₂₅H₃₂N₂O₃Calculated value of molecular weight of (c): 408.24, respectively; m/z found: 409.4[ M + H]⁺。

The diastereomer was separated (SFC HPLC) to give example 260A (first elution) and example 260B (second elution).

Example 261 (mixture), 261A (diastereomer 1) and 261B (diastereomer 2): 7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Example 261. Yield: 150mg (68%) as a diastereomer mixture. Ms (esi): c₂₅H₃₂N₂O₃Calculated value of molecular weight of (c): 408.24, respectively; m/z found: 409.4[ M + H]⁺。

The diastereomer was separated (SFC HPLC) to give example 261A (first elution) and example 261B (second elution).

Example 262: 7- (4-isopropyl-morpholin-2-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 83mg (75%) as a diastereomer mixture. Ms (esi): c₂₅H₃₄N₂O₂Calculated value of molecular weight of S: 426.23, respectively; m/z found: 427.4[ M + H]⁺。

Example 263: 7- (4-cyclopropyl-morpholin-2-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 15mg (13%) as a diastereomer mixture. Ms (esi): c ₂₅H₃₂N₂O₂Calculated value of molecular weight of S: 424.22, respectively; m/z found: 425.3[ M + H]⁺。

Example 264: 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (morpholin-2-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 200mg (84%) as a diastereomer mixture. Ms (esi): c₂₂H₂₈N₂O₂Calculated value of molecular weight of S: 384.19, respectively; m/z found: 385.4[ M + H]⁺。

The compound of example 265-270 was prepared in analogy to the procedure described in example 1.

Example 265: 4- (4-methoxy-phenyl) -2, 6-dimethyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 40mg (10%). Ms (esi): c₂₆H₃₆N₂O₂Calculated value of molecular weight of (c): 408.28, respectively; m/z found: 409.5[ M + H]⁺。

¹H NMR(CDCl₃): 7.10(d, J ═ 8.7, 2H), 6.83(d, J ═ 8.7, 2H), 6.61(s, 1H), 6.50(s, 1H), 4.14 to 4.08(m, 1H), 3.98(t, J ═ 6.2, 2H), 3.79(s, 3H), 3.66(d, J ═ 14.7, 1H), 3.56(d, J ═ 14.6, 1H), 2.98 to 2.91(m, 1H), 2.52 to 2.47(m, 3H), 2.44 to 2.38(m, 7H), 2.05(s, 3H), 2.02 to 1.95(m, 2H), 1.61 (quintuple peak), 2.7 (quintuple peak)，J＝5.7，4H)，1.48-1.40(m，2H).

Example 266: 4- (4-methoxy-phenyl) -2, 6-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 200mg (36%). Ms (esi): c ₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.10(d，J＝8.7，2H)，6.83(d，J＝8.8，2H)，6.62(s，1H)，6.50(s，1H)，4.14-4.08(m，1H)，4.00(t，J＝6.2，2H)，3.80(s，3H)，3.75-3.71(m，4H)，3.66(d，J＝14.6，1H)，3.56(d，J＝14.6，1H)，2.98-2.92(m，1H)，2.56-2.51(m，3H)，2.51-2.45(m，4H)，2.40(s，3H)，2.05(s，3H)，2.021.94(m，2H).

Example 267: 4- (3-fluoro-4-methoxy-phenyl) -2, 6-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 79.9mg (12%). Ms (esi): c₂₅H₃₃FN₂O₃Calculated value of molecular weight of (c): 428.25, respectively; m/z found: 429.5[ M + H]⁺。

¹H NMR(CDCl₃)：6.94(m，3H)，6.62(s，1H)，6.50(s，1H)，4.10-4.04(m，1H)，4.00(t，J＝6.2，2H)，3.87(s，3H)，3.74(t，J＝4.7，4H)，3.60(br s，2H)，2.94-2.89(m，1H)，2.57-2.50(m，3H)，2.50-2.45(m，4H)，2.40(s，3H)，2.06(s，3H)，2.02-1.94(m，2H).

Example 268: 4- (3-fluoro-4-methoxy-phenyl) -2, 8-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 111mg (3%, 3 steps). Ms (esi): c₂₅H₃₃FN₂O₃Calculated value of molecular weight of (c): 428.25, respectively; m/z found: 429.4[ M + H]⁺。

¹H NMR(CDCl₃)：6.93-6.84(m，3H)，6.69-6.62(m，2H)，4.16-4.18(m，1H)，3.98(t，J＝6.3，2H)，3.87(s，3H)，3.73(t，J＝4.6，4H)，3.64(d，J＝15.3，1H)，3.49(d，J＝15.3，1H)，2.94-2.88(m，1H)，2.57-2.51(m，3H)，2.50-2.44(m，6H)，2.12(s，3H)，2.01-1.93(m，2H)，1.37-1.25(m，1H).

Example 269: 4- (4-methoxy-phenyl) -2, 8-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 8.5mg (2%). Ms (esi): c₂₅H₃₄N₂O₃Calculated value of molecular weight of (c): 410.26, respectively; m/z found: 411.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.09(d，J＝8.7，2H)，6.82(d，J＝8.7，2H)，6.66(q，J＝8.6，2H)，4.20-4.14(m，1H)，3.97(t，J＝6.2，2H)，3.79(s，3H)，3.74-3.69(m，5H)，3.45(d，J＝15.3，1H)，2.98-2.92(m，1H)，2.57-2.44(m，10H)，2.12(s，3H)，2.01-1.92(m，2H).

Example 270: 2, 6-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline

Yield: 25mg (8%). Ms (esi): c₂₆H₃₆N₂Calculated molecular weight of OS: 424.25, respectively; m/z found: 425.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.19(d，J＝8.4，2H)，7.11(d，J＝8.3，2H)，6.60(s，1H)，6.50(s，1H)，4.15-4.08(m，1H)，3.98(t，J＝6.2，2H)，3.61(q，J＝15.7，2H)，2.97-2.91(m，1H)，2.53-2.36(m，13H)，2.05(s，3H)，2.04-1.95(m，2H)，1.64-1.56(m，4H)，1.49-1.40(m，2H).

Example 271: 7- (4-piperidin-1-yl-but-1-ynyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: (4-bromo-phenyl) -pyridin-3-yl-acetonitrile . A solution of (4-bromo-phenyl) -acetonitrile (1.38g, 7.04mmol) in THF (30ml) was treated with NaH (60% oil dispersion; 0.41g, 10.7 mmol). The mixture was heated at 60 ℃ for 20 minutes, then treated with 3-fluoropyridine (0.44ml, 4.99mmol) and heated at 65 ℃ for 16 hours. The mixture was cooled, concentrated, and diluted with saturated NaHCO₃Dilute the aqueous solution and extract with EtOAc. The combined organic layers were concentrated and the residue was purified by FCC (EtOAc/hexanes) to give 0.53g (39%). Ms (esi): c₁₃H₉BrN₂Calculated value of molecular weight of (c): 271.99, respectively; m/z found: 273.3, 275.3[ M + H]⁺。

¹H NMR(CDCl₃)：8.63-8.61(m，2H)，7.68-7.65(m，1H)，7.54(d，J＝8.6，2H)，7.23(d，J＝8.3，2H)，5.14(s，1H).

Step 2: 2- (4-bromo-phenyl) -2-pyridin-3-yl-ethylamine. A solution of (4-bromo-phenyl) -pyridin-3-yl-acetonitrile (0.50g, 1.83mmol) in THF (5ml) was treated with NaBH₄(0.166g, 4.38mmol) in THF (10 ml). The mixture is cooled to 0 ℃ and I is added₂(0.78g) in THF (5 ml). After 3 hours at 65 ℃, the mixture was cooled to room temperature and MeOH (5ml) was added dropwise. After 1 hour, the mixture was diluted with 20% KOH and extracted with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. The residue was treated with HCl/MeOH and the resulting precipitate was Et₂And O washing. The precipitate was purified by FCC to give the title compound (0.191g, 38%). Ms (esi): c₁₃H₁₃BrN₂Calculated value of molecular weight of (c): 277.16, respectively; m/z found: 277.3, 279.3[ M + H ]⁺。

¹HNMR(CDCl₃)：8.53(d，2.3，1H)，8.49(dd，J＝4.8，1.7，1H)，7.52-7.49(m，1H)，7.46(d，J＝8.5，2H)，7.26-7.23(m，1H)，7.13(d，J＝8.3，2H)，3.98(t，J＝7.6，1H)，3.33(dd，J＝7.5，1.4，2H).

And step 3: [2- (4-bromo-phenyl) -2-pyridin-3-yl-ethyl]-carbamic acid methyl ester. A solution of 2- (4-bromo-phenyl) -2-pyridin-3-yl-ethylamine (0.178g, 0.642mmol) and TEA (0.279ml, 1.94mmol) in DCM (2ml) was treated with methyl chloroformate (0.060ml, 0.777 mmol). After 2 hours, the mixture was diluted with water and extracted with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. Purification by FCC gave the title compound (0.148g, 69%). Ms (esi): c₁₅H₁₅BrN₂O₂Calculated value of molecular weight of (c): 335.20, respectively; m/z found: 337.30, 335.30[ M + H ]]⁺。

¹H NMR(CDCl₃)：8.47(d，J＝2.3，1H)，8.45(dd，J＝4.9，1.6，2H)，7.53-7.49(m，1H)，7.48(d，J＝8.6，2H)，7.25-7.21(m，1H)，7.10(d，J＝8.4，2H)，5.20(m，1H)，4.21(m，1H)，3.62(s，3H).

And 4, step 4: 7-bromo-4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline. Reacting [2- (4-bromo-phenyl) -2-pyridin-3-yl-ethyl]A mixture of methyl carbamate (0.148g, 0.441mmol), paraformaldehyde (0.040mg) and concentrated HCl (2ml) was stirred at room temperature for 22 hours, then at 35 ℃ for 4 hours. The mixture was cooled to room temperature and saturated NaHCO was used₃The aqueous solution was neutralized and extracted with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. Purification by FCC gave methyl 7-bromo-4-pyridin-3-yl-3, 4-dihydro-1H-isoquinoline-2-carboxylate (0.150g), which was diluted with 6N HCl, heated at 80 ℃ for 14 hours and then at 105 ℃ for 4 days. The mixture was cooled to room temperature, neutralized with 20% KOH, and saturated NaHCO ₃Dilute the aqueous solution and extract with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. The residue was purified by FCC to give an oil, which was diluted with DCM and washed with HCl/Et₂And (4) O treatment. Trituration with hexanes and concentration gave the title compound (0.845g, 61%, HCl salt). Ms (esi): c₁₄H₁₃BrN₂Calculated value of molecular weight of (c): 289.17, respectively; m/z found: 291.3, 289.3[ M + H ]]⁺。

¹H NMR(CDCl₃)：8.49(dd，J＝4.8，1.8，1H)，8.44(d，J＝1.9，1H)，7.39-7.32(m，1H)，7.29-7.19(m，3H)，6.74(d，J＝8.2，1H)，4.19-4.01(m，3H)，3.30(dd，J＝12.9，8.6，1H)，3.05(dd，J＝12.9，6.2，1H).

Step 5: 7-bromo-4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline hydrochloride (0.070g, 0.214mmol) and Et₂NH (1ml) solution in DMF (0.3ml) pH₃P (0.011g, 0.042mmol), CuI (0.0055g, 0.029mmol), 1-but-3-ynyl-piperidine (0.060ml) and dichlorobis (triphenylphosphine) palladium (II) (0.0077g, 0.011 mmol). The mixture was heated at 128 ℃ for 1 hour, cooled to room temperature and treated with Et₂O dilution and filtration. Concentrating the filtrate, purifying with FCC to obtainTo the title compound (0.0487g, 66%). Ms (esi): c₂₃H₂₇N₃Calculated value of molecular weight of (c): 345.48, respectively; m/z found: 346.50[ M + H]⁺。

¹H NMR(CDCl₃)：8.48(dd，J＝4.8，1.7，1H)，8.44(d，J＝1.8，1H)，7.37-7.33(m，1H)，7.22-7.18(m，1H)，7.16-7.12(m，2H)，6.77(d，J＝8.1，1H)，4.15-4.00(m，3H)，3.40(dd，J＝12.7，5.3，1H)，3.05(dd，J＝12.8，6.8，1H)，2.70-2.35(m，8H)，1.62-1.40(m，6H).

With 2N HCl/Et₂O treated and concentrated with DCM/hexane to its HCl salt.

Example 272: 7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline

At H₂A solution of 7- (4-piperidin-1-yl-but-1-ynyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline dihydrochloride (0.030g, 0.072mmol) in MeOH (2ml) was treated with Pd/BaSO (1 atm) ₄(-20 mg) treated and stirred for 1 hour. 5% Pd/C (. about.25 mg) was added and the mixture was in H₂Stirring was continued for an additional 1 hour (1 atmosphere). The mixture was filtered and concentrated. The residue was washed with 2N HCl/Et₂O dilution and concentration gave the title compound (0.025g, 83%, HCl salt). Ms (esi): c₂₃H₃₁N₃Calculated value of molecular weight of (c): 349.51, respectively; m/z found: 350.50[ M + H]⁺。

¹HNMR(MeOD)：8.71(m，2H)，8.11(d，J＝8.0，1h)，7.78(m，1H)，7.23(s，1H)，7.16(dd，J＝8.3，1.2，1H)，6.82(d，J＝8.0，1H)，4.78(dd，J＝10.3，6.5，1H)，4.61(d，J＝15.9，1H)，4.47(d，J＝15.8，1H)，3.86(dd，J＝12.3，6.2，1H)，3.60-3.50(m，4H)，3.15-3.05(m，2H)，2.95-2.85(m，2H)，2.00-1.40(m，11H).

Example 273: 2-methyl-7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline

7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline dihydrochloride (0.020mg, 0.047mmol) was diluted with saturated NaHCO₃The aqueous solution was diluted and the free base was extracted with DCM. The organic layer was collected and dried (Na)₂SO₄) And concentrated. The resulting oil was diluted with MeOH (3ml) and treated with paraformaldehyde (0.044 g). The mixture was heated at reflux for 45 minutes, cooled to room temperature and then Pd (OH)₂(about 20 mg). At H₂After 3 days (1 atm), the mixture was filtered and concentrated. By preparative TLC (2M NH)₃MeOH/DCM) gave the title compound (0.008g, 47%). Ms (esi): c₂₄H₃₃N₃Calculated value of molecular weight of (c): 363.54, respectively; m/z found: 364.55[ M + H]⁺。

¹H NMR(CDCl₃)：8.52(d，J＝1.9，1H)，8.47(dd，J＝4.9，1.6，1H)，7.48(ddd，J＝7.8，2.0，2.0，1H)，7.19(ddd，J＝8.0，4.9，0.8，1H)，6.92-6.80(m，2H)，6.74(d，J＝8.4，1H)，4.24-4.19(m，1H)，3.65(s，2H)，2.96(dd，J＝11.5，5.5，1H)，2.63-2.54(m，3H)，2.41(s，3H)，2.39-2.26(m，6H)，1.63-1.38(m，10H).

Example 274: 7- [4- (4, 4-difluoro-piperidin-1-yl) -but-1-ynyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Step 1: (3-bromo-benzyl) -methyl-amine. The title compound is prepared using procedures analogous to those described for 3- (3-methylaminomethyl-phenoxy) -propan-1-ol.

Step 2: 2- [ (3-bromo-benzyl-methyl-amino)]-1- (4-methoxy-phenyl) -ethanone. With an analogue of 2- { [3- (3-hydroxy-propoxy) -benzyl]-methyl-amino } -1- (4-methoxy-phenyl) -ethanone the procedure described to prepare the title compound.

And step 3: 2- [ (3-bromo-benzyl) -methyl-amino]-1- (4-methoxy-phenyl) -ethanol. Reacting 2- [ (3-bromo-benzyl) -methyl-amino at 0 deg.C]A solution of (E) -1- (4-methoxy-phenyl) -ethanone (4.5g, 13mmol) in MeOH (65ml) was treated with NaBH in 4 portions₄(1.0g, 27 mmol). The mixture was allowed to warm to room temperature. After 16 h, the mixture was diluted with water and extracted with DCM (4 times). The combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated to give the crude product (4 g).

And 4, step 4: 7-bromo-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline. Reacting 2- [ (3-bromo-benzyl) -methyl-amino at 0 deg.C]A solution of (E) -1- (4-methoxy-phenyl) -ethanol in DCM (230ml) was treated with MSA (7.5 ml). After 5 min, the mixture was basified with 2N NaOH, diluted with water and extracted with DCM (3 × 100 ml). The combined organic layers were washed with brine and dried (Na) ₂SO₄) And concentrated to give an oil which was purified by FCC (EtOAc/hexanes) and reverse phase HPLC to give the desired product (1.1g, 29%). Ms (esi): c₁₇H₁₈Molecular weight calculation of BrNO: 331.06; m/z found: 332.3[ M + H]⁺。

¹H NMR(MeOD)：7.48(d，J＝1.8，1H)，7.38(dd，J＝8.3，1.8，1H)，7.17(d，J＝8.8，2H)，6.93(d，J＝8.8，2H)，6.83(br d，J＝8.3，1H)，4.57-4.56，m，2H)，4.49(dd，J＝11.4，6.0，1H)，3.82-3.78(m，1H)，3.79(s，3H)，3.56-3.42(m，1H)，3.06(s，3H).

And 5: 4- [4- (4-methoxy-phenyl)) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl]- But-3-yn-1-ol. 7-bromo-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (95.0mg, 0.29mmol), but-3-yn-1-ol (40mg, 0.57mmol), Ph in a high pressure reaction vessel₃A mixture of P (13.4mg, 0.05mmol), CuI (2.7mg, 0.10mmol) and dichlorobis (triphenylphosphine) palladium (II) (10mg, 0.01mmol) in DMF (0.5ml) and Et₂NH (2.5 ml). The mixture was heated at 125 ℃ for 30 min, then cooled to room temperature and treated with Et₂Dilution with O, filtration through a pad of Celite, and Et₂And O washing. The filtrate was taken up with water (2 times), saturated NaHCO₃Washed with aqueous solution and brine, dried (Na)₂SO₄) And concentrated to give a brown residue, which was purified by FCC (EtOAc/hexanes) to give the desired product (39mg, 42%). Ms (esi): c₂₁H₂₃NO₂Calculated value of molecular weight of (c): 321.17, respectively; m/z found: 322.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.21-7.08m，4H，6.91-6.81(m，3H)，4.28-4.20(m，1H)，3.86-3.80(m，5H)，3.76(d，J＝14.5Hz，1H)，3.62(d，J＝14.9Hz，1H)，3.09-3.01(m，1H)，2.70(t，J＝6.3，2H)，2.60-2.52(m，1H)，2.47(s，3H)，2.17-1.98(m，1H).

Step 6: methanesulfonic acid 4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline -7-yl]-but-3-ynyl ester. Reacting 4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl]A solution of-but-3-yn-1-ol (39mg, 0.12mmol) and TEA (19. mu.l, 13mmol) in DCM (1.2ml) was treated with MsCl (10. mu.l, 0.13 mmol). After 3 days, MsCl (1.1 equiv) was added. After 1 hour, the mixture was diluted with brine and extracted with DCM. The organic layer was dried (Na)₂SO₄) And concentrated. The residue was purified by FCC (EtOAc/hexanes) to give the desired product (42mg, 87%). Ms (esi): c₂₂H₂₅NO₄Calculated value of molecular weight of S: 399.15, respectively; m/z found: 400.4[ M + H]⁺。

¹H NMR(CDCl₃)：7.08-7.05(m，1H)，7.04-6.98(m，3H)，6.78-6.72(m，3H)4.30(t，J＝6.8Hz，2H)，4.15-4.09(m，1H)，3.71(s，3H)，3.65(d，J＝14.9Hz，1H)，3.48(d，J＝15.1Hz，1H)，2.99(s，3H)，2.96-2.90(m，1H)，2.80(t，J＝6.9Hz，2H)，2.48-2.40(m，1H)，2.35(s，3H).

Step 7: methanesulfonic acid 4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl]A solution of-but-3-ynyl ester (42mg, 0.11mmol) and TEA (36.7. mu.l) in EtOH (2ml) was treated with 4, 4-difluoropiperidine hydrochloride (25mg, 0.16 mmol). After 18 hours, the mixture was heated to 50 ℃. After 2 hours, the mixture was heated to 75 ℃. After 2 days, the mixture was cooled to room temperature, diluted with water and extracted with DCM. The organic layer was washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified by reverse phase HPLC to give the desired product (13mg, 29%, TFA salt). Ms (esi): c₂₆H₃₀N₂F₂Calculated value of molecular weight of O: 424.23, respectively; m/z found: 425.5[ M + H ]⁺。

¹H NMR(CDCl₃)：7.15-7.07(m，2H)，7.03-6.93(m，2H)，6.85-6.72(m，3H)，4.69-4.43(br m，2H)，4.08-3.91(br m，1H)，3.73(s，3H)，3.20(t，J＝6.6，3H)，2.92-2.77(m，10H)，2.44-2.14(br m，4H).

The compounds of example 275-279 were prepared in analogy to the procedure described for example 274.

Example 275: 4- (4-methoxy-phenyl) -2-methyl-7- (4-piperidin-1-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₆H₃₂N₂Calculated value of molecular weight of O: 388.3, respectively; m/z found: 389.5[ M + H]⁺。

¹H NMR(MeOD)：7.35-7.27(m，2H)，7.18-7.14(m，2H)，6.96-6.88(m，3H)，4.63-4.45(m，3H)，3.86-3.76(m，1H)，3.79(s，3H)，3.66-3.58(m，2H)，3.55-3.41(m，1H)，3.37(dd，J＝7.3，7.1，3H)，3.06(s，3H)，3.05-2.98(m，2H)，2.96(dd，J＝7.3，7.3，2H)，2.02-1.89(m，2H)，1.80-1.71(m，3H)，1.60-1.44(m，1H).

Example 276: 4- (4-methoxy-phenyl) -2-methyl-7- (4-morpholin-4-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₀N₂O₂Calculated value of molecular weight of (c): 390.2; m/z found: 391.5[ M + H]⁺。

¹H NMR(MeOD)：7.34-7.33(m，1H)，7.30-7.28(m，1H)，7.16-7.14(m，2H)，6.96-6.92(m，2H)，6.89-6.87(m，1H)，4.63-4.46(m，3H)，4.16-3.93(m，2H)，3.88-3.72(m，3H)，3.79(s，3H)，3.69-3.49(m，2H)，3.44(dd，J＝7.3，7.1，3H)，3.29-3.16(m，2H)，3.06(s，3H)，2.99(dd，J＝7.3，7.2，2H).

Example 277: 4- (4-methoxy-phenyl) -2-methyl-7- (4-thiomorpholin-4-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₀N₂Calculated molecular weight of OS: 406.2; m/z found: 407.5[ M + H]⁺。

¹H NMR(MeOD)：7.36-7.22(m，2H)，7.19-7.08(m，2H)，6.96-6.81(m，3H)，4.62-4.43(m，3H)，3.86-3.72(m，5H)，3.61-3.36(m，1H)，3.33-3.23(m，5H)，3.11-2.85(m，9H).

Example 278: 7- [4- (4-isopropyl-piperazin-1-yl) -but-1-ynyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₈H₃₇N₃Calculated value of molecular weight of O: 431.3, respectively; m/z found: 432.5[ M + H]⁺。

¹H NMR(MeOD)：7.32-7.21(m，2H)，7.19-7.11(m，2H)，6.97-6.80(m，3H)，4.61-4.44(m，3H)，3.85-3.76(m，1H)，3.79(s，3H)，3.58-3.34(m，6H)，3.33-3.27(m，2H)，3.10-3.02(m，1H)，3.06(s，3H)，3.00-2.89(m，3H)，2.79-2.70(m，2H)，1.36(d，J＝6.6，6H).

Example 279: 4- (4-fluoro-phenyl) -2-methyl-7- (4-piperidin-1-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₂₉FN₂Calculated value of molecular weight of (c): 376.2, respectively; m/z found: 377.5[ M + H]⁺。

¹H NMR(MeOD)：7.37-7.33(m，1H)，7.32-7.23(m，3H)，7.13(dd，J＝8.8，8.6，2H)，6.93-6.83(m，1H)，4.66-4.49(m，3H)，3.84(dd，J＝11.4，5.5，1H)，3.66-3.47(m，2H)，3.37(dd，J＝7.3，7.3，2H)，3.07(s，3H)，3.04-3.00(m，2H)，2.96(dd，J＝7.3，7.3，2H)，2.03-1.91(m，2H)，1.90-1.70(m，4H)，1.59-1.46(m，1H)

Example 280: 7- [4- (4, 4-difluoro-piperidin-1-yl) -butyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

Reacting 7- [4- (4, 4-difluoro-piperidin-1-yl) -but-1-ynyl]A solution of (E) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (11mg, 0.02mmol) in MeOH (1.0ml) and EtOH (0.5ml) was treated with Pd/BaSO₄(10mg) treatment. System charge N₂Evacuation and recharge H₂(2 times). At H₂After 2 hours (1 atmosphere) the mixture was filtered through a pad of celite, washing with MeOH. The filtrate was concentrated and the residue was purified by FCC to give the title compound (3.1mg, 43%). Ms (esi): c₂₆H₃₄F₂N₂Calculated value of molecular weight of O: 428.26, respectively; m/z found: 429.5[ M + H]⁺。

¹H NMR(CDCl₃)：7.04(d，J＝8.8，2H)，6.86-6.79(m，2H)，6.77(d，J＝8.8，2H)，6.71(d，J＝7.6，1H)，4.24-4.16(m，1H)，3.76-3.70(m，4H)，3.65-3.55(m，1H)，3.07-2.96(m，1H)，2.59-2.35(m，9H)，2.38-2.25(m，2H)，2.03-1.83(m，4H)，1.62-1.35(m，6H).

Example 281: 4- (4-methoxy-phenyl) -2-methyl-7- (4-morpholin-4-yl-butyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₄N₂O₂Calculated value of molecular weight of (c): 394.3, respectively; m/z found: 395.5[ M + H]⁺。

¹H NMR(MeOD)：7.14(d，J＝8.8，2H)，7.12-7.09(m，2H)，6.93(d，J＝8.8，2H)，6.87(br d，J＝8.3，1H)，4.50-4.46(m，3H)，3.88-3.82(m，4H)，3.79(s，3H)，3.78-3.73(m，1H)，3.44(dd，J＝11.9，11.8，2H)，3.28-3.16(m，3H)，3.11(dd，J＝7.6，5.6，2H)，3.03(s，3H)，2.67(dd，J＝7.6，7.3，2H)，1.82-1.62(m，4H).

Example 282: 4- (4-methoxy-phenyl) -2-methyl-7- (4-thiomorpholin-4-yl-butyl) -1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₅H₃₄N₂Calculated molecular weight of OS: 410.2; m/z found: 411.5[ M + H]⁺。

¹H NMR(MeOD)：7.11(d，J＝8.8，2H)，7.07-7.01(m，2H)，6.91(d，J＝8.8，2H)，6.78(d，J＝8.6，1H)，4.45-4.15(m，3H)，3.78(s，3H)，3.61-3.50(m，1H)，3.27-3.10(m，4H)，2，94-2.80(m，5H)，2.86(s，3H)，2.68-2.60(m，2H)，1.75-1.57(m，4H)，1.33-1.23(m，2H).

Example 283: 7- [4- (4-isopropyl-piperazin-1-yl) -butyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

MS(ESI)：C₂₈H₄₁N₃Calculated value of molecular weight of O: 435.3, respectively; m/z found: 436.6[ M + H]⁺。

¹H NMR(MeOD)：7.13(d，J＝8.8，2H)，7.06-7.04(m，2H)，6.91(d，J＝8.8，2H)，6.80(br d，J＝8.8，1H)，4.45-4.38(m，1H)，4.37-4.28(m，2H)，3.79(s，3H)，3.62(dd，J＝12.1，6.3，1H)，3.31-3.21(m，2H)，3.19-2.95(m，4H)，2.94-2.87(m，1H)，2.92(s，3H)，2.63(dd，J＝7.6，7.0，5H)，1.70-1.53(m，4H)，1.28-1.26(m，2H)，1.27(d，J＝6.6，6H).

Biological method

H₃ Receptor binding

Conjugation of Compounds with cloned human H stably expressed in SK-N-MC cells ₃Receptor binding (Lovenberg, T.W., et al, J.Pharmacol. Exp. Ther.2000, 293, 771-778). In short, human H will be expressed₃Cell pellets of the recipient SK-N-MC cells were homogenized in 50mM Tris-HCl/5mM EDTA and then centrifuged again at 30,000g for 30 minutes. The pellet was re-homogenized in 50mM Tris/5mM EDTA (pH 7.4). Contacting the cell membrane with 0.8nM N-, [ 2 ]³H]Alpha-methyl histamine (+/-test compound) was incubated together at 25 ℃ for 60 min and then harvested by rapid filtration over GF/C glass fiber filters (pretreated with 0.3% polyethyleneimine) and washed 4 times with ice cold buffer. Nonspecific binding was determined in the presence of 10. mu.M histamine. According to N-, [ 2 ]³H]-alpha-methyl Histamine K_dAt 800pM and a ligand concentration of 800pM, the IC was determined by a single point curve fitting program (GraphPad, San Diego, Calif.)₅₀Value and conversion to K_iValues (Cheng and Prusoff, biochem. Pharmacol.1973, 22, 3099-3108). The data are shown in Table 1.

Rat brain SERT

The brain of a rat without cerebellum (Zivic Laboratories, Inc. -Pittsburgh, Pa.) was homogenized in a 52.6mM Tris pH 8/126.4mM NaCl/5.26mM KCl mixture and centrifuged at 1,000rpm for 5 minutes. The supernatant was removed and centrifuged again at 15,000rpm for 30 minutes. The pellet was re-homogenized in a 52.6mM Tris pH 8/126.4mM NaCl/5.26mM KCl mixture. Contacting the cell membrane with 0.6nM [ 2 ] ³H]Citalopram (+/-test compound) incubated together at 25 ℃ for 60 min and then filtered over GF/C glass fibresHarvested by rapid filtration on a container (pretreated with 0.3% polyethyleneimine) and washed 4 times with ice-cold buffer. Nonspecific binding was determined in the presence of 100. mu.M fluoxetine. According to³H]Citalopram K_dAt 0.6nM and a ligand concentration of 0.6nM, IC was determined by the single point curve fitting program (GraphPad, San Diego, Calif.)₅₀Value and conversion to K_iValues (Cheng and Prusoff, biochem. Pharmacol.1973, 22, 3099-3108). The data are shown in Table 1.

TABLE 1

Examples	Rat SERTK_i(nM)	Human H₃K_i(nM)	Examples	Rat SERTK_i(nM)	Human H₃K_i(nM)
Examples	Rat SERTK_i(nM)	Human H₃K_i(nM)	Examples	Rat SERTK_i(nM)	Human H₃K_i(nM)	1	2	2	133	50	2
1A	6	2	134	28	2	1	2	2	133	50	2
1A	6	2	134	28	2	1B	2	2	135	27	2
2	13	70	136	9	4	1B	2	2	135	27	2
2	13	70	136	9	4	3	3	0.7	137	77	5000

4	33	4000	138	4	11
4	33	4000	138	4	11	5	27	594	139	6	3
6	15	534	140	28	8	5	27	594	139	6	3
6	15	534	140	28	8	7	14	315	141	3	3
8	6	4	142	4	3	7	14	315	141	3	3
8	6	4	142	4	3	9	5	3	143	18	4
10	4	1	144	5	6	9	5	3	143	18	4
10	4	1	144	5	6	11	2	0.6	145	3	5
12	6	59	146	12	3	11	2	0.6	145	3	5
12	6	59	146	12	3	13	10	2400	147	18	9
14	19	2000	148	3	262	13	10	2400	147	18	9
14	19	2000	148	3	262	15	11	499	149	4	240
16	6	25	150	7	175	15	11	499	149	4	240
16	6	25	150	7	175	17	10	273	151	3	119
18	1	74	152	6	5	17	10	273	151	3	119
18	1	74	152	6	5	19	8	2000	153	2	8
20	4	2	154	5	13	19	8	2000	153	2	8
20	4	2	154	5	13	21	2	9	155	6	9
22	3	11	156	4	6	21	2	9	155	6	9
22	3	11	156	4	6	23	2	2	157	3	10
24	2	2	158	2	11	23	2	2	157	3	10
24	2	2	158	2	11	25	10	7	165A	91	2
26	2	12	172	14	89	25	10	7	165A	91	2
26	2	12	172	14	89	27	3	104	173	18	15
28	12	140	178	6	18	27	3	104	173	18	15
28	12	140	178	6	18	29	14	7	179	3	5
29A	NT	35	182	2	59	29	14	7	179	3	5
29A	NT	35	182	2	59	29B	8	13	183A	1	6
30	2	3	184	1	2	29B	8	13	183A	1	6
30	2	3	184	1	2	31	2	2	186	10	6
32	8	21	187	3	5	31	2	2	186	10	6

33	5	172	188	37	22
33	5	172	188	37	22	34	11	3	189	108	12
35	2	1	190	119	29	34	11	3	189	108	12
35	2	1	190	119	29	36	2	7	191	69	26
37	8	9	192	9	3	36	2	7	191	69	26
37	8	9	192	9	3	37A	9	89	193	5	3
37B	4	6	194	7	1	37A	9	89	193	5	3
37B	4	6	194	7	1	38	29	38	195	8	3
39	3	3	196	2000	4	38	29	38	195	8	3
39	3	3	196	2000	4	40	9	20	197	5	15
41	6	14	198	2	10	40	9	20	197	5	15
41	6	14	198	2	10	42	3	3	199	2	8
43	3	18	200	3	227	42	3	3	199	2	8
43	3	18	200	3	227	44	4	2	201	4	134
45A	9	2	202	3	43	44	4	2	201	4	134
45A	9	2	202	3	43	45B	5	3	203	8	504
46	14	3	204	10	2	45B	5	3	203	8	504
46	14	3	204	10	2	47	27	10	205	44	2000
48	31	6	206	3	37	47	27	10	205	44	2000
48	31	6	206	3	37	49	14	18	207	15	78
50	3	8	208	4	137	49	14	18	207	15	78
50	3	8	208	4	137	51	34	2	209	12	176
52	3	6	210	10	99	51	34	2	209	12	176
52	3	6	210	10	99	53	5	7	211	27	823
54	32	16	212	9	43	53	5	7	211	27	823
54	32	16	212	9	43	55	209	8	213	6	11
56	42	20	214	3	17	55	209	8	213	6	11
56	42	20	214	3	17	57	22	0.9	215	1	5
58	8	9	216	4	22	57	22	0.9	215	1	5
58	8	9	216	4	22	59	48	1	217	58	42
60	14	2	218	36	38	59	48	1	217	58	42

61	4	2	219	39	33
61	4	2	219	39	33	62	10	0.6	220	4	6
63	1	0.8	221	11	9	62	10	0.6	220	4	6
63	1	0.8	221	11	9	64	222	1	222	30	30
65	3000	7	223	5	59	64	222	1	222	30	30
65	3000	7	223	5	59	66	5	1	224	32	61
67	104	0.5	225	1	46	66	5	1	224	32	61
67	104	0.5	225	1	46	68	22	1	226	1	107
69	9	1	227	1	52	68	22	1	226	1	107
69	9	1	227	1	52	70	49	1	228	1	38
71	16	1	229	2	18	70	49	1	228	1	38
71	16	1	229	2	18	72	15	1	230	1	17
73	83	2	231	2	61	72	15	1	230	1	17
73	83	2	231	2	61	74	NT	NT	232	1	20
75	79	14	233	3	4	74	NT	NT	232	1	20
75	79	14	233	3	4	75A	2000	7	234	3	3
76	11	5	235	7	6	75A	2000	7	234	3	3
76	11	5	235	7	6	77	27	3	236	6	10
78	2	96	237	3	5	77	27	3	236	6	10
78	2	96	237	3	5	79	5	183	238	4	5
80	3	130	239	2	30	79	5	183	238	4	5
80	3	130	239	2	30	81	1	70	240	3	4
82	6	64	240A	2	3	81	1	70	240	3	4
82	6	64	240A	2	3	83	6	3	240B	5	21
84	7	3	241	NT	39	83	6	3	240B	5	21
84	7	3	241	NT	39	85	7	8	242	6	124
86	5	11	243	5	22	85	7	8	242	6	124
86	5	11	243	5	22	87	4	2	244	7	129
88	15	3	245	7	336	87	4	2	244	7	129
88	15	3	245	7	336	89	5	2	246	10	3
90	9	NT	247	5	2	89	5	2	246	10	3

91	11	1	248	7	5
91	11	1	248	7	5	92	12	2	249	6	4
93	22	6	250	4	34	92	12	2	249	6	4
93	22	6	250	4	34	94	15	4	251	12	67
95	15	2	252	2	233	94	15	4	251	12	67
95	15	2	252	2	233	96	14	182	253	2	263
97	45	6	254	9	9	96	14	182	253	2	263
97	45	6	254	9	9	98	11	2	255	16	2
99	20	2	256	NT	NT	98	11	2	255	16	2
99	20	2	256	NT	NT	100	10	2	256A	12	7
101	18	2	256B	8	7	100	10	2	256A	12	7
101	18	2	256B	8	7	102	13	2	257	8	11
103	8	7	258	8	32	102	13	2	257	8	11
103	8	7	258	8	32	104	5	11	259	13	13
105	6	5	260	29	3	104	5	11	259	13	13
105	6	5	260	29	3	106	25	6	260A	17	2
107	10	5	260B	26	29	106	25	6	260A	17	2
107	10	5	260B	26	29	108	13	12	261	32	62
109	10	8	261A	32	73	108	13	12	261	32	62
109	10	8	261A	32	73	110	4	5	261B	17	64
111	4	8	262	5	10	110	4	5	261B	17	64
111	4	8	262	5	10	112	5	9	263	11	11
113	10	8	264	6	3254	112	5	9	263	11	11
113	10	8	264	6	3254	114	9	4	265	13	2
115	8	10	266	31	14	114	9	4	265	13	2
115	8	10	266	31	14	116	6	8	267	25	12
117	9	1	268	12	18	116	6	8	267	25	12
117	9	1	268	12	18	118	8	1	269	23	44
119	9	1	270	18	6	118	8	1	269	23	44
119	9	1	270	18	6	120	10	1	271	413	0.7
121	10	2	272	540	3	120	10	1	271	413	0.7

122	26	372	273	47	5
122	26	372	273	47	5	123	18	346	274	14	65
124	13	3	275	5	3	123	18	346	274	14	65
124	13	3	275	5	3	125	45	2	276	18	86
126	3	8	277	37	45	125	45	2	276	18	86
126	3	8	277	37	45	127	5000	39	278	25	315
128	40	12	279	90	6	127	5000	39	278	25	315
128	40	12	279	90	6	129	7	14	280	4	96
130	6	2	281	6	23	129	7	14	280	4	96
130	6	2	281	6	23	131	9	85	282	6	25
132	19	4	283	4	13	131	9	85	282	6	25

NT is not determined

Human SERT

Homogenizing HEK293 (human embryonic kidney) cell membrane expressing human SERT³H-citalopram (SERT) was incubated together in 50mM Tris, 120mM NaCl, 5mM KCl (pH7.4) for 1 hour at room temperature. Non-specific binding was determined in the presence of 100. mu.M fluoxetine (for SERT). The cell membranes were washed as above and the radioactivity counted. K of SERT_iIs based on³K of H-citalopram_dValues and ligand concentration of 3.1 nM. The data for the compounds tested in this assay are shown in table 2.

TABLE 2

Examples	Human SERTK_i(nM)	Practice ofExample (b)	Human SERTK_i(nM)
Examples	Human SERTK_i(nM)	Practice ofExample (b)	Human SERTK_i(nM)	1	3	84	7
1A	9	91	11	1	3	84	7
1A	9	91	11	1B	3	92	9
2	56	103	3	1B	3	92	9
2	56	103	3	3	4	104	3
4	21	109	3	3	4	104	3
4	21	109	3	5	18	110	5
6	15	112	6	5	18	110	5

7	14	116	7
7	14	116	7	8	8	117	10
9	6	118	4	8	8	117	10
9	6	118	4	10	5	121	6
11	5	124	56	10	5	121	6
11	5	124	56	12	16	126	15
13	11	129	5	12	16	126	15
13	11	129	5	14	18	130	9
17	7	134	30	14	18	130	9
17	7	134	30	20	3	135	15
21	4	136	20	20	3	135	15
21	4	136	20	22	5	138	8
23	4	139	6	22	5	138	8
23	4	139	6	24	3	140	23
25	6	141	2	24	3	140	23
25	6	141	2	26	5	142	7
29	8	145	5	26	5	142	7
29	8	145	5	29A	13	146	12
29B	6	148	5	29A	13	146	12
29B	6	148	5	30	2	152	11
31	3	153	2	30	2	152	11
31	3	153	2	32	9	154	4
34	4	156	10	32	9	154	4
34	4	156	10	35	3	157	5
36	3	158	3	35	3	157	5
36	3	158	3	37	6	179	4
37A	13	195	34	37	6	179	4
37A	13	195	34	37B	6	198	2
39	3	199	2	37B	6	198	2
39	3	199	2	40	8	204	5
42	8	214	12	40	8	204	5

44	7	215	5
44	7	215	5	45A	7	216	8
45B	6	220	12	45A	7	216	8
45B	6	220	12	46	26	222	18
47	11	236	9	46	26	222	18
47	11	236	9	48	118	241	10
50	3	243	6	48	118	241	10
50	3	243	6	51	103	247	7
52	2	254	7	51	103	247	7
52	2	254	7	53	4	256B	4
57	53	257	11	53	4	256B	4
57	53	257	11	59	160	259	22
60	7	271	3000	59	160	259	22
60	7	271	3000	61	5	272	3000
62	15	273	158	61	5	272	3000
62	15	273	158	63	2	274	27
64	252	275	4	63	2	274	27
64	252	275	4	66	4	276	9
68	89	277	13	66	4	276	9
68	89	277	13	71	31	278	9
72	29	279	98	71	31	278	9
72	29	279	98	76	9	280	13
77	28	281	8	76	9	280	13
77	28	281	8	83	5	282	17
		283	7	83	5	282	17

Accumulation of cyclic AMP

Generation of expression reporter constructs and human H₃An SK-N-MC cell subline of receptors. The reporter gene (β -galactosidase) is under the control of multiple cyclic AMP response elements. In 96-well plates, histamine was added directly to the cell culture medium and forskolin (5 μ M final concentration) was added 5 minutes later. Where appropriate, the antagonist is added first and the agonist is added after 10 minutes. After 6 hours incubation at 37 ℃, the medium was aspirated and the cells were washed with 200 μ l phosphate buffered saline and subjected to a second aspiration. Cells were assayed with 25. mu.l of 0.1 Xassay buffer (10mM sodium phosphate, pH8, 0.2mM MgSO)₄，0.01mM MnCl₂) Dissolve and incubate for 10 min at room temperature. The cells were then incubated with 100. mu.l of 1 × assay buffer (containing 0.5% Triton and 40 mM. beta. -mercaptoethanol) for 10 minutes. Color was developed with 25. mu.l of 1mg/ml substrate solution (chlorophenol Red. beta. -D-galactopyranoside; Roche Molecular Biochemicals, Indianapolis, IN). The absorbance of the color was measured at 570nM on a microplate reader. By pairing pEC₅₀Schild regression analysis of values to determine pA₂The values, data for the compounds tested are shown in table 3.

TABLE 3

Examples	pA₂	Examples	pA₂
Examples	pA₂	Examples	pA₂	1	8.6	71	9.6
1A	8.4	72	9.1	1	8.6	71	9.6
1A	8.4	72	9.1	1B	8.9	73	9.0
3	9.4	76	8.4	1B	8.9	73	9.0
3	9.4	76	8.4	8	8.3	77	7.7
9	8.6	83	8.9	8	8.3	77	7.7
9	8.6	83	8.9	10	8.4	85	8.2
11	9.4	146	8.7	10	8.4	85	8.2
11	9.4	146	8.7	20	9.0	147	8.0
21	7.9	155	8.5	20	9.0	147	8.0
21	7.9	155	8.5	37	8.2	158	8.1
37B	8.3	165A	8.5	37	8.2	158	8.1
37B	8.3	165A	8.5	44	9.1	213	8.0
45A	8.9	214	8.2	44	9.1	213	8.0
45A	8.9	214	8.2	45B	9.1	236	8.1
50	8.4	237	7.8	45B	9.1	236	8.1
50	8.4	237	7.8	51	9.3	238	7.9
52	8.3	256A	8.3	51	9.3	238	7.9
52	8.3	256A	8.3	53	8.2	256B	8.4

55	8.3	260A	9.0
55	8.3	260A	9.0	57	10.0	262	8.2
58	7.5	263	8.1	57	10.0	262	8.2
58	7.5	263	8.1	59	9.9	265	8.8
60	8.6	271	9.6	59	9.9	265	8.8
60	8.6	271	9.6	61	9.3	272	8.5
62	9.3	273	8.7	61	9.3	272	8.5
62	9.3	273	8.7	63	9.5	275	8.9
69	9.1	279	8.5	63	9.5	275	8.9

Claims

1. A method for treating or preventing a central nervous system disorder selected from the group consisting of: sleep/wake and wake/vigilance disorders, insomnia, jet lag, disturbed sleep, Attention Deficit Hyperactivity Disorder (ADHD), attention deficit disorder, learning and memory disorders, learning decline, memory loss, cognitive disorders, migraine, neuroinflammation, dementia, mild cognitive decline, pre-dementia, Alzheimer's disease, epilepsy, narcolepsy with or without cataplexy, sleep/wake homeostasis disorders, idiopathic somnolence, Excessive Daytime Sleepiness (EDS), circadian rhythm disorders, sleep/fatigue disorders, fatigue, sleep apnea-related drowsiness, decreased sleep due to perimenopausal hormonal changes, Parkinson-related fatigue, MS-related fatigue, depression-related fatigue, chemotherapy-induced fatigue, work-related fatigue, Parkinson-related fatigue, MS-related fatigue, depression-related fatigue, work-related fatigue, Somnolence, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, mania and depression; the method comprises the step of administering to a mammal suffering from such diseases an effective amount of a compound of formula (I) and enantiomers, diastereomers, hydrates, solvates thereof, and pharmaceutically acceptable salts, esters and amides thereof:

Wherein

L is-O-, and n is 1 or 2; or L is-C ≡ C-or-CH₂CH₂-n is 0 or 1;

wherein R is^bAnd R^cEach independently is-H or-C_1-6An alkyl group;

R²and R³Each independently selected from: -H;

C) A naphthyl group,

wherein R is^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

alternatively, the first and second electrodes may be,

Wherein R is^fSelected from:

wherein R is^zIs fluorine, -CN, -OH, -OC_1-4Alkyl, -C_3-7Cycloalkyl or-CF₃；

Wherein R is^gAnd R^hEach independently is-H or-C_1-6An alkyl group; and

m is 0, 1 or 2;

R⁵is selected from-C_1-6Alkyl, -OH, -OC_1-6Alkyl, -SC_1-6Alkyl and halogen;

Ar¹is an aryl or heteroaryl ring selected from:

wherein R is^jSelected from:

1)-OH、-C_1-6alkyl, -OC optionally mono-, di-or trisubstituted by halogen_1-6Alkyl, -C_2-6Alkenyl, -OC_3-6Alkenyl, optionally trimethylsilyl-substituted-C_2-6Alkynyl, -OC_3-6Alkynyl, -C_3-6Cycloalkyl, -OC_3-6Cycloalkyl, -CN, -NO₂、-N(R^k)R¹、-N(R^k)C(O)R¹、-N(R^k)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -C (O) N (R)^m)Rⁿ、-SO₂N(R^m)Rⁿ、-SCF₃Halogen, -CF₃、-COOH、-COOC_1-6Alkyl and-COOC_3-7A cycloalkyl group;

wherein R is^kAnd R^lEach independently is-H or-C_1-6An alkyl group;

wherein R is^tIs a substituent independently selected from: -OH, -C_1-6Alkyl, OC_1-6Alkyl, phenyl, -CN, -NO₂、-N(R^u)R^v、-C(O)N(R^u)R^v、-N(R^u)C(O)R^v、-N(R^u)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^u)R^v、-SCF₃Halogen, -CF₃、-OCF₃、-OCHF₂-COOH and-COOC_1-6An alkyl group;

wherein R is^uAnd R^vEach independently is-H or C_1-6An alkyl group;

f) monocyclic aromatic hydrocarbon groups having 6 ring atoms, having carbon atoms as points of attachment, having 1 or 2 carbon atoms replaced by-N ═ optionally by R ^jMono-or disubstituted and optionally benzo-or pyridine-fused at two adjacent carbon atoms, wherein the benzo-or pyridine-fused moiety is optionally substituted with R^tMono-or di-substitution.

2. The method of claim 1, wherein L is-O-and n is 1.

3. The method of claim 1, wherein L is-C ≡ C-and n is 0.

4. The method of claim 1, wherein L is-CH₂CH₂-, n is 0.

5. The method of claim 1, wherein R¹Methyl, ethyl, propyl, tert-butyl, allyl, propargyl or benzyl.

6. The method of claim 1, wherein R¹Is hydrogen or methyl.

7. The method of claim 1, wherein when R is²When it is methyl, R³Is not methyl.

8. The method of claim 1, wherein R²And R³May be taken together with the nitrogen atom to which they are attached to form a 4-to 8-membered heterocyclic ring selected from piperidine, pyrrolidine and morpholine, said ring being substituted with 1 or 2 substituents R^ffAnd (4) substitution.

9. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of:

(1)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(2)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(3)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(4)1- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -ethanone;

(5) diethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(6) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -pyridin-4-yl-methanone;

(7)1- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -2-methyl-propan-1-one;

(8) cyclobutyl- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -methanone;

(9) cyclopropyl- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -methanone;

(10)7- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(11)4- (4-methoxy-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(12) (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -pyrrolidin-3-yl) -dimethyl-amine;

(13)7- [3- ((2R, 5R) -trans-dimethyl-pyrrolidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(14)4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazine-1-carboxylic acid ethyl ester;

(15) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) - (1-methyl-1H-pyrrol-2-yl) -methanone;

(16) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) - (1-methyl-1H-imidazol-4-yl) -methanone;

(17) (1, 3-dimethyl-tetrahydro-pyrimidin-2-ylidene) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(18)7- [3- (1, 3-dihydro-isoindol-2-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(19) bis- (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(20)7- [3- (5, 6-dihydro-4H-pyrimidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(21) benzothiazol-2-yl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -methyl-amine;

(22)1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-3-ol;

(23)1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-4-ol;

(24) (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-4-yl) -methanol;

(25) (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-3-yl) -methanol;

(26) (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-2-yl) -methanol;

(27)4- (4-methoxy-phenyl) -2-methyl-7- [3- (3-trifluoromethyl-piperidin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(28)2- (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-4-yl) -ethanol;

(29)7- [3- (1, 1-dioxo-1. lamda.) -1⁶-thiomorpholin-4-yl) -propoxy]-4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(30)4- (4-methoxy-phenyl) -2-methyl-7- [3- ((2S) -trifluoromethyl-pyrrolidin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(31)7- [3- (3, 3-difluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(32)7- [3- (3, 3-difluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(33)7- [3- (3, 3-difluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(34) (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -pyrrolidin- (2R) -yl) -methanol;

(35)1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (R) -pyrrolidin-3-ol;

(36)7- [3- (2, 6-dimethyl-morpholin-4-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(37)1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidine-4-carboxylic acid ethyl ester;

(38)7- (3-azetidin-1-yl-propoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(39)4- (4-methoxy-phenyl) -2-methyl-7- [3- (2-methyl-pyrrolidin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(40)2- (1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidin-2-yl) -ethanol;

(41)1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidine-4-carbonitrile;

(42)1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidine-4-carbonitrile (enantiomer 1);

(43)1- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperidine-4-carbonitrile (enantiomer 2);

(44)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-trifluoromethyl-piperidin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(45)7- [3- (3-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(46) ethyl- (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(47)7- [3- (1, 4-dioxa-8-aza-spiro [4.5] decan-8-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(48)1- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -3-piperidin-1-yl-propan-2-ol;

(49)7- [ 2-fluoro-3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(50)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(51)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(52)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(53)4- (3-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(54)4- (4-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(55)4- (3-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(56)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(57)4- (4-difluoromethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(58)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methanesulfonyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(59)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(60)4- (3-chloro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(61)4- (2, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(62)4- (2, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(63)4- (3, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(64) 2-methyl-7- (3-piperidin-1-yl-propoxy) -4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(65)4- (3, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(66) 2-methyl-7- (3-piperidin-1-yl-propoxy) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(67) 2-methyl-7- (3-piperidin-1-yl-propoxy) -4- (trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(68)4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (racemate);

(69)4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(70)4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(71) 2-tert-butyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(72) 2-benzyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(73) 2-ethyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(74)4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -2-propyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(75) 2-isopropyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(76)4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(77)3- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl ] -propan-1-ol;

(78)2- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl ] -ethanol;

(79)2- (2-fluoro-ethyl) -4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(80) 2-cyclopropyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(81)4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(82)4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(83)4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(84)4- (3, 4-dichloro-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(85)4- (3, 4-dichloro-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(86)4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(87)4- (3-chloro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(88) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(89)4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(90)4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(91)7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(92)4- (4-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(93)4- (4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(94)7- (1-cyclopentyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(95)7- (1-ethyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(96)4- (3-chloro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(97)4- (3-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(98)4- (2-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(99)7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(100)4- (3-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(101)4- (3-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(102)7- (1-cyclopentyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(103)7- (1-ethyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(104)4- (3-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(105)4- (3-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(106)7- (1-isopropyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(107)7- (1-cyclobutyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(108)7- (1-ethyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(109)7- (1-cyclopentyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(110)4- (3-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(111)7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(112)7- (1-cyclobutyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(113)7- (1-ethyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(114)4- (3-chloro-4-methoxy-phenyl) -7- (1-cyclobutyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(115)4- (3-chloro-4-methoxy-phenyl) -7- (1-ethyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(116)4- (3-chloro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(117) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(118)7- (1-isobutyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(119)7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (3-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(120)4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(121)7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (2-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(122)4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(123)4- (2-fluoro-4-methoxy-phenyl) -7- (1-isobutyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(124)7- [1- (2-fluoro-ethyl) -piperidin-4-ylmethoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(125)7- (1-isopropyl-piperidin-4-yloxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(126)7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(127)4- (2-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(128)4- (3-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(129)4- (4-methoxy-phenyl) -2-methyl-7- [1- (tetrahydro-pyran-4-yl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(130)2, 2, 2-trifluoro-1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -ethanone;

(131)4- (4-methoxy-phenyl) -2-methyl-7- [1- (2, 2, 2-trifluoro-ethyl) -piperidin-4-ylmethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

(132)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4-phenyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(133)4- (2-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(134)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4-p-tolyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(135) 2-benzyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(136)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (3-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(137)7- [3- (3, 3-difluoro-pyrrolidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(138)4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(139) dicyclopropylmethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(140)4- (2-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(141) 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-morpholin-4-yl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(142)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-morpholin-4-yl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(143)4- { 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -benzonitrile;

(144)4- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -benzonitrile;

(145)7- [3- (3-benzhydryl-azetidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(146) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(147)4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (racemate);

(148)4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(149)4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(150)4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (racemate);

(151)4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(152)4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(153)4- (4-ethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(154) 2-ethyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(155)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(156)4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(157) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(158)4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(159)4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(160)7- [1- (2-fluoro-ethyl) -piperidin-4-yloxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(161)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(162)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(163)4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(164)4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(165) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(166) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(167)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(168)4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(169)7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(170)4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(171)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methylsulfinyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;

(172)4- (4-methylsulfinyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(173)4- (4-methylsulfinyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(174)4- (4-methanesulfonyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(175)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2, 6-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(176)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(177)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ol;

(178)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-8-ol;

(179)2, 8-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(180)2, 6-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(181) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinolin-8-ol;

(182) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinolin-6-ol;

(183) 8-fluoro-2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(184) 6-fluoro-2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(185)7- [1- (2-fluoro-ethyl) -piperidin-4-ylmethoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(186)7- [1- (2-fluoro-ethyl) -piperidin-4-yloxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(187)4- (4-methoxy-phenyl) -7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(188)4- (4-methylsulfinyl-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(189)7- [3- (3, 3-difluoro-azetidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(190) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-3-yl) -methanol;

(191) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-3S-yl) -methanol;

(192) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-2-yl) -methanol;

(193) {3- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (2H-pyrazol-3-yl) -amine;

(194)4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(195)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-methylsulfanyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(196) (5- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -pyridin-2-yl) -dimethyl-amine;

(197)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-trimethylsilylethynyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(198)4- (6-ethynyl-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(199)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-thiophenyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(200)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (6-imidazol-1-yl-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(201)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (6-methoxy-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(202)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-pyrazol-1-yl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(203)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- [6- (1H-imidazol-2-ylsulfanyl) -pyridin-3-yl ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(204)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- [6- (pyrimidin-2-ylsulfanyl) -pyridin-3-yl ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(205)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(206)7- [3- (4-ethyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(207)7- [3- (4-isopropyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(208)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-thiazol-2-yl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(209)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-thiophen-2-ylmethyl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(210)2- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -ethanol;

(211)2- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -phenol;

(212)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-pyridin-4-yl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(213)4- (4-methoxy-phenyl) -2-methyl-7- {3- [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl ] -propoxy } -1, 2, 3, 4-tetrahydro-isoquinoline;

(214)7- [3- (4-allyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(215)7- [3- (4- [1, 3] -dioxolan-2-ylmethyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(216)4- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -benzonitrile;

(217)7- {3- [4- (2-methoxy-ethyl) -piperazin-1-yl ] -propoxy } -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(218)4- (4-methoxy-phenyl) -2-methyl-7- {3- [4- (tetrahydro-furan-2-ylmethyl) -piperazin-1-yl ] -propoxy } -1, 2, 3, 4-tetrahydro-isoquinoline;

(219)4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazine-1-carboxylic acid tert-butyl ester;

(220)7- [3- (4-cyclopropyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(221)4- (4-bromo-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(222)4- (4-difluoromethoxy-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(223) 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(224)7- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(225)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(226) 2-methyl-7- (3-morpholin-4-yl-propoxy) -4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(227) 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(228)4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(229)4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(230) 2-methyl-7- (3-piperidin-1-yl-propoxy) -4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(231) {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (tetrahydro-pyran-4-yl) -amine;

(232) Cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (1-methyl-piperidin-4-yl) -amine;

(233) (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(234)3- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propylamino } -propan-1-ol;

(235) allyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(236) isobutyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(237) cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(238) isopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(239) {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -propyl-amine;

(240) ethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(241) isopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -methyl-amine;

(242) Cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -methyl-amine;

(243) bicyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(244)7- (1-isopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(245)7- (1-cyclopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(246)7- (1-cyclobutyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(247)7- [1- (2-fluoro-ethyl) -azetidin-3-ylmethoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(248)4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(249)4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(250)4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(251)4- (3-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(252) {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -acetonitrile;

(253) 2-methyl-7- (1-methyl-piperidin-4-yloxy) -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(254) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- [1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(255) {4- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -piperidin-1-yl } -acetonitrile;

(256) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- [1- (tetrahydro-pyran-4-yl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(257)7- (1-cyclopropyl-piperidin-4-yloxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(258)7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(259)7- (1-cyclopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(260)1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -2-methyl-propan-2-ol;

(261)4- (4-methoxy-phenyl) -2-methyl-7- (4-methyl-morpholin-2-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(262)4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2S-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(263)4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2R-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(264)7- (4-isopropyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(265)7- (4-isopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(266)7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(267)7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(268)7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(269)7- (4-ethyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(270)7- [4- (2-fluoro-ethyl) -morpholin-2-ylmethoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(271)7- (4-cyclopropyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(272)7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(273)7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(274)7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(275)7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(276)7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(277)7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(278)7- (4-isopropyl-morpholin-2-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(279)7- (4-cyclopropyl-morpholin-2-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(280) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (morpholin-2-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(281)4- (4-methoxy-phenyl) -2, 6-dimethyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(282)4- (4-methoxy-phenyl) -2, 6-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(283)4- (3-fluoro-4-methoxy-phenyl) -2, 6-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(284)4- (3-fluoro-4-methoxy-phenyl) -2, 8-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(285)4- (4-methoxy-phenyl) -2, 8-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(286)2, 6-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(287)7- (4-piperidin-1-yl-but-1-ynyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(288)7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(289) 2-methyl-7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(290)7- [4- (4, 4-difluoro-piperidin-1-yl) -but-1-ynyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(291)4- (4-methoxy-phenyl) -2-methyl-7- (4-piperidin-1-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(292)4- (4-methoxy-phenyl) -2-methyl-7- (4-morpholin-4-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(293)4- (4-methoxy-phenyl) -2-methyl-7- (4-thiomorpholin-4-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(294)7- [4- (4-isopropyl-piperazin-1-yl) -but-1-ynyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(295)4- (4-fluoro-phenyl) -2-methyl-7- (4-piperidin-1-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(296)7- [4- (4, 4-difluoro-piperidin-1-yl) -butyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(297)4- (4-methoxy-phenyl) -2-methyl-7- (4-morpholin-4-yl-butyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(298)4- (4-methoxy-phenyl) -2-methyl-7- (4-thiomorpholin-4-yl-butyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(299)7- [4- (4-isopropyl-piperazin-1-yl) -butyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

and salts thereof.

10. A method for treating or preventing a central nervous system disorder selected from the group consisting of: depression, disturbed sleep, fatigue, lethargy, cognitive decline, memory loss, learning decline and attention deficit disorder; the method comprises the step of administering to a mammal suffering from such diseases an effective amount of a compound of formula (I) and enantiomers, diastereomers, hydrates, solvates thereof, and pharmaceutically acceptable salts, esters and amides thereof:

Wherein

L is-O-, and n is 1 or 2; or L is-C ≡ C-or-CH₂CH₂-n is 0 or 1;

wherein R is^bAnd R^cEach independently is-H or-C_1-6An alkyl group;

R²and R³Each independently selected from: -H;

C) A naphthyl group,

wherein each of said B) -E) is optionally mono-, di-or trisubstituted with a moiety selected from: -C_1-4Alkyl, -OH, -C_1-4Alkyl OH, -OC_1-6Alkyl, -CN, -NO₂、-N(R^d)R^e-C(O)N(R^d)R^e、-N(R^d)C(O)R^d、-N(R^d)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^d)R^e、-SCF₃Halogen, -CF₃、-OCF₃、-COOH、-COOC_1-6Alkyl, -OC (O) N (R)^d)R^eAnd OC (O) OC_1-6An alkyl group;

wherein R is^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

alternatively, the first and second electrodes may be,

Wherein R is^fSelected from:

wherein R is^zIs fluorine, -CN, -OH, -OC_1-4Alkyl, -C_3-7Cycloalkyl or-CF₃；

Wherein R is^gAnd R^hEach independently is-H or-C_1-6An alkyl group; and

m is 0, 1 or 2;

R⁵is selected from-C_1-6Alkyl, -OH, -OC_1-6Alkyl, -SC_1-6Alkyl and halogen;

Ar¹is an aryl or heteroaryl ring selected from:

wherein R is^jSelected from:

wherein R is^kAnd R^lEach independently is-H or-C_1-6An alkyl group;

3)4-8 membered saturated or partially saturated heterocycle having 1 or 2 members selected from > O, > S (O)_0-2NH and > NC_1-6A ring hetero atom of an alkyl group and having 0 or 1 carbonyl groupThe ring is optionally substituted with R^pMono-, di-or tri-substituted;

b) phenyl or pyridyl fused to a 3-membered hydrocarbon moiety at two adjacent ring carbon atoms to form a fused 5-membered aromatic ring, one carbon atom in said moiety being substituted with > O, > S, > NH, > N (C) _1-4Alkyl) and up to one further carbon atom in said moiety is optionally replaced by-N ═ and fused rings are optionally substituted by R^tMono-, di-or tri-substituted;

wherein R is^uAnd R^vEach independently is-H or C_1-6An alkyl group;

11. A method for treating or preventing a central nervous system disorder selected from the group consisting of: sleep/wake and wake/vigilance disorders, insomnia, jet lag, disturbed sleep, Attention Deficit Hyperactivity Disorder (ADHD), attention deficit disorder, learning and memory disorders, learning decline, memory loss, cognitive disorders, migraine, neuroinflammation, dementia, mild cognitive decline, pre-dementia, Alzheimer's disease, epilepsy, narcolepsy with or without cataplexy, sleep/wake homeostasis disorders, idiopathic somnolence, Excessive Daytime Sleepiness (EDS), circadian rhythm disorders, sleep/fatigue disorders, fatigue, sleep apnea-related drowsiness, decreased sleep due to perimenopausal hormonal changes, Parkinson-related fatigue, MS-related fatigue, depression-related fatigue, chemotherapy-induced fatigue, work-related fatigue, Parkinson-related fatigue, MS-related fatigue, depression-related fatigue, work-related fatigue, Somnolence, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, mania and depression; the method comprises the step of administering to a mammal suffering from these diseases an effective amount of a compound of formula (II):

Wherein

n is 1 or 2; x is 0 or 1; wherein n + x is 1 or 2;

wherein R is^aSelected from-OH, -OC_1-6Alkyl, optionally substituted by-OC_1-4Alkyl or halogen substituted phenyl, -CN, -NO₂、-N(R^b)R^c、-C(O)N(R^b)R^c、-N(R^b)C(O)R^b、-N(R^b)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2C_1-6Alkyl, -SO₂N(R^b)R^c、-SCF₃Halogen, -CF₃、-OCF₃-COOH and-COOC_1-6An alkyl group;

wherein R is^bAnd R^cEach independently is-H or-C_1-6An alkyl group;

R³selected from: -H;

C) A naphthyl group,

E) monocyclic aromatic hydrocarbon radicalHaving 5 or 6 ring atoms, having carbon atoms as attachment points, having one carbon atom replaced by: > O, > S, > NH, > N (C)_1-4Alkyl) or > NC (O) OC_1-4Alkyl, up to one carbon atom being optionally replaced by-N ═ and optionally benzo-fused or pyridine-fused;

wherein R is^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

R⁴is-OH, -OC_1-6Alkyl, -CF₃、-C_1-6An alkyl group or a halogen, in which,

m is 0, 1 or 2;

R⁵is selected from-C_1-6Alkyl, -OH, -OC_1-6Alkyl, -SC _1-6Alkyl and halogen;

Ar¹is an aryl or heteroaryl ring selected from:

wherein R is^jSelected from:

1)-OH、-C_1-6alkyl, -OC optionally mono-, di-or trisubstituted by halogen_1-6Alkyl, -C_2-6Alkenyl, -OC_3-6Alkenyl, optionally trimethylsilyl-substituted-C_2-6Alkynyl, -OC_3-6Alkynyl, -C_3-6Cycloalkyl, -OC_3-6Cycloalkyl, -CN, -NO₂、-N(R^k)R^l、-N(R^k)C(O)R^l、-N(R^k)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -C (O) N (R)^m)Rⁿ、-SO₂N(R^m)Rⁿ、-SCF₃Halogen, -CF₃、-COOH、COOC_1-6Alkyl and-COOC_3-7A cycloalkyl group;

wherein R is^kAnd R^lEach independently is-H or-C_1-6An alkyl group;

wherein R is^mAnd RⁿEach independently is-H or-C_1-6Alkyl, or R^mAnd RⁿMay be taken together with the nitrogen atom to which they are attached to form a 4-8 membered heterocyclic ring having 1 or 2 ring heteroatoms selected from: > O, > S (O)_0-2NH and > NC_1-6Alkyl, and having 0 or 1 double bond, having 0 or 1 carbonyl;

2)-G-Ar²wherein G is a bond, -O-or-S-, Ar²Is phenyl or is a monocyclic aromatic hydrocarbon radical having 5 or 6 ring atoms, having one carbon atom replaced by: > O, > S, > NH or > N (C) _1-4Alkyl) and up to one further carbon atom is optionally replaced by-N ═ and the radicals are optionally substituted by R^pMono-, di-or tri-substituted;

b) phenyl or pyridyl fused to a 3-membered hydrocarbon moiety on two adjacent ring carbon atoms to form a fused 5-membered aromatic ring, one carbon atom in said moiety being substituted by > O, > S, > NH or > N (C)_1-4Alkyl) and up to one further carbon atom in said moiety is optionally replaced by-N ═ and fused rings are optionally substituted by R^tMono-, di-or tri-substituted;

wherein R is^tIs a substituent independently selected from: -OH, -C_1-6Alkyl, -OC_1-6Alkyl, phenyl, -CN, -NO₂、-N(R^u)R^v、-C(O)N(R^u)R^v、-N(R^u)C(O)R^v、-N(R^u)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^u)R^v、-SCF₃Halogen, -CF₃、-OCF₃、-OCHF₂-COOH and-COOC _1-6An alkyl group;

wherein R is^uAnd R^vEach independently is-H or C_1-6An alkyl group;

c) a phenyl group fused on two adjacent ring atoms to a 4-membered hydrocarbon moiety to form a fused 6-membered aromatic ring, wherein 1 or 2 carbon atoms are replaced by-N ═ and the fused ring is optionally substituted by R^tOne, two or threeSubstitution;

f) monocyclic aromatic hydrocarbon groups having 6 ring atoms, having carbon atoms as points of attachment, having 1 or 2 carbon atoms replaced by-N ═ optionally by R^jMono-or disubstituted and optionally benzo-or pyridine-fused at two adjacent carbon atoms, wherein the benzo-or pyridine-fused moiety is optionally substituted with R^tMono-or di-substitution.

12. A method for treating or preventing a neurological disease or central nervous system disease selected from the group consisting of: depression, disturbed sleep, fatigue, lethargy, cognitive decline, memory loss, learning decline and attention deficit disorder; the method comprises the step of administering to a mammal suffering from these diseases an effective amount of a compound of formula (II):

Wherein

n is 1 or 2; x is 0 or 1; wherein n + x is 1 or 2;

R¹is-H; or is-C_1-6Alkyl, -C_3-6Alkenyl, -C_3-6Alkynyl, -C_3-7Cycloalkyl, -C_1-6Alkyl radical C_3-7Cycloalkyl, -COOC_1-6Alkyl or-COObenzyl, each of which is optionally substituted by R^aOne, two or threeSubstitution;

wherein R is^bAnd R^cEach independently is-H or-C_1-6An alkyl group;

R³selected from: -H;

C) A naphthyl group,

E) monocyclic aromatic hydrocarbon group having5 or 6 ring atoms having as a point of attachment a carbon atom having one carbon atom replaced with: > O, > S, > NH, > N (C)_1-4Alkyl) or > NC (O) OC_1-4Alkyl, up to one carbon atom being optionally replaced by-N ═ and optionally benzo-fused or pyridine-fused;

wherein R is^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

R⁴is-OH, -OC_1-6Alkyl, -CF₃、-C_1-6An alkyl group or a halogen, in which,

m is 0, 1 or 2;

R⁵is selected from-C_1-6Alkyl, -OH, -OC_1-6Alkyl, -SC _1-6Alkyl and halogen;

Ar¹is an aryl or heteroaryl ring selected from:

wherein R is^jSelected from:

1)-OH、-C_1-6alkyl, -OC optionally mono-, di-or trisubstituted by halogen_1-6Alkyl, -C_2-6Alkenyl, -OC_3-6Alkenyl, optionally trimethylsilyl-substituted-C_2-6Alkynyl, -OC_3-6Alkynyl, -C_3-6Cycloalkyl, -OC_3-6Cycloalkyl, -CN, -NO₂、-N(R^k)R^l、-N(R^k)C(O)R^l、-N(R^k)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -C (O) N (R)^m)Rⁿ、-SO₂N(R^m)Rⁿ、-SCF₃Halogen, -CF₃、-COOH、-COOC_1-6Alkyl and-COOC_3-7A cycloalkyl group;

wherein R is^kAnd R^lEach independently is-H or-C_1-6An alkyl group;

wherein R is^pIs a substituent independently selected from: -OH, -C_1-6Alkyl, OC_1-6Alkyl, phenyl, -CN, -NO₂、-N(R^q)R^r、-C(O)N(R^q)R^r、-N(R^q)C(O)R^r、-N(R^q)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^q)R^r、-SCF₃Halogen, -CF₃、-OCF₃、-OCHF₂-COOH and-COOC_1-6An alkyl group;

wherein R is^uAnd R^vEach independently is-H or C_1-6An alkyl group;

13. A compound of the following formula (I) and enantiomers, diastereomers, hydrates, solvates thereof and pharmaceutically acceptable salts, esters and amides thereof:

Wherein

L is-O-, and n is 1 or 2; or L is-C ≡ C-or-CH₂CH₂-n is 0 or 1;

wherein R is^bAnd R^cEach independently is-H or-C_1-6An alkyl group;

R²and R³Each independently selected from: -H;

C) A naphthyl group,

E) monocyclic aromatic hydrocarbon groups having 5 or 6 ring atoms, having carbon atoms as attachment points, having one carbon atom replaced with: > O, > S, > NH, > N (C)_1-4Alkyl) or > NC (O) OC_1-4Alkyl, up to one further carbon atom being optionally replaced by-N ═ and anyBenzene-or pyridine-fused;

wherein R is^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

alternatively, the first and second electrodes may be,

Wherein R is^fSelected from:

i) optionally substituted with R^zsubstituted-C_1-6Alkyl, -C_3-6Alkenyl, -C_3-6Alkynyl, -C (O) N (R)^g)R^h、-C(O)R¹、-S(O)_0-2-C_1-6Alkyl and COOC_1-6An alkyl group, a carboxyl group,

wherein R is^zIs fluorine, -CN, -OH, -OC_1-4Alkyl, -C_3-7Cycloalkyl or-CF₃；

Wherein R is^gAnd R^hEach independently is-H or-C_1-6An alkyl group; and

m is 0, 1 or 2;

R⁵is selected from-C_1-6Alkyl, -OH, -OC_1-6Alkyl, -SC_1-6Alkyl and halogen;

Ar¹is an aryl or heteroaryl ring selected from:

wherein R is^jSelected from:

wherein R is^kAnd R^lEach independently is-H or-C_1-6An alkyl group;

b) phenyl or pyridyl fused to a 3-membered hydrocarbon moiety on two adjacent ring carbon atoms to form a fused 5-membered aromatic ring, one carbon atom in said moiety being substituted by > O, > S, > NH or > N (C) _1-4Alkyl) and at most one carbon atom in said moietyOptionally substituted by-N-condensed rings, optionally substituted by R^tMono-, di-or tri-substituted;

wherein R is^uAnd R^vEach independently is-H or C_1-6An alkyl group;

the precondition is that:

when n is 1, L is-O-, Ar is unsubstituted phenyl, and R is²And R³When all are methyl, thenR⁴Is not-OH.

14. The compound of claim 13, wherein L is-O-and n is 1.

15. The compound of claim 13, wherein L is-C ≡ C-and n is 0.

16. The compound of claim 13, wherein L is-CH₂CH₂-, n is 0.

17. The compound of claim 13, wherein R¹is-C_1-4An alkyl group.

18. The compound of claim 13, wherein R¹Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, benzyl, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, -COOCH₃-COO-tert-butyl and-COObenzyl.

19. The compound of claim 13, wherein R¹Methyl, ethyl, propyl, tert-butyl, allyl, propargyl or benzyl.

20. The compound of claim 13, wherein R¹Is hydrogen or methyl.

21. The compound of claim 13, wherein R¹Is methyl.

22. The compound of claim 13, wherein when R ²When it is methyl, R³Is not methyl.

23. The compound of claim 13, wherein R²And R³Is hydrogen, or is optionally substituted with a group independently selected from:

C) a naphthyl group,

D) azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and

24. The compound of claim 13, wherein R²And R³Independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, sec-butyl, hydroxyethyl, 2-hydroxy-2-methylpropyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, dicyclopropylmethyl, pyrrolidinyl, piperidinyl, N-methylpiperidinyl, tetrahydropyranyl, 2-benzothiazolyl and methoxyethyl.

25. In the application ofThe compound of claim 13, wherein R²And R³Each independently hydrogen, ethyl, isopropyl, methoxyethyl, 2-benzothiazolyl, cyclopropyl, cyclobutyl, or cyclopentyl.

26. The compound of claim 13, wherein R²And R³Optionally substituted and taken together with the nitrogen atom to which they are attached form a tetrahydro-pyrimidin-2-ylidene or a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, 1, 3-dihydro-isoindol-2-yl, 5, 6-dihydro-4H-pyrimidin-1-yl, and 1, 1-dioxo-1. lamda⁶-thiomorpholin-4-yl.

27. The compound of claim 13, wherein R^fOptionally substituted, and is methyl, ethyl, isopropyl, allyl, cyclopropyl, tert-butoxycarbonyl, tetrahydrofuryl methyl, [1, 3 ] ]-dioxolan-ylmethyl, thiazolyl, thienyl, thienylmethyl, pyridyl, phenyl, acetyl, isobutyryl, cyclopropanecarbonyl, cyclobutanecarbonyl, pyridyl, pyridine-carbonyl, 1H-pyrrole-carbonyl and 1H-imidazole-carbonyl.

28. The compound of claim 13, wherein R²And R³Taken together with the nitrogen atom to which they are attached to form a 4-to 8-membered heterocyclic ring selected from piperidine, pyrrolidine and morpholine, said ring being substituted with 1 or 2 substituents R^ffAnd (4) substitution.

29. The compound of claim 13, wherein R^ffSelected from methyl, ethyl, isopropyl, butyl, hexyl, -CHF₂Benzhydryl, -CF₃Vinyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclobutylethyl, bromo, chloro, fluoro, iodo, -OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, isopropoxy, pentyloxy, -O (CH)₂)₂O-、-O(CH₂)₃O-, -CN, amino, methylamino, dimethylamino, diethylamino, diethylcarbamoyl, methylthio, methylsulfonyl, methanesulfonamido, -C (O) Rⁱ-COOH and ethoxycarbonyl.

30. The compound of claim 13, wherein R^ffSelected from methyl, fluoro, -OH, -CF₃Hydroxymethyl, hydroxyethyl, benzhydryl, dimethylamino, ethoxycarbonyl, cyano and-O (CH) ₂)₂O-。

31. The compound of claim 13, wherein RⁱSelected from the group consisting of methyl, pyridyl, isopropyl, cyclobutyl, cyclopropyl, N-methylpyrrolyl and 1-methylimidazolyl.

32. The compound of claim 13, wherein R²And R³Combined with the nitrogen atom to which they are attached to form azetidinyl, 3-difluoroazetidinyl, 3-benzhydryl-azetidinyl, 2-methylpyrrolidyl, 3-hydroxypyrrolidinyl, 3-dimethylaminopyrrolidinyl, 2, 5-dimethylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3-difluoropyrrolidinyl, piperidinyl, 4-fluoropiperidinyl, 3-difluoropiperidinyl, 4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl, 4-trifluoromethylpiperidinyl, 1, 4-dioxa-8-aza-spiro [4.5]Decan-8-yl, 4-cyanopiperidinyl, 4-ethoxycarbonylpiperidyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 2-hydroxymethylpiperidyl, 3-hydroxymethylpiperidyl, 4-hydroxymethylpiperidyl, 3-hydroxyethylpiperidyl, 4-hydroxyethylpiperidyl, morpholinyl, 2-methylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin-yl, 4-allyl-piperazin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4- (2-hydroxyethyl) -piperazin-1-yl, 4- (2-methoxyethyl) -piperazin-1-yl, 4- (tert-butoxycarbonyl) -piperazin-1-yl, 4- (tetrahydrofuran-2-ylmethyl) -piperazin-1-yl, 4- [1, 3]-dioxolan-2-ylmethyl-piperazin-1-yl, 4-thiazol-2-yl-piperazin-1-yl, 4- (2-thienyl) piperazinyl, 4-thiophen-2-ylmethyl-piperazin-1-yl, 4- (pyridin-4-yl) -piperazin-1-yl, 4-phenyl-piperazin-1-yl, 4- (2-hydroxyphenyl) piperazinyl, 4- (4-trifluoromethyl-phenyl) -piperazin-1-yl, 4- (4-cyanophenyl) -piperazin-1-yl, 4-acetyl-piperazin-1-yl, 4-isobutyryl-piperazin-1-yl, 4-cyclopropanecarbonyl-piperazin-1-yl, 4-cyclobutanecarbonyl-piperazin-1-yl, 4-pyridin-4-yl-piperazin-1-yl, 4- (pyridine-4-carbonyl) -piperazin-1-yl, 4- (1-methyl-1H-pyrrole-2-carbonyl) -piperazin-1-yl, 4- (1-methyl-1H-imidazole-4-carbonyl) -piperazin-1-yl, 1-dioxo-1. lambda⁶Thiomorpholin-4-yl, 2, 6-dimethylmorpholin-4-yl and 1, 3-dihydro-isoindol-2-yl, 5, 6-dihydro-4H-pyrimidin-1-yl.

33. The compound of claim 13, wherein R²And R³Taken together with the nitrogen atom to which they are attached to form piperidinyl, 4-fluoropiperidinyl, 4-difluoropiperidinyl, morpholinyl or 3-methylmorpholin-4-yl.

34. The compound of claim 13, wherein R⁴Is hydroxy, methoxy, ethoxy, isopropoxy, pentyloxy, -CF₃Methyl, ethyl, propyl, isobutyl, pentyl, chlorine or fluorine.

35. The compound of claim 13, wherein R⁴Is hydroxy, methyl, methoxy, fluoro or-CF₃。

36. The compound of claim 13, wherein two R' s⁴Taken together to form a methylene group.

37. The compound of claim 13, wherein R²And one R⁴Combined together to form methylene, ethylene or-CH₂CH₂O-。

38. The compound of claim 13, wherein m is 0.

39. The compound of claim 13, wherein R⁵Is methyl, ethyl, isopropyl, hexyl, hydroxyl, methoxy, ethoxy, isopropoxy, methylthio, bromo, chloro, fluoro or iodo.

40. The compound of claim 13, wherein R⁵Is methyl, hydroxy or fluorine.

41. The compound of claim 13, wherein Ar¹Is optionally substituted, and is selected from:

d) a naphthyl group,

f) pyridyl, pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, 1-, 3-or 4-isoquinolinyl, 2-, 3-or 4-quinolyl, 2-or 3-quinoxalinyl, 2-or 4-quinazolinyl, [1, 5], [1, 6], [1, 7] or [1, 8] naphthyridin-2-, 3-or 4-yl, [2, 5], [2, 6], [2, 7], [2, 8] naphthyridin-1-, 3-or 4-yl.

42. The compound of claim 13, wherein Ar¹Optionally substituted, and is selected from phenyl, pyridyl, pyrazinyl, thiazolyl, pyrazolyl, and thienyl.

43. The compound of claim 13, wherein G is a bond or-S-.

44. The compound of claim 13, wherein Ar²Selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or pyrazinyl.

45. The compound of claim 13, wherein Ar¹Selected from the group consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-ethoxyphenyl, 2, 4-dimethoxyphenyl, 2, 5-dimethoxyphenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethoxyphenyl, 3, 4, 5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methoxyphenyl, and the like, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3-trifluoromethoxyphenyl group, 4-bisFluoromethoxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 3-acetylphenyl group, 4-acetylphenyl group, 3, 4-difluorophenyl group, 3, 4-dichlorophenyl group, 2, 3-difluorophenyl group, 2, 3-dichlorophenyl group, 2, 4-difluorophenyl group, 2, 4-dichlorophenyl group, 2, 5-dichlorophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 3-chloro-4-fluorophenyl group, 3-chloro-4-methoxyphenyl group, 3-chloro-4-difluoromethoxyphenyl group, 3-fluoro-4-chlorophenyl group, 2-fluoro-4-methoxyphenyl group, 3-fluoro-4-methoxyphenyl group, Benzo [1, 3 ] ]Dioxol-4-or 5-yl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3, 4-dihydroxyphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-morpholin-4-yl-phenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, 4-trifluoromethylthiophenyl, thiophen-2-yl, thiophen-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chloro-5-pyridyl, 2-hydroxy-3-yl, 4-morpholin-4-yl-phenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, 4-, 2-dimethylamino-5-pyridinyl, 6-methoxy-pyridin-3-yl, 6-methylsulfanyl-pyridin-3-yl, 2-hydroxy-5-pyridinyl, 6-pyrazol-1-yl-pyridin-3-yl, 6-bromo-pyridin-3-yl, 6-ethynyl-pyridin-3-yl, 6-trimethylsilylethynyl-pyridin-3-yl, 6-thiophenyl-pyridin-3-yl, 6-imidazol-1-yl-pyridin-3-yl, 6- (1H-imidazol-2-ylsulfanyl) -pyridin-3-yl, optionally substituted phenyl and unsubstituted phenyl, 6- (pyrimidin-2-ylsulfanyl) -pyridin-3-yl, oxazol-5-yl, thiazol-2-yl, 2H-pyrazol-3-yl, pyrazin-2-yl, 1-naphthyl, 2-naphthyl, 4-imidazol-1-ylphenyl, 4-pyrazol-1-ylphenyl, 1H-indol-5-yl, 1H-benzimidazol-5-yl, benzo [ b [ -b]Thiophen-7-yl and 4-biphenyl.

46. The compound of claim 13, wherein Ar¹Optionally substituted by halogen and is 4-methoxyphenyl, 4-methylthiophenyl or 4-chlorophenyl.

47. The compound of claim 13, wherein said pharmaceutically acceptable salt is a potent amino addition salt.

48. The compound of claim 13, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate and laurylsulfonate.

49. The compound of claim 13, which is isotopically labeled and detected by PET or SPECT.

50. A medicinal preparation for treating histamine H₃A method of studying a receptor and 5-hydroxytryptamine mediated disease, said method comprising the use of¹⁸F-labelled or¹¹A step of C-labeling the compound of claim 13 as a Positron Emission Tomography (PET) molecular probe.

51. A compound of the following formula (II) and enantiomers, diastereomers, hydrates, solvates thereof and pharmaceutically acceptable salts, esters and amides thereof:

Wherein

n is 1 or 2;

x is 0 or 1;

wherein n + x is 1 or 2;

wherein R is^bAnd R^cEach independently is-H or-C_1-6An alkyl group;

R³selected from: -H;

C) A naphthyl group,

E) monocyclic aromatic hydrocarbon groups having 5 or 6 ring atoms, having carbon atoms as attachment points, having one carbon atom replaced with: > O, >, CS、＞NH、＞N(C_1-4Alkyl) or > NC (O) OC_1-4Alkyl, up to one carbon atom being optionally replaced by-N ═ and optionally benzo-fused or pyridine-fused;

wherein R is^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

R⁴is-OH, -OC_1-6Alkyl, -CF₃、-C_1-6An alkyl group or a halogen, in which,

m is 0, 1 or 2;

R⁵is selected from-C_1-6Alkyl, -OH, -OC_1-6Alkyl, -SC_1-6Alkyl and halogen;

Ar¹Is an aryl or heteroaryl ring selected from:

wherein R is^jSelected from:

wherein R is^kAnd R^lEach independently is-H or-C_1-6An alkyl group;

2)-G-Ar²wherein G is a bond, -O-or-S-, Ar²Is phenyl or is a monocyclic aromatic hydrocarbon radical having 5 or 6 ring atoms, having one carbon atom replaced by: > O, > S, > NH or > N (C)_1-4Alkyl) and up to one further carbon atom is optionally replaced by-N ═ and the radicals are optionally substituted by R ^pMono-, di-or tri-substituted;

wherein R is^uAnd R^vEach independently is-H or C_1-6An alkyl group;

c) a phenyl group fused on two adjacent ring atoms to a 4-membered hydrocarbon moiety to form a fused 6-membered aromatic ring, wherein 1 or 2 carbon atoms are replaced by-N ═ and the fused ring is optionally substituted by R ^tMono-, di-or tri-substituted;

52. The compound of claim 51, wherein n is 1 and x is 0.

53. The compound of claim 51, wherein n is 1 and x is 1.

54. The compound of claim 51, wherein n is 2 and x is 0.

55. The compound of claim 51, wherein R¹Is methyl.

56. The compound of claim 51, wherein R³Is hydrogen, ethyl, isopropyl, methoxyethyl, 2-benzothiazolyl, cyclopropyl, cyclobutyl or cyclopentyl.

57. The compound of claim 51, wherein R⁴Is methyl, hydroxy, methoxy, -CF₃Methyl, fluoro or chloro.

58. The compound of claim 51, wherein m is 0.

59. The compound of claim 51, wherein R⁵Is methyl, hydroxyl, methoxyl, methylthio, fluorine or chlorine.

60. The compound of claim 51, wherein Ar¹Optionally substituted by halogen and is 4-methoxyphenyl, 4-methylthiophenyl or 4-chlorophenyl.

61. The compound of claim 51, wherein-R²-R⁴-is methylene.

62. The compound of claim 51, wherein-R²-R⁴-is ethylene.

63. The compound of claim 51, wherein-R²-R⁴is-CH₂CH₂O-。

64. A compound selected from the group consisting of:

(48)7- [ 2-fluoro-3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(49)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(50)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(51)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(52)4- (3-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(53)4- (4-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(54)4- (3-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(55)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(56)4- (4-difluoromethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(57)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methanesulfonyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(58)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(59)4- (3-chloro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(60)4- (2, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(61)4- (2, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(62)4- (3, 5-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(63) 2-methyl-7- (3-piperidin-1-yl-propoxy) -4-thiophen-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(64)4- (3, 4-dichloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(65) 2-methyl-7- (3-piperidin-1-yl-propoxy) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(66) 2-methyl-7- (3-piperidin-1-yl-propoxy) -4- (trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(67)4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (racemate);

(68)4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(69)4- (4-methoxy-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(70) 2-tert-butyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(71) 2-benzyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(72) 2-ethyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(73)4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -2-propyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(74) 2-isopropyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(75)4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(76)3- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl ] -propan-1-ol;

(77)2- [4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -3, 4-dihydro-1H-isoquinolin-2-yl ] -ethanol;

(78)2- (2-fluoro-ethyl) -4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(79) 2-cyclopropyl-4- (4-methoxy-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(80)4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(81)4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(82)4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -2- (1-phenyl-ethyl) -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(83)4- (3, 4-dichloro-phenyl) -2-methyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(84)4- (3, 4-di-chloro-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(85)4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(86)4- (3-chloro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(87) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(88)4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(89)4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(90)7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(91)4- (4-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(92)4- (4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(93)7- (1-cyclopentyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(94)7- (1-ethyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(95)4- (3-chloro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(96)4- (3-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(97)4- (2-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(98)7- (1-isopropyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(99)4- (3-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(100)4- (3-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(101)7- (1-cyclopentyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(102)7- (1-ethyl-piperidin-4-ylmethoxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(103)4- (3-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(104)4- (3-methoxy-phenyl) -2-methyl-7- (1-methyl-piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(105)7- (1-isopropyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(106)7- (1-cyclobutyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(107)7- (1-ethyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(108)7- (1-cyclopentyl-piperidin-4-yloxy) -4- (3-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(109)4- (3-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(110)7- (1-isopropyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(111)7- (1-cyclobutyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(112)7- (1-ethyl-piperidin-4-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(113)4- (3-chloro-4-methoxy-phenyl) -7- (1-cyclobutyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(114)4- (3-chloro-4-methoxy-phenyl) -7- (1-ethyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(115)4- (3-chloro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(116) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(117)7- (1-isobutyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(118)7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (3-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(119)4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(120)7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (2-fluoro-4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(121)4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (1-propyl-piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(122)4- (2-fluoro-4-methoxy-phenyl) -7- (1-isobutyl-piperidin-4-ylmethoxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(123)7- [1- (2-fluoro-ethyl) -piperidin-4-ylmethoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(124)7- (1-isopropyl-piperidin-4-yloxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(125)7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(126)4- (2-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(127)4- (3-fluoro-4-methoxy-phenyl) -7- (1-isopropyl-piperidin-4-yloxy) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(128)4- (4-methoxy-phenyl) -2-methyl-7- [1- (tetrahydro-pyran-4-yl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(129)2, 2, 2-trifluoro-1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -ethanone;

(130)4- (4-methoxy-phenyl) -2-methyl-7- [1- (2, 2, 2-trifluoro-ethyl) -piperidin-4-ylmethoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(131)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4-phenyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(132)4- (2-fluoro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(133)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4-p-tolyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(134) 2-benzyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(135)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (3-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(136)7- [3- (3, 3-difluoro-pyrrolidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(137)4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(138) dicyclopropylmethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(139)4- (2-chloro-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(140) 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-morpholin-4-yl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(141)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-morpholin-4-yl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(142)4- { 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -benzonitrile;

(143)4- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -benzonitrile;

(144)7- [3- (3-benzhydryl-azetidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(145) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(146)4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (racemate);

(147)4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(148)4- (2-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(149)4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (racemate);

(150)4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(151)4- (3-fluoro-4-methoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(152)4- (4-ethoxy-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(153) 2-ethyl-7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(154)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(155)4- (4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(156) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(157)4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(158)4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- (piperidin-4-yloxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(159)7- [1- (2-fluoro-ethyl) -piperidin-4-yloxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(160)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(161)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(162)4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(163)4- (4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(164) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(165) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 2);

(166)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(167)4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(168)7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(169)4- (4-methoxy-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(170)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methylsulfinyl-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(171)4- (4-methylsulfinyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(172)4- (4-methylsulfinyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline (enantiomer 1);

(173)4- (4-methanesulfonyl-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(174)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2, 6-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(175)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(176)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ol;

(177)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-8-ol;

(178)2, 8-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(179)2, 6-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(180) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinolin-8-ol;

(181) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinolin-6-ol;

(182) 8-fluoro-2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(183) 6-fluoro-2-methyl-4- (4-methylsulfanyl-phenyl) -7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(184)7- [1- (2-fluoro-ethyl) -piperidin-4-ylmethoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(185)7- [1- (2-fluoro-ethyl) -piperidin-4-yloxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(186)4- (4-methoxy-phenyl) -7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(187)4- (4-methylsulfinyl-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(188)7- [3- (3, 3-difluoro-azetidin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(189) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-3-yl) -methanol;

(190) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-3S-yl) -methanol;

(191) (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -morpholin-2-yl) -methanol;

(192) {3- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (2H-pyrazol-3-yl) -amine;

(193)4- (6-bromo-pyridin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(194)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-methylsulfanyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(195) (5- {7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-yl } -pyridin-2-yl) -dimethyl-amine;

(196)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-trimethylsilylethynyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(197)4- (6-ethynyl-piperidin-3-yl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(198)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-thiophenyl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(199)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (6-imidazol-1-yl-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(200)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- (6-methoxy-pyridin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(201)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (6-pyrazol-1-yl-pyridin-3-yl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(202)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -4- [6- (1H-imidazol-2-ylsulfanyl) -pyridin-3-yl ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(203)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- [6- (pyrimidin-2-ylsulfanyl) -pyridin-3-yl ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(204)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(205)7- [3- (4-ethyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(206)7- [3- (4-isopropyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(207)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-thiazol-2-yl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(208)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-thiophen-2-ylmethyl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(209)2- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -ethanol;

(210)2- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -phenol;

(211)4- (4-methoxy-phenyl) -2-methyl-7- [3- (4-pyridin-4-yl-piperazin-1-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(212)4- (4-methoxy-phenyl) -2-methyl-7- {3- [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl ] -propoxy } -1, 2, 3, 4-tetrahydro-isoquinoline;

(213)7- [3- (4-allyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(214)7- [3- (4- [1, 3] -dioxolan-2-ylmethyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(215)4- (4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazin-1-yl) -benzonitrile;

(216)7- {3- [4- (2-methoxy-ethyl) -piperazin-1-yl ] -propoxy } -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(217)4- (4-methoxy-phenyl) -2-methyl-7- {3- [4- (tetrahydro-furan-2-ylmethyl) -piperazin-yl ] -propoxy } -1, 2, 3, 4-tetrahydro-isoquinoline;

(218)4- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -piperazine-1-carboxylic acid tert-butyl ester;

(219)7- [3- (4-cyclopropyl-piperazin-1-yl) -propoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(220)4- (4-bromo-phenyl) -7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(221)4- (4-difluoromethoxy-phenyl) -2-methyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(222) 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(223)7- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(224)7- [3- (4-fluoro-piperidin-1-yl) -propoxy ] -2-methyl-4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(225) 2-methyl-7- (3-morpholin-4-yl-propoxy) -4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(226) 2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -4- (4-trifluoromethylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(227)4- (2-fluoro-4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(228)4- (3-fluoro-4-methoxy-phenyl) -2-methyl-7- [3- (3S-methyl-morpholin-4-yl) -propoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(229) 2-methyl-7- (3-piperidin-1-yl-propoxy) -4- (4-trifluoromethoxy-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(230) {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (tetrahydro-pyran-4-yl) -amine;

(231) cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } - (1-methyl-piperidin-4-yl) -amine;

(232) (2-methoxy-ethyl) - {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(233)3- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propylamino } -propan-1-ol;

(234) Allyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(235) isobutyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(236) cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(237) isopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(238) {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -propyl-amine;

(239) ethyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(240) isopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -methyl-amine;

(241) cyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -methyl-amine;

(242) bicyclopropyl- {3- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -propyl } -amine;

(243)7- (1-isopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(244)7- (1-cyclopropyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(245)7- (1-cyclobutyl-azetidin-3-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(246)7- [1- (2-fluoro-ethyl) -azetidin-3-ylmethoxy ] -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(247)4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(248)4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(249)4- (4-methoxy-phenyl) -2-methyl-7- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(250)4- (3-methoxy-phenyl) -2-methyl-7- (piperidin-4-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(251) {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -acetonitrile;

(252) 2-methyl-7- (1-methyl-piperidin-4-yloxy) -4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(253) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- [1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

hydrogen (254) {4- [ 2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxy ] -piperidin-1-yl } -acetonitrile;

(255) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- [1- (tetrahydro-pyran-4-yl) -piperidin-4-yloxy ] -1, 2, 3, 4-tetrahydro-isoquinoline;

(256)7- (1-cyclopropyl-piperidin-4-yloxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(257)7- (1-cyclobutyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(258)7- (1-cyclopropyl-piperidin-4-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(259)1- {4- [4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yloxymethyl ] -piperidin-1-yl } -2-methyl-propan-2-ol;

(260)4- (4-methoxy-phenyl) -2-methyl-7- (4-methyl-morpholin-2-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(261)4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2S-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(262)4- (4-methoxy-phenyl) -2-methyl-7- (morpholin-2R-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(263)7- (4-isopropyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(264)7- (4-isopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(265)7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(266)7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(267)7- (4-isopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(268)7- (4-ethyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(269)7- [4- (2-fluoro-ethyl) -morpholin-2-ylmethoxy ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(270)7- (4-cyclopropyl-morpholin-2-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(271)7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(272)7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(273)7- (4-cyclopropyl-morpholin-2S-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(274)7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(275)7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 1);

(276)7- (4-cyclopropyl-morpholin-2R-ylmethoxy) -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (diastereomer 2);

(277)7- (4-isopropyl-morpholin-2-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(278)7- (4-cyclopropyl-morpholin-2-ylmethoxy) -2-methyl-4- (4-methylsulfanyl-phenyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(279) 2-methyl-4- (4-methylsulfanyl-phenyl) -7- (morpholin-2-ylmethoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(280)4- (4-methoxy-phenyl) -2, 6-dimethyl-7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(281)4- (4-methoxy-phenyl) -2, 6-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(282)4- (3-fluoro-4-methoxy-phenyl) -2, 6-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(283)4- (3-fluoro-4-methoxy-phenyl) -2, 8-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(284)4- (4-methoxy-phenyl) -2, 8-dimethyl-7- (3-morpholin-4-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(285)2, 6-dimethyl-4- (4-methylsulfanyl-phenyl) -7- (3-piperidin-1-yl-propoxy) -1, 2, 3, 4-tetrahydro-isoquinoline;

(286)7- (4-piperidin-1-yl-but-1-ynyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(287)7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(288) 2-methyl-7- (4-piperidin-1-yl-butyl) -4-pyridin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline;

(289)7- [4- (4, 4-difluoro-piperidin-1-yl) -but-1-ynyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(290)4- (4-methoxy-phenyl) -2-methyl-7- (4-piperidin-1-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(291)4- (4-methoxy-phenyl) -2-methyl-7- (4-morpholin-4-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(292)4- (4-methoxy-phenyl) -2-methyl-7- (4-thiomorpholin-4-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(293)7- [4- (4-isopropyl-piperazin-1-yl) -but-1-ynyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(294)4- (4-fluoro-phenyl) -2-methyl-7- (4-piperidin-1-yl-but-1-ynyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(295)7- [4- (4, 4-difluoro-piperidin-1-yl) -butyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

(296)4- (4-methoxy-phenyl) -2-methyl-7- (4-morpholin-4-yl-butyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(297)4- (4-methoxy-phenyl) -2-methyl-7- (4-thiomorpholin-4-yl-butyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

(298)7- [4- (4-isopropyl-piperazin-1-yl) -butyl ] -4- (4-methoxy-phenyl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline;

and salts thereof.

65. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I) and enantiomers, diastereomers, hydrates, solvates thereof and pharmaceutically acceptable salts, esters and amides thereof:

wherein

L is-O-, and n is 1 or 2; or L is-C ≡ C-or-CH₂CH₂-n is 0 or 1;

wherein R is^aSelected from-OH, -OC _1-6Alkyl, optionally substituted by-OC_1-4Alkyl or halogen substituted phenyl, -CN, -NO₂、-N(R^b)R^c、-C(O)N(R^b)R^c、-N(R^b)C(O)R^b、-N(R^b)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -SO₂N(R^b)R^c、-SCF₃Halogen, -CF₃、-OCF₃-COOH and-COOC_1-6An alkyl group;

wherein R is^bAnd R^cEach independently is-H or-C_1-6An alkyl group;

R²and R³Each independently selected from: -H;

C) a naphthyl group,

E) Monocyclic aromatic hydrocarbon groups having 5 or 6 ring atoms, having carbon atoms as attachment points, havingOne carbon atom is replaced by: > O, > S, > NH, > N (C)_1-4Alkyl) or > NC (O) OC_1-4Alkyl, up to one carbon atom being optionally replaced by-N ═ and optionally benzo-fused or pyridine-fused;

wherein R is^dAnd R^eEach independently is-H or-C_1-6An alkyl group;

alternatively, the first and second electrodes may be,

Wherein R is^fSelected from:

wherein R is^zIs fluorine, -CN, -OH, -OC_1-4Alkyl, -C_3-7Cycloalkyl or-CF₃；

Wherein R is^gAnd R^hEach independently is-H or-C_1-6An alkyl group; and

m is 0, 1 or 2;

R⁵is selected from-C_1-6Alkyl, -OH, -OC_1-6Alkyl, -SC_1-6Alkyl and halogen;

Ar¹is an aryl or heteroaryl ring selected from:

wherein R is^jSelected from:

1)-OH、-C_1-6alkyl, -OC optionally mono-, di-or trisubstituted by halogen_1-6Alkyl, -C_2-6Alkenyl, -OC_3-6Alkenyl, optionally trimethylsilyl-substituted-C_2-6Alkynyl, -OC_3-6Alkynyl, -C_3-6Cycloalkyl, -OC_3-6Cycloalkyl, -CN, -NO₂、-N(R^k)R^l、-N(R^k)C(O)R^l、-N(R^k)SO₂C_1-6Alkyl, -C (O) C_1-6Alkyl, -S (O)_0-2-C_1-6Alkyl, -C (O) N (R)^m)Rⁿ、-SO₂N(R^m)Rⁿ、-SCF₃Halogen compoundsCF₃、-COOH、-COOC_1-6Alkyl and-COOC_3-7A cycloalkyl group;

wherein R is^kAnd R^lEach independently is-H or-C_1-6An alkyl group;

b) phenyl or pyridyl fused to a 3-membered hydrocarbon moiety at two adjacent ring carbon atoms Combine to form a fused 5-membered aromatic ring, one carbon atom in said moiety being replaced by > O, > S, > NH or > N (C)_1-4Alkyl) and up to one further carbon atom in said moiety is optionally replaced by-N ═ and fused rings are optionally substituted by R^tMono-, di-or tri-substituted;

wherein R is^uAnd R^vEach independently is-H or C_1-6An alkyl group;

e) a monocyclic aromatic hydrocarbon group having 5 ring atoms, having a carbon atom as a point of attachment, having one carbon atom replaced with: > O, > S, > NH or > N (C)_1-4Alkyl) up to one further carbon atom being optionally replaced by-N ═ optionally by R^jMono-or disubstituted and optionally benzo-or pyridine-fused at two adjacent carbon atoms, wherein the benzo-or pyridine-fused moiety is optionally substituted with R ^tMono-, di-or tri-substituted; and