KR100872023B1 - 2- (1H-indolylsulfanyl) -benzyl amine derivative as SSR - Google Patents

Abstract

The present invention relates to aniline derivatives of the general formula It is about a use.

Description

2- (1H-indolylsulfanyl) -benzyl amine derivative {2- (1H-INDOLYLSULFANYL) -BENZYL AMINE DERIVATIVES AS SSRI} as SSR}

Field of technology

The present invention relates to compounds which are serotonin reuptake inhibitors and preferably also norepinephrine reuptake inhibitors, and the medical uses of such compounds, such as depression and anxiety, affective disorders, pain disorders, attention deficit multiple dysfunction disorders (ADHD) and incontinence To use in therapy.

Prior art

The majority of currently available antidepressants can be divided into three classes:

1) monoamine oxidase inhibitor (MAOI),

2) bioreactive amine neurotransmitter [serotonin (5-HT), norepinephrine (NE) and dopamine (DA)] transporter reuptake blockers, and

3) blockers of modulators, in particular one or more 5-HT and / or NE receptors.

Since depression is associated with relative deficiency of bio-based amines, the use of 5-HT and / or NE-receptor blockers (i.e. of 5-HT and / or NE-antagonists) is very useful in the treatment of depression and anxiety. It has not been demonstrated that successful, preferred and presently most effective treatments are based on enhancing 5-HT and / or NE-neurotransmission by re-blocking their reabsorption from synaptic niches (Slattery, DA et al., “The evolution of antidepressant mechanisms ", fundamental and clinical pharmacology , 2004 , 18, 1-21; Schloss, P. et al.," new insights into the mechanism of antidepressant therapy ", Pharmacology and therapeutics , 2004 , 102, 47-60).

For many years, monoamines, in particular monoamine serotonin (5-HT), norepinephrine (NE) and dopamine (DA) reuptake inhibition, have been studied for the treatment of depression.

Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) are generally efficient, highly resistant, and have an advantageous safety profile when compared to traditional tricycle antidepressants, and thus are useful in the treatment of depression, some forms of anxiety, and social phobia. It has been the first treatment of choice. Examples of drugs claimed by SSRIs are fluoxetine, sertraline and paroxetine.

However, clinical studies on depression show that the nonresponse to known SSRIs is significant, up to 30%. Another element of antidepressant therapy, which is often overlooked, is that it has a rather sufficient effect in terms of acceptance, ie the patient is continuously motivated to drug therapy. First of all, there is generally a delay in the therapeutic effect of SSRIs. Occasionally, symptoms even worse during the first week of treatment. Second, sexual dysfunction is a common and common side effect of SSRIs. Without addressing the above problem, no real progress will be made in pharmacotherapy of depression and anxiety disorders. Therefore, there is a need for the development of compounds that can improve the treatment of depression and other serotonin-related diseases.

A newer strategy is the development of dual reuptake inhibitors, for example, the effects of combined serotonin reuptake inhibition and norepinephrine (norepinephrine, also referred to as noradrenaline, NA) repression of depression can be attributed to duloxetine ( Duloxetine: Wong, "Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate", Expert Opinion on Investigational Drugs , 1998 , 7, 10, 1691-1699)) and venlafaxine: Khan- A et al., 30, in clinical studies of compounds such as "Venlafaxine in depressed outpatients", Psychopharmacology Bulletin , 1991 , 27 , 141-144). Compounds with this dual effect are also referred to as SNRI "serotonin and noradrenaline reuptake inhibitors", or NSRI "noradrenaline and serotonin reuptake inhibitors".

Treatment with the selective NE reuptake inhibitor reboxetine appears to stimulate 5-HT neurons and modulate 5-HT release in the brain (Svensson, T. et al . , J. Neural. Transmission , 2004 , 111, 127). There may be synergistic benefits of using SNRI to treat depression or anxiety.

Clinical studies have shown that the use of SNRI has a beneficial effect on pain (fibromyalgia syndrome, general pain, back pain, shoulder pain, headache, pain during daytime activities and while awake) and especially pain associated depression (Berk , M. Expert Rev. Neurotherapeutics 2003 , 3, 47-451; Fishbain, DA, et al. "Evidence-based data from animal and human experimental studies on pain relief with antidepressants: A structured review" Pain Medicine 2000 1: 310-316 ).

SNRI has also been shown in clinical studies to have a beneficial effect on attention deficit hyperactivity disorder (ADHD) (N. M. Mukaddes; Venlafaxine in attention deficit hyperactivity disorder, European Neuropsychopharmacology, Volume 12, Supplement 3, October 2002, Page 421).

Moreover, SNRI has been shown to be effective for treating incontinence urinary incontinence (Dmochowski R. R. et al. "Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence", Journal of Urology 2003, 170: 4, 1259-1263).

Moreover, Axford L et al. Described the development of triple 5-HT, NE and DA reuptake inhibitors for the treatment of depression (2003, Bioorganic & Medical Chemistry Letters , 13, 3277-3280: “Bicyclo [2.2.1.]. heptanes as novel triple re-uptake inhibitors for the treatment of depression "). Wellbutrin (bupropion) with DA reuptake activity in vitro and in vivo shows antidepressant efficacy. Other combinatorial studies have shown that the addition of certain affinity at the site of DA uptake may have clinical benefit (Nelson, JCJ Clin . Psychiatry 1998 , 59, 65; Masand, PS et al. Depression Anxiety 1998 , 7, 89; Bodkin, J. A et al . J. Clin . Psychiatry 1997 , 58, 137).

The present invention provides a 2- (1H-indolylsulfanyl) -benzyl amine derivative of Formula I, which is a serotonin reuptake inhibitor. In particular, the present invention provides compounds having a combined effect of inhibiting serotonin reuptake and inhibiting norepinephrine reuptake. Moreover, some of these compounds are also triple 5-HT, NE and DA reuptake inhibitors.

Diphenyl sulfides of formula XVI and variants thereof have been disclosed as serotonin reuptake inhibitors and have been proposed for the treatment of depression. See, for example, US 5095039, US 4056632, EP 396827 A1 and WO 9312080. EP 402097 discloses halogen substituted diphenylsulfides claimed as selective serotonin inhibitors for the treatment of depression. Likewise, WO 9717325 discloses derivatives of N, N-dimethyl-2- (arylthio) benzylamine claimed as selective serotonin transfer inhibitors and recommends its use as an antidepressant. J. Jilek et al., 1989, Collect. Czeck Chem. Commun., 54, 3294-3338, also discloses various derivatives of diphenyl sulfide, “phenyl-thio-benzylamine,” as antidepressants. Moreover, diphenyl sulfide is also disclosed in US 3803143 and claimed to be useful as an antidepressant.

[Formula XVI]

Some publications relate to the use of derivatives of diphenyl sulfide as "radiopharmaceuticals" for shooting SERTs with SPECT or PET (see, eg, "S. Oya et al., J. Med Chem. 2002, 45, 4716-). 4723 "and" S. Oya et al. J. Med. Chem. 42, 3, 333-335 ". P. Emond et al. (J. Med. Chem (2002) 45, 1253-1258) and “S. Oya et al. (J. Med. Chem. 42, 3, 333-335) further added dopamine, serotonin and norepinephrine. In vitro affinity measurements in the delivery vehicle tested and discussed "diphenyl sulfide" substituted as a selective serotonin transporter ligand for dopamine and norepinephrine transporters (DAT, NET).

WO 0066537 also discloses certain derivatives of diphenyl sulfide claimed to have higher selectivity for SERT than NET and DAT.

US 4,018,830 and US 4,055,665 refer to “ Ar ₁ -S- Ar ₂ , wherein Ar ₁ is a phenylalkyl amine substituent and Ar ₂ is a substituted or unsubstituted 5 to 6 atom homocyclic or heterocyclic ring such as aromatic Ring, heteroaromatic ring) and "phenylthioaralkylamine" and "2-phenylthiobenzylamine." The compounds have been claimed to be useful for preventing "cardiac arrhythmias".

K. Sindelar et al., "" Collection of Czechoslovak Chemical Communications, (1991), 56 (2), 449-58, K. Sindelar et al. "] Are the 5-HT reuptake inhibitors and NA for one of the rings to be used as antidepressant. Selectivity testing as each reuptake inhibitor is used to disclose the release of compounds of formula XVI substituted with thiophene rings.

US 6,596,741 B2 and US 6,436,938 B1 and US 6,410,736 B1 disclose biaryl ether derivatives (formula XVII below) reported to inhibit reabsorption of monoamines such as serotonin, dopamine and / or norepinephrine.

Formula XVII]

None of the above references discloses compounds comprising indole groups such as the indolyl-sulfanyl benzyl amines of the invention.

Summary of the Invention

The present invention relates to compounds having the general formula (I) as free base or salts thereof:

[Formula I]

[Wherein, the sulfur atom is attached to indole through any carbon ring of indole and R ¹ -R ¹³ are as follows].

In a further aspect the present invention provides the above compound of formula I according to the above as a pharmaceutically acceptable salt or free base thereof for use as a medicament.

The present invention also provides a pharmaceutical composition comprising a compound according to the above and at least one pharmaceutically acceptable carrier or diluent as a pharmaceutically acceptable salt or free base thereof.

The present invention further provides a free base or a salt thereof, such as a pharmaceutically acceptable salt, in a live animal body, including a human, comprising administering a therapeutically effective amount of a compound according to the above, in an affective disorder such as depression, Provided are methods of treating anxiety disorders including general anxiety disorders, social anxiety disorders, post-traumatic stress disorders, obsessive-compulsive disorders, panic disorders, panic attacks, specific phobias, social phobias, or agoraphobia. The invention furthermore relates to the use of the compounds according to the above in methods of treating pain disorders, ADHD and stress incontinence.

Further, the present invention is for treating anxiety disorders including affective disorders such as depression, general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, panic attack, specific phobia, social phobia or agoraphobia To prepare a pharmaceutical composition of the invention, there is provided the use of a compound according to the above as a free base or a salt thereof, such as a pharmaceutically acceptable salt. The present invention furthermore provides the use of a compound according to the above for the preparation of a pharmaceutical composition for the treatment of pain disorders, ADHD and stress incontinence.

Justice

The term "halogen" means fluoro, chloro, bromo or iodo. "Halo" means halogen.

Expression "C _{1 -6-alk} (en / in) yl" is C _{1 -6-yl} means a group kinil -alkyl, C _{2 -6-alkenyl,} or C _{2 -6.}

The term "C _{1 -6} alkyl" refers to a branched or unbranched alkyl group having 1 to 6 carbon atoms comprising the following include, but are not limited to: methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl. Likewise, the term "C _{1 -4} alkyl" refers to a branched or unbranched alkyl group having 1 to 6 carbon atoms comprising the following, but are not limited to: methyl, ethyl, 1-propyl, 2-propyl, 1-butyl , 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.

The term "C _{2 -6} alkenyl" refers to a group having 2 to 6 carbon atoms wherein the group containing one double bond, comprising the following, but are not limited to: ethenyl, phenyl and ethenyl pro unit.

The term "C _{2 -6} il kinil" refers to a group having 2 to 6 carbon atoms wherein the group containing one triple bond, including but not limited to: ethynyl, propynyl and butynyl.

Expression "C _{3 -8-cycloalkyl} alk (en) yl" is C _{3 -8} - means a cycloalkenyl-cycloalkyl or C _{3 -8.}

The term "C _{3 -8} - cycloalkyl" refers to monocyclic or bicyclic carbocyclic click having 3 to 8 carbon atoms comprising the following, but are not limited to: cyclopropyl, cyclopentyl and cyclohexyl.

The term "C _{3 -8} - cycloalkenyl" refer to summon carbon limitation is comprising the following is not, the number of carbon atoms is 3 to 8 and click monocyclic or bicyclic with one double bond: cyclopropyl-propenyl, Cyclopentenyl and cyclohexenyl.

Expression "C _{3 -8} - cycloalkyl alk (en) yl -C _{1 -6} - alk (en / in) yl", the terms "C _{3 -8} - cycloalkyl alk (en) yl" and "C _{1 -6} - Alk (en / yn) yl "is as defined above.

The term "C _{1 -6} - alk (en / in) yloxy" has the formula C _{1 -6} - refers to a group of -O- yl alk (en / a), where C _{1 -6} - alk (en / in) Work is as defined above.

The term "C _{1 -6-alk} (en / in) yl-carbonyl", "C _{1 -6-alk} (en / in) yl-aminocarbonyl" and "di - (C _{1 -6-alk} (en / in) yl) aminocarbonyl "are each formula C _{1 -6} - alk (en / in) one -CO-, C _{1 -6} - alk (en / in) one -NH-CO- and (C _{1 - 6-alk} (en / in) yl) refers to the group of the ₂ -N-CO-, wherein C _{1 -6-alk} (en / in) work as defined above.

Expression "C _{1 -6-alk} (en / in) yl-amino", "di - (C _{1 -6-alkyl)} amino", "C _{1 -6-alk} (en / in) ylthio", "halo -C _{1 -6-alk} (en / in) yl "," halo -C _{1 -6-alk} (en / in) yl-sulfonyl "," halo -C _{1 -6-alk} (en / in) one - sulfanyl "," C _{1 -6-alk} (en / in) ilsul sulfonyl ", and" C _{1 -6-alk} (en / in) ilsul isoquinoline "etc., the terms" C _{1 -6-alk} (en / In) yl "and" halo "are as defined above.

The expression "R with nitrogen ¹ And R ² forms a 4 to 7 membered ring comprising 0 or 1 double bond, and optionally the ring comprises one additional heteroatom selected from nitrogen, oxygen and sulfur in addition to said nitrogen. " , 5, 6 or 7 membered heterocyclic ring system such as azetidine, pyrrolidine, piperidine, piperazine, homopiperazine or morpholine, which ring may be unsubstituted, or for example, the may include one or more substituents, for example up to 1 or 2 substituents selected from the group constituting of: halogen, hydroxy, C _{1 -6} - alkyl, C _{1 -6} - alkoxy, C _{1 6} - alkylthio, alkylsulfonyl, a methyl, trifluoromethyl trifluoromethyl sulfonyl and C _{1 -6-alkyl-carbonyl.}

Indole atoms are numbered according to the IUPAC Committee on Organic Chemistry Nomenclature Guidelines (Rigaudy, J .; Klesney, SP Nomenclature of Organic Chemistry Pergamon Press, (1979) ISBN 0080223699).

As used herein in connection with a disease or disorder, the term “treatment” also includes prophylaxis, as the case may be.

Compound of the Invention

The present invention relates to compounds of formula (I) as free bases or salts thereof:

[Formula I]

[In the meal,

Sulfur atoms are attached to indole through any ring carbon of the indole,

- R ¹ -R ² are independently hydrogen, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, and C _{3 -8} - cycloalkyl alk (en) yl -C _1-6-alk (en / in), or selected from one, or R ¹ together with the nitrogen And R ² forms a 4 to 7 membered ring comprising 0 or 1 double bond, and optionally the ring comprises one additional heteroatom selected from nitrogen, oxygen and sulfur in addition to said nitrogen;

- R ³ -R ¹² are independently, hydrogen, halogen, cyano, nitro, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - bicyclo alk (en) yl -C _{1 -6} - alk (en / in), amino, C _{1 -6} - alk (en / in) ylamino, di - (C _{1 -6} - alk (en / in) one ) amino, C _{1 -6} - alk (en / in) ylcarbonyl, aminocarbonyl, C _{1 -6} - alk (en / in) yl-aminocarbonyl, di - (C _{1 -6} - alk (en / a) yl) aminocarbonyl, hydroxy, C _{1 -6} - alk (en / in) yloxy, C _{1 -6} - alk (en / in) ylthio, halo -C _{1 -6} - alk (en / from the alk (en / in) ilsul sulfonyl-in) yl, halo -C _{1 -6-alk} (en / in) ilsul sulfonyl, halo -C _{1 -6-alk} (en / in) ilsul isoquinoline and C _{1 -6} Selected;

- R ¹³ is hydrogen, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, and C _{3 -8} - cycloalkyl alk (en) yl alk -C _1- 6- ( Yen / in) days;

only:

Sulfur atom indole nr. When attached via 2, R ⁷ is absent;

Sulfur atom indole nr. When attached via 3, R ¹² is absent;

Sulfur atom indole nr. When attached to 4, R ⁸ is absent;

Sulfur atom indole nr. When attached to 5, R ⁹ is absent;

Sulfur atom indole nr. When attached to 6, R ¹⁰ is absent;

Sulfur atom indole nr. When attached to 7, R ¹¹ is absent.

Without limiting, and to further illustrate the invention, the following embodiments of R ¹ -R ² are within the scope of the invention and in particular for compounds of the invention as free bases and salts thereof:

R ¹ -R ² are independently hydrogen, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, and C _{3 -8} - cycloalkyl alk (en) yl -C _{1 - 6} -alk (en / yn) yl;

R ¹ -R ² are independently selected from the group consisting of hydrogen and C _{1 -6} - selected from alkyl;

R ¹ -R ² are independently selected from the group consisting of hydrogen and C _{1 -4} - selected from alkyl;

R ¹ is hydrogen and R ² is methyl;

R ¹ And R ² is methyl;

R ¹ And R ² is hydrogen.

Without limiting, and to further illustrate the invention, the following embodiments of R ¹ -R ² are within the scope of the invention and in particular for compounds of the invention as free bases and salts thereof:

R ¹ -R ² are independently selected from the group consisting of hydrogen and C _{1 -6} - selected from the alk (en / person) or one; Or together with nitrogen R ¹ and R ² form a 4 to 7 membered ring comprising 0 or 1 double bond, optionally said ring being in addition to said nitrogen one further heteroatom selected from nitrogen, oxygen and sulfur Including.

Without limiting, and to further illustrate the invention, the following embodiments of R ¹ -R ² also fall within the scope of the invention and in particular for compounds of the invention as free bases and salts thereof:

R ¹ with nitrogen And R ² forms a 4 to 7 membered ring (ie including 5 or 6), including 0 or 1 double bond, optionally wherein said ring is selected from nitrogen, oxygen and sulfur in addition to said nitrogen; Further heteroatoms, wherein the ring system is unsubstituted;

R ¹ with nitrogen And R ² forms a 4 to 7 membered ring comprising 5 or 6, including 0 or 1 double bond, optionally wherein said ring is in addition to said nitrogen one additional hetero selected from nitrogen, oxygen and sulfur It includes an atom, wherein the ring system is, for example hydroxy, C _{1 -6} - alkyl (e.g., methyl), halogen (e.g., fluoro or chloro), C _{1 -6} - alkoxy (e. g., methoxy), C _{1 -6} - alkylthio, alkylsulfonyl, a methyl, trifluoromethyl trifluoromethyl sulfonyl and C _{1 -6} - one or more substituents selected from the group consisting of alkylcarbonyl, for example up to Including one or two substituents;

R ¹ with nitrogen And R ² forms a ring selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, homopiperazine or morpholine, and the ring may be unsubstituted, or for example hydroxy, C _1-6-alkyl (e.g., methyl), halogen (e.g., fluoro or chloro), C _1-6 - alkoxy (e.g., methoxy), C _1-6 - alkylthio, alkylsulfonyl And may include one or more substituents, such as at most one or two substituents, selected from the group consisting of fonyl, trifluoromethyl, trifluoromethylsulfonyl, and C _{1-6 -alkylcarbonyl} .

Without limitation, and to further illustrate the invention, the following embodiments of R ³ -R ¹² are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ³ -R ¹² are independently hydrogen, halogen, cyano, C _{1 -6} - alkyl, C _{3 -8} - cycloalkyl, C _{3 -8} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkyloxy, C _{1 -6} - selected from methyl-alkylthio and trifluoromethyl;

R ³ -R ¹² are independently selected from hydrogen, chloro, fluoro, cyano, methyl, methoxy, methylthio and trifluoromethyl;

R ³ -R ¹² are hydrogen;

R ³ -R ¹² are independently selected from hydrogen and halogen;

R ³ -R ¹² are independently selected from hydrogen, chloro and fluorine;

R ³ -R ¹² are independently selected from hydrogen and chloro;

R ³ -R ¹² are independently selected from hydrogen and fluorine;

^At least one of R ³ -R ¹² is fluoro or chloro;

R ³ -R ¹² are independently selected from hydrogen and cyano;

R ³ -R ¹² are independently hydrogen and C _{1 -6} - selected from alk (en / in) yl;

R ³ -R ¹² are independently hydrogen and C _{1 -6} - selected from alkyl, such as methyl;

R ³ -R ¹² Are independently hydrogen and C _{1 -6} - alk (en / in) yloxy, preferably C _{1 -6} - selected from alkoxy, such as methoxy;

R ³ -R ¹² are independently hydrogen and C _{1 -6} - alkylthio, for example selected from methylthio;

R ³ -R ¹² are independently selected from hydrogen and trifluoromethyl.

The following embodiments are within the present invention:

A limited number of R ³ -R ¹² differs from hydrogen, eg, at least 3, or at least 5 or at least 6 R ³ -R ¹² are hydrogen;

All of R ³ -R ¹² are hydrogen;

Only 1, 2, 3 or 4 R ³ -R ¹² are different from hydrogen.

In one embodiment of the invention, only one, two or three of R ³ -R ¹² are different from hydrogen, preferably hydrogen, chloro, fluoro, cyano, methyl, methoxy, methylthio and trifluor Romethyl.

Without limiting, and to further illustrate the invention, the following embodiments of R ³ -R ¹² are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ³ -R ¹² are independently hydrogen, halogen, cyano, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - cycloalkyl alk (en) selected from alk (en / in) one day -C _{1 -6} - alk (en / in) yl, hydroxy, C _{1 -6} - - alk (en / in) yloxy and halo -C _{1 -6;}

R ³ -R ¹² are independently hydrogen, halogen, cyano, C _{1 -6} - alk (en / in) yl, hydroxy, C _{1 -6} - alk (en / in) yloxy and halo -C _{1 - 6} -alk (en / yn) yl;

One of R ³ -R ¹² is halogen, such as chloro or bromo or iodo or fluoro;

One of R ³ -R ¹² is cyano;

R ³ -R ¹² is one of the C _{1 -6} - (a yen /) alk yl, such as C _{1 -6} - alkyl, e.g., methyl or ethyl being;

R ³ -R ¹² One is hydroxy;

When alk (en / in) yloxy, such as C _{1 -6} - - R ³ -R ¹² is one of the C _{1 -6} alkyloxy, e.g., methoxy Im;

R ³ -R ¹² is one of halo -C _{1 -6-alk} (en / in) yl, such as halo -C _{1 -6-alkyl,} for, example, trifluoro-methyl Im.

The following embodiments are within the scope of the present invention:

One of R ³ -R ¹² is different from hydrogen;

Two of R ³ -R ¹² are different from hydrogen;

^{Three of} R ³ -R ¹² are different from hydrogen;

4 of R ³ -R ¹² are different from hydrogen.

Without further limitation, and to further illustrate the invention, the following embodiments of R ³ -R ⁶ are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ³ -R ⁶ are independently hydrogen, halogen, cyano, nitro, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - cycloalkyl alk ( yen) be -C _{1 -6} - alk (en / in), amino, C _{1 -6} - alk (en / in) ylamino, di - (C _{1 -6} - alk (en / in)) amino , C _{1 -6} - alk (en / in) ylcarbonyl, aminocarbonyl, C _1-6 - alk (en / in) yl-aminocarbonyl, di - (C _{1 -6} - alk (en) yl) aminocarbonyl, hydroxy, C _1-6 - alk (en / in) yloxy, C _{1 -6} - alk (en / in) ylthio, halo -C _{1 -6} - alk (en / in) one, halo -C _{1 -6} - alk (en / in) ilsul sulfonyl, halo -C _{1 -6} - alk (en / in) ilsul isoquinoline and C _{1 -6} - alk (en / a) selected from ilsul sulfonyl;

R ³ -R ⁶ are independently selected from hydrogen, halogen, cyano, C _{1 -6} - alkyl, C _{3 -8} - cycloalkyl, C _{3 -8} - cycloalkyl, -C _{1 -6} - alkyl, amino, C _{1 - 6} - alkylamino, di - (C _{1 -6-alkyl)} amino, C _{1 -6-alkyl-carbonyl,} aminocarbonyl, C _{1 -6-alkylamino-carbonyl,} di - (C _{1 -6-alkylamino} ) carbonyl, hydroxy, C _{1 -6} - alkoxy, C _{1 -6} - alkylthio, halo -C _{1 -6} - alkyl, halo -C _{1 -6} - alkylsulfonyl, halo -C _{1 -6} - alkyl Selected from sulfanyl and C _1-6 -alkylsulfonyl;

R ³ -R ⁶ are independently hydrogen, halogen, C _{1 -6} - alkyloxy and C _{1 -6} - selected from alkyl;

R ³ -R ⁶ are independently selected from hydrogen, halogen, methoxy and methyl;

R ³ -R ⁶ are independently selected from hydrogen, fluoro, chloro, methoxy and methyl.

Embodiments in which a limited number of R ³ -R ⁶ are different from hydrogen are within the present invention, for example:

Only one or two of R ³ -R ⁶ are different from hydrogen;

^{Three of} R ³ -R ⁶ are hydrogen and one of R ³ -R ⁶ is halogen;

^{Three of} R ³ -R ⁶ are hydrogen and one of R ³ -R ⁶ is methyl;

R ⁴ is different from hydrogen;

R ⁵ is different from hydrogen;

R ⁴ is different from hydrogen, for example chloro, fluoro, methyl or methoxy and the remaining of R ³ -R ⁶ are hydrogen;

R ⁵ is different from hydrogen, for example chloro, fluoro, methyl or methoxy, and the remaining of R ³ -R ⁶ are hydrogen;

Only one of R ³ -R ⁶ is different from hydrogen and is selected from the group consisting of fluoro, chloro, methyl and methoxy;

R ³ -R ⁶ is hydrogen.

Without limitation, and to further illustrate the invention, the following embodiments of R ³ -R ⁶ are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ³ -R ⁶ are independently selected from hydrogen, halogen, cyano, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, and C _{3 -8} - cycloalkyl alk (en) Selected from _{1 -} C _1-6 -alk (en / yn) yl;

R ³ -R ⁶ are independently selected from hydrogen, halogen and C _{1 -6} - selected from alk (en / in) yl;

R ³ is hydrogen;

R ⁴ is hydrogen, halogen and C _{1 -6} - selected from alk (en / in) yl;

R ⁴ is hydrogen;

R ⁴ is halogen, such as chloro or fluoro;

R ⁴ is C _{1 -6} - alk (en / in) yl, such as C _{1 -6} - alkyl, for example, being methyl;

R ⁵ is selected from hydrogen and halogen;

R ⁵ is hydrogen;

R ⁵ is halogen, such as chloro;

R ⁶ is hydrogen.

Without limiting, and to further illustrate the invention, the following embodiments of R ⁷ -R ¹² are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ⁷ -R ¹² are independently hydrogen, halogen, cyano, nitro, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - cycloalkyl alk ( yen) be -C _{1 -6} - alk (en / in), amino, C _{1 -6} - alk (en / in) ylamino, di - (C _{1 -6} - alk (en / in)) amino , C _{1 -6} - alk (en / in) ylcarbonyl, aminocarbonyl, C _1-6 - alk (en / in) yl-aminocarbonyl, di - (C _{1 -6} - alk (en) yl) aminocarbonyl, hydroxy, C _1-6 - alk (en / in) yloxy, C _{1 -6} - alk (en / in) ylthio, halo -C _{1 -6} - alk (en / in) one, halo -C _{1 -6} - alk (en / in) ilsul sulfonyl, halo -C _{1 -6} - alk (en / in) ilsul isoquinoline and C _{1 -6} - alk (en / a) selected from ilsul sulfonyl.

Embodiments in which a limited number of R ⁷ -R ¹² are different from hydrogen are within the scope of the present invention, for example:

Only one or two of R ⁷ -R ¹² differ from hydrogen;

R ⁷ -R ¹² Only one of which is different from hydrogen and the substituent is selected from the group consisting of hydrogen, methyl, fluoro, chloro or methoxy;

Only two of R ⁷ -R ¹² are different from hydrogen and the substituents are independently selected from the group consisting of hydrogen, methyl, fluoro, chloro or methoxy.

Without limitation, and to further illustrate the present invention, the following embodiments of R ⁷ -R ¹² are within the scope of the present invention and in particular for such compounds as free bases or salts thereof:

R ⁷ -R ¹² are independently hydrogen, halogen, cyano, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - cycloalkyl alk (en) selected from alk (en / in) one day -C _{1 -6} - alk (en / in) yl, hydroxy, C _{1 -6} - - alk (en / in) yloxy and halo -C _{1 -6;}

R ⁷ -R ¹² are independently hydrogen, halogen, cyano, C _{1 -6} - alk (en / in) yl, hydroxy, C _{1 -6} - alk (en / in) yloxy and halo -C _{1 - 6} -alk (en / yn) yl;

R ⁷ is hydrogen or C _{1 -6} - selected from one alk (en / in);

R ⁷ is C _{1 -6} - alk (en / in) yl, such as C _{1 -6} - alkyl;

R ⁸ is hydrogen, halogen, cyano, C _{1 -6-selected} from alk (en / in) yl-oxy-alk (en / in) yl, hydroxy, C _{1 -6;}

R ⁸ is hydrogen;

R ⁸ is halogen, such as fluoro, chloro or bromo;

R ⁸ is cyano;

R ⁸ is C _{1 -6} - alk (en / in) yl, such as C _{1 -6} - alkyl, for example, being methyl;

R ⁸ is hydroxy;

R ⁸ is C _{1 -6} - alk (en / in) yloxy, such as C _{1 -6} - alkyloxy, for example, methoxy Im;

R ⁹ is hydrogen, halogen, cyano, C _{1 -6-selected} from alk (en / in) yl-oxy-alk (en / in) yl, hydroxy, C _{1 -6;}

R ⁹ is hydrogen;

R ⁹ is halogen, such as fluoro, chloro, iodo or bromo;

R ⁹ is cyano;

R ⁹ is C _{1 -6} - alk (en / in) yl, such as C _{1 -6} - for example alkyl, such as methyl Im;

R ⁹ is hydroxy;

R ⁹ is C _{1 -6} - alk (en / in) yloxy, such as C _{1 -6} - alkyloxy, for example, methoxy Im;

R ¹⁰ is hydrogen, halogen, cyano, C _{1 -6} - alk (en / in) yl, hydroxy, C _{1 -6} - alk (en / in) yloxy and halo -C _{1 -6} - alk (en Selected from;

R ¹⁰ is hydrogen;

R ¹⁰ is halogen, such as fluoro, chloro or bromo;

R ¹⁰ is cyano;

R ¹⁰ is C _{1 -6} - alk (en / in) yl, such as C _{1 -6} - alkyl, for example, being methyl;

R ¹⁰ is hydroxy;

R ¹⁰ is C _{1 -6} - alk (en / in) yloxy, such as C _{1 -6} - alkyloxy, for example, methoxy Im;

R ¹⁰ is halo -C _{1 -6-alk} (en / in) yl, such as halo -C _{1 -6-alkyl,} for example, trifluoro-methyl-Lim;

R ¹¹ is hydrogen, halogen, C _{1 -6-selected} from alk (en / in) yl-oxy-alk (en / in) yl and C _{1 -6;}

R ¹¹ is hydrogen;

R ¹¹ is halogen, such as fluoro or chloro;

R ¹¹ is C _{1 -6} - alk (en / in) yl, such as C _{1 -6} - alkyl such as methyl or ethyl being;

R ¹¹ is C _{1 -6} - alk (en / in) yloxy, such as C _{1 -6} - alkyloxy, for example, methoxy Im;

R ¹² is hydrogen and C _{1 -6} - selected from one alk (en / in);

R ¹² is hydrogen;

R ¹² is C _{1 -6} - alk (en / in) yl, such as C _{1 -6} - alkyl, for example, p-methyl.

Without limiting and further illustrating the invention, the following embodiments of R ⁷ fall within the scope of the invention and in particular for compounds as bases or salts thereof:

R ⁷ is hydrogen;

R ⁷ is methyl.

Without limiting, and to further illustrate the invention, the following embodiments of R ¹³ are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ¹³ is hydrogen and C _{1 -6} - selected from one alk (en / in);

R ¹³ is hydrogen;

R ¹³ is C _{1 -6} - alk (en / in) yl, such as C _{1 -6} - alkyl, for example, p-methyl.

The above embodiments relate to compounds of the present emissive of formula (I). In particular, the present invention relates to compounds of formula I as sulfur bases attached to indole as shown in formulas IA to IF, wherein R ¹ -R ¹³ are as defined herein, in particular as free bases or salts thereof will be:

- R ¹ -R ² are independently hydrogen, C _{1 -6} - alk (en / in) (e. G., Methyl), C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - cycloalkyl -C _{1 -6} - or selected from alkyl, or R ¹ together with the nitrogen And R ² forms a 4 to 7 membered ring comprising 0 or 1 double bond, wherein the ring optionally comprises one additional heteroatom selected from nitrogen, oxygen and sulfur in addition to the nitrogen;

- R ³ -R ¹² are independently hydrogen, halogen (e.g., fluoro or chloro), cyano, nitro, C _{1 -6} - alk (en / in) (e. G., C _{1 -6} - alkyl, such as methyl), C _{3 -8} - cycloalkyl alk (en) yl (e. g., C _{3 -8} - cycloalkyl), C _{3 -8} - cycloalkyl alk (en) yl -C _{1 -6} - alk ( Yen / in) days (for example, C _3-8 - cycloalkyl, -C _{1 -6} - alkyl), amino, C _{1 -6} - alk (en / in) ylamino (for example, C _{1 -6} - alkylamino), di - (C _{1 6-} alk (en / in) yl) amino (e.g., di - (C _{1 -6-alkyl)} amino), C _{1 -6-alk} (en / in) ylcarbonyl (e.g. C _{1-6-alkylcarbonyl),} aminocarbonyl, C _1-6-alk (en / in) yl-aminocarbonyl (e.g., C _1-6 -alkyl-amino-carbonyl), di - (C _{1 - 6-alk} (en) yl) aminocarbonyl (e. g., di - (C _{1 -6-alkyl)} aminocarbonyl)), hydroxy, C _{1 -6-alk} (en / in) yloxy (e.g. for example, C _{1 -6} - alkoxy, such as methoxy), C _{1 -6} - alk (en / in) ylthio (e.g., C _1-6 - alkylthio, such as methylthio), halo -C _{1 6-} alk (en / in) yl (e.g., halo ₁ -C ₆ - alkyl, for example trifluoromethyl), halo -C _{1 -6-alk} (en / in) ilsul sulfonyl (e.g. to, trifluoromethyl sulfonyl), halo -C _{1 -6} - alk (en / in) ylsulfanyl (e. g. , Trifluoromethyl sulfanyl), and C _{1 -6} - alk (en / in) ilsul sulfonyl (for example, C _{1 -6} - selected from alkylsulfonyl);

- R ¹³ is hydrogen, C _{1 -6} - alk (en / in) (e. G., C _{1 -6} - alkyl, such as methyl), C _{3 -8} - cycloalkyl alk (en) yl (e. C _{3 -8} - cycloalkyl), and C _{3 -8} - cycloalkyl alk (en) yl -C _{1 -6} - alk (en / in) (e. g., C _{3 -8} - cycloalkyl, -C _{1 - 6} -alkyl).

Preferred embodiments relate to compounds of the invention having the general formula (IA). Any of the above embodiments is also an embodiment of Formula IA, wherein conditions R ¹² are not present in the compound of Formula IA. Another embodiment is directed to compounds of the invention that are not formula IA.

Further embodiments relate to compounds of the present invention having Formula IB. Any of the above embodiments are also embodiments of formula IB provided that R ⁷ is not present in the compound of formula IB. Another embodiment is directed to compounds of the invention that are not formula IB.

Further embodiments relate to compounds of the invention which are of formula IC. Any of the above embodiments is also an embodiment of formula IC in which R ⁸ is not present in the formula IC compound. Another embodiment relates to compounds of the invention that are not formula IC.

Further embodiments relate to compounds of the present invention having Formula ID. Any of the above embodiments is an embodiment of formula ID in which R ⁹ is free of compounds of formula ID. Another embodiment relates to compounds of the invention that are not compounds of Formula ID.

Further embodiments relate to compounds of the invention having the formula IE. Any of the above embodiments is also an embodiment of formula IE in which R ¹⁰ is not present in a compound of formula IE. Another embodiment relates to compounds of the invention that are not of compounds of Formula (IE).

Further embodiments relate to compounds of the present invention having the formula IF. Any of the above embodiments is also an embodiment of formula IE in which R ¹¹ is not present in the compound of formula IF. Another embodiment relates to compounds of the invention that are not of formula IF.

Without limiting, and to further illustrate the invention, the following embodiments of formula IA are within the scope of the invention and in particular for compounds as free bases or salts thereof: R ⁸ -R ¹¹ are independently hydrogen, halogen , cyano, C _{1 -6} - alkyl, C _{3 -8} - cycloalkyl, C _{3 -8} - cycloalkyl, -C _{1 -6} - alkyl, amino, C _{1 -6} - alkylamino, di _- (C ₁ - _6-alkyl) amino, C _{1 -6-alkyl-carbonyl,} aminocarbonyl, C _{1 -6-alkylamino-carbonyl,} di - (C _{1 -6-alkyl)} carbonyl, hydroxy, C _{1 -6} -alkoxy, C _{1 -6-alkylthio,} halo -C _{1 -6-alkyl,} halo -C _{1 -6-alkylsulfonyl,} halo -C _{1 -6-alkyl} sulfanyl, and a C _{1 -6-alkyl} alcohol Selected from ponyls;

R ⁸ -R ¹¹ are independently selected from hydrogen, halogen, cyano, methyl, hydroxy, methoxy and trifluoromethyl;

R ⁸ -R ¹¹ are independently selected from hydrogen, halogen, methyl and methoxy;

R ⁸ -R ¹¹ are independently selected from hydrogen, fluoro, chloro, methyl and methoxy.

Embodiments in which a limited number of R ⁸ -R ¹¹ are different from hydrogen are within the present invention, for example:

Only one of R ⁸ -R ¹¹ is different from hydrogen, preferably is selected from the group consisting of hydrogen, fluoro, chloro, methyl and methoxy, and the remaining R ⁸ -R ¹¹ is hydrogen;

R 2 out of ^{8 -11} is selected from hydrogen, fluoro is made different from hydrogen, preferably, chloro, the group consisting of methyl and methoxy, R ^{8 -11} Two of them are hydrogen.

Without limitation, and to further illustrate the invention, the following embodiments of formula (IA) are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ⁸ Is selected from the group consisting of halogen (preferably fluoro or chloro), methyl and methoxy, R ⁷ And R ^{9 -11} is hydrogen;

R ⁹ Is selected from the group consisting of halogen (preferably fluoro or chloro), methyl and methoxy and R ⁷ , R ⁸ And R ^{10 -11} are hydrogen.

Without limiting, and to further illustrate the invention, the following embodiments of formula IA fall within the scope of the invention and in particular for compounds as free bases or salts thereof: only one of R ^8-11 is different from hydrogen. And selected from the group consisting of halogen (eg fluoro or chloro), methyl, methoxy, hydroxy and cyano.

Without limitation, and to further illustrate the invention, the following embodiments of formula (IA) are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ⁸ is hydroxy; R ⁸ is methoxy; R ⁸ Is methyl; R ⁸ is cyano; R ⁸ is chloro; R ⁸ is fluoro; In a preferred embodiment, the remainder of R ⁸ to R ¹¹ is hydrogen.

Without limitation, and to further illustrate the invention, the following embodiments of formula (IA) are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ⁹ is fluoro; R ⁹ is chloro; R ⁹ is bromine; R ⁹ is iodo; R ⁹ is methoxy; R ⁹ is methyl; R ⁹ is hydroxy; In a preferred embodiment, the remainder of R ⁸ to R ¹¹ is hydrogen.

Without limiting, and to further illustrate the invention, the following embodiments of formula IA are within the scope of the invention and in particular for compounds as free bases or salts thereof:

R ¹⁰ is fluoro; R ¹⁰ is chloro; R ¹⁰ is bromine; R ¹⁰ is methyl; R ¹⁰ is cyano; R ¹⁰ is CF ₃ ; R ¹⁰ is methoxy; In a preferred embodiment, the remainder of R ⁸ to R ¹¹ is hydrogen.

Without limiting, and to further illustrate the present invention, the following embodiments of formula IA are within the scope of the present invention and in particular for compounds as free bases or salts thereof:

R ¹¹ is methyl; R ¹¹ is ethyl; R ¹¹ is methoxy; R ¹¹ Is chloro; R ¹¹ is fluoro; In a preferred embodiment, the remainder of R ⁸ to R ¹¹ is hydrogen.

Without limiting, and to further illustrate the invention, the following embodiments of formula IA are within the scope of the invention and in particular for compounds as free bases or salts thereof: R ¹⁰ and R ¹¹ is independently selected from the group consisting of hydrogen, methyl, fluoro and chloride.

Without limitation, and to further illustrate the invention, the following embodiments of R ¹³ are within the scope of the invention and in particular for free bases or salts thereof:

R ¹³ is hydrogen;

R ¹³ is C _{1 -6} - alkyl;

R ¹³ is C _{1 -4} - alkyl;

R ¹³ is methyl.

One embodiment R ¹³ is hydrogen or C _{1 -6} - alkyl, for, example, C _{1 -4} - alkyl, for example methyl and R ¹ -R ¹¹ is directed to compounds of formula IA as described herein.

Without limiting, and to further illustrate the invention, the following embodiments are within the invention and in particular for compounds as free bases or salts thereof: wherein the compound is R ¹ is hydrogen and R ² is hydrogen or C _{1 − 6-alkyl,} preferably C _{1 -4-alkyl,} such as methyl, R ³ -R ⁶ are independently, for a hydrogen, methyl and halogen, e.g., selected from chloro or fluoro, R ⁷ is hydrogen or methyl and, R ^{8 -11} g is independently hydrogen, methyl, methoxy and halogen, e.g., selected from chloro or fluoro, R ¹³ is hydrogen, R is -R ⁸ one or more than two of the ¹¹ hydrogen And at least one of R ³ -R ⁶ has a different formula (IA) than hydrogen.

In a further embodiment, the compounds according to the invention are selected from the following list as free bases or salts thereof, such as pharmaceutically acceptable salts:

Compound number Compound name One [2- (1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 2 [2- (5-cyano-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 3 [2- (4-Fluoro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 4 [2- (4-chloro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 5 [2- (5-Fluoro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 6 [2- (5-chloro-lH-indol-3-ylsulfanyl) benzyl] dimethyl amine 7 Dimethyl- [2- (7-methyl-1H-indol-3-ylsulfanyl) benzyl] -amine 8 [2- (7-methoxy-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 9 [2- (5-methoxy-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 10 [2- (6-Fluoro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 11 [2- (6-chloro-lH-indol-3-ylsulfanyl) benzyl] dimethyl amine 12 Dimethyl- [2- (2-methyl-1H-indol-3-ylsulfanyl) benzyl] -amine 13 Dimethyl- [2- (6-methyl-1H-indol-3-ylsulfanyl) benzyl] -amine 14 [2- (4-cyano-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 15 Dimethyl- [2- (1-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 16 Dimethyl- [2- (4-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 17 [2- (4-hydroxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 18 [2- (6-cyano-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 19 [2- (7-chloro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 20 [2- (6-methoxy-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 21 [2- (4-methoxy-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 22 [2- (1H-indol-3-ylsulfanyl) benzyl] methyl amine 23 [2- (6-Fluoro-1H-indol-3-ylsulfanyl) benzyl] methyl amine 24 [2- (5-Fluoro-1H-indol-3-ylsulfanyl) benzyl] methyl amine 25 Methyl- [2- (4-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 26 [2- (4-chloro-1H-indol-3-ylsulfanyl) benzyl] methyl amine 27 Methyl- [2- (2-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 28 [2- (5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 29 Methyl- [2- (5-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 30 Methyl- [2- (7-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 31 [2- (4-fluoro-1H-indol-3-ylsulfanyl) benzyl] methyl amine 32 [2- (7-ethyl-1H-indol-3-ylsulfanyl) benzyl] methyl amine 33 [2- (6-methoxy-1H-indol-3-ylsulfanyl) benzyl] methyl amine 34 [2- (5-chloro-lH-indol-3-ylsulfanyl) benzyl] methyl amine 35 [2- (6-chloro-1H-indol-3-ylsulfanyl) benzyl] methyl amine 36 [2- (5-methoxy-4-methyl-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 37 [2- (5,6-Dimethoxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 38 [2- (6-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 39 Methyl- [2- (6-methyl-1H-indol-3-ylsulfanyl) -benzyl] amine 40 [2- (4,7-Dimethoxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 41 [2- (5-methoxy-1H-indol-3-ylsulfanyl) benzyl] methyl amine 42 [2- (4-methoxy-1H-indol-3-ylsulfanyl) benzyl] methyl amine 43 [2- (5-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 44 [2- (7-methoxy-1H-indol-3-ylsulfanyl) benzyl] methyl amine 45 [5-Chloro-2- (1H-indol-3-ylsulfanyl) -benzyl] methyl amine 46 Methyl- [2- (6-trifluoromethyl-1H-indol-3-ylsulfanyl) -benzyl] amine 47 [2- (5-hydroxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 48 [2- (4-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 49 [2- (7-Chloro-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 50 [2- (5-iodo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 51 [2- (6-cyano-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 52 [2- (1H-Indol-3-ylsulfanyl) -5-methyl-benzyl] methyl amine 53 Methyl- [2- (3-methyl-1H-indol-2-ylsulfanyl) -benzyl] amine 54 [2- (5,6-Dimethoxy-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine  55 [5-Fluoro-2- (3-methyl-1H-indol-2-ylsulfanyl) -benzyl] -methyl-amine 56 [5-Fluoro-2- (4-fluoro-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 57 [2- (4-Chloro-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 58 [2- (7-Chloro-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 59 [5-Fluoro-2- (6-trifluoromethyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 60 [5-Fluoro-2- (7-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 61 [2- (4-Bromo-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 62 3- (4-Fluoro-2-methylaminomethyl-phenylsulfanyl) -2-methyl-1H-indol-4-ol 63 3- (4-Fluoro-2-methylaminomethyl-phenylsulfanyl) -1 H-indol-6-ol 64 [5-Fluoro-2- (5-fluoro-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 65 [5-Fluoro-2- (4-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 66 [2- (6-Chloro-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 67 [2- (5-Chloro-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 68 [5-Fluoro-2- (6-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 69 [5-Fluoro-2- (5-methoxy-4-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 70 [2- (5-Bromo-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 71 [5-Fluoro-2- (5-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 72 [2- (6-Bromo-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 73 [5-Fluoro-2- (6-fluoro-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 74 [5-Fluoro-2- (6-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 75 [5-Fluoro-2- (2-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 76 [5-Fluoro-2- (5-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 77 [5-Fluoro-2- (4-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 78 [5-Fluoro-2- (7-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 79 [5-Fluoro-2- (1-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 80 [5-Fluoro-2- (5-fluoro-2-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 81 [5-Chloro-2- (5-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 82 [5-Chloro-2- (5-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 83 [5-Chloro-2- (7-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 84 [5-Chloro-2- (1-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 85 [5-Chloro-2- (4-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 86 [5-Chloro-2- (7-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 87 [5-Chloro-2- (6-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 88 [5-Chloro-2- (5-fluoro-2-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 89 [2- (5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 90 Methyl- [5-methyl-2- (4-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -amine 91 [2- (7-Ethyl-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 92 [2- (6-methoxy-1 H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 93 Methyl- [5-methyl-2- (2-methyl-1H-indol-3-ylsulfanyl) -benzyl] -amine 94 [2- (4-methoxy-1 H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 95 [2- (6-Bromo-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 96 [2- (6-Fluoro-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 97 [2- (4-Fluoro-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 98 3- (4-Methyl-2-methylaminomethyl-phenylsulfanyl) -1 H-indole-6-ol 99 [5-Chloro-2- (5-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 100 [2- (6-Chloro-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 101 [2- (5-Chloro-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 102 5-Fluoro-3- (2-piperidin-1-ylmethyl-phenylsulfanyl) -1H-indole 103 5-Fluoro-3- (2-morpholin-4-ylmethyl-phenylsulfanyl) -1 H-indole 104 5-Fluoro-3- (2-pyrrolidin-1-ylmethyl-phenylsulfanyl) -1H-indole 105 [4-Chloro-2- (6-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 106 [4-Chloro-2- (2-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 107 [4-Chloro-2- (5-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 108 [4-Chloro-2- (7-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 109 [4-Chloro-2- (4-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine  110 [4-Chloro-2- (5-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 111 [4-Chloro-2- (6-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 112 [4-Chloro-2- (4-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 113 [4-Chloro-2- (7-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 114 [4-Chloro-2- (7-ethyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 115 [4-Chloro-2- (5-methoxy-4-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 116 [4-Chloro-2- (5-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 117 [4-Chloro-2- (6-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 118 [4-Chloro-2- (7-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 119 [4-Chloro-2- (4-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 120 [4-Chloro-2- (5-chloro-lH-indol-3-ylsulfanyl) -benzyl] -methyl-amine 121 [4-Chloro-2- (6-chloro-lH-indol-3-ylsulfanyl) -benzyl] -methyl-amine 122 [4-Chloro-2- (4-chloro-lH-indol-3-ylsulfanyl) -benzyl] -methyl-amine 123 [4-Chloro-2- (7-chloro-lH-indol-3-ylsulfanyl) -benzyl] -methyl-amine 124 [4-Chloro-2- (1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 125 [4-Chloro-2- (1-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 126 [4-Chloro-2- (3-methyl-1 H-indol-2-ylsulfanyl) -benzyl] -methyl-amine 127 [4-Chloro-2- (5-fluoro-2-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 128 2- (5-Fluoro-1H-indol-3-ylsulfanyl) -benzylamine 129 [2- (5-Fluoro-4-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 130 [2- (4,5-Difluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 131 [2- (4,6-Difluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 132 3- (2-Methylaminomethyl-phenylsulfanyl) -1 H-indol-4-ol 133 2- (6-Fluoro-1H-indol-3-ylsulfanyl) -benzylamine 134 [2- (5,6-Difluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 135 6-Fluoro-3- (2-methylaminomethyl-phenylsulfanyl) -1 H-indol-5-ol 136 [2- (4-Chloro-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 137 [2- (1H-Indol-5-ylsulfanyl) -benzyl] -methyl-amine 138 [2- (1H-Indol-4-ylsulfanyl) -benzyl] -methyl-amine 139 [2- (1H-Indol-6-ylsulfanyl) -benzyl] -methyl-amine 140 [2- (1H-Indol-7-ylsulfanyl) -benzyl] -methyl-amine

A non-limiting aspect of the invention relates to such compounds according to the following embodiments 1 to 87:

1. a compound represented by formulas IA to IF or a salt thereof:

[In the meal,

- R ¹ -R ² are independently hydrogen, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, and C _{3 -8} - cycloalkyl alk (en) yl -C _1-6-alk selected from (/ person) or one; Or R ¹ with nitrogen And R ² forms a 4 to 7 membered ring comprising 0 or 1 double bond, and optionally the ring comprises one additional hetero atom selected from nitrogen, oxygen and sulfur in addition to said nitrogen;

- R ³ -R ¹² are independently hydrogen, halogen, cyano, nitro, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - cycloalkyl alk (en) yl -C _{1 -6} - alk (en / in), amino, C _{1 -6} - alk (en / in) ylamino, di - (C _{1 -6} - alk (en / in) yl) amino, C _{1 -6} - alk (en / in) ylcarbonyl, aminocarbonyl, C _1-6 - alk (en / in) yl-aminocarbonyl, di - (C _{1 -6} - alk (en) yl ) aminocarbonyl, hydroxy, C _1-6 - alk (en / in) yloxy, C _{1 -6} - alk (en / in) ylthio, halo -C _{1 -6} - alk (en / in) one , halo, -C _{1 -6} - alk (en / in) ilsul sulfonyl, halo -C _{1 -6} - alk (en / in) ilsul isoquinoline, and C _{1 -6} - alk (en / a) is selected from sulfonyl ilsul ;

- R ¹³ is hydrogen, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, and C _{3 -8} - cycloalkyl alk (en) yl -C _1-6 - alk (Yen / in) is selected from].

2. R ¹ -R ² are independently hydrogen, C _{1 -6-alk} (en / in) yl, C _{3 -8-cycloalkyl} alk (en) yl, and C _3-8 - cycloalkyl alk (en) yl- C _{1 -6} - compound of embodiment 1 selected from the alk (en / in) yl; Or salts thereof.

The compounds of embodiment 1 is selected from alkyl - 3. R ¹ -R ² are hydrogen and C _{1 -6} independently; Or salts thereof.

4. A compound of embodiment 1 wherein R ¹ is hydrogen and R ² is methyl; Or salts thereof.

5. R ¹ And A compound of embodiment 1 wherein R ² is methyl; Or salts thereof.

6. R ¹ And A compound of embodiment 1 wherein R ² is hydrogen; Or salts thereof.

7. R ¹ with nitrogen And Of Embodiment 1, wherein R ² forms a 4 to 7 membered ring comprising 0 or 1 double bond, and optionally wherein said ring comprises one additional heteroatom selected from nitrogen, oxygen and sulfur in addition to said nitrogen; compound; Or salts thereof.

8. R ¹ with nitrogen And A compound of embodiment 1 wherein R ² forms a ring selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, homopiperazine or morpholine; Or salts thereof.

9. R ³ -R ¹² are independently hydrogen, halogen, cyano, C _{1 -6} - alkyl, C _{3 -8} - cycloalkyl, C _3-8 - cycloalkyl, -C _{1 -6} - alkyl, amino, C _1-6 - alkylamino, di - (C _1-6 -alkyl) amino, C _1-6 -alkyl-carbonyl, aminocarbonyl, C _1-6 -alkyl-aminocarbonyl, di - (C _1-6 - alkylamino) carbonyl, hydroxy, C _{1 -6} - alkoxy, C _{1 -6} - alkylthio, halo -C _{1 -6} - alkyl, halo -C _{1 -6} - alkylsulfonyl, halo -C _{1 -6} The compound of any of embodiments 1-8 selected from -alkylsulfanyl, and C _{1-6 -alkylsulfonyl} ; Or salts thereof.

10. R ³ -R ⁶ are independently hydrogen, halogen, cyano, nitro, C _{1 -6} - alk (en / in) yl, C _3-8 - cycloalkyl alk (en) yl, C _{3 -8} - bicyclo alk (en) yl -C _{1 -6} - alk (en / in), amino, C _{1 -6} - alk (en / in) ylamino, di - (C _{1 -6} - alk (en / in) one ) amino, C _{1 -6} - alk (en / in) ylcarbonyl, aminocarbonyl, C _{1 -6} - alk (en / in) yl-aminocarbonyl, di - (C _{1 -6} - alk (en) yl) aminocarbonyl, hydroxy, C _{1 -6} - alk (en / in) yloxy, C _{1 -6} - alk (en / in) ylthio, halo -C _{1 -6} - alk (en / in) yl, halo -C _{1 -6} - alk (en / in) ilsul sulfonyl, halo -C _{1 -6} - alk (en / in) ilsul isoquinoline, and C _{1 -6} - alk (en / in) ilsul selected from sulfonyl The compound of any of embodiments 1-8; Or salts thereof.

11. R ³ -R ⁶ are independently hydrogen, halogen, cyano, C _{1 -6} - alkyl, C _{3 -8} - cycloalkyl, C _3- 8- cycloalkyl -C _{1 -6} - alkyl, amino, C _1-6 - alkylamino, di - (C _1-6 -alkyl) amino, C _1-6 -alkyl-carbonyl, aminocarbonyl, C _1-6 -alkyl-aminocarbonyl, di - (C _1-6 - alkylamino) carbonyl, hydroxy, C _{1 -6} - alkoxy, C _{1 -6} - alkylthio, halo -C _{1 -6} - alkyl, halo -C _{1 -6} - alkylsulfonyl, halo -C _{1 -6} The compound of any of embodiments 1-8 selected from -alkylsulfanyl, and C _{1-6 -alkylsulfonyl} ; Or salts thereof.

12. R ³ -R ⁶ are independently hydrogen, halogen, C _{1 -6} - alkyloxy and C _{1 -6} - any embodiments 1 to 8 of a compound selected from alkyl-ray; Or salts thereof.

13. The compound of any of embodiments 1-8, wherein R ³ -R ⁶ are independently selected from hydrogen, halogen, methoxy and methyl; Or salts thereof.

14. The compound of any of embodiments 1-13, wherein only 1 or 2 of R ³ -R ⁶ are different from hydrogen.

15. A compound of any of embodiments 1 to 13, wherein only one of R ³ -R ⁶ is different from hydrogen; Or salts thereof.

16. The compound of any of embodiments 1-9, wherein three of R ³ -R ⁶ are hydrogen and one of R ³ -R ⁶ is halogen; Or salts thereof.

17. R ³ -R ^{6 3} dogs are hydrogen and R ³ -R ⁶ is one of the compounds of any of embodiments 1 to 9 of methyl; Or salts thereof.

18. A compound of any of embodiments 15-17 wherein R ⁴ is different from hydrogen; Or salts thereof.

19. A compound of any of embodiments 15-17 wherein R ⁵ is different from hydrogen; Or salts thereof.

20. The compound of any of embodiments 1-9, wherein R ³ -R ⁶ are hydrogen; Or salts thereof.

21. A compound of any of embodiments 1-20, wherein R ¹³ is hydrogen; Or salts thereof.

22. R ¹³ is C _{1 -6} - alkyl compound of any of embodiments 1 to 20; Or salts thereof.

23. A compound of any of embodiments 1-20 wherein R ¹³ is methyl; Or salts thereof.

24. A compound of any of embodiments 1 to 23 having formula IA; Or salts thereof.

25. A compound of any embodiment 1 to 23 having the formula IB; Or salts thereof.

26. A compound of any of embodiments 1 to 23 having the formula IC; Or salts thereof.

27. A compound of any of embodiments 1 to 23 having the formula ID; Or salts thereof.

28. A compound of any of embodiments 1 to 23 having the formula IE; Or salts thereof.

29. A compound of any of embodiments 1 to 23 having the formula IF; Or salts thereof.

30. R ⁷ is hydrogen, halogen, cyano has the formula IA, nitro, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - cycloalkyl alk (en) yl -C _{1 -6} - alk (en / in), amino, C _{1 -6} - alk (en / in) ylamino, di - (C _{1 -6} - alk (en / in) yl) amino, C _{1 -6} - alk (en / in) ylcarbonyl, aminocarbonyl, C _{1 -6} - alk (en / in) yl-aminocarbonyl, di - (C _{1 -6} - alk (en) yl ) aminocarbonyl, hydroxy, C _{1 -6} - alk (en / in) yloxy, C _{1 -6} - alk (en / in) ylthio, halo -C _{1 -6} - alk (en / in) one , halo, -C _{1 -6} - alk (en / in) ilsul sulfonyl, halo -C _{1 -6} - alk (en / in) ilsul isoquinoline, and C _{1 -6} - alk (en / a) the group consisting of sulfonyl ilsul A compound of any of embodiments 1-23 selected from; Or salts thereof.

31 has the formula IA, R ⁷ is hydrogen, halogen, cyano, C _{1 -6} - alkyl, C _{3 -8} - cycloalkyl, C _{3 -8} - cycloalkyl, -C _{1 -6} - alkyl, amino, C _1-6 - alkylamino, di - (C _1-6 -alkyl) amino, C _1-6 -alkyl-carbonyl, aminocarbonyl, C _1-6 -alkyl-aminocarbonyl, di - (C _1-6 - alkylamino) carbonyl, hydroxy, C _{1 -6} - alkoxy, C _{1 -6} - alkylthio, halo -C _{1 -6} - alkyl, halo -C _{1 -6} - alkylsulfonyl, halo -C _{1 -6} The compound of any of embodiments 1 to 23 selected from the group consisting of -alkylsulfanyl, and C _{1-6 -alkylsulfonyl} ; Or salts thereof.

32. A compound of any of embodiments 1 to 23 having the formula IA and R ⁷ is hydrogen; Or salts thereof.

33. The compound of any of embodiments 1-23, having the formula IA and R ⁷ is methyl; Or salts thereof.

34 has the formula IA, R ⁸ -R ¹¹ are independently hydrogen, halogen, cyano, nitro, C _1-6 - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _3-8 - cycloalkyl alk (en) yl -C _{1 -6-alk} (en / in), amino, C _{1 -6-alk} (en / in) ylamino, di - (C _{1 -6-alk} ( / person) yl) amino, C _{1 -6} - alk (en / in) ylcarbonyl, aminocarbonyl, C _{1 -6} - yl alk (/ person) aminocarbonyl, di - (C _{1 -6} -alk (en) yl) aminocarbonyl, hydroxy, C _{1 -6-alk} (en / in) yloxy, C _1-6-alk (en / in) ylthio, halo -C _{1 -6} - alk (/ person) yl, halo -C _{1 -6} - alk (en / in) ilsul sulfonyl, halo -C _{1 -6} - alk (en / in) ilsul isoquinoline, and C _{1 -6} - alk (en / person A compound of any embodiment 1 to 23 or any embodiment 30 to 33 selected from ilsulfonyl; Or salts thereof.

35 has the formula IA, R ⁸ -R ¹¹ are independently hydrogen, halogen, cyano, C _{1 -6} - alkyl, C _3-8 - cycloalkyl, C _{3 -8} - cycloalkyl, -C _{1 -6} - alkyl, amino, C _{1 -6-alkylamino,} di- (C _{1 -6-alkyl)} amino, C _{1 -6-alkyl-carbonyl,} aminocarbonyl, C _{1 -6-alkyl-aminocarbonyl,} di- ( C _{1 -6} - alkylamino) carbonyl, hydroxy, C _{1 -6} - alkoxy, C _{1 -6} - alkylthio, halo -C _{1 -6} - alkyl, halo -C _{1 -6} - alkylsulfonyl, halo -C _{1 -6} - alkyl sulfanyl, and a C _{1 -6} - any embodiments 1 to 23 or a compound of any of embodiments 30 to 33 selected from alkylsulfonyl; Or salts thereof.

36. Any embodiment 1-23 or any embodiments 30-, having formula IA, wherein R ⁸ -R ¹¹ is independently selected from hydrogen, halogen, cyano, methyl, hydroxy, methoxy and trifluoromethyl. Compound of 33; Or salts thereof.

37. A compound of any of embodiments 1 to 23 or any of embodiments 30 to 33, wherein formula ⁸ IA and R ⁸ -R ¹¹ are independently selected from hydrogen, halogen, methyl and methoxy; Or salts thereof.

38. The compound of any of embodiments 34-36, wherein only one of R ⁸ -R ¹¹ is different from hydrogen while the other R ⁸ -R ¹¹ is hydrogen; Or salts thereof.

39 and has the formula IA, two of R ^{8 -11} different from hydrogen, R ^{8 -11} The compound of any of embodiments 34 to 36, wherein two of them are hydrogen; Or salts thereof.

40. Having Formula IA, R ⁸ A compound of any one of embodiments 1 to 23 or 30 to 37 selected from the group consisting of halogen, methyl and methoxy; Or salts thereof.

41. R ^{9 -11} compound of embodiment 40 is hydrogen; Or salts thereof.

42. A compound of embodiment 41 wherein R ⁷ is hydrogen; Or salts thereof.

43. Having Formula IA and R ⁹ A compound of embodiments 1 to 23 or 30 to 37 selected from the group consisting of halogen, methyl and methoxy; Or salts thereof.

44.R ⁸ And R ¹⁰ is a compound of embodiment 43 ^-11 H; Or salts thereof.

45. A compound of embodiment 44 wherein R ⁷ is hydrogen; Or salts thereof.

46. Compounds of formula IA have an R ^{8 -11} are any embodiments 1 to 23 or 30 to 33 are hydrogen; Or salts thereof.

The compounds of the substituent (s) of the implement ¹¹ is selected from halogen, methyl, methoxy, hydroxy, cyano group consisting of for example 38 or 39 ^- 47 is different from hydrogen R ^8; Or salts thereof.

48. A compound of Embodiment 1 having Formula IA and wherein

- R ¹ is hydrogen, R ² is hydrogen or C _{1 -6} - alkyl;

R ³ -R ⁶ are independently selected from hydrogen, halogen and methyl, wherein up to two of R ³ -R ⁶ are different from hydrogen;

R ⁷ is hydrogen or methyl;

- R ^{8 -11} are independently selected from hydrogen and are selected from halogen, methyl and methoxy, in which not more than two of R ⁸ -R ¹¹ are different from hydrogen;

R ¹³ is hydrogen;

Or salts thereof.

49. A compound having Formula IA and wherein:

R ¹ is hydrogen and R ² is methyl;

R ³ -R ⁶ are as defined in any of claims 13 to 20;

R ⁷ is hydrogen;

R ⁸ -R ¹¹ are as defined in claims 36 to 47;

R ¹³ is hydrogen;

Or salts thereof.

50. A compound of any of embodiments 1-23 or any embodiment 30-33, having the formula IA and R ⁸ is hydroxy; Or salts thereof.

51. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, having the formula IA and R ⁸ is methoxy; Or salts thereof.

52. Having Formula IA, R ⁸ Is a compound of any embodiment 1 to 23 or any embodiment 30 to 33; Or salts thereof.

53. A compound of any embodiment 1 to 23 or any embodiment 30 to 33, wherein Formula IA is wherein R ⁸ is cyano; Or salts thereof.

54. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, having the formula IA and R ⁸ is Cl; Or salts thereof.

55. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, having the formula IA and R ⁸ is F; Or salts thereof.

56. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 wherein R ⁹ is cyano; Or salts thereof.

57. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 having formula IA and R ⁹ is F; Or salts thereof.

58. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 having the formula IA and R ⁹ is Cl; Or salts thereof.

59. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, having the formula IA and R ⁹ is Br; Or salts thereof.

60. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 having the formula IA and R ⁹ is I; Or salts thereof.

61. A compound of any embodiment 1 to 23 or any embodiment 30 to 33, having the formula IA and R ⁹ is methoxy; Or salts thereof.

62. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, wherein Formula IA is wherein R ⁹ is methyl; Or salts thereof.

63. The compound of any embodiment 1-23 or any embodiment 30-33, having the formula IA and R ⁹ is hydroxy; Or salts thereof.

64. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 having formula IA and R ¹⁰ is F; Or salts thereof.

65. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 having the formula IA and R ¹⁰ is Cl; Or salts thereof.

66. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 having formula IA and R ¹⁰ is Br; Or salts thereof.

67. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, wherein Formula IA is wherein R ¹⁰ is methyl; Or salts thereof.

68. A compound of any embodiment 1 to 23 or any embodiment 30 to 33, wherein Formula IA is wherein R ¹⁰ is cyano; Or salts thereof.

69. Having Formula IA, R ¹⁰ is CF ₃ The compound of any embodiment 1 to 23 or any embodiment 30 to 33; Or salts thereof.

70. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, having the formula IA and R ¹⁰ is methoxy; Or salts thereof.

71. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, wherein Formula ¹¹ is wherein R ¹¹ is methyl; Or salts thereof.

72. The compound of any embodiment 1 to 23 or any embodiment 30 to 33, wherein Formula ¹¹ is IA and R ¹¹ is ethyl; Or salts thereof.

73. A compound of any embodiment 1 to 23 or any embodiment 30 to 33, wherein Formula IA is R ¹¹ is methoxy; Or salts thereof.

74. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 having the formula IA and R ¹¹ is Cl; Or salts thereof.

75. A compound of any embodiment 1 to 23 or any embodiment 30 to 33 having the formula IA and R ¹¹ is F; Or salts thereof.

76. The compound of any of embodiments 50-75, wherein the remainder of R ⁸ to R ¹¹ is hydrogen; Or salts thereof.

77. Having Formula IA, R ¹⁰ And R ¹¹ is independently a compound of any of embodiments 1 to 23 or any of embodiments 30 to 33 selected from the group consisting of hydrogen, methyl, fluoro and chloride; Or salts thereof.

78.R ¹⁰ And A compound of embodiment 77 wherein at least one of R ¹¹ is hydrogen; Or salts thereof.

79. A compound of claim 1 selected from the group consisting of:

[2- ( 1H -indol-3-ylsulfanyl) benzyl] dimethyl amine;

[2- (5-cyano-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (4-Fluoro- 1H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (4-chloro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (5-Fluoro- 1H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (5-chloro -1 H - indol-3-ylsulfanyl) benzyl] dimethyl amine

Dimethyl- [2- (7-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

[2- (7-methoxy-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (5-methoxy-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (6-Fluoro- 1H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (6-chloro -1 H - indol-3-ylsulfanyl) benzyl] dimethyl amine

Dimethyl- [2- (2-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

Dimethyl- [2- (6-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

[2- (4-cyano-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

Dimethyl- [2- (1-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

Dimethyl- [2- (4-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

Dimethyl- [2- (4-hydroxy-1 H -indol-3-ylsulfanyl) benzyl] amine

[2- (6-cyano-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (7-chloro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (6-methoxy-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (4-methoxy-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

[2- (1H-indol-3-ylsulfanyl) benzyl] methyl amine

[2- (6-Fluoro- 1H -indol-3-ylsulfanyl) benzyl] methyl amine

[2- (5-Fluoro- 1H -indol-3-ylsulfanyl) benzyl] methyl amine

Methyl- [2- (4-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

[2- (4-chloro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

Methyl- [2- (2-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

[2- (5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

Methyl- [2- (5-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

Methyl- [2- (7-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

[2- (4-fluoro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

[2- (7-ethyl-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

[2- (6-methoxy-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

[2- (5-chloro -1 H - indol-3-ylsulfanyl) benzyl] methyl amine

[2- (6-chloro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

[2- (5-methoxy-4-methyl-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

[2- (5,6-Dimethoxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

[2- (6-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

Methyl- [2- (6-methyl-1H-indol-3-ylsulfanyl) -benzyl] amine

[2- (4,7-Dimethoxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

[2- (5-methoxy-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

[2- (4-methoxy-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

[2- (5-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

[2- (7-methoxy-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

[5-Chloro-2- ( 1H -indol-3-ylsulfanyl) -benzyl] methyl amine

Methyl- [2- (6-trifluoromethyl- 1H -indol-3-ylsulfanyl) -benzyl] amine;

[5-hydroxy-2- ( 1H -indol-3-ylsulfanyl) -benzyl] methyl amine;

[2- (4-Bromo- 1H -indol-3-ylsulfanyl) -benzyl] methyl amine;

[2- (7-chloro- 1H -indol-3-ylsulfanyl) -benzyl] methyl amine;

[2- (5-iodo- 1H -indol-3-ylsulfanyl) -benzyl] methyl amine;

[2- (6-cyano- 1H -indol-3-ylsulfanyl) -benzyl] methyl amine;

[2- ( 1H -Indol-3-ylsulfanyl) -5-methyl-benzyl] methyl amine;

[2- (3-Methyl- 1H -indol-2-ylsulfanyl) -benzyl] methyl amine;

[2- (5,6-Dimethoxy-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine;

[5-Fluoro-2- (3-methyl-1 H -indol-2-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (4-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (4-Chloro-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine;

[2- (7-Chloro-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine;

[5-Fluoro-2- (6-trifluoromethyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (7-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (4-Bromo-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine;

3- (4-fluoro-2-methylaminomethyl-phenylsulfanyl) -2-methyl-1 H -indol-4-ol;

3- (4-fluoro-2-methylaminomethyl-phenylsulfanyl) -1 H -indol-6-ol;

[5-Fluoro-2- (5-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-fluoro-2- (4-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (6-Chloro-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine;

[2- (5-Chloro-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine;

[5-Fluoro-2- (6-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (5-methoxy-4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (5-Bromo-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine;

[5-fluoro-2- (5-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (6-Bromo-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine;

[5-Fluoro-2- (6-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (6-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (5-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (7-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Fluoro-2- (1-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-fluoro-2- (5-fluoro-2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-chloro-2- (5-fluoro -1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Chloro-2- (5-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Chloro-2- (7-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Chloro-2- (1-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Chloro-2- (4-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Chloro-2- (7-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-chloro-2- (6-fluoro -1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[5-Chloro-2- (5-fluoro-2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (5-Fluoro-2-methyl-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

Methyl- [5-methyl-2- (4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -amine;

[2- (7-Ethyl-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

[2- (6-methoxy-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

Methyl- [5-methyl-2- (2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -amine;

[2- (4-methoxy-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

[2- (6-Bromo-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

[2- (6-Fluoro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

[2- (4-Fluoro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

3- (4-methyl-2-methylaminomethyl-phenylsulfanyl) -1 H -indol-6-ol;

[5-Chloro-2- (5-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (6-Chloro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

[2- (5-Chloro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

5-fluoro-3- (2-piperidin-1-ylmethyl-phenylsulfanyl) -1 H -indole;

5-fluoro-3- (2-morpholin-4-ylmethyl-phenylsulfanyl) -1 H -indole;

5-fluoro-3- (2-pyrrolidin-1-ylmethyl-phenylsulfanyl) -1 H -indole;

[4-Chloro-2- (6-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (5-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (7-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-chloro -2- (5-fluoro -1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-chloro -2- (6-fluoro -1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (4-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (7-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (7-ethyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (5-methoxy-4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (5-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (6-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (7-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (4-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-chloro-2- (5-chloro -1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (6-chloro-l H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-chloro-2- (4-chloro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (7-chloro-l H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- ( 1H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (1-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (3-methyl-1 H -indol-2-ylsulfanyl) -benzyl] -methyl-amine;

[4-Chloro-2- (5-fluoro-2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

2- (5-fluoro-1 H -indol-3-ylsulfanyl) -benzylamine;

[2- (5-Fluoro-4-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (4,5-Difluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

[2- (4,6-Difluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

3- (2-methylaminomethyl-phenylsulfanyl) -1 H -indol-4-ol;

2- (6-Fluoro-1 H -indol-3-ylsulfanyl) -benzylamine;

[2- (5,6-Difluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine;

6-fluoro-3- (2-methylaminomethyl-phenylsulfanyl) -1 H -indol-5-ol;

[2- (4-Chloro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine;

[2- (1H-Indol-5-ylsulfanyl) -benzyl] -methyl-amine;

[2- (1H-Indol-4-ylsulfanyl) -benzyl] -methyl-amine;

[2- (1H-Indol-6-ylsulfanyl) -benzyl] -methyl-amine; And

[2- (1H-Indol-7-ylsulfanyl) -benzyl] -methyl-amine;

Or salts thereof.

80. A compound of any of embodiments 1 to 23 having the formula IB and R ¹² is hydrogen or methyl; Or salts thereof.

81. A compound of any of embodiments 1-80 or a pharmaceutically acceptable salt thereof for use in medicament.

82. Use of a compound of any one of embodiments 1 to 80 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of affective disorder.

83. Embodiment 1 for the manufacture of a medicament for the treatment of anxiety disorders including depression, general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, panic attack, specific phobia, social phobia or agoraphobia Use of a compound of any one of claims 80-80 or a pharmaceutically acceptable salt thereof.

84. Use of a compound of any one of embodiments 1 to 80 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of depression.

85. A method of treating affective disorder comprising administering a therapeutically effective amount of a compound of any one of embodiments 1 to 80 or a pharmaceutically acceptable salt thereof.

86. Depression, general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, panic, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-80 or a pharmaceutically acceptable salt thereof Methods of treating anxiety disorders, including disorders, panic attacks, specific phobias, social phobias, or agoraphobia.

87. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 80 or a pharmaceutically acceptable salt thereof.

The present invention includes the free base of the compound of the present invention. Moreover, the present invention includes salts of the compounds of the present invention, typically pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, sulfamic acid, nitric acid and the like.

Examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, methanesulfonic acid, maleic acid, malic acid, malonic acid, mandelic acid , Oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methane sulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, palmic acid, bismethylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA , Glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetic acid, as well as 8-halothephylline, such as 8-bromotheophylline and the like.

Also contemplated are the hydrates that the compounds of the present invention can form as pharmaceutically acceptable acid addition salts.

In addition, the compounds of the present invention may exist in solvated forms as well as unsolvated with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The compounds of the present invention may have one or more asymmetric centers and include any optical isomers (ie, enantiomers or diastereomers) and racemic mixtures, such as isolated, pure or partially purified optical isomers. Any mixtures thereof, ie mixtures of stereoisomers, are intended to be included within the scope of the present invention.

Racemic forms can be separated into optical isomers by known methods, for example, by separating diastereomeric salts thereof with an optically active acid and treating with a base to liberate the optically active amine compound. Another method of degrading racemates with optical isomers is based on chromatography on an optically active matrix. The racemic compounds of the invention can be separated into their optical isomers, for example, by fractional crystals. Compounds of the invention can also be degraded by forming diastereomeric derivatives. Additional methods of resolving optical isomers known to those skilled in the art can be used. Such methods include those discussed in J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials.

In addition, geometric isomers may be formed when a double bond or a wholly or partially saturated ring system is present in a molecule. Any geometric isomer, such as isolated, pure or partially purified geometric isomers or mixtures thereof is intended to be included within the scope of the present invention. Likewise, molecules with bonds with limited rotation can form geometric isomers. It may also be included within the scope of the present invention.

In addition, the compounds of the present invention may exist in different tautomeric forms, and any tautomeric forms that the compounds may form are intended to be included within the scope of the present invention.

The present invention may include drug precursors of the present compounds, which, upon administration, undergo chemical conversion by metabolic processes before they become pharmacologically active substances. In general, the drug precursor may be a functional derivative of a compound of Formula I, IA, IB, IC, IE or IF, which is readily available in vivo as an essential compound of Formula I, IA, IB, IC, IE or IF. Can be switched. Conventional procedures for the selection and preparation of suitable drug precursor derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The invention also includes active metabolites of the compounds.

As described above, the 2- (1H-indolylsulfanyl) -benzyl amine derivative, which is a compound of the present invention, is a serotonin reuptake inhibitor.

Accordingly, one embodiment of the invention relates to compounds of formula I, IA, IB, IC, IE or IF (eg, formula IA) as a free base or salt thereof, wherein R ¹ -R ¹³ are herein As described, the compound has a serotonin reuptake inhibitor, i.e., a binding affinity (IC50), preferably measured by the method described in Example 9 (carrier binding assay), is 5 μM or less, typically 1 μM or less, Preferably it is a serotonin reuptake inhibitor that is less than 500 nM or less than 100 nM or less than 50 nM.

One embodiment of the invention relates to a compound of formula I, IA, IB, IC, IE or IF (eg, formula IA) as free base or salt thereof, wherein R ¹ -R ¹³ are as described herein. And the compound has a norepinephrine reuptake inhibitor, i.e., a binding affinity (IC50), preferably measured by the method described in Example 9 (carrier binding assays) of 5 μM or less, typically 1 μM or less, preferably Preferably a norepinephrine reuptake inhibitor that is less than 500 nM, less than 100 nM or less than 50 nM.

A further embodiment of the invention relates to a compound of formula I, IA, IB, IC, IE or IF (eg, formula IA) as a free base, or salt thereof, wherein R ¹ -R ¹³ are herein As described, the compound has a dopamine reuptake inhibitor, i.e., a binding affinity (IC50), preferably measured by the method described in Example 9 (carrier binding assays) of 5 μM or less, typically 1 μM or less, Preferably a dopamine reuptake inhibitor that is less than 500 nM, less than 100 nM or less than 50 nM.

In particular, the present invention provides compounds having a combined effect of inhibiting serotonin reuptake and inhibiting norepinephrine reuptake. Thus, a preferred embodiment is a compound of the invention (i.e., a compound of the invention that is a dual serotonin and norepinephrine reuptake inhibitor, ie a compound of the invention, each of which is both a norepinephrine reuptake inhibitor and a serotonin reuptake inhibitor as described above) R ¹ -R ¹³ are directed to compounds of Formula I, IA, IB, IC, IE or IF (eg, compounds of Formula IA) as described herein.

In one embodiment, compounds of the invention having a combined effect of serotonin reuptake inhibition and norepinephrine reuptake inhibition as described above are preferred, wherein the compound is not a dopamine reuptake inhibitor. Thus, said embodiment is preferably at least 5, preferably at least 10, or even more preferably 20 or more than the binding affinity for the dopamine transporter, as measured by the method described in Example 9 (deliveryer binding assay). A compound of the present invention having a binding affinity for a serotonin transporter at least 30 times higher.

In a further aspect of the invention, there is provided a compound having the combined effect of inhibiting serotonin reuptake, norepinephrine and dopamine reuptake inhibition.

Accordingly, preferred embodiments are compounds of the invention wherein the triple inhibitors of serotonin, norepinephrine and dopamine reuptake, ie, each of which is described above, at the same time a norepinephrine reuptake inhibitor, a serotonin reuptake inhibitor and a dopamine reuptake inhibitor , Compounds of the invention (ie, R ¹ -R ¹³ are compounds of formula IA, IB, IC, IE or IF (eg, formula IA) as described herein).

Pharmaceutical use

In a further aspect of the invention, there is provided a compound of formula I, IA, IB, IC, ID, IE or IF for use as a medicament.

As mentioned above, the compounds of the present invention are inhibitors of serotonin transporters. In particular, compounds of the invention are provided that are dual inhibitors of serotonin and noradrenaline transporters. The compounds of the present invention may thus be useful for the treatment of disorders or diseases involving serotonin and / or noradrenaline.

Thus, in a further aspect, the present invention provides a compound of the invention as a free base or salt thereof, ie as a free base or salt thereof, for use as a medicament, with the formula I, IA, IB, IC, IE or IF, for example For example, the present invention relates to a compound represented by Formula IA, wherein

- R ¹ -R ² are independently hydrogen, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, and C _{3 -8} - cycloalkyl alk (en) yl -C _1-6-alk selected from (/ person) or one; Or R ¹ with nitrogen And R ² forms a 4 to 7 membered ring comprising 0 or 1 double bond, wherein the nitrogen is added and optionally the ring comprises one additional heteroatom selected from nitrogen, oxygen and sulfur; The ring structure is substituted or unsubstituted as described herein;

- R ³ -R ¹² are independently hydrogen, halogen, cyano, nitro, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, C _{3 -8} - cycloalkyl alk (en) yl -C _{1 -6} - alk (en / in), amino, C _{1 -6} - alk (en / in) ylamino, di - (C _{1 -6} - alk (en / in) yl) amino, C _{1 -6} - alk (en / in) ylcarbonyl, aminocarbonyl, C _1-6 - alk (en / in) yl-aminocarbonyl, di - (C _{1 -6} - alk (en) yl ) aminocarbonyl, hydroxy, C _1-6 - alk (en / in) yloxy, C _{1 -6} - alk (en / in) ylthio, halo -C _{1 -6} - alk (en / in) one , halo, -C _{1 -6} - alk (en / in) ilsul sulfonyl, halo -C _{1 -6} - alk (en / in) ilsul isoquinoline, and C _{1 -6} - alk (en / a) is selected from sulfonyl ilsul ;

- R ¹³ is hydrogen, C _{1 -6} - alk (en / in) yl, C _{3 -8} - cycloalkyl alk (en) yl, and C _{3 -8} - cycloalkyl alk (en) yl alk -C _1- 6- (Yen / in) days;

only,

Sulfur atom indole nr. When attached via 2, R ⁷ is absent;

Sulfur atom indole nr. When attached via 3, R ¹² is absent;

Sulfur atom indole nr. When attached via 4, R ⁸ is absent;

Sulfur atom indole nr. When attached via 5, R ⁹ is absent;

Sulfur atom indole nr. When attached via 6, R ¹⁰ is absent;

Sulfur atom indole nr. When attached via 7, R ¹¹ is absent.

By way of expression, a compound of the present invention means an embodiment of any one of formulas I, IA, IB, IC, IE or IF described herein, in particular formula IA.

The invention also relates to a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier or diluent as a free base or salt thereof.

In an embodiment of the pharmaceutical composition, the amount of a compound of the present invention is about 0.001 to about 100 mg / kg body weight per day.

The invention also relates to the use of the compounds of the invention as free bases or salts thereof for the preparation of pharmaceutical compositions for the treatment of diseases or disorders in which serotonin reuptake inhibitors are beneficial. The medicament may comprise Formula I, IA, IB, IC, IE or IF of any one of the embodiments described herein.

The present invention further relates to the use of the compounds of the invention as free bases or salts thereof for the preparation of pharmaceutical compositions for the treatment of diseases or disorders in which the combined effect of inhibiting serotonin reuptake and norepinephrine reuptake is beneficial. The medicament may comprise Formula I, IA, IB, IC, IE or IF of any one of the embodiments described herein.

The present invention further relates to the use of the compounds of the invention as free bases or salts thereof for the preparation of pharmaceutical compositions for the treatment of diseases or disorders in which the combined effect of serotonin reuptake inhibition and norepinephrine and dopamine reuptake inhibition is beneficial. . The medicament may comprise Formula I, IA, IB, IC, IE or IF of any one of the embodiments described herein.

A further embodiment of the present invention relates to the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE) or (IF) for the preparation of a pharmaceutical composition for the treatment of affective disorders, pain disorders, ADHD and stress incontinence.

In particular the invention also relates to the use of the compounds of the invention as free bases or salts thereof for the preparation of pharmaceutical compositions for the treatment of affective disorders. To further illustrate without limiting the invention, the affective disorder to be treated is selected from the group consisting of depressive disorder and anxiety disorder.

A further embodiment relates to the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE) or (IF) for the preparation of a pharmaceutical composition for treating a depressive disorder. Typically the depressive disorder to be treated is selected from the group consisting of major depressive disorder, postpartum depression, hypothyroidism and bipolar disorder, Alzheimer's disease, psychosis or Parkinsonism linked depression. To further illustrate without limiting the invention, embodiments of the invention relate to treatment of major depressive disorders; Another embodiment relates to the treatment of depression after childbirth; Another embodiment relates to treating hypothyroidism; Another embodiment relates to the treatment of bipolar disorder, Alzheimer's disease, psychosis or Parkinsonism linked depression. To further illustrate without limiting the invention, embodiments of the invention relate to the treatment of bipolar disorder linked depression; Another embodiment relates to the treatment of Alzheimer's disease linked depression; Another embodiment relates to treating psychotic linked depression; Another embodiment relates to the treatment of Parkinsonism linked depression.

In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the manufacture of a pharmaceutical composition for treating depression.

In a further embodiment, the invention relates to the use of a compound of the invention as a free base or salt for the manufacture of a pharmaceutical composition for the treatment of anxiety disorders. Typically, the anxiety disorder to be treated is selected from the group consisting of general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, panic attack, specific phobia, social phobia and agoraphobia. In a further embodiment, the invention also relates to the use of the compounds of the invention as free bases or salts thereof for the preparation of pharmaceutical compositions for the treatment of general anxiety disorders. In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the preparation of a pharmaceutical composition for the treatment of social anxiety disorder. In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the preparation of a pharmaceutical composition for the treatment of posttraumatic stress disorder. In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the manufacture of a pharmaceutical composition for the treatment of OCD. In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the preparation of a pharmaceutical composition for the treatment of panic disorder. In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the preparation of a pharmaceutical composition for treating panic attacks. In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the preparation of a pharmaceutical composition for the treatment of certain phobias. In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the preparation of a pharmaceutical composition for treating social phobia. In a further embodiment, the invention also relates to the use of a compound of the invention as a free base or salt thereof for the preparation of a pharmaceutical composition for treating agoraphobia.

A further aspect of the present invention is directed to administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as a free base or a salt thereof, in particular a compound represented by formula (IA, IB, IC, IE or IF, such as formula IA). Affective disorders, such as depression, general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, panic attack, certain phobias, social phobia and agoraphobia in living animal bodies, including humans It relates to a method for treating a disease or disorder selected from the group consisting of anxiety disorders comprising a.

In a further embodiment, the invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as a free base or salt thereof for the preparation of a pharmaceutical composition for the treatment of panic disorder. To further illustrate without limiting the invention, the pain disorder to be treated is selected from the group consisting of fibromyalgia syndrome (FMS), general pain, back pain, shoulder pain, headache as well as pain during daytime activities and while awake . To further illustrate without limiting the invention, embodiments of the invention relate to the treatment of fibromyalgia syndrome; Another embodiment relates to overall pain treatment; Another embodiment relates to the treatment of back pain; Another embodiment relates to treating shoulder pain; Another embodiment relates to headache treatment; Another embodiment relates to the treatment of pain during daytime activity and while awake.

In a further embodiment, the present invention relates to the use of a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) as a free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of attention deficit hyperactivity disorder.

In a further embodiment, the present invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as a free base or salt thereof for the preparation of a pharmaceutical composition for treating urinary incontinence.

Pharmaceutical composition

The compounds of the present invention as free base or salts thereof may be administered alone or in combination with pharmaceutically acceptable carriers or excipients in single or multiple doses. Pharmaceutical compositions according to the invention may be prepared according to conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. It can be formulated with other known auxiliaries and excipients as well as pharmaceutically acceptable carriers or diluents.

Pharmaceutical compositions may be administered by oral, rectal, nasal, pulmonary, topical (including oral and sublingual), transdermal, intracranial, intraperitoneal, vaginal and parenteral routes (including subcutaneous, intramuscular, intradural, intravenous and dermal). It may be specifically formulated by administration by any suitable route, such as oral administration being preferred. Preferred routes will be assessed depending on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient selected.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, sugars, pills, lozenges, powders and granules. Where appropriate, they may be prepared with coatings such as enteric coatings or formulated to provide controlled release of the active ingredient, such as sustained release or prolonged release according to methods well known to those skilled in the art. Can be.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous solutions and non-aqueous injectable solutions, dispersions, suspensions, emulsions, as well as sterile powders to be reconstituted with sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.

Still other suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, transplants, and the like.

In an embodiment of the pharmaceutical composition, the compound of the present invention is administered in an amount of about 0.001 to about 100 mg / kg body weight per day.

Typically, a compound of this invention is administered in unit dosage form containing the compound in an amount of about 0.01 to 100 mg. The total daily dose usually ranges from about 0.05 to 500 mg.

Typical oral dosages range from about 0.001 to about 100 mg / kg body weight per day, preferably from about 0.01 to about 50 mg / kg body weight per day, administered in one or more doses, such as 1-3 doses. . The exact dosage depends on the dosage form and frequency, the sex, age, weight and general condition of the subject to be treated, the nature and severity of the condition to be treated and any incidental diseases to be treated and other factors that will be evident to those skilled in the art.

The formulations may conveniently be presented in unit dosage form according to methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day, such as 1-3 times per day, ranges from 0.01 to about 1000 mg, preferably about 0.05 to about 500 mg, more preferably about 0.5 mg to about 200 mg. It may contain.

For parenteral routes such as intravenous, intradural, intramuscular and similar administration, typical dosages are about half of those utilized for oral administration.

The compounds of the present invention are generally utilized as salts, such as free substances or pharmaceutically acceptable salts thereof. An acid addition salt of a compound having the utility of a free base is one example. If the compound of the present invention comprises a free base, the salt is prepared by conventional methods by treating a suspension or solution of the free base of the present invention with a chemical equivalent of an acid such as a pharmaceutically acceptable acid. Representative examples are mentioned above.

For parenteral administration, solutions of the compounds of the invention in sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame oil or peanut oil can be used. The aqueous solution should be suitably buffered if necessary and the liquid diluent first becomes isotonic with sufficient salt or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used are all readily available by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lower alkyl ethers of lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Likewise, the carrier or diluent may comprise any sustained release release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in admixture with wax. Pharmaceutical compositions formed by the combination of a compound of the invention with a pharmaceutically acceptable carrier are readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be present in unit dosage form by methods known in pharmacy.

Formulations of the invention suitable for oral administration may be presented as individual units, such as capsules or tablets, each comprising a precalculated amount of the active ingredient, which may comprise suitable excipients. In addition, orally available formulations may be present in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions.

When a solid carrier is used for oral administration, the preparation may be a hard gelatin capsule in the form of a tablet, such as a powder or pellet, or may be in the form of a lozenge tablet or troche. The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g.

When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

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

For example: tablets may be prepared by mixing the normal adjuvant and / or diluent with the active ingredient followed by pressing the mixture into a conventional tableting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other auxiliaries or additives commonly used for this purpose, such as coloring, flavoring, preservatives and the like, can be used if they are miscible with the active ingredient.

Solutions for injection can be prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably sterile water, applying the solution in the desired volume, sterilizing the solution and placing it in a suitable ampoule or vial. Can be. Typically any suitable additives used in the art may be added, such as osmotic agents, preservatives, antioxidants and the like.

In a further aspect, the present invention relates to a method for preparing a compound of the present invention as described below.

Process for preparing compound of the present invention

Compounds of the present invention can be prepared as follows:

Method 1 ( Method for Preparing Compound of Formula IA) Alkylation of an amine of Formula III with an alkylation inducer of Formula II, whereby the compound of Formula IA is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt :

Wherein R ¹ -R ¹³ are as defined herein and L is a leaving group such as halogen, mesylate or tosylate.

Method 2 ( Method for Preparing Compound of Formula IA) Reduction of the amide derivative of Formula (IV), whereby the compound of Formula (IA) is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ -R ¹³ are as defined herein.

Method 3 (Formula IA, also a method for preparing a compound of formula IB wherein R ¹² ≠ hydrogen) Indole of formula V is reacted with a reagent of formula VI for catalytic use, resulting in a compound of formula IA or formula R ¹² ≠ hydrogen Compounds of IB are isolated as free base or salts thereof, such as pharmaceutically acceptable acid addition salts:

Wherein R ¹ -R ¹³ are as defined herein.

Method 4 ( Method for Preparing Compound of Formula IC) Reduction of the amide derivative of Formula (VII), whereby the compound of Formula (IC) is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ -R ¹³ are as defined herein.

Method 5 (Method for Preparing Compound of Formula ID) Reduction of an amide derivative of Formula (VIII), whereby the compound of Formula (ID) is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ -R ¹³ are as defined herein.

Method 6 ( Method for Making Compound of Formula IE) Reduction of the amide derivative of Formula (IX), as a result, the compound of Formula (IE) is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ -R ¹³ are as defined herein.

Method 7 ( Method for Preparing Compound of Formula IF) Reduction of an amide derivative of formula (X) wherein the compound of formula IF is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ -R ¹³ are as defined herein.

Method 8 ( Method for Preparing Compound of Formula (IB) wherein R ¹² = Hydrogen) Reduction of the amide derivative of Formula (XI), whereby the compound of Formula (IB) is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ -R ¹³ are as defined herein.

Method 9 (Method for Preparing Compound of Formula IC wherein R ² = Hydro) Deprotection of a compound of Formula XII, whereby the compound of Formula IC is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ , R ³ -R ¹³ are as defined herein and R 'is a protecting group such as carbamate (such as methyl-, ethyl-, tert -butyl-, allyl-, or benzyl-carba Mate).

Method 10 (Method for Preparing Compound of Formula ID wherein R ² = Hydro) Deprotection of a compound of Formula XIII, whereby the compound of Formula ID is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt. :

[Wherein R ¹ , R ³ -R ¹³ are as defined herein and R ′ is a protecting group such as carbamate (eg methyl-, ethyl-, tert -butyl-, allyl-, or benzyl-carr) Barmate);

Method 11 ( Method for Preparing Compound of Formula IE wherein R ² = Hydro) Deprotection of a compound of Formula XIV, whereby the compound of Formula IE is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ , R ³ -R ¹³ are as defined herein, and R 'is a protecting group such as carbamate (eg, methyl-, ethyl-, tert -butyl-, allyl-, or benzyl-carr Barmate).

Method 12 ( Method for Preparing Compound of Formula IF wherein R ² = Hydro) Deprotection of a compound of Formula XV, whereby the compound of Formula IF is isolated as a free base or salt thereof, such as a pharmaceutically acceptable acid addition salt:

Wherein R ¹ , R ³ -R ¹³ are as defined herein, and R 'is a protecting group such as carbamate (eg, methyl-, ethyl-, tert -butyl-, allyl-, or benzyl-carr) Barmate).

Alkylation according to process 1 is usually carried out in the presence of an organic or inorganic base (potassium carbamate, diisopropylethylamine or triethylamine) at an organic solvent such as a suitable boiling alcohol or ketone, preferably at reflux temperature. Alternatively, the alkylation can be carried out at one of the abovementioned solvents, or dimethyl formamide (DMF), dimethylsulfoxide (DMSO), or N-methylpyrrolidin-2-one (NMP) at a fixed temperature that is different from the boiling point. Among them, preferably in the presence of a base. The alkylated derivatives of formula (II) can be derived from the corresponding benzyl alcohols which are in turn synthesized from the corresponding benzoic acids by the use of standard reduction methods such as lithium aluminum hydride. Corresponding benzoic acids are described in Hamel, P .; Girard, M .; Tsou, NN; J. Heterocycl. Chem; 36, 1999, 643-652 can be synthesized by a similar method. Amines of formula III are commercially available.

Reduction according to Method 2 is carried out by standard literature methods such as the use of reducing agents such as borane, alan or lithium aluminum hydride. Amides of formula (V) are described in Hamel, P .; Girard, M .; Tsou, NN; J. Heterocycl . Chem . ; 36, 1999 , 643-652 and Hamel, P .; Zajac, N .; Atkinson, JG ; Girard, Y .; J. Org. Chem .; 59 ; 21; 1994 ; 6372-6377) and the corresponding benzoic acid, synthesized in a manner analogous to that described in standard methods such as carboxylic acid chlorides, activated esters. Or by coupling with an amine of formula III, for example by using a carboxylic acid combined with a coupling reagent such as dicyclohexyl carbodiimide.

The reaction in Method 3 is carried out by reacting N -alkyl-2,3-dihydro-benzo [d] isothiazole of formula VI with indole of formula V, for example an activator such as Lewis acid or an oxidizing agent such as N-chlorosuccinimide. It can be carried out by reacting in the presence of. N -alkyl-2,3-dihydro-benzo [d] isothiazoles of formula VI are described, for example, in Hoffmann, RW; Goldmann, S .; Chem . Ber . 111, 1978 , 2716-2725 and Kanakarajan, K .; Meier, H .; Angew . Chem . 96, 1984 , 220]. Indoles of Formula V are commercially available or are described, for example, in Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York, and can be prepared by standard methods as described.

Reduction according to Method 4 is carried out by using standard literature methods, namely reducing agents such as borane, alan or lithium aluminum hydride. Amides of formula (VII) are described, for example, in Schopfer, U .; Schlapbach, A. Tetrahedron; 57, 2001, 3069-3073, by methods similar to those described in, for example, Elworthy, TR; Ford, APDW; Bantle, GW; Morgans, DJ; Ozer, RS; et al. J. Med. Chem . 40 , 1997 , 2674-2687, a couple of the corresponding 2-mercapto-benzamide and 4-halo or 4- pseudohalo indole (synthesized by reduction of the corresponding 2,2'-dithiobenzamide) similar to those described in It may be prepared as a ring, wherein "halo" is bromo or iodo, or "pseudohalo" is for example triflate or nonaplate. When R ¹³ = H in formula VII, the position is protected prior to the coupling reaction and desorbed after the coupling reaction according to standard literature procedures using standard protecting groups such as 4-methyl-phenyl-sulfonyl groups or tert -butoxy-carbonyl groups Protected.

Reduction according to Method 5 is carried out by using standard literature methods, namely reducing agents such as borane, alan or lithium aluminum hydride. Amide of formula VIII is (for example, similar to that described in the corresponding literature [Elworthy, TR; Ford, APDW ; Bantle, GW; Morgans, DJ;; Ozer, RS.... Etc Med Chem 40, 1997, 2674-2687] Corresponding 2-mercapto-benzamides (synthesized by reduction of 2,2'-dithiobenzamides) are described in, for example, Schopfer, U .; Schlapbach, A. Tetrahedron ; 57, 2001 , 3069-3073, can be prepared by coupling with 5-halo- or 5-pseudohalo indole, in a manner similar to that described herein, wherein "halo" is bromo or iodo or "pseudohalo""Is for example triflate or nonaplate. When R ¹³ = H in formula VIII, the position is protected prior to the coupling reaction and desorbed after the coupling reaction according to standard literature procedures using standard protecting groups which are, for example, 4-methyl-phenyl-sulfonyl groups or tert -butoxy-carbonyl groups. Protected.

Reduction according to Method 6 is carried out by using standard literature methods, namely reducing agents such as borane, alan or lithium aluminum hydride. Amides of Formula (IX) are described in, for example, Elworthy, TR; Ford, APDW; Bantle, GW; Morgans, David. J .; Ozer, Rachel. S .; et al. J. Med . Chem . 40, 1997 , 2674- Corresponding 2-mercapto-benzamides (synthesized by reduction of the corresponding 2,2'-dithiobenzamides) similar to those described in 2687, are described in Schopfer, U .; Schlapbach, A. Tetrahedron ; 57, 2001 , 3069-3073, can be prepared by coupling with 6-halo- or 6-pseudohalo indole, in a manner similar to that described herein, where "halo" is bromo or iodo or "pseudohalo" Is for example triflate or nonaplate. In the case of R ¹³ = hydrogen in the formula IX, the position is protected before the coupling reaction and desorbed after the coupling reaction according to the standard literature procedure using standard protecting groups such as 4-methyl-phenyl-sulfonyl group or tert -butoxy-carbonyl group. Protected.

Reduction according to Method 7 is carried out by using standard literature methods, namely reducing agents such as borane, alan or lithium aluminum hydride. Amides of Formula (X) are similar to those described in, for example, Elworthy, TR; Ford, APDW; Bantle, GW; Morgans, DJ; Ozer, RS; et al. J. Med . Chem . 40, 1997 , 2674-2687 . Corresponding 2-mercapto-benzamides (synthesized by reduction of the corresponding 2,2'-dithiobenzamides) are described in, eg, Schopfer, U .; Schlapbach, A. T etrahedron ; 57, 2001 , 3069-3073, can be prepared by coupling with 7-halo- or 7-pseudohalo indole, in a manner similar to that described herein, wherein "halo" is bromo or iodo or "pseudohalo" Is for example triflate or nonaplate. In the case of R ¹³ = hydrogen in the formula X, the position is protected before the coupling reaction and desorbed after the coupling reaction according to standard literature procedures using standard protecting groups, for example 4-methyl-phenyl-sulfonyl group or tert -butoxy-carbonyl group. Protected.

Reduction according to Method 8 is carried out by using standard literature methods, namely reducing agents such as borane, alan or lithium aluminum hydride. Amides of formula (X) are described in Hamel, P .; Girard, M .; Tsou, NN; J. Heterocyclic Chem . 36, 1999 , 643-652; Hamel, P .; Girard, Y .; Atkinson, JG; J. Org . Chem . 57, 1992 ; 2694-2699, which can be prepared by acidic rearrangement of amides of formula IV similar to the method described in (eg, treatment in solution of trifluoroacetic acid).

Deprotection according to Method 9 is known to those skilled in the art and described in Protective Groups in Organic Synthesis Greene, TW; Wuts, PGM Wiley Interscience, (1991) ISBN 0471623016. Protected amines can be prepared in a manner analogous to that described in the literature by reaction of suitably substituted (2-methcapto-benzyl) -methyl-carbamic acid esters with appropriately substituted 4-halo indole or 4-pse indole; , Wherein "halo" is bromo or iodo and "pseudohalo" is for example triflate or nonaplate and is described in Schopfer, H .; Schlapbach, U .; Tetrahedron 2001 , 57, 3069-3073. When R ¹³ = hydrogen in formula (XII), the position is protected prior to the coupling reaction and desorbed after the coupling reaction according to standard literature procedures using standard protecting groups which are, for example, 4-methyl-phenyl-sulfonyl groups or tert -butoxy-carbonyl groups. Protected. Properly substituted (2-mercapto-benzyl) -methyl-carbamic acid esters are suitably used in dissilylation with fluoride donors such as tetrabutylammonium fluoride after a palladium catalytic coupling reaction with trialkylsilane thiols. substituted (2-iodo-benzyl) -methyl-carbamic acid ester or properly substituted (2-bromo-benzyl) -methyl-carbamic acid ester can be prepared from (Winn, M .; et al. J. Med . Chem . 2001, 44, 4393-4403).

Deprotection according to method 10 may be carried out as described in method 9. Protected amines can be prepared from suitably substituted (2-mercapto-benzyl) -methyl-carbamic acid esters and suitably substituted 5-halo indole or 5-pseudohalo indole, where "halo" Bromo or iodo and 'pseudohalo' is, for example, triflate or nonaplate as described in 9. When R ¹³ = hydrogen in Formula XIII, the position is for example 4-methyl-phenyl-sulfonyl or tert Protected before the coupling reaction and deprotected after the coupling reaction according to standard literature procedures using standard protecting groups which are -butoxy-carbonyl groups.

Deprotection according to Method 11 may be carried out as described in Method 9. Protected amines may be prepared from suitably substituted (2-mercapto-benzyl) -methyl-carbamic acid esters and suitably substituted 6-halo indole or 6-pseudohalo indole, where "halo" Bromo or iodo and 'pseudohalo' is, for example, triflate or nonaplate, as described in 9. When R ¹³ = hydrogen in Formula XIV, the position is for example a 4-methyl-phenyl-sulfonyl group or tert Protected before the coupling reaction and deprotected after the coupling reaction according to standard literature procedures using standard protecting groups which are -butoxy-carbonyl groups.

Deprotection according to method 12 may be carried out as described in method 9. Protected amines can be prepared from suitably substituted (2-mercapto-benzyl) -methyl-carbamic acid esters and suitably substituted 7-halo indole or 7-pseudohalo indole, where "halo" Bromo or iodo and 'pseudohalo' is, for example, triflate or nonaplate, as described in 9. When R ¹³ = hydrogen in Formula XV, the position is for example 4-methyl-phenyl-sulfonyl or tert Protected before the coupling reaction and deprotected after the coupling reaction according to standard literature procedures using standard protecting groups which are -butoxy-carbonyl groups.

The invention disclosed herein is further illustrated by the following non-limiting examples.

EXAMPLE

Common way

Analytical LC-MS data were obtained on a PE Sciex API 150EX device equipped with a Shimadzu LC-8A / SLC-10A LC system and a photoionization (APPI) ion source. LC conditions (symmetric C18 column 4.6 × 30 mm, particle size 3.5 μm) were linear gradient elution with eluent A (0.05% TFA containing) and B (5% water and acetonitrile containing 0.035% TFA). Gradient (hours [min] /% B): 2 mL / min, (0.00 / 10.0); (4.00 / 100.0); (4.10 / 10.0); (5.00 / 10.0). Purity was measured by integrating UV trace (254 nm) and ELS (SEDERE SEDEX 55 with Heto CBN 8-30 cooling bath). Retention time, R _t was expressed in minutes.

Mass spectra were obtained by turning to the scan method to provide molecular weight information. Molecular ions, MH +, were obtained at low orifice voltage (5V) and fragmentation was obtained at high orifice voltage (100V).

Preparative LC-MS-separation was carried out in the same apparatus. LC conditions (symmetric C18 column 10 x 50 mm) were linear gradient elution with eluent A (0.05% TFA containing water) and B (5% water and 0.035% TFA containing acetonitrile): (hours [minute] /% B ): (0.00 / 20.0); (7.00 / 100.0); (7.10 / 20.0); (8.00 / 20.0), 5.7 mL / min. Fraction collection was performed with split-flow MS detection.

For column chromatography silica gel of formula Kieselgel 60, 230-400 mesh ASTM was used. Ion exchange chromatography (SCX, 1 g, Varian Mega Bond Elut® Chrompack cat.No. 220776) was used. Before using the SCX-column, the conditions were preconditioned with 10% acetic acid solution (30 mL) in methanol.

Intermediate manufacturing

Example  One 2- (1H-indole-3- Sulsulfanil ) -N, N-dimethyl Benzamide

N, N, N ', N'- tetramethyl-2,2'-dithiodibenzamide (Elworthy, Todd R .; Ford, Anthony PDW; Bantle, Gary W .; Morgans, David J .; Ozer, Rachel S J. Med. Chem . 40, 1997 , 2674-2687) (12.80 g, 35.5 mmol) was dissolved under Ar, in 1,2-dichloroethane (200 mL), and sulfurylchloride (2.9 mL, 4.84 g, 35.9 mmol) was added carefully with stirring under Ar. The reaction mixture was stirred for 15 minutes at room temperature and the resulting solution was slowly (dropwise) added to a cold solution (0 ° C.) of indole (8.4 g, 71.7 mmol) in dry DMF (180 mL) under Ar. The mixture was stirred under Ar for 2.5 h at 0 ° C. and then the reaction was stopped by addition of water (180 mL) and saturated aqueous NaHCO ₃ (150 mL). To the resulting emulsion was added ethyl acetate (250 mL). The organic phase was combined and washed with brine (100 mL). The water phase is further extracted with ethyl acetate (2x100 mL), the combined organic phases are washed with brine, MgSO ₄ Dry over phase and evaporate in vacuo to dark orange oil, which crystallizes upon standing. The product was purified and isolated by recrystallization (acetonitrile) to give 5.53 g (26%) recrystallization product (mp195.6-197.6 ° C.). An additional 4.45 g (21%) product was isolated from the mother liquor (mp194.3-196.4 ° C).

The following compounds were prepared in a similar manner:

2- (4-Chloro- 1H -indol-3-ylsulfanyl) -N, N -dimethyl benzamide

2- (4-Fluoro- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (4-Fluoro- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (5-Fluoro- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (5-chloro -1 H - indol-3-ylsulfanyl) - N, N- dimethylbenzamide

N, N- Dimethyl-2- (7-methyl-1 H -indol-3-ylsulfanyl) benzamide

2- (5-methoxy-1 H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (6-Fluoro- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (6-Chloro- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

N, N- dimethyl-2- (2-methyl-1 H -indol-3-ylsulfanyl) benzamide

2- (6-hydroxy- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (7-methoxy-1 H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

N, N- dimethyl-2- (4-methyl-1 H -indol-3-ylsulfanyl) benzamide

N, N- dimethyl-2- (7-nitro-1 H -indol-3-ylsulfanyl) benzamide

2- (4-hydroxy- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (4-cyano- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (6-cyano- 1H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (7-chloro-1 H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

2- (6-methoxy-1 H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

N, N- dimethyl-2- (1-methyl-1 H -indol-3-ylsulfanyl) benzamide

2- (4-methoxy-1 H -indol-3-ylsulfanyl) -N, N- dimethyl benzamide

N, N- Dimethyl-2- (6-methyl-1 H -indol-3-ylsulfanyl) benzamide

Example  2 2- (1H-indole-3- Sulsulfanil )- N - methyl Benzamide

Carbonyldiimidazole (11 mmol) is added to a solution of 2- (1 H -indol-3-ylsulfanyl) benzoic acid (10 mmol) in dry THF (200 mL) (Hamel, P .; Girard, M. ; Tsou, NN;.. J. Heterocycl Chem 36, 1999, 643 - 652), was refluxed under argon for 60 minutes. Methyl amine (1M in THF; 40 ml) was slowly added to the reaction mixture and the mixture was stirred at rt for 16 h. The mixture was evaporated in vacuo and the product was purified by column chromatography on silica gel using ethyl acetate as eluent.

The following compounds were prepared in a similar manner:

2- (5-Fluoro- 1H -indol-3-ylsulfanyl) -N -methyl benzamide

2- (6-Fluoro- 1H -indol-3-ylsulfanyl) -N -methyl benzamide

2- (2-Methyl-1 H -indol-3-ylsulfanyl) -N -methyl benzamide

2- (4-Methyl-1 H -indol-3-ylsulfanyl) -N -methyl benzamide

2- (4-Chloro-1 H -indol-3-ylsulfanyl) -N -methyl benzamide

Example  3 (2- Mercapto -benzyl)- methyl - Carbamic acid tert -Butyl ester

(2-iodo-benzyl) -methyl-carbamic acid tert -butyl ester (5.0 g, 14.4 mmol) in dry toluene (30 mL) was placed in two Emrys Optimizer EXP 20 mL tubes. Tris (dibenzylideneacetone) dipalladium (66 mg, 0.072 mmol), bis (2-diphenylphosphinophenyl) ether (78 mg, 0.14 mmol), triisopropylsilanethiol (1.44 g, 7.56 mmol) in each tube ) And sodium tert -butoxide (900 mg, 9.36 mmol) were added sequentially. The tube was sealed and microwave heating was applied at 160 ° C. for 15 minutes. After cooling the mixture, the product was eluted with ethyl acetate-heptane (1:10) through silica plug and 5.2 g (88%) of methyl- (2-triisopropylsilanylsulfanyl-benzyl) -carr Chest acid tert -butyl ester was obtained. The product was dissolved in THF (70 mL) and cooled to 0 ° C. Tetrabutylammonium fluoride trihydrate (4.21 g, 13.3 mmol) dissolved in THF (40 mL) was added dropwise at 0 ° C. and the mixture was stirred at this temperature for 15 minutes. The crude mixture was poured onto a silica gel plug and the product eluted with ethyl acetate-heptane (1: 2) to 3.2 g (100%) of (2-mercapto- contaminated with triisopropylsilane fluoride trace. Benzyl) -methyl-carbamic acid tert -butyl ester was obtained.

Example  4 Chemical Formula Of I  Compound of the Invention

Synthesis of

1. [2- (1H-indole-3- Sulsulfanil ) Benzyl] Dimethyl Amine

2- (1H-indol-3-ylsulfanyl) -N, N-dimethyl benzamide (1 mmol) was dissolved in dry tetrahydrofuran (30 mL). To the mixture was added 1 M borane in 3 ml of tetrahydrofuran and the mixture was stirred at rt for 24 h. Methanol (5 mL) was added and the mixture was stirred at rt for 30 min and then evaporated in vacuo. The mixture is redissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate (20 mL) and dried over anhydrous MgSO ₄ Dry over phase and evaporate in vacuo. The product was dissolved in acetone and crystallized as an oxalate salt by addition of 1 equivalent of oxalic acid.

The following compounds were prepared in a similar manner and the analytical data is shown in Table 1:

2. [2- (5-Cyano-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

3. [2- (4-Fluoro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

4. [2- (4-Chloro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

5. [2- (5-Fluoro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

6. [2- (5-Chloro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

7. Dimethyl- [2- (7-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

8. [2- (7-methoxy-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

9. [2- (5-methoxy-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

10. [2- (6-Fluoro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

11. [2- (6-Chloro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

12. Dimethyl- [2- (2-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

13. Dimethyl- [2- (6-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

14. [2- (4-cyano-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

15. Dimethyl- [2- (1-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

16. Dimethyl- [2- (4-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

17. Dimethyl- [2- (4-hydroxy-1 H -indol-3-ylsulfanyl) benzyl] amine

18. [2- (6-cyano-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

19. [2- (7-Chloro-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

20. [2- (6-methoxy-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

21. [2- (4-methoxy-1 H -indol-3-ylsulfanyl) benzyl] dimethyl amine

Example  5 Chemical Formula Of I  Chemical formula

Synthesis of

22. [2- (1H-indole-3- Sulsulfanil )benzyl] methyl  Amine

2-methyl-2,3-dihydro-benzoisothiazole (VI) (Hoffmann, RW; Goldman, S. Chem. Ber. 111, 1978 , 2716-2725) (75 mg, 0.50 mmol) was dissolved in THF (1 mL) and added to indole (V) (140 mg, 0.60 mmol) under Ar. Trichloroacetic acid (90 mg, 0.55 mmol) was added and the reaction mixture was stirred at rt for 16 h. 2 mL 1N NaOH (aq) was added. Extract with ethyl acetate (2 × 10 mL) and purify by flash chromatography on silica gel (eluent: ethyl acetate then ethyl acetate / methanol / triethylamine) to give 88 mg [2- (1H-indol-3-ylsulfanyl) ) Benzyl] methyl amine (67% yield) was obtained.

The following compounds were prepared in a similar manner and the analytical data is shown in Table 1 :

23. [2- (6-Fluoro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

24. [2- (5-Fluoro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

25. Methyl- [2- (4-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

26. [2- (4-Chloro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

27. Methyl- [2- (2-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

28. [2- (5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

29. Methyl- [2- (5-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

30. Methyl- [2- (7-methyl-1 H -indol-3-ylsulfanyl) benzyl] amine

31. [2- (4-Fluoro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

32. [2- (7-ethyl-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

33. [2- (6-methoxy-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

34. [2- (5-Chloro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

35. [2- (6-Chloro-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

36. [2- (5-methoxy-4-methyl-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

37. [2- (5,6-Dimethoxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

38. [2- (6-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

39. Methyl- [2- (6-methyl-1H-indol-3-ylsulfanyl) -benzyl] amine

40. [2- (4,7-Dimethoxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

41. [2- (5-methoxy-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

42. [2- (4-methoxy-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

43. [2- (5-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine

44. [2- (7-methoxy-1 H -indol-3-ylsulfanyl) benzyl] methyl amine

45. [5-Chloro-2- ( 1H -indol-3-ylsulfanyl) -benzyl] methyl amine

46. Methyl- [2- (6-trifluoromethyl- 1H -indol-3-ylsulfanyl) -benzyl] amine

47. [5-hydroxy-2- ( 1H -indol-3-ylsulfanyl) -benzyl] methyl amine

48. [2- (4-Bromo- 1H -indol-3-ylsulfanyl) -benzyl] methyl amine

49. [2- (7-Chloro- 1H -indol-3-ylsulfanyl) -benzyl] methyl amine

50. [2- (5-iodo- 1H -indol-3-ylsulfanyl) -benzyl] methyl amine

51. [2- (6-Cyano- 1H -indol-3-ylsulfanyl) -benzyl] methyl amine

52. [2- ( 1H -Indol-3-ylsulfanyl) -5-methyl-benzyl] methyl amine

53. [2- (3-Methyl- 1H -indol-2-ylsulfanyl) -benzyl] methyl amine

54. [2- (5,6-Dimethoxy-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine

55. [5-Fluoro-2- (3-methyl-1 H -indol-2-ylsulfanyl) -benzyl] -methyl-amine

56. [5-Fluoro-2- (4-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

57. [2- (4-Chloro-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine

58. [2- (7-Chloro-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine

59. [5-Fluoro-2- (6-trifluoromethyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

60. [5-Fluoro-2- (7-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

61. [2- (4-Bromo-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine

62. 3- (4-Fluoro-2-methylaminomethyl-phenylsulfanyl) -2-methyl-1 H -indol-4-ol

63. 3- (4-Fluoro-2-methylaminomethyl-phenylsulfanyl) -1 H -indol-6-ol

64. [5-Fluoro-2- (5-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

65. [5-Fluoro-2- (4-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

66. [2- (6-Chloro-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine

67. [2- (5-Chloro-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine

68. [5-Fluoro-2- (6-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

69. [5-Fluoro-2- (5-methoxy-4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

70. [2- (5-Bromo-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine

71. [5-Fluoro-2- (5-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

72. [2- (6-Bromo-1 H -indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine

73. [5-Fluoro-2- (6-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

74. [5-Fluoro-2- (6-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

75. [5-Fluoro-2- (2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

76. [5-Fluoro-2- (5-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

77. [5-Fluoro-2- (4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

78. [5-Fluoro-2- (7-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

79. [5-Fluoro-2- (1-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

80. [5-Fluoro-2- (5-fluoro-2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

81. [5-Chloro-2- (5-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

82. [5-Chloro-2- (5-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

83. [5-Chloro-2- (7-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

84. [5-Chloro-2- (1-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

85. [5-Chloro-2- (4-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

86. [5-Chloro-2- (7-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

87. [5-Chloro-2- (6-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

88. [5-Chloro-2- (5-fluoro-2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

89. [2- (5-Fluoro-2-methyl-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

90. Methyl- [5-methyl-2- (4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -amine

91. [2- (7-Ethyl-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

92. [2- (6-methoxy-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

93. Methyl- [5-methyl-2- (2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -amine

94. [2- (4-methoxy-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

95. [2- (6-Bromo-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

96. [2- (6-Fluoro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

97. [2- (4-Fluoro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

98. 3- (4-Methyl-2-methylaminomethyl-phenylsulfanyl) -1 H -indol-6-ol

99. [5-Chloro-2- (5-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

100. [2- (6-Chloro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

101. [2- (5-Chloro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

105. [4-Chloro-2- (6-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

106. [4-Chloro-2- (2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

107. [4-Chloro-2- (5-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

108. [4-Chloro-2- (7-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

109. [4-Chloro-2- (4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

110. [4-Chloro-2- (5-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

111. [4-Chloro-2- (6-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

112. [4-Chloro-2- (4-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

113. [4-Chloro-2- (7-fluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

114. [4-Chloro-2- (7-ethyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

115. [4-Chloro-2- (5-methoxy-4-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

116. [4-Chloro-2- (5-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

117. [4-Chloro-2- (6-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

118. [4-Chloro-2- (7-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

119. [4-Chloro-2- (4-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

120. 4-Chloro-2- (5-chloro-l H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

121. [4-Chloro-2- (6-chloro-l H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

122. [4-Chloro-2- (4-chloro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

123. [4-Chloro-2- (7-chloro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

124. [4-Chloro-2- ( 1H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

125. [4-Chloro-2- (1-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

126. [4-Chloro-2- (3-methyl-1 H -indol-2-ylsulfanyl) -benzyl] -methyl-amine

127. [4-Chloro-2- (5-fluoro-2-methyl-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

129. [2- (5-Fluoro-4-methoxy-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

130. [2- (4,5-Difluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

131. [2- (4,6-Difluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

132. 3- (2-methylaminomethyl-phenylsulfanyl) -1 H -indol-4-ol

134. [2- (5,6-Difluoro-1 H -indol-3-ylsulfanyl) -benzyl] -methyl-amine

135. 6-Fluoro-3- (2-methylaminomethyl-phenylsulfanyl) -1 H -indol-5-ol

136. [2- (4-Chloro-1 H -indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine

Example  6 Chemical Formula Of I  compound

The following synthesis:

102. 5- Fluoro -3- (2-piperidine-1- Methyl - Phenylsulfanyl ) -1H-indole

6 mL concentrated H ₂ SO ₄ was added to 2,2'-dithiodibenzoic acid (20 g, 65.3 mmol) in 150 mL methanol. The reaction mixture was refluxed for 3 days, cooled to room temperature and neutralized with saturated aqueous NaHCO ₃ . Methanol was removed in vacuo. The residue was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford 17.8 g of dimethyl 2,2'-dithiodibenzoic acid ester (53.2 mmol, 82%). 1.20 mL of sulfurylchloride (15 mmol) was added to 5.00 g of dimethyl 2,2'-dithiodibenzoic acid ester (15 mmol) in 40 mL of dry 1,2-dichloroethane at 0 ° C. under Ar. The reaction mixture was stirred 15 minutes at room temperature and added to 4.10 g fluoro-1 H -indole (30.3 mmol) in 50 mL of dry THF under Ar. The reaction mixture is stirred for 2 hours at room temperature and then saturated aqueous NaHCO ₃ The reaction was stopped by addition. Ethyl acetate was added, the two phases were separated and the organic phase was washed with brine, dried over MgSO ₄ and concentrated in vacuo. 8.30 g of 2- (5-fluoro-1 H -indol-3-ylsulfanyl) -benzoic acid methyl ester (27.5 mmol, 92%) were isolated after flash chromatography on silica gel. 4.15 g of 2- (5-fluoro-1 H -indol-3-ylsulfanyl) -benzoic acid methyl ester (13.8 mmol) in 50 mL of dry THF is 0.58 g of LiAlH in 20 mL dry diethyl ether at 0 ° C. ₄ (15.4 mmol) dropwise. 150 mL of dry THF was added and the reaction mixture was stirred for 16 hours at room temperature. The reaction was stopped with 1 mL water and 1 mL 2N NaOH. The reaction mixture was stirred for 1 hour, then 2.5 mL water was added and stirred for 1 hour more. Filter the mixture, and with MgSO ₄ Drying and concentration in vacuo gave 3.00 g of 2- (5-fluoro-1 H -indol-3-ylsulfanyl) -phenyl] -methanol (11.0 mmol, 80%). 0.275 g of p -toluenesulfonylchloride (1.44 mmol) was added to 0.375 g of 2- (5-fluoro-1 H -indol-3-ylsulfanyl) -phenyl] -methanol in 5 mL of dry THF at 0 ° C. 1.37 mmol). The reaction mixture was stirred for 2 h at 0 ° C. and then added to 2.75 mmol of piperidine in 10 mL of dry THF and stirred at rt for 16 h. Water and ethyl acetate were added to the reaction mixture. The two phases were separated and the organic phase was washed with brine, dried over MgSO ₄ and concentrated in vacuo. 5-Fluoro-3- (2-piperidin-1-ylmethyl-phenylsulfanyl) -1 H -indole was isolated after flash chromatography.

The following compounds were prepared in a similar manner and the analytical data is shown in Table 1:

103. 5-Fluoro-3- (2-morpholin-4-ylmethyl-phenylsulfanyl) -1 H -indole

104. 5-Fluoro-3- (2-pyrrolidin-1-ylmethyl-phenylsulfanyl) -1 H -indole

Example  7 Formula I Compound

The following synthesis:

128. 2- (5- Fluoro -1H-indole-3- Sulsulfanil ) -Benzylamine

4.50 g NaBH ₄ (119 mmol) was partitioned and 2,2 'through 8.35 g 2,2'-dithiodibenzamide (27.4 mmol, 2,2'-dithiodibenzoic acid chloride in 80 mL of ethanol at 0 ° C. -Made from dithiodibenzoic acid) and 7.50 g of allyl bromide (62.0 mmol). The reaction mixture was stirred for 1 hour at room temperature. 50 mL of 1N HCl was added and stirring continued for 1 hour. Methanol was removed in vacuo. The residue was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford 10.0 g of 2-allylsulfanyl-benzamide (51.7 mmol, 94%). 2.1 g of LiAlH ₄ (55 mmol) was added to 6.0 g of 2-allylsulfanyl-benzamide (31 mmol) in 50 mL of dry THF at 0 ° C. The reaction mixture was stirred for 16 hours at room temperature. The reaction was stopped with 4 mL water and 3 mL 2N NaOH. The reaction mixture was stirred for 1 hour, then 9 mL water was added and stirring continued for another hour. The mixture was filtered, dried over MgSO ₄ and concentrated in vacuo to give 5.05 g 2-allylsulfanyl-benzylamine (28.2 mmol, 91%). 2.05 g di- tert -butyl dicarbonate (9.37 mmol) was added to 1.40 g 2-allylsulfanyl-benzylamine (7.81 mmol) and a catalytic amount of N , N -dimethyl-4-amino pyridine in 20 mL of THF. . The reaction mixture was stirred for 15 minutes at room temperature. 10 mL of 20% citric acid was added and the reaction mixture was stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate, the two phases are separated and the organic phase is washed with brine, dried over MgSO ₄ and concentrated in vacuo to give (2-allylsulfanyl-benzyl) -carbamic acid tert -butyl ester Obtained in quantitative yield. 0.70 g NaIO ₄ (3.3 mmol) in 20 mL of water is added to 0.75 g (2-allylsulfanyl-benzyl) -carbamic acid tert -butyl ester (2.7 mmol) in 20 mL of methanol and at room temperature for 2 hours. Stirred. The reaction mixture was filtered and methanol was removed in vacuo. The residue was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue is redissolved in 5 mL of THF and added to 0.65 g of trichloroacetic acid (4.0 mmol) and 0.50 g of fluoro-1 H -indole (3.7 mmol) in 5 mL of THF and 50 for 16 h. It stirred at ° C. Saturated aqueous NaHCO ₃ And ethyl acetate were added, the two phases were separated and the organic phase was washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash chromatography and 0.157 g of [2- (5-Fluoro-1H-indol-3-ylsulfanyl) -benzyl] -carbamic acid tert -butyl ester (0.42 mmol, 16%) was ethyl Isolated after recrystallization from acetate / heptane. 8 mL diethyl ether saturated with HCl was diluted with 0.157 g of [2- (5-fluoro-1H-indol-3-ylsulfanyl) -benzyl] -carbamic acid tert -butyl ester (0.42 mmol) in 8 mL of methanol. Was added and stirred for 16 h. The reaction was neutralized with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo to yield 0.112 g of 2- (5-fluoro-1 H -indol-3-ylsulfanyl) -benzylamine (98%).

The following compounds were prepared in a similar manner and the analytical data is shown in Table 1:

133. 2- (6-Fluoro- 1H -indol-3-ylsulfanyl) -benzylamine

Example  8 Compound of Formula (I)

The following synthesis:

[2- (1H-indole-5- Sulsulfanil )-benzyl]- methyl -Amine

(2-mercapto-benzyl) -methyl-carbamic acid tert -butyl ester (1.85 g, 7.30 mmol) in dry toluene (15 mL) was placed in an Emrys Optimizer EXP 20 mL tube. Tris (dibenzylideneacetone) dipaladium (334 mg, 0.37 mmol), bis (2-diphenylphosphinophenyl) ether (197 mg, 0.37 mmol), tert -butyl-5- bromoindole -1-carboxyl Rate (2.38 g, 8.03 mmol) and potassium tert -butoxide (860 mg, 7.67 mmol) were added. The reaction vessel was sealed and subjected to microwave heating at 160 ° C. for 15 minutes. Upon cooling the mixture was poured into silica plug and the product eluted with ethyl acetate-heptane (1: 4). 0.67 g (20%) of 5- {2-[( tert -butoxycarbonyl-methyl-amino) -methyl] -phenylsulfanyl} -indole-1-carboxylic acid tert -butyl ester is isolated and further purified Was used in the next step without. 5- {2-[( tert -butoxycarbonyl-methyl-amino) -methyl] -phenylsulfanyl} -indole-1-carboxylic acid tert -butyl ester (0.67 g, 1.43 mmol) in methanol (15 mL) ) And diethyl ether saturated with hydrochloric acid (15 mL) were stirred at rt for 1 h and concentrated in vacuo. Ice / water was added to the residue and 28% aqueous NaOH was added until pH 9. The aqueous fraction was extracted with ethyl acetate (3 x 15 mL). The combined organic fractions were dried over MgSO ₄ and concentrated in vacuo. The product was purified by silica gel chromatography eluting with ethyl acetate-triethyl amine (100: 4) followed by ethyl acetate-ethanol-triethyl amine (100: 5: 5). As soon as the volatiles were evaporated, 40 mg (10%) of [2- ( 1H -indol-5-ylsulfanyl) -benzyl] -methyl-amine was isolated.

The following compounds were prepared in a similar manner:

[2- ( 1H -Indol-4-ylsulfanyl) -benzyl] -methyl-amine

[2- ( 1H -Indol-6-ylsulfanyl) -benzyl] -methyl-amine

[2- ( 1H -Indol-7-ylsulfanyl) -benzyl] -methyl-amine

Table 1. Measured molecular mass, measured HPLC-retention time (R _t , min) and UV- and ELSD-purity (%).

compound R _t  (minute) UV-purity (%) ELSD -Purity (%) M + H ⁺ One 1.79 97.9 100 283.2 2 1.75 80.6 96.5 307.9 3 1.83 98.0 97.1 300.8 4 1.91 95.4 98.2 317.1 5 1.83 98.8 99.3 301.1 6 2.04 99.4 99.1 317.1 7 2.00 97.9 97.4 297.2 8 1.91 96.8 98.3 313.1 9 1.79 98.9 100 313.2 10 1.91 99.5 100 301.1 11 2.08 96.1 100 316.8 12 1.87 95.2 99.1 297 13 1.82 98.7 100.0 297.2 14 1.56 95.2 100.0 308 15 1.88 98.3 100.0 297.1 16 1.81 99.2 100.0 297.1 17 1.49 75.0 91.5 299 18 1.68 90.0 95.0 308 19 1.96 90.5 95.6 316.8 20 1.77 88.7 96.0 313.1 21 1.75 87.3 96.9 313 22 1.79 98.5 97.5 269 23 1.95 100 95.4 287 24 1.94 99.2 95.8 286.8 25 1.93 97.2 97.0 283.3 26 1.90 98.2 96.3 303 27 1.87 97.4 96.8 283.1 28 2.01 97.0 99.1 301.1 29 1.85 98.0 99.9 283 30 1.89 98.1 99.8 283 31 1.72 97.9 99.7 286.9 32 2.02 97.9 100 297.1 33 1.72 99.5 99.9 299.1 34 1.92 97.7 100 303.1 35 1.97 96.5 99.9 303.1 36 1.81 98.8 99.8 313.2 37 1.51 97.7 99.6 329.1 38 2.00 97.5 99.8 346.9 39 1.87 80.6 99.0 283.1 40 1.73 84.1 97.9 329.1 41 1.68 87.5 98.5 299.1 42 1.66 87.6 99.4 299 43 1.98 93.7 98.7 348.8 44 1.78 93.7 99.3 299.1 45 2.45 84.3 85.4 303.3 46 2.05 96.8 100 337.1 47 1.30 93.4 100 285.1 48 1.83 92.4 100 348.8 49 1.92 90.6 99.9 303 50 2.00 88.6 99.6 395.1 51 1.62 86.1 98.5 293.8 52 1.82 97.0 99.7 283.3 53 2.04 95.9 99.7 283.4  54 1.56 73.92 98.05 347.0 55 2.10 74.19 96.08 299.1 56 1.76 78.09 100.00 304.9 57 1.88 80.25 99.77 320.8 58 1.97 80.83 98.86 320.9 59 2.12 84.31 99.11 355.1 60 1.83 86.68 99.15 317.1 61 1.90 87.33 99.75 367.0 62 1.64 88.10 99.61 317.0 63 1.41 88.77 99.74 303.1 64 1.83 91.91 100.00 304.8 65 1.74 92.27 100.00 317.1 66 2.00 93.20 99.91 321.1 67 1.97 93.68 100.00 320.9 68 1.92 93.80 99.97 301.0 69 1.85 94.35 100.00 329.1 70 2.00 94.52 99.86 367.0 71 1.73 95.29 99.88 317.1 72 2.04 95.56 99.80 367.0 73 1.85 95.67 100.00 305.0 74 1.76 96.68 99.95 317.1 75 1.82 97.23 100.00 301.1 76 1.91 97.71 100.00 301.1 77 1.89 97.73 99.96 301.1 78 1.93 97.79 99.95 301.1 79 1.96 98.85 99.95 301.0 80 1.88 99.01 99.86 319.0 81 1.94 86.65 99.91 320.9 82 1.85 72.56 100.00 332.8 83 2.03 94.94 99.91 317.1 84 2.05 92.54 99.90 317.1 85 1.85 86.79 99.70 332.9 86 1.95 82.70 99.69 333.0 87 1.97 85.03 99.85 320.9 88 1.99 88.12 100.00 335.0 89 1.95 99.44 100.00 315.1 90 1.97 98.16 100.00 297.2 91 2.12 95.13 99.74 311.3 92 1.83 93.40 100.00 313.1 93 1.78 92.78 98.90 297.0 94 1.79 92.77 100.00 313.1 95 2.11 90.80 100.00 363.0 96 1.94 89.78 99.94 301.1 97 1.84 87.54 100.00 301.0 98 1.49 87.12 99.49 299.1 99 1.51 86.97 100.00 318.9 100 2.07 85.51 98.57 317.1 101 2.04 81.67 94.01 317.0 102 2.00 82.20 80.30 341.1 103 1.86 90.90 82.40 342.9 104 1.95 90.40 78.70 327.1 105 2.06 92.49 99.44 317.1 106 1.96 87.25 98.90 317.0 107 2.03 90.96 99.55 316.8 108 2.04 91.97 99.87 316.8  109 2.02 83.80 98.60 317.1 110 1.96 90.04 99.61 320.9 111 1.99 97.66 99.69 321.0 112 1.89 88.36 99.15 320.9 113 1.98 90.52 99.39 320.9 114 2.18 87.86 99.70 331.0 115 1.97 87.81 99.17 347.0 116 1.88 89.22 99.38 333.0 117 1.89 95.36 99.65 332.9 118 1.96 82.34 98.84 332.7 119 1.87 90.44 99.82 333.0 120 2.08 89.98 99.57 337.2 121 2.13 87.91 99.27 337.1 122 2.00 84.01 98.48 337.2 123 2.11 80.98 99.08 337.1 124 1.91 91.92 99.81 303.1 125 2.08 84.95 98.14 316.7 126 2.25 70.89 87.20 317.1 127 2.01 83.89 98.73 335.1 128 1.74 88.20 98.40 273.0 129 1.77 93.93 99.83 317.1 130 1.78 95.85 99.64 305.0 131 1.80 97.04 99.88 305.0 132 1.42 80.84 97.76 285.1 133 1.78 97.33 99.29 273.0 134 1.84 97.99 99.48 305.0 135 1.38 92.53 98.73 303.1 136 1.86 93.25 97.20 317.0

Example  9 Carrier Binding Assay

Rat  Cerebral cortex With cynabolite  [ ³ H] -5-HT absorption measurement

Whole brains were homogenized except for the cerebellum of Wistar rats (125-225 g) in 0.32 M sucrose supplemented with 1 mM nialamide with a glass / teflon homogenizer. Homogenates were centrifuged at 600 × g at 4 ^° C. for 10 minutes. The pellet was discarded and the supernatant centrifuged at 20.000 × g for 55 minutes. The final pellet was homogenized (20 seconds) in the assay buffer (0.5 mg raw tissue / well). Test compound (or buffer) and 10 nM [ ³ H] -5-HT were added to a 96 well plate and shaken briefly. Composition of assay buffer: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl ₂ , 1.12 mM MgSO ₄ , 12.66 mM Na ₂ HPO ₄ , 2.97 mM NaH ₂ PO ₄ , 0.162 mM EDTA, 10 mM glucose, and 1 mM ascorbic acid. The buffer was oxygenated to 95% 0 ₂ /5% C0 ₂ at 37 ° C. for 10 minutes and the pH was adjusted to 7.4. Incubation was started by adding the tissue to a final assay volume of 0.2 mL. After 15 minutes incubation with spin ligand at 37 ° C., the samples were filtered directly under vacuum, on a Unifilter GF / C glass fiber filter (soaked in 0.1% polyethyleneimine for 1 hour) and immediately washed with 3 × 0.2 ml assay buffer. did. Nonspecific uptake was measured using citalopram (10 μM final concentration). Citalopram is included as reference in all experiments as a dose-response curve.

Rat  Cerebral cortex With cynabolite  [ ³ H] Noradrenaline reuptake measurement

Fresh cerebral cortex derived from male Wistar rats (125-225 g) was homogenized in 0.4 M sucrose using a glass / teflon homogenizer. Homogenates were centrifuged at 600 × g at 4 ^° C. for 10 minutes. The pellet was discarded and the supernatant centrifuged at 20,000 × g for 55 minutes. The final pellet was homogenized (20 seconds) in the assay buffer (6 mg raw tissue / mL = 4 mg / well). Test compound (or buffer) and 10 nM [ ³ H] -noradrenaline were added to a deep 96 well plate and shaken briefly. Assay buffer composition: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl ₂ , 1.12 mM MgSO ₄ , 12.66 mM Na ₂ HPO ₄ , 2.97 mM NaH ₂ PO ₄ , 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. The buffer was oxygenated with 95% 0 ₂ /5% CO ₂ for 10 minutes at 37 ° C. and the pH was adjusted to 7.4. Incubation was started by adding tissue to 1 ml of the final assay volume. After 15 minutes incubation with spin ligand at 37 ° C., the samples were directly filtered under vacuum on a Unifilter GF / C glass fiber filter (soaked in 0.1% polyethyleneimine for 1 hour) and washed immediately with 3 × 1 mL assay buffer. . Nonspecific uptake was measured using dehydrated (10 μM final concentration). Duloxetine was included for reference in all experiments shown as dose-response curves. The results of this experiment showed that the test compound of the present invention inhibited serotonin and norepinephrine reuptake with an IC ₅₀ of less than 200 nM.

Rat With cynabolite   [ ³ H] Dopamine Resorption Measurement

Tissue Preparation: Male wistar rats (125-250 g) were sacrificed on the neck, streatum was quickly dissected and placed in 40 volumes (w / v) cold 0.40 M sucrose. The tissue was slowly homogenized (Glass Teflon Homogenizer), P2 fractions were obtained by centrifugation (1000 g, 10 min and 40000 g, 20 min, 4 ° C.) and 560 volumes of modified Krebs-Ringer-Phosphate buffer, pH 7.4 Suspended in. 0.25 mg / well (140 μl) of tissue (raw tissue) was mixed with the test suspension. After 5 min preincubation, 12.5 nM 3H-dopamine was added and the mixture was incubated at RT for 5 min.

Incubation was terminated by filtering the sample under vacuum through a Whatman GF / C filter and washing with 1 ml buffer. The filtrate was dried and an appropriate flash fluid (Optiphase Supermix) was added. After storage in the dark for 2 hours, the radioactive content was measured by liquid scintillation counting. Uptake was obtained by subtracting active delivery and nonspecific binding as measured in the presence of 100 μM benztropin. For determination of inhibition of reuptake, 10 concentrations of drug applied to six 10 units were used.

³ H-DA = 3,4- (ring-2,5,6- ³ H) dopamine hydrochloride, New England Nuclear, specific activity 30-50 Ci / mmol.

Hyttel, Biochem. Pharmacol. 1978, 27 , 1063-1068;

Hyttel, Prog. Neuro-Psychopharmacol. & bil. Psychiat. 1982, 6 , 277-295;

Hyttel & Larsen, Acta Pharmacol. Tox. 1985, 56 , suppl. 1, 146-153.

The present invention relates to compounds which are serotonin reuptake inhibitors and preferably also norepinephrine reuptake inhibitors, and the medical uses of such compounds, such as depression and anxiety, affective disorders, pain disorders, attention deficit multiple dysfunction disorders (ADHD) and incontinence incontinence Provides use in therapy.

Claims (39)

A compound of formula I as a free base or salt thereof: [Formula I]

[Wherein, sulfur atoms are attached to indole through any ring carbon of indole, R ¹ and R ² are independently hydrogen, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en) yl, and C _3-8 -cycloalk (en) yl- C _1-6 -alk (en / yn) yl, or together with nitrogen, R ¹ and R ² forms a 4 to 7 membered ring comprising 0 or 1 double bond, and optionally the ring comprises one additional heteroatom selected from nitrogen, oxygen and sulfur in addition to said nitrogen; R ³ to R ⁹ , R ¹¹ and R ¹² are independently hydrogen, halogen, cyano, nitro, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yn) yl, amino, C _1-6 -alk (en / yn) ylamino, di- (C _1-6 -alk (En / yn) yl) amino, C _1-6 -alk (en / yn) ylcarbonyl, aminocarbonyl, C _1-6 -alk (en / yn) ylaminocarbonyl, di- (C _{1- 6} -alk (en / yn) yl) aminocarbonyl, hydroxy, C _1-6 -alk (en / yn) yloxy, C _1-6 -alk (en / yn) ylthio, halo-C _{1- 6} -alk (en / yn) yl, halo-C _1-6 -alk (en / yn) ylsulfonyl, halo-C _1-6 -alk (en / yn) ylsulfanyl and C _1-6 -alk (en / In) ylsulfonyl; R ¹⁰ is hydrogen; R ¹³ is selected from hydrogen and C _1-6 -alkyl; only, Sulfur atom indole nr. When attached via 2, R ⁷ is absent; Sulfur atom indole nr. When attached via 3, R ¹² is absent; Sulfur atom indole nr. When attached via 4, R ⁸ is absent; Sulfur atom indole nr. When attached via 5, R ⁹ is absent; Sulfur atom indole nr. When attached via 6, R ¹⁰ is absent; Sulfur atom indole nr. When attached via 7, R ¹¹ is absent. The compound of claim 1, wherein R ¹ And R ² is independently selected from the group consisting of hydrogen and C _{1 -6} - selected from the alk (en / person) or one; Or R ¹ with nitrogen And R ² forms a 4 to 7 membered ring comprising 0 or 1 double bond, and optionally said ring comprises one additional heteroatom selected from nitrogen, oxygen and sulfur in addition to said nitrogen. ^{3. The} compound of claim 1, wherein R ³ to R ⁹ , R ¹¹ and R ¹² are independently hydrogen, halogen, cyano, C _1-6 -alk (en / yn) yl, hydroxy, C _{1- 6} -alk (en / yn) yloxy and halo-C _1-6 -alk (en / yn) yl. ^3. R ³ according to claim 1 or 2 To R ⁶ are independently selected from hydrogen, halogen and C _{1 -6} - alk (en / in) a compound selected from one. A compound according to claim 1 or 2, wherein R ⁷ to R ⁹ , R ¹¹ and R ¹² are independently hydrogen, halogen, cyano, C _1-6 -alk (en / yn) yl, hydroxy, C _{1- 6} -alk (en / yn) yloxy and halo-C _1-6 -alk (en / yn) yl. The compound as claimed in claim 1, which is selected from the following compound list: Compound number Compound name One [2- (1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 2 [2- (5-cyano-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 3 [2- (4-Fluoro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 4 [2- (4-chloro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 5 [2- (5-Fluoro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 6 [2- (5-chloro-lH-indol-3-ylsulfanyl) benzyl] dimethyl amine 7 Dimethyl- [2- (7-methyl-1H-indol-3-ylsulfanyl) benzyl] -amine 8 [2- (7-methoxy-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 9 [2- (5-methoxy-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 12 Dimethyl- [2- (2-methyl-1H-indol-3-ylsulfanyl) benzyl] -amine 14 [2- (4-cyano-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 15 Dimethyl- [2- (1-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 16 Dimethyl- [2- (4-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 17 [2- (4-hydroxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 19 [2- (7-chloro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 21 [2- (4-methoxy-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine 22 [2- (1H-indol-3-ylsulfanyl) benzyl] methyl amine 24 [2- (5-Fluoro-1H-indol-3-ylsulfanyl) benzyl] methyl amine 25 Methyl- [2- (4-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 26 [2- (4-chloro-1H-indol-3-ylsulfanyl) benzyl] methyl amine 27 Methyl- [2- (2-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 28 [2- (5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 29 Methyl- [2- (5-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 30 Methyl- [2- (7-methyl-1H-indol-3-ylsulfanyl) benzyl] amine 31 [2- (4-fluoro-1H-indol-3-ylsulfanyl) benzyl] methyl amine 32 [2- (7-ethyl-1H-indol-3-ylsulfanyl) benzyl] methyl amine 34 [2- (5-chloro-lH-indol-3-ylsulfanyl) benzyl] methyl amine 36 [2- (5-methoxy-4-methyl-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 40 [2- (4,7-Dimethoxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 41 [2- (5-methoxy-1H-indol-3-ylsulfanyl) benzyl] methyl amine 42 [2- (4-methoxy-1H-indol-3-ylsulfanyl) benzyl] methyl amine 43 [2- (5-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 44 [2- (7-methoxy-1H-indol-3-ylsulfanyl) benzyl] methyl amine 45 [5-Chloro-2- (1H-indol-3-ylsulfanyl) -benzyl] methyl amine 47 [2- (5-hydroxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 48 [2- (4-Bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 49 [2- (7-Chloro-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 50 [2- (5-iodo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine 52 [2- (1H-Indol-3-ylsulfanyl) -5-methyl-benzyl] methyl amine 53 Methyl- [2- (3-methyl-1H-indol-2-ylsulfanyl) -benzyl] amine 55 [5-Fluoro-2- (3-methyl-1H-indol-2-ylsulfanyl) -benzyl] -methyl-amine 56 [5-Fluoro-2- (4-fluoro-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 57 [2- (4-Chloro-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 58 [2- (7-Chloro-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 60 [5-Fluoro-2- (7-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 61 [2- (4-Bromo-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 62 3- (4-Fluoro-2-methylaminomethyl-phenylsulfanyl) -2-methyl-1H-indol-4-ol 63 3- (4-Fluoro-2-methylaminomethyl-phenylsulfanyl) -1 H-indol-6-ol 64 [5-Fluoro-2- (5-fluoro-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 65 [5-Fluoro-2- (4-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 67 [2- (5-Chloro-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine 69 [5-Fluoro-2- (5-methoxy-4-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 70 [2- (5-Bromo-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine  71 [5-Fluoro-2- (5-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 75 [5-Fluoro-2- (2-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 76 [5-Fluoro-2- (5-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 77 [5-Fluoro-2- (4-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 78 [5-Fluoro-2- (7-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 79 [5-Fluoro-2- (1-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 80 [5-Fluoro-2- (5-fluoro-2-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 81 [5-Chloro-2- (5-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 82 [5-Chloro-2- (5-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 83 [5-Chloro-2- (7-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 84 [5-Chloro-2- (1-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 85 [5-Chloro-2- (4-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 86 [5-Chloro-2- (7-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 88 [5-Chloro-2- (5-fluoro-2-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 89 [2- (5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 90 Methyl- [5-methyl-2- (4-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -amine 91 [2- (7-Ethyl-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 93 Methyl- [5-methyl-2- (2-methyl-1H-indol-3-ylsulfanyl) -benzyl] -amine 94 [2- (4-methoxy-1 H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 97 [2- (4-Fluoro-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 98 3- (4-Methyl-2-methylaminomethyl-phenylsulfanyl) -1 H-indole-6-ol 99 [5-Chloro-2- (5-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 101 [2- (5-Chloro-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 102 5-Fluoro-3- (2-piperidin-1-ylmethyl-phenylsulfanyl) -1H-indole 103 5-Fluoro-3- (2-morpholin-4-ylmethyl-phenylsulfanyl) -1 H-indole 104 5-Fluoro-3- (2-pyrrolidin-1-ylmethyl-phenylsulfanyl) -1H-indole 106 [4-Chloro-2- (2-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 107 [4-Chloro-2- (5-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 108 [4-Chloro-2- (7-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 109 [4-Chloro-2- (4-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 110 [4-Chloro-2- (5-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 112 [4-Chloro-2- (4-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 113 [4-Chloro-2- (7-fluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 114 [4-Chloro-2- (7-ethyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 115 [4-Chloro-2- (5-methoxy-4-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 116 [4-Chloro-2- (5-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 118 [4-Chloro-2- (7-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 119 [4-Chloro-2- (4-methoxy-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 120 [4-Chloro-2- (5-chloro-lH-indol-3-ylsulfanyl) -benzyl] -methyl-amine 122 [4-Chloro-2- (4-chloro-lH-indol-3-ylsulfanyl) -benzyl] -methyl-amine 123 [4-Chloro-2- (7-chloro-lH-indol-3-ylsulfanyl) -benzyl] -methyl-amine 124 [4-Chloro-2- (1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 125 [4-Chloro-2- (1-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 126 [4-Chloro-2- (3-methyl-1 H-indol-2-ylsulfanyl) -benzyl] -methyl-amine 127 [4-Chloro-2- (5-fluoro-2-methyl-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 128 2- (5-Fluoro-1H-indol-3-ylsulfanyl) -benzylamine 129 [2- (5-Fluoro-4-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 130 [2- (4,5-Difluoro-1 H-indol-3-ylsulfanyl) -benzyl] -methyl-amine 132 3- (2-Methylaminomethyl-phenylsulfanyl) -1 H-indol-4-ol 135 6-Fluoro-3- (2-methylaminomethyl-phenylsulfanyl) -1 H-indol-5-ol 136 [2- (4-Chloro-1H-indol-3-ylsulfanyl) -5-methyl-benzyl] -methyl-amine 137 [2- (1H-Indol-5-ylsulfanyl) -benzyl] -methyl-amine 138 [2- (1H-Indol-4-ylsulfanyl) -benzyl] -methyl-amine 139 [2- (1H-Indol-6-ylsulfanyl) -benzyl] -methyl-amine 140 [2- (1H-Indol-7-ylsulfanyl) -benzyl] -methyl-amine delete delete delete delete delete delete delete delete delete delete delete delete delete The compound of claim 1, which is [2- (1H-indol-3-ylsulfanyl) benzyl] dimethyl amine as a free base or salt thereof. A compound according to claim 1, which is [2- (5-cyano-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine as a free base or salt thereof. 2. Compounds according to claim 1, which are [2- (4-fluoro-1H-indol-3-ylsulfanyl) benzyl] dimethyl amine as a free base or salt thereof. A compound according to claim 1, which is dimethyl- [2- (7-methyl-1H-indol-3-ylsulfanyl) benzyl] -amine as a free base or salt thereof. A compound according to claim 1, which is methyl- [2- (4-methyl-1H-indol-3-ylsulfanyl) benzyl] amine as a free base or salt thereof. The compound of claim 1, which is [2- (4-chloro-lH-indol-3-ylsulfanyl) benzyl] methyl amine as a free base or salt thereof. The compound of claim 1, which is [2- (5-bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine as a free base or salt thereof. The compound of claim 1, which is [2- (5-hydroxy-1H-indol-3-ylsulfanyl) -benzyl] methyl amine as a free base or salt thereof. The compound of claim 1, which is [2- (4-bromo-1H-indol-3-ylsulfanyl) -benzyl] methyl amine as a free base or salt thereof. The compound of claim 1, which is [5-fluoro-2- (3-methyl-1H-indol-2-ylsulfanyl) -benzyl] -methyl-amine as a free base or salt thereof. The compound of claim 1, which is [2- (4-bromo-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine as a free base or salt thereof. The compound according to claim 1, which is [5-fluoro-2- (5-methoxy-4-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine as a free base or a salt thereof. The compound of claim 1, which is [2- (5-bromo-1H-indol-3-ylsulfanyl) -5-fluoro-benzyl] -methyl-amine as a free base or salt thereof. The compound of claim 1, which is [5-chloro-2- (1-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine as a free base or salt thereof. The compound of claim 1, which is [5-chloro-2- (4-methoxy-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine as a free base or salt thereof. The 5-fluoro-3- (2-piperidin-1-ylmethyl-phenylsulfanyl) -1H-indole as claimed in claim 1 as a free base or salt thereof. The 5-fluoro-3- (2-morpholin-4-ylmethyl-phenylsulfanyl) -1H-indole as claimed in claim 1 as a free base or a salt thereof. The 5-fluoro-3- (2-pyrrolidin-1-ylmethyl-phenylsulfanyl) -1H-indole as claimed in claim 1 as a free base or salt thereof. A compound according to claim 1, which is [4-chloro-2- (2-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine as a free base or salt thereof. The compound of claim 1, which is [4-chloro-2- (5-methyl-1H-indol-3-ylsulfanyl) -benzyl] -methyl-amine as a free base or salt thereof.