HK1104554A

HK1104554A - Indole derivatives as histamine receptor antagonists

Info

Publication number: HK1104554A
Application number: HK07112871.2A
Authority: HK
Inventors: S‧G‧麦克阿瑟; C‧赫特尔; M‧H‧内科文; S‧拉夫; O‧罗什; R‧M‧罗德里格斯-萨尔米恩托; F‧舒勒; J-M‧普兰凯尔
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2004-06-21
Filing date: 2005-06-13
Publication date: 2008-01-18

Description

Indole derivatives as histamine receptor antagonists

no marking

The present invention relates to novel indole derivatives, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The active compounds of the present invention are useful in the treatment of obesity and other disorders.

In particular, the invention relates to compounds of the general formula,

wherein

X is O or S;

R¹selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

a lower hydroxyalkyl group,

a lower alkoxyalkyl group,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

phenyl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, lower haloalkoxy or lower hydroxyalkyl,

lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl,

lower heteroarylalkyl, wherein the heteroaryl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl, and

lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups;

R²selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups; or

R¹And R²Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered saturated or partially unsaturated heterocyclic ring, which optionally contains a further heteroatom selected from nitrogen, oxygen or sulfur,

said saturated heterocyclic ring being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, halogen, haloalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or

Fused to a phenyl ring, said phenyl ring being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, lower alkoxy and halogen;

R³selected from the group consisting of: hydrogen, lower alkyl, lower alkoxyalkyl, lower haloalkyl, lower cycloalkylalkyl, lower alkylsulfonyl and lower alkanoyl;

R⁴is-O-Het and R⁵Is hydrogen, or

R⁴Is hydrogen or fluorine and R⁵is-O-Het;

het is selected from

Or

Wherein

m is 0, 1 or 2;

R⁶selected from the group consisting of lower alkyl, cycloalkyl, lower cycloalkylalkyl and lower phenylalkyl;

n is 0, 1 or 2;

R⁷is a lower alkyl group;

p is 0, 1 or 2;

q is 0, 1 or 2;

x is selected from CR¹⁰R^10′O and S;

R⁸，R^8′，R⁹，R^9′，R¹⁰，R^10′，R¹¹and R^11′Independently of each other selected from the group consisting of: hydrogen, lower alkyl, hydroxy, halogen and dialkylamino, or

R⁹And R¹⁰Together form a double bond;

R¹²is a lower alkyl group;

R¹³is C₃-C₆-an alkyl group;

and pharmaceutically acceptable salts thereof.

The compounds of formula I are antagonists and/or inverse agonists at the histamine 3 receptor (H3 receptor).

Histamine (2- (4-imidazolyl) ethylamine) is one of the aminergic neurotransmitters and is widely distributed throughout the body, for example, in the gastrointestinal Tract (Burks 1994, Johnson L.R.ed., Physiology of the gastrointestinal Tract, Raven Press, NY, p. 211-242). Histamine regulates a variety of digestive pathophysiological events such as gastric acid secretion, intestinal motility (Leurs et al, Br J. Pharmacol.1991, 102, pp.179-185), vasomotor responses, intestinal inflammatory responses and allergies (Raithel et al, int. Arch. allergy immunol.1995, 108, 127-133). In the mammalian brain, histamine is synthesized in histaminergic cell bodies found in the center of the tuberomamillary nucleus of the posterior hypothalamus. From there, histamine can project into different brain regions in the cell body (Panula et al, Proc. Natl. Acad. Sci. USA 1984, 81, 2572-.

To the present knowledge, histamine mediates all its effects in the CNS and periphery through four different histamine receptors (histamine H1, H2H 3 and H4 receptors).

The H3 receptor is primarily localized in the Central Nervous System (CNS). As autoreceptors, the H3 receptor constitutively inhibits the synthesis and secretion of histamine from histaminergic neurons (Arrag et al, Nature 1983, 302, 832-As837; Arrag et al, Neuroscience 1987, 23, 149-Asn 157). As heterologous receptors (heteroreceptors), the H3 receptor also modulates the release of other neurotransmitters, such as acetylcholine, dopamine, 5-hydroxytryptamine and norepinephrine, especially in the central nervous system and peripheral organs such as the lungs, cardiovascular system and gastrointestinal tract (Clapham & kilpatrick, br.j. pharmacol.1982, 107, 919-923; the Histamine H3 Receptor of Blandina et al (Leurs RL and Timmermann H eds, 1998, pages 27-40, Elsevier, Amsterdam, The Netherlands.) The H3 Receptor is constitutively active, meaning that The Receptor is activated by potentiation (tonicaly) even in The absence of exogenous Histamine, in The case of inhibitory receptors such as The H3 Receptor, this intrinsic activity leads to an enhanced inhibition of neurotransmitter release, therefore, it may be important that H3R antagonists will also have inverse agonist activity to block exogenous histamine effects and to convert the receptor from its constitutively active (inhibitory) form to a neutral state.

The widespread distribution of the H3 receptor in the mammalian CNS is indicative of the physiological role of this receptor. Therefore, therapeutic potential has been proposed as a target for the development of new drugs for various indications.

Administration of H3R ligand-as an antagonist, inverse agonist, agonist or partial agonist-may affect histamine levels or neurotransmitter secretion in the brain and periphery and thus may be useful in the treatment of several conditions. These disorders include obesity, (Masaki et al; Endocrinol.2003, 144, 2741-2748; Hancock et al, European J.of Pharmacol.2004, 487, 183-197), cardiovascular disorders such as acute myocardial infarction, dementia and cognitive disorders such as Attention Deficit Hyperactivity Disorder (ADHD) and Alzheimer's disease, neurological disorders such as schizophrenia, depression, epilepsy, Parkinson's disease, pain, gastrointestinal disorders, vestibular disorders such as Meniere's disease (Morbus Meniere), drug abuse and motion sickness (Timmermann, J.Med.Chem.1990, 33, 4-11).

It is therefore an object of the present invention to provide selective, direct acting H3 receptor antagonists, inverse agonists. These antagonists/inverse agonists are useful as therapeutically active substances, in particular for the treatment and/or prevention of diseases which are associated with the modulation of the H3 receptor.

In the present specification, the term "alkyl", alone or in combination with other groups, denotes a branched or straight chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably 1 to 10 carbon atoms.

The term "lower alkyl" or "C₁-C₈-alkyl ", alone or in combination, represents a linear or branched alkyl group of 1 to 8 carbon atoms, preferably a linear or branched alkyl group of 1 to 6 carbon atoms, particularly preferably a linear or branched alkyl group of 1 to 4 carbon atoms. Straight and branched C₁-C₈Examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyl, the isomeric hexyl, the isomeric heptyl and octyl, preferably methyl and ethyl, most preferably methyl.

The term "lower alkenyl" or "C_2-8Alkenyl ", alone or in combination, denotes a straight-chain or branched hydrocarbon radical comprising an olefinic bond and up to 8, preferably up to 6, particularly preferably up to 4, carbon atoms. Examples of alkenyl are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferred example is 2-propenyl.

The term "lower alkynyl" or "C_2-8Alkynyl ", alone or in combination, denotes a straight-chain or branched hydrocarbon residue containing a triple bond and up to 8, preferably up to 6, particularly preferably up to 4, carbon atoms. Examples of alkynyl groups are ethynyl, 1-propynyl, or 2-propynyl. A preferred example is 2-propynyl.

The term "cycloalkyl" or "C_3-7Cycloalkyl "denotes a saturated carbocyclic group containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Particularly preferred are cyclopropyl, cyclopentyl and cyclohexyl.

The term "lower cycloalkylalkyl" or "C_3-7-cycloalkyl-C_1-8-alkyl "refers to a lower alkyl group as defined above wherein at least one hydrogen atom of said lower alkyl group is replaced by a cycloalkyl group. A preferred example is cyclopropylmethyl.

The term "alkoxy" refers to the group R '-O-, wherein R' is lower alkyl and the term "lower alkyl" has the previously given meaning. Examples of lower alkoxy groups are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy, most preferably methoxy.

The term "lower alkoxyalkyl" or "C_1-8-alkoxy-C_1-8-alkyl "means a lower alkyl group as defined above wherein at least one hydrogen atom of the lower alkyl group is replaced by an alkoxy group, preferably methoxy or ethoxy. Among the preferred lower alkoxyalkyl groups are 2-methoxyethyl or 3-methoxypropyl.

The term "alkylsulfanyl" or "C_1-8By-alkylsulfanyl "is meant the group R '-S-, wherein R' is lower alkyl and the term" lower alkyl "has the previously given meaning. Examples of alkylsulfanyl groups are, for example, methylthio or ethylthio.

The term "lower alkylsulfanyl" orC_1-8Alkyl sulfanyl-C_1-8-alkyl "means a lower alkyl group as defined above wherein at least one hydrogen atom of the lower alkyl group is replaced by an alkylsulfanyl group, preferably methylthio. An example of a preferred lower alkylsulfanyl alkyl group is 2-methylthioethyl.

The term "alkylsulfonyl" or "lower alkylsulfanyl" refers to the group R' -S (O)₂-, wherein R' is lower alkyl and the term "lower alkyl" has the previously given meaning. Examples of alkylsulfonyl are, for example, methylsulfonyl or ethylsulfonyl.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

The term "lower haloalkyl" or "halogen-C_1-8-alkyl "means a lower alkyl group as defined above, wherein at least one hydrogen atom of said lower alkyl group is replaced by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. Preferred halogenated lower alkyl groups are trifluoromethyl, difluoromethyl, fluoromethyl and chloromethyl, with trifluoromethyl being particularly preferred.

The term "lower haloalkoxy" or "halogen-C_1-8-alkoxy "means a lower alkoxy group as defined above, wherein at least one hydrogen atom of said lower alkoxy group is replaced by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. Preferred halogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy, fluoromethoxy and chloromethoxy, with trifluoromethoxy being particularly preferred.

The term "lower hydroxyalkyl" or "hydroxy-C_1-8-alkyl "refers to a lower alkyl group as defined above wherein at least one hydrogen atom of the lower alkyl group is replaced by a hydroxyl group. Examples of lower hydroxyalkyl are hydroxymethyl or hydroxyethyl.

The term "dialkylamino" refers to the group-NR 'R "where R' and R" are lower alkyl and the term "lower alkyl" has the previously given meaning. The preferred dialkylamino group is dimethylamino.

The term "lower dialkylaminoalkyl" or "C_1-8-dialkylamino-C_1-8-alkyl "means a lower alkyl group as defined above wherein at least one hydrogen atom of said lower alkyl group is replaced by a dialkylamino group, preferably a dimethylamino group. A preferred lower dialkylaminoalkyl group is 3-dimethylaminopropyl.

The term "lower alkanoyl" refers to the group-CO-R ', wherein R' is lower alkyl and the term "lower alkyl" has the previously given meaning. Preferred are the groups-CO-R 'wherein R' is methyl, representing acetyl.

The term "carbamoyl" refers to the group-CO-NH₂。

The term "dialkylcarbamoyl" or "C_1-8-dialkylcarbamoyl "means a radical-CO-NR 'R" wherein R' and R "are lower alkyl, the term" lower alkyl "having the meaning given hereinbefore. The preferred dialkylcarbamoyl group is dimethylcarbamoyl.

The term "lower dialkylcarbamoylalkyl" or "C_1-8-dialkylcarbamoyl-C_1-8-alkyl "refers to a lower alkyl group as defined above wherein at least one hydrogen atom of said lower alkyl group is replaced by a dialkylcarbamoyl group as defined herein above. A preferred lower dialkylcarbamoylalkyl group is dimethylcarbamoylmethyl.

The term "lower phenylalkyl" or "phenyl-C_1-8-alkyl "refers to a lower alkyl group as defined above wherein at least one hydrogen atom of the lower alkyl group is replaced by a phenyl group. Preferred lower phenylalkyl groups are benzyl or phenethyl.

The term "heteroaryl" refers to an aromatic 5-or 6-membered ring which may contain one, two or three atoms selected from nitrogen, oxygen and/or sulfur. Examples of heteroaryl groups are, for example, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, or pyrrolyl. Particular preference is given to furyl and pyridyl.

The term "lower heteroarylalkyl" or "heteroaryl-C_1-8-alkyl "refers to a lower alkyl group as defined above wherein at least one hydrogen atom of the lower alkyl group is replaced by a heteroaryl group as defined above.

The term "heterocyclyl" refers to a saturated or partially unsaturated 5-or 6-membered ring which may contain one, two or three atoms selected from nitrogen, oxygen and/or sulfur. Examples of heterocyclyl rings include piperidinyl, piperazinyl, aza  yl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, and thiomorpholinyl (thiomorpholinyl). A preferred heterocyclyl group is piperidinyl.

The term "lower heterocyclylalkyl" or "heterocyclyl-C_1-8-alkyl "refers to a lower alkyl group as defined above wherein at least one hydrogen atom of said lower alkyl group is replaced by a heterocyclyl group as defined above.

The term "form a 4-, 5-, 6-or 7-membered saturated heterocyclic ring optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur" refers to a saturated N-heterocyclic ring which may optionally contain an additional nitrogen, oxygen or sulfur atom, such as azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl. "4-, 5-, 6-or 7-membered partially unsaturated heterocycle" means a heterocycle as defined above which contains a double bond, for example 2, 5-dihydropyrrolyl or 3, 6-dihydro-2H-pyridyl. The heterocyclic ring may be unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, lower alkoxy and oxo. The heterocyclic ring may also be fused to a phenyl ring, which is unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, lower alkoxy and halogen. An example of such a fused heterocycle is 3, 4-dihydro-1H-isoquinoline.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological potency and properties of the free base or free acid, which are not biologically or otherwise undesirable. The salts are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. Alternatively, these salts may be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like. The compounds of formula I may also be present in zwitterionic form. A particularly preferred pharmaceutically acceptable salt of a compound of formula I is the hydrochloride salt.

The compounds of formula I may also be solvated, e.g. hydrated. The solvation can be carried out during the preparation or it can be carried out, for example, as a result of the hygroscopic nature of the initially anhydrous compound of the formula I (hydration). The term pharmaceutically acceptable salts also includes physiologically acceptable solvates.

"isomers" are compounds that have the same molecular formula but differ in the nature and order of their bonding of the atoms or in the arrangement of their atoms in space. Isomers that differ in the spatial arrangement of their atoms are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", while non-superimposable mirror images are referred to as "enantiomers", or sometimes optical isomers. The carbon atoms bonded to the four non-identical substituents are referred to as "chiral centers".

In detail, the present invention relates to compounds of the following general formula,

wherein

X is O or S;

R¹selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

a lower hydroxyalkyl group,

a lower alkoxyalkyl group,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

phenyl, unsubstituted or substituted by one or two groups independently selected from lower alkyl, lower

A haloalkoxy group or a lower hydroxyalkyl group,

R²selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

R⁴is-O-Het and R⁵Is hydrogen, or

R⁴Is hydrogen or fluorine and R⁵is-O-Het;

het is selected from

Or

Wherein

m is 0, 1 or 2;

n is 0, 1 or 2;

R⁷is a lower alkyl group;

p is 0, 1 or 2;

q is 0, 1 or 2;

x is selected from CR¹⁰R^10′O and S;

R⁹And R¹⁰Together form a double bond;

R¹²is a lower alkyl group;

R¹⁵is C₃-C₆-an alkyl group;

and pharmaceutically acceptable salts thereof.

In one embodiment, the invention relates to compounds of formula I, wherein

X is O or S;

R¹selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

a lower hydroxyalkyl group,

a lower alkoxyalkyl group,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

R²selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

R¹And R²Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered saturated or partially unsaturated heterocyclic ringOptionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated heterocyclic ring being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, halogen, haloalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or

R³is hydrogen or lower alkyl;

R⁴is-O-Het and R⁵Is hydrogen, or

R⁴Is hydrogen or fluorine and R⁵is-O-Het;

het is selected from

Wherein

m is 0, 1 or 2;

R⁶is a lower alkyl group;

n is 0, 1 or 2;

R⁷is a lower alkyl group;

p is 0, 1 or 2;

q is 0, 1 or 2;

R⁸is hydrogen or lower alkyl;

and pharmaceutically acceptable salts thereof.

Preferred compounds of the formula I according to the invention are those of the formula I, in which

R¹Selected from the group consisting of:

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

a lower alkyl sulfanyl alkyl group,

lower dialkylaminoalkyl,

lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups, and

R²is hydrogen or lower alkyl.

Particularly preferred are compounds of the formula I, in which

R¹Selected from the group consisting of:

lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower alkoxyalkyl,

a lower phenylalkyl group,

lower heteroarylalkyl, and

R²is hydrogen or lower alkyl.

Even more preferred are compounds of formula I wherein R¹And R²Is a lower alkyl group.

Preference is furthermore given to compounds of the formula I according to the invention in which R¹And R²Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered saturated or partially unsaturated heterocyclic ring, optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated heterocyclic ring being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, halogen, haloalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or fused to a phenyl ring which is unsubstituted or substituted by one, two or three groups independently selected from: lower alkyl, lower alkoxy and halogen.

More preferred are compounds of formula I according to the invention, wherein R¹And R²Together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of: morpholine, piperidine, 2, 5-dihydropyrrole, pyrrolidine, azepane, piperazine, azetidine, thiomorpholine and 3, 6-dihydro-2H-pyridine, said saturated heterocycle being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, halogen, haloalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or fused to a phenyl ring which is unsubstituted or substituted by one, two or three groups independently selected from: lower alkyl, lower alkoxy and halogen.

Still more preferably, R¹And R²Together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of: morpholine, piperidine, azepane, pyrrolidine and azetidine, wherein the ring is unsubstituted or substituted with lower alkyl. Particularly preferred are those compounds of formula I, wherein R¹And R²Together with the nitrogen atom to which they are attached form a heterocyclic ring selected from morpholinyl, 2, 6-dimethylmorpholinyl, azepanyl, piperidinyl, 2-methylpiperidinyl, 4-methylpiperidinyl, pyrrolidinyl, 2-methylpyrrolidinyl, and azetidinyl.

Preference is furthermore given to compounds of the formula I in which R³Is hydrogen.

Another preferred group of compounds of formula I are those wherein R is³Selected from the group consisting of: lower alkyl, lower alkoxyalkyl, lower haloalkyl, lower cycloalkylalkyl, lower alkylsulfonyl and lower alkanoyl.

Particular preference is given to compounds of the formula I according to the invention in which R⁴is-O-Het and R⁵Is hydrogen.

Also preferred are compounds of formula I, wherein R⁴Is hydrogen or fluorine and R⁵is-O-Het. Particular preference is given to compounds of the formula I in which R⁴Is hydrogen and R⁵is-O-Het.

Preferably, Het is a group selected from:

or

Wherein m, n, p, q, R⁶，R⁷，R⁸，R^8′，R⁹，R^9′，R¹¹，R^11′And X is as defined herein above. Particularly preferred compounds of the formula I according to the invention are those in which Het represents

Wherein m is 0, 1 or 2, and R⁶Selected from the group consisting of lower alkyl, cycloalkyl, lower cycloalkylalkyl and lower phenylalkyl, particularly preferably wherein R is⁶Those that are lower alkyl.

Within this group, preference is given to those compounds of the formula I in which m is 0 and therefore preferably represents a pyrrolidine group.

Another preferred group comprises those compounds of formula I, wherein m is 1, thus also preferably representing a piperidine group.

Another group of preferred compounds includes those of formula I, wherein Het represents

Wherein n is 0, 1 or 2; and R is⁷Is lower alkyl, more preferably those compounds wherein n is 0, thus representing a pyrrolidine derivative.

Another preferred group of compounds of the formula I are those in which Het represents

Wherein p is 0, 1 or 2; q is 0, 1 or 2; x is selected from CR¹⁰R^10′O and S; and is

R⁸，R^8′，R⁹，R^9′，R¹⁰，R^10′R¹¹And R^11′Independently of each other selected from the group consisting of: hydrogen, lower alkyl, hydroxy, halogen and dialkylamino.

Preferred are compounds wherein p is 0 or 1.

R⁹And R¹⁰Together, may also form a double bond, representing a compound of the formula,

wherein p, q, R⁸、R^8′、R^9′、R^10′、R¹¹And R^11′As defined above.

Further preferred compounds of the formula I according to the invention are those in which Het represents

Wherein p is 0, 1 or 2, q is 0, 1 or 2, and R⁸Is hydrogen or lower alkyl.

Within this group, preference is given to those compounds of formula I in which p is 1 and q is 1, thus representing a piperidine group.

Another group of preferred compounds are those, wherein Het represents

Wherein q is 0, 1 or 2, R¹²Is lower alkyl and R¹³Is C₃-C₆-an alkyl group.

Examples of preferred compounds of formula I are the following:

morpholin-4-yl- [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

(3, 4-dihydro-1H-isoquinolin-2-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

(3, 4-dihydro-1H-isoquinolin-2-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-propyl-amide,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid diethylamide,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl-methyl-amide,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid methyl-propyl-amide,

(2, 6-dimethyl-morpholin-4-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid methyl-phenethyl-amide,

(2, 5-dihydro-pyrrol-1-yl) - [ 5-1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclohexyl-methyl-amide,

(3-hydroxy-pyrrolidin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

azepan-1-yl- [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (4-methyl-piperidin-1-yl) -methanone,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid isopropyl-methyl-amide,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid isobutyl-amide,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (2-methyl-piperidin-1-yl) methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-propyl-amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid diethylamide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid isopropylamide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid tert-butylamide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropylamide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl-methyl-amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid propionamide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl-propyl-amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid allyl amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid prop-2-ynylamide,

(2, 6-dimethyl-morpholin-4-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl-phenethyl-amide,

(2, 5-dihydro-pyrrol-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclohexyl-methyl-amide,

(3-hydroxy-pyrrolidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

azepan-1-yl- [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl- (2-methoxy-ethyl) -amide,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (4-methyl-piperidin-1-yl) -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid isopropyl-methyl-amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid isobutyl-amide,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (2-methyl-piperidin-1-yl) -methanone,

(4-benzyl-piperazin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid cyclopropylmethyl-propyl-amide,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid diethylamide,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid isopropylamide,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid tert-butylamide,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid ethyl-methyl-amide,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid methyl-propyl-amide,

(2, 6-dimethyl-morpholin-4-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid methyl-phenethyl-amide,

(2, 5-dihydro-pyrrol-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } methanone,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid cyclohexyl-carboxamide,

(3-hydroxy-pyrrolidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

azepan-1-yl- (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl) -methanone,

(4-methyl-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid isopropyl-methyl-amide,

(2-methyl-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid methyl- (2-pyridin-2-yl-ethyl) -amide,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclohexanamide,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (2-piperidin-1-yl-ethyl) -amide,

azetidin-1-yl- [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

(4-isopropyl-piperazin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (2-methyl-pyrrolidin-1-yl) -methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -pyrrolidin-1-yl-methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -piperidin-1-yl-methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -thiomorpholin-4-yl-methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (4-methoxy-piperidin-1-yl) -methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (4-methyl-piperazin-1-yl) -methanone,

(4-benzyl-piperidin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

(3, 6-dihydro-2H-pyridin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (3-methyl-piperidin-1-yl) -methanone,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid methyl-pyridin-3-ylmethyl-amide,

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid [2- (2-methyl-piperidin-1-yl) -ethyl ] -amide,

(4-hydroxymethyl-piperidin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

(1, 3-dihydro-isoindol-2-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl- (2-pyridin-2-yl-ethyl) -amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl-pyridin-4-ylmethyl-amide,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - ((S) -2-trifluoromethyl-pyrrolidin-1-yl) -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (furan-2-ylmethyl) -amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (2-morpholin-4-yl-ethyl) -amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (3-methoxy-propyl) -amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (3-dimethylamino-propyl) -amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopentamide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclohexanamide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (2-piperidin-1-yl-ethyl) -amide,

azetidin-1-yl- [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone; the hydrochloride salt of the compound (I) is,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (3-pyridin-2-yl-pyrrolidin-1-yl) -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (1-ethyl-piperidin-3-yl) -amide,

(4-isopropyl-piperazin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (2-methyl-pyrrolidin-1-yl) -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -pyrrolidin-1-yl-methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -piperidin-1-yl-methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -thiomorpholin-4-yl-methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-amide,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (4-methoxy-piperidin-1-yl) -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (4-methyl-piperazin-1-yl) -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (3-methoxy-piperidin-1-yl) -methanone,

(4-benzyl-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (2-methylsulfanyl-ethyl) -amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (1-phenyl-propyl) -amide,

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl- (2-fluoro-benzyl) -amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid 4-methyl-benzylamide,

1- [5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carbonyl ] -piperidine-4-carboxylic acid amide,

(3, 6-dihydro-2H-pyridin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (3-methyl-piperidin-1-yl) -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl-pyridin-3-ylmethyl-amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid [2- (2-methyl-piperidin-1-yl) -ethyl ] -amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid dimethylcarbamoylmethyl-methyl-amide,

(4-hydroxymethyl-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

(1, 3-dihydro-isoindol-2-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid cyclopentamide,

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid (2-piperidin-1-yl-ethyl) -amide,

azetidin-1-yl- (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl) -methanone,

{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } - (3-pyridin-2-yl-pyrrolidin-1-yl) -methanone,

(4-isopropyl-piperazin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

(2-methyl-pyrrolidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -pyrrolidin-1-yl-methanone,

{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] 1H-indol-2-yl) -piperidin-1-yl-methanone,

{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -morpholin-4-yl-methanone,

{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy) -1H-indol-2-yl } -thiomorpholin-4-yl-methanone,

(4-methoxy-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

(4-methyl-piperazin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

(3-methoxy-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

(4-benzyl-piperidin-1-yl) - (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl) -methanone,

(4-hydroxy-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

(4, 4-difluoro-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

(3, 6-dihydro-2H-pyridin-1-yl) - (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl) -methanone,

(3-methyl-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

(4-hydroxymethyl-piperidin-1-yl) - (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

(1, 3-dihydro-isoindol-2-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - ((S) -2-trifluoromethyl-pyrrolidin-1-yl) -methanone,

{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } - ((S) -2-trifluoromethyl-pyrrolidin-1-yl) -methanone,

[5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[5- ((R) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[5- ((S) -1-cyclopropylmethyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

morpholin-4-yl- [5- ((S) -1-propyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -thiomorpholin-4-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -piperidin-1-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (4-methyl-piperidin-1-yl) -methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (4-methoxy-piperidin-1-yl) -methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -pyrrolidin-1-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (2-methyl-pyrrolidin-1-yl) -methanone,

azepan-1-yl- [6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

(2, 6-dimethyl-morpholin-4-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-amide,

6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid 4-fluoro-benzylamide,

6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (furan-2-ylmethyl) -amide,

azepan-1-yl- {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -methanone,

{6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indol-2-yl } -pyrrolidin-1-yl-methanone,

[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -thiomorpholin-4-yl-methanone,

[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -piperidin-1-yl-methanone,

[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (4-methyl-piperidin-1-yl) -methanone,

[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (4-methoxy-piperidin-1-yl) -methanone,

[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -pyrrolidin-1-yl-methanone,

azepan-1-yl- [6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

(2, 6-dimethyl-morpholin-4-yl) - [6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-amide,

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -thiomorpholin-4-yl-methanone,

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -piperidin-1-yl-methanone,

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (4-methyl-piperidin-1-yl) -methanone,

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (4-methoxy-piperidin-1-yl) -methanone,

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -pyrrolidin-1-yl-methanone,

azepan-1-yl- [ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropyl-methyl-amide,

[ 1-ethyl-5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[ 1-isopropyl-5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

(4, 4-difluoro-piperidin-1-yl) - [5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [5- ((R) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone,

[5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -pyrrolidin-1-yl-methanone,

(3, 3-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [6- (3-piperidin-1-yl-propyl) -1H-indol-2-yl ] -methanone,

morpholin-4-yl- [6- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [ 5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone,

(5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl) -morpholin-4-yl-methanone,

(4, 4-difluoro-piperidin-1-yl) - [ 1-isopropyl-5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1- (2-methoxy-ethyl) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [ 1-ethyl-5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1- (2, 2, 2-trifluoro-ethyl) -1H-indol-2-yl ] -methanone,

[ 1-cyclopropylmethyl-5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] - (4, 4-difluoro-piperidin-1-yl) -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1- (2, 2, 2-trifluoro-ethyl) -1H-indol-2-yl ] -pyrrolidin-1-yl-methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1- (2, 2, 2-trifluoro-ethyl) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

(3, 3-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1- (2, 2, 2-trifluoro-ethyl) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [1- (2-hydroxy-ethyl) -5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1-methanesulfonyl-1H-indol-2-yl ] -methanone,

1- [2- (4, 4-difluoro-piperidine-1-carbonyl) -5- (1-isopropyl-piperidin-4-yloxy) -indol-1-yl ] -ethanone,

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1-methyl-1H-indol-2-yl ] -methanone,

[5- (-cyclopropylmethyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[5- (1-benzyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (methyl-propyl-amino) -propoxy ] -1H-indol-2-yl } -methanone, as formate salt,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (ethyl-propyl-amino) -propoxy ] -1H-indol-2-yl } -methanone, as formate salt,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (isopropyl-methyl-amino) -propoxy ] -1H-indol-2-yl } -methanone, as formate salt,

(4, 4-difluoro-piperidin-1-yl) - [5- (3-pyrrolidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone as formate salt,

[5- (3-azepan-1-yl-propoxy) -1H indol-2-yl ] - (4, 4-difluoro-piperidin-1-yl) -methanone, as formate salt,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (3-methyl-piperidin-1-yl) -propoxy ] -1H-indol-2-yl } -methanone as formate salt,

(4, 4-difluoro-piperidin-1-yl) - (5- [3- (2, 6-cis-dimethyl-piperidin-1-yl) -propoxy ] -1H-indol-2-yl) -methanone as a formate salt,

(4, 4-difluoro-piperidin-1-yl) - [5- (3-thiomorpholin-4-yl-propoxy) -1H-indol-2-yl ] -methanone as formate salt,

(4, 4-difluoro-piperidin-1-yl) - (5- [3- (2, 5-dihydro-pyrrol-1-yl) -propoxy ] -1H-indol-2-yl) -methanone as a formate salt,

(4, 4-difluoro-piperidin-1-yl) - (5- [3- (2-methyl-pyrrolidin-1-yl) -propoxy ] -1H-indol-2-yl) -methanone, as a formate salt,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (2, 5-cis/trans-dimethyl-pyrrolidin-1-yl) -propoxy ] -1H-indol-2-yl } -methanone as formate salt,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (3S-hydroxy-pyrrolidin-1-yl) -propoxy ] -1H-indol-2-yl } -methanone as formate salt,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (3-dimethylamino-pyrrolidin-1-yl) -propoxy ] -1H-indol-2-yl } -methanone as formate salt,

(4, 4-difluoro-piperidin-1-yl) - [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone,

(4, 4-difluoro-piperidin-1-yl) - [5- (3-morpholin-4-yl-propoxy) -1H-indol-2-yl ] -methanone,

(5- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy ] -1H-indol-2-yl) -morpholin-4-yl-methanone,

[5- (1-cyclopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone, and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I according to the invention are the following:

morpholin-4-yl- [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (2-piperidin-1-yl-ethyl) amide,

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (1-ethyl-piperidin-3-yl) amide,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[5- (1-cyclopropylmethyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (2-methyl-pyrrolidin-1-yl) -propoxy ] -1H-indol-2-yl } -methanone as formate salt,

Particularly preferred are the following compounds of formula I according to the invention:

morpholin-4-yl- [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[5- (1-cyclopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

and pharmaceutically acceptable salts thereof.

In addition, pharmaceutically acceptable salts and pharmaceutically acceptable esters of the compounds of formula I alone constitute preferred embodiments of the invention.

The compounds of formula I may form acid addition salts with acids such as the customary pharmaceutically acceptable acids, for example the hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulphate, pyruvate, citrate, lactate, mandelate, tartrate, and methanesulfonate salts. The hydrochloride salt is preferred. Solvates of the compounds of formula I as well as hydrates and their salts also form part of the invention.

The compounds of the formula I may contain one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of diastereoisomeric racemates. The optically active forms can be obtained, for example, by resolution of the racemates by asymmetric synthesis or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). The present invention includes all of these forms.

It will be appreciated that the compounds of formula I of the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives capable of producing the parent compound of formula I in vivo are also within the scope of the invention.

Another aspect of the invention is a process for the preparation of a compound of formula I as defined above, which process comprises

a) The compound of the formula II is reacted with a compound of the formula II,

wherein X, R¹And R²As defined herein above, and

R⁴and R⁵One of which is-OH and the other is H,

with an alcohol of the formula III in the presence of trialkylphosphine or triphenylphosphine and in the presence of a diazo compound,

HO-Het III

wherein Het is as defined herein above,

to obtain the compound of formula Ia,

wherein R is³Is a hydrogen atom, and is,

and optionally alkylating the compound to obtain a compound of formula Ia',

wherein R is³Is a lower alkyl group, and is,

and, if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt,

or in the alternative,

b) the compound of the formula IV is reacted with a compound of the formula IV,

wherein R is⁴And R⁵One is-O-Het as defined herein above and the other is H, with an amine of formula V,

H-NR¹R² V

wherein R is¹And R²As defined herein above, the amount of the compound,

to obtain the compound of the formula Ib,

wherein R is³Is a hydrogen atom, and is,

and optionally alkylating the compound to obtain a compound of formula Ib',

wherein R is³Is a lower alkyl group, and is,

and if so desired, the user can then,

the compound obtained is converted into a pharmaceutically acceptable acid addition salt.

More specifically, the compounds of formula I may be prepared by the methods provided below, by the methods provided in the examples, or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The starting materials are either commercially available or can be prepared by methods analogous to those provided below, by methods described by the references cited herein, or by methods known in the art.

The preparation of the compounds of the formula I according to the invention can be carried out either sequentially or via a convergent synthetic route. The synthesis of the present invention is shown in the following reaction scheme. The techniques required to carry out the reaction and to purify the product obtained are known to the person skilled in the art. Substituents and symbols used in the following description of the methods have the meanings provided above, unless indicated to the contrary.

Reaction scheme 1

The compounds of formula I can be prepared according to the following scheme 1:

a) the coupling of carboxylic acids with amines is widely described in the literature and methods are known to the person skilled in the art (see for example: comprehensive Organic Transformations: a Guide to Functional groups precursors, 2nd Edition, Richard C.Larock.John Wiley & Sons, New York, NY.1999). The 5-hydroxy-indole-2-carboxylic acid IV can be conveniently converted into the respective amide by coupling with an amine V using a coupling agent (either commercially available or obtainable by methods described in the literature or by methods known in the art; as appropriate). For example, the conversion can be carried out equally well using coupling agents such as N, N '-Carbonyldiimidazole (CDI), N, N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) methylene ] -1H-1, 2, 3-triazolo [4, 5-b ] pyridinium-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU), and the like. We have found that it is convenient to carry out the reaction in a solvent such as Dimethylformamide (DMF) and in the presence of a base. There is no particular limitation on the nature of the solvent employed, as long as it does not adversely affect the reaction or the reagents involved and it can dissolve the solvent at least to some extent. Examples of suitable solvents include: DMF, Dichloromethane (DCM), dioxane, THF, etc. There is no particular limitation on the nature of the base used at this stage, and any base commonly used in this type of reaction may be used equally here. Examples of such bases include triethylamine, diisopropylethylamine and the like. The reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the reaction. We have found that it is convenient to carry out the reaction under heating to room temperature to reflux. The time required for the reaction may also vary over a wide range, depending on a number of factors, notably the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will generally be sufficient to produce the amide derivative VIII.

b) The synthesis of esters is widely described in the literature and methods are known to the person skilled in the art (see for example: comprehensive organic Transformations: a Guide to Functional Group preambles, 2nd edition, Richrd C.Larock.John Wiley&Sons, New York, ny.1999). The conversion may be carried out by employing reaction conditions which are commonly used in the so-called "Mitsunobu reaction" which is known to the person skilled in the art and is widely described (Hughes, David L. the Mitsunobu reaction. organic reactions (New York) (1992), 42, 335. sub. 656.). We have found that it is convenient to couple the amide VIII with the alcohol HO-Het III (either commercially available or obtainable by methods described in the references or by methods known in the art; where appropriate) under conditions using phosphines, such as trialkylphosphines, for example tributylphosphine ((n-Bu), and diazo compounds, in the solvents customarily used for this conversion₃P), triphenylphosphine (Ph)₃P), such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) (optionally polymer bound), tetramethyl azodicarboxamide, etc., and the like, such as Tetrahydrofuran (THF), toluene, methylene chloride, etc. There is no particular limitation on the nature of the solvent employed, as long as it does not adversely affect the reaction or the reagents involved and it can dissolve the solvent at least to some extent. The reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the reaction. We have found that it is convenient to carry out the reaction under heating to room temperature to reflux. The time required for the reaction may also vary over a wide range, depending on a number of factors, notably the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will generally be sufficient to produce the title compound Ib.

c) Compound Ib may be the final product, however, they may optionally be subjected to a sequential step wherein the indole NH is substituted by a lower alkyl substituent by reaction with an alkylating agent. The conditions generally used in this type of transformation are widely described in the literature and are known to the person skilled in the art. The reaction may be carried out in the presence or absence of a solvent and preferably in the presence of a base. Solvents such as N, N-diethylacetamide, Tetrahydrofuran (THF), diethyl ether, dioxane and the like can be conveniently used. There is no particular limitation on the nature of the solvent employed, as long as it is available for the reaction or the reagents involvedThe agent does not adversely affect and it can dissolve the solvent to at least some extent. Typically the reaction is carried out in the presence of a base. Suitable bases include NaH, DIPEA, Na₂CO₃And the like. The reaction can be carried out over a wide temperature range, and the precise reaction temperature is not critical to the reaction. We have found that it is convenient to carry out the reaction under heating to room temperature to reflux. The time required for the reaction may also vary over a wide range, depending on a number of factors, notably the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will generally be sufficient to produce the title compound Ic.

Alternatively, the compounds of formula I may be prepared according to scheme 2 below.

Reaction scheme 2

Starting from ethyl 5-hydroxy-indole-2-carboxylate, the compounds of formula I can be prepared as follows:

d) the ether of formula X is prepared from 5-hydroxy-indole-2-carboxylic acid ethyl ester IX under the conditions described above under point b) of the so-called "Mitsunobu reaction".

e) The compound of formula X is converted to the free acid of formula XI under basic conditions, for example by using lithium hydroxide monohydrate as base.

f) The acid of formula XI is further reacted with the amine of formula V by an amide coupling step under conditions as described above under a).

g) The indoles Ib can be the desired products, however they can optionally be subjected to a subsequent alkylation reaction as described above under c) to provide the desired compounds Ic.

Alternatively, the compounds of formula I may be prepared according to scheme 3 below. Exemplified is a stereospecific synthetic route, optionally starting from the starting material synonym of the enantiomerically pure N-protected-3-pyrrolidinol shown (synonymous).

h) the ether of formula XIII is prepared from 5-hydroxy-indole-2-carboxylic acid ethyl ester IX and suitably N-protected (PG ═ benzyl, tert-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) and the like under the conditions described in point b) above, so-called "Mitsunobu reaction"; are commercially available or can be prepared by methods described in the literature or by methods known in the art; when appropriate) of 3-pyrrolidinol (R or S, but also for racemization, when appropriate).

i) The compound of formula XIII is converted to the free acid under basic conditions, for example by using lithium hydroxide monohydrate as base, and those intermediates are then coupled with the amine of formula V under conditions as described above under a) by an amide coupling step to provide the compound of formula XIV.

j) The N-protected indole derivatives XIV are further converted into the respective free amines by cleaving PG by suitable methods, e.g. in the case of PG ═ benzyl, the protecting groups are removed under hydrogenolysis conditions widely described in the literature. Those intermediates are conveniently alkylated with an appropriate alkylating agent under basic conditions to obtain the indole derivative Id.

k) The indoles Id may be the desired product, however, they may optionally be subjected to a subsequent alkylation reaction as described above at point c) to provide the desired compound Ie.

Reaction scheme 3

Alternatively, the compounds of formula I may be prepared according to scheme 4 below.

Reaction scheme 4

l) starting from the appropriate aldehyde 3-fluoro-4-hydroxy-benzaldehyde XIV, the hydroxyl functionality is protected with the appropriate groups (PG ═ benzyl, allyl, and any other groups conventionally used to prevent the hydroxyl functionality from adversely participating in any proceeding reaction sequence) to afford aldehyde XV.

m) the aldehyde XV is conveniently converted to the respective indole derivative XVI by reaction with methyl 2-azidoacetate (commercially available) under basic conditions and at elevated temperature (Synthesis 1985, 186-188).

n) depending on the nature of the protecting group, the removal of the protecting group PG can be accomplished, in the case of PG ═ benzyl, the reaction is most conveniently accomplished under hydrogenolysis conditions to give the free alcohol, which is used as an intermediate to undergo the reaction called the "Mitsunobu reaction" as described above under b) to give the indole derivative XVII.

o) converting the compound of formula XVII to the free acid under basic conditions, for example by using lithium hydroxide monohydrate as base, and then coupling those intermediates with an amine of formula V under conditions as described above under point a) by an amide coupling step to provide the compound of formula If.

p) indoles If may be the desired products, however, they may optionally be subjected to a subsequent alkylation reaction as described above under c) to provide the desired compound Ig.

As mentioned above, the compounds of formula I according to the invention can be used as medicaments for the treatment and/or prophylaxis of diseases which are associated with the modulation of the H3 receptor. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficits, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, movement disorders and sleep disorders including narcolepsy, and other diseases including asthma, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders. Preferably as a medicament for the treatment and/or prevention of obesity.

The invention therefore also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Furthermore, the present invention relates to compounds as defined above for use as therapeutically active substances, in particular as therapeutically active substances for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficits, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, movement disorders and sleep disorders including narcolepsy, and other diseases including asthma, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders.

In another embodiment, the invention relates to a method for the treatment and/or prevention of diseases which are associated with the modulation of the H3 receptor. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficits, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, movement disorders and sleep disorders including narcolepsy, and other diseases including asthma, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders. Methods of treating and/or preventing obesity are preferred.

The invention furthermore relates to the use of compounds of the formula I as defined above for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficits, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, movement disorders and sleep disorders including narcolepsy, and other diseases including asthma, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders. The use of compounds of formula I as defined above for the treatment and/or prevention of obesity is preferred.

Furthermore, the present invention relates to the use of compounds of formula I as defined above for the preparation of medicaments for the treatment and/or prevention of diseases which are associated with the modulation of the H3 receptor. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficits, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, movement disorders and sleep disorders including narcolepsy, and other diseases including asthma, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders. The use of a compound of formula I as defined above for the preparation of a medicament for the treatment and/or prevention of obesity is preferred.

The compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. In particular, the compounds of the present invention have been found to be good histamine 3 receptor (H3R) antagonists and/or inverse agonists.

The following tests were carried out in order to determine the activity of the compounds of formula (I).

And³binding assay for H- (R) alpha-methyl histamine

Saturation binding experiments were performed using HR3-CHO membranes, which were prepared as described in Takahashi, K, Tokita, S., Kotani, H. (2003) J.Pharmacol.exp.therapeutics 307, 213-218.

Appropriate amounts of membrane (60 to 80. mu.g protein/well) were mixed with increasing concentrations³H (R) alpha-methyl histamine dihydrochloride (0.10 to 10nM) incubation. Non-specific binding was determined using a 200-fold excess of cold (R) alpha-methyl histamine dihydrobromide (500nM final concentration). Incubations were performed at room temperature (3 hours in deep-well plates with shaking). The final volume in each well was 250. mu.l. The incubation was followed by rapid filtration on GF/B filters (pre-soaked with 100. mu.l of 0.5% PEI in Tris 50mM, shaking at 200rpm for 2 hours). Filtration was performed using a cell harvester, and then the filter plates were washed 5 times with ice-cold wash buffer containing 0.5m nacl. After washing, the plates were dried at 55 ℃ for 60 minutes, then we added scintillation fluid (Microscint 40, 40 μ Ι per well), and the amount of radioactivity on the filter was determined in a Packard top-counter after shaking the plates at 200rpm for 2 hours at room temperature.

Binding buffer: 50mM Tris-HCl pH7.4 and 5mM MgCl₂ 6H₂O pH 7.4. Washing buffer solution: 50mM Tris-HCl pH7.4 and 5mM MgCl₂x 6H₂O and 0.5M NaCl pH 7.4.

Indirect measurement of affinity of H3R inverse agonists: selected compounds at 12 increasing concentrations (ranging from 10. mu.M to 0.3nM) were consistently tested in competitive binding experiments using membranes of the human HR3-CHO cell line. Appropriate amounts of protein, e.g., about 500cpm of RAMH bound at Kd, in a final volume of 250 μ l in 96-well plates³H (r) α -methyl histamine (1nM final concentration ═ Kd) was incubated at room temperature for 1 hour. Nonspecific binding was determined using a 200-fold excess of cold (R) alpha-methyl histamine dihydrobromide.

All compounds were tested in duplicate at a single concentration. Display [2 ]³H]Compounds with over 50% inhibition of RAMH were tested again to determine IC in serial dilution experiments₅₀. Ki's from IC₅₀Calculated based on the Cheng-Prusoff equation (Cheng, Y, Prusoff, WH (1973) biochem Pharmacol 22, 3099-3108).

K shown by the compound of the invention_iValues range from about 1nM to about 1000nM, preferably from about 1nM to about 100nM, and more preferably from about 1nM to about 30 nM. The following table shows the measured values for selected compounds of the invention.

	K_i(nM)
	K_i(nM)	Example 2	23
Example 117	77	Example 2	23
Example 117	77	Example 140	93

The compounds of formula (I) and their pharmaceutically acceptable salts and esters are useful as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They may be administered, for example, orally in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions; rectal administration, such as in the form of suppositories; parenteral administration, e.g. in the form of injections or infusions; or topically, such as in the form of an ointment, cream, or oil.

The preparation of pharmaceutical preparations can be carried out in a manner familiar to the person skilled in the art by bringing the compounds of the formula (I) and their pharmaceutically acceptable salts into a galenical administration form together with suitable, nontoxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, conventional pharmaceutical adjuvants.

Suitable support materials are not only inorganic support materials but also organic support materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient, soft gelatine capsules may not require a carrier). Suitable carrier materials for the preparation of solutions or syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical formulations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

The usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavoring agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.

The dosage of the compounds of the formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients, a daily dosage of about 1 to 1000mg, in particular about 1 to 100mg, is contemplated. Depending on the dose, it is convenient to administer the daily dose in several dosage units.

The pharmaceutical formulation conveniently comprises from about 0.1 to 500mg, preferably from 0.5 to 100mg, of a compound of formula (I).

The following examples serve to illustrate the invention in more detail. However, they are not intended to limit the scope of the present invention in any way.

Examples

Example 1

Morpholin-4-yl- [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl]-methanones

a) Step 1: (5-hydroxy-1H-indol-2-yl) -morpholin-4-yl-methanones

A mixture of 1.77g (0.01mol) of 5-hydroxy-indole-2-carboxylic acid in 25ml of DMF is cooled to 0 ℃ and treated with 3.53g (0.011mol) of 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, 0.96g (0.011mol) of morpholine and 8.6ml (0.05mol) of N-ethyldiisopropylamine. The mixture was allowed to warm to room temperature and stirred for another 16 hours. After evaporation to dryness, the residue is taken up in 75ml of ethyl acetate, 75ml of THF, 100ml of water and 50ml of 10% NaHCO₃In solution. The aqueous phase is extracted with 50ml of ethyl acetate and 50ml of THF. The combined organic layers were washed with 100ml of saturated aqueous NaCl solution and passed over Na₂SO₄Dried, filtered and evaporated to dryness. The residue was suspended in 30ml of an ethyl acetate/methanol 9/1 mixture, filtered and resuspended in 20ml of an ethyl acetate/methanol 9/1 mixture. The residue was washed in diethyl ether and dried under vacuum at 40 ℃ to yield 2.04g (83%) of the title compound as a white solid. MS (m/e): 247.4 (MH)⁺，100％)。

b) Step 2: morpholin-4-yl- [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone

A mixture of 246mg (1mmol) (5-hydroxy-1H-indol-2-yl) -morpholin-4-yl-methanone, 1g (ca. 3mmol) polymer-bound triphenylphosphine (Fluka), 179mg (1.25mmol) piperidinepropanol and 461mg (2mmol) di-tert-butyl azedicarboxylate in 20ml THF is stirred at room temperature for a long time. The mixture was filtered through silica gelThe pad was washed with 30ml THF. The mixture was evaporated to dryness, purified on silica gel, 2N NH in DCM/MeOH₃98/2 to 2N NH in DCM/methanol₃9/1 gradient elution. The product fractions were evaporated and the residue triturated with diethyl ether to obtain after vacuum drying at 40 ℃ 47mg (13%) of the title compound as a white solid. MS (m/e): 372.4 (MH)⁺，100％)。

Example 2

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

The title compound was synthesized as a white solid in 8% yield from (5-hydroxy-1H-indol-2-yl) -morpholin-4-yl-methanone and 1-isopropyl-pyrrolidinol according to the procedure described for the synthesis of example 1. MS (m/e): 358.1 (MH)⁺，100％)。

Example 3

(3, 4-dihydro-1H-isoquinolin-2-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl] Ketone

a) Step 1: (3, 4-dihydro-1H-isoquinolin-2-yl) - (5-hydroxy-1H-indol-2-yl) -methanone

(3, 4-dihydro-1H-isoquinolin-2-yl) - (5-hydroxy-1H-indol-2-yl) -methanone was synthesized from 5-hydroxy-indole-2-carboxylic acid and 1, 2, 3, 4-tetrahydro-isoquinoline according to the procedure described for the synthesis of example 1/step 1, in 72% yield as a white solid. MS (m/e): 293.0 (MH)⁺，100％)。

b) Step 2: (3, 4-dihydro-1H-isoquinolin-2-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone

The title compound was synthesized as a white solid in 28% yield from (3, 4-dihydro-1H-isoquinolin-2-yl) - (5-hydroxy-1H-indol-2-yl) -methanone and 1-isopropyl-pyrrolidinol according to the procedure described for the synthesis of example 1/step 2. MS (m/e): 404.5 (MH)⁺，100％)。

Example 4

(3, 4-dihydro-1H-isoquinolin-2-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2- Radical-ketone

The title compound was synthesized in 3% yield as a white solid from (3, 4-dihydro-1H-isoquinolin-2-yl) - (5-hydroxy-1H-indol-2-yl) -methanone and 1-methyl-2-pyrrolidineethanol (commercially available) according to the procedure described for the synthesis of example 1. MS (m/e): 404.5 (MH)⁺，100％)。

Example 5

5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-propyl-amide

a) Step 1: 5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester

A mixture of 3.08g (15mmol) of ethyl 5-hydroxy-1H-indole-2-carboxylate, 2.51g (20mmol) of 1-isopropyl-3-pyrrolidinol and 8.7ml (30mmol) of tri-N-butylphosphine in 75ml is treated at room temperature with 7.57g (30mmol) of 1, 1' - (azodicarbonyl) -dipiperidine in 75ml of THF. The mixture was allowed to stir for a long time and then evaporated to dryness. The residue was suspended in 40ml of DCM/n-heptane 1/1, filtered and washed again with 40ml of DCM/n-heptane 1/1. The filtrate was evaporated, purified on silica gel with 2N NH in DCM/MeOH₃99/1 to 2N NH in DCM/methanol₃93/7 gradient elution. The product fractions were evaporated, the residue triturated with diethyl ether, filtered, washed and the residue dried under vacuum at 50 ℃ to yield 2.1g (44%) of the title compound as an off-white solid. MS (m/e): 317.1 (MH)⁺，100％)。

b) Step 2: 5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid

A mixture of 2.05g (6mmol) of ethyl 5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylate and 0.299g (7mmol) of lithium hydroxide monohydrate in 30ml of THF, 30ml of methanol and 15ml of water is heated to 100 ℃ for 2 hours. Removal of organic solventsAdding 1N HCl aqueous solution, and adjusting the pH of the solution to 2-3. Subsequently, the mixture was evaporated to dryness and the mixture was used in the next step without further purification. MS (m/e): 289.1 (MH)⁺，100％)。

c) And step 3: 5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-propyl-amide

A mixture of 0.07mmol of 5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid, 1.25 equivalents of 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, 1.25 equivalents of cyclopropylmethyl-propyl-amine and 5 equivalents of N-ethyldiisopropyl-amine in 0.7ml of DMF was stirred at room temperature for 16H. The mixture was diluted with 0.8ml of methanol and subjected to preparative HPLC purification on reversed phase material eluting with a gradient of acetonitrile/water/triethylamine. The product fractions were evaporated to dryness to afford 9.1mg (37%) of the title compound as a light brown solid. MS (m/e): 384.5 (MH)⁺，100％)。

Intermediate 1

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid

a) Step 1: 5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester

Ethyl 5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylate was synthesized from ethyl 5-hydroxy-1H-indole-2-carboxylate (commercially available) and 1-isopropyl-piperidin-4-ol (commercially available) according to the procedure described for the synthesis of example 5/step 1. The title compound was obtained in 33% yield as an off-white solid. MS (m/e): 331.1(MH +, 100%).

b) Step 2: 5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid

5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid was synthesized from 5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester and lithium hydroxide monohydrate according to the procedure described for the synthesis of example 5/step 2.

The title compound was obtained as a light brown foam and used without further purification. MS (m/e): 303.1 (MH)⁺，100％)。

Intermediate 2

5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid

a) Step 1: 5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid ethyl ester

Synthesis of 5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] from ethyl 5-hydroxy-1H-indole-2-carboxylate (commercially available) and 2- (1-methyl-pyrrolidin-2-yl) -ethanol (commercially available) according to the procedure described for the synthesis of example 5/step 1]-1H-indole-2-carboxylic acid ethyl ester. The title compound was 38% yield as a light brown foam. MS (m/e): 317.1 (MH)⁺，100％)。

b) Step 2: 5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid

Following the procedure described for the synthesis of example 5/step 2, starting from 5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]Synthesis of 5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -5H-indole-2-carboxylic acid ethyl ester and lithium hydroxide monohydrate]-1H-indole-2-carboxylic acid. The title compound was obtained as a white solid and used without further purification. MS (m/e): 289.1 (MH)⁺，100％)。

According to the method described for the synthesis of example 5, further indole derivatives have been obtained from 5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid, 5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid or 5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid, respectively, by the coupling steps described for example 5/step 3 with the respective amines mentioned in table 1. For some examples, the purification process has been modified as a result of precipitating the respective compounds from the respective mixtures. In those cases, the title compound was filtered off, washed with methanol (containing HCl in the case of example 85) and diethyl ether and dried. The results are shown in table 1 and include example 6 to example 134.

TABLE 1

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	6	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid diethylamide	343.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and diethylamine (commercially available)	344.3
7	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl-methyl-amide	329.4	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and ethyl-methyl-amine (commercially available)	330.3	6		343.5		344.3
7		329.4		330.3	8	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid methyl-propyl-amide	343.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and methyl-propyl-amine (commercially available)	344.3
9	(2, 6-dimethyl-morpholin-4-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	385.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 2, 6-dimethyl-morpholine (commercially available)	386.5	8		343.5		344.3
9		385.5		386.5	10	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid methyl-phenethyl-amide	405.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and methyl-phenethyl-amine (commercially available)	406.5
11	(2, 5-dihydro-pyrrol-1-yl) - [ 5-1-isopropyl-pyrrolidin-3-yloxy]-1H-indol-2-yl]-methanones	339.4	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 2, 5-dihydro-pyrrole (commercially available)	340.4	10		405.5		406.5

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	12	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclohexyl-methyl-amide	383.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and cyclohexyl-methyl-amide (commercially available)	384.4
13	(3-hydroxy-pyrrolidin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	357.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 3-hydroxy-pyrrolidine (commercially available)	358.3	12		383.5		384.4
13		357.5		358.3	14	Azepan-1-yl- [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	369.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and azepane (commercially available)	370.3
15	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]- (4-methyl-piperidin-1-yl) -methanones	369.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 4-methyl-piperidine (commercially available)	370.3	14		369.5		370.3
15		369.5		370.3	16	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid isopropyl-methyl-amide	343.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and isopropyl-methyl-amine (commercially available)	344.3
17	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid isobutyl-amide	343.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and isobutyl-amine (commercially available)	344.3	16		343.5		344.3
17		343.5		344.3	18	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl) - (2-methyl-piperidin-1-yl) methanone	369.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 2-methyl-piperidine (commercially available)	370.3

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	19	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-propyl-amide	397.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and cyclopropylmethyl-propyl-amide (commercially available)	398.5
20	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid diethylamide	357.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and diethylamine (commercially available)	358.5	19		397.6		398.5
20		357.5		358.5	21	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid isopropylamide	343.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and isopropylamine (commercially available)	344.1
22	5- ((1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid tert-butylamide	357.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and tert-butylamine (commercially available)	358.4	21		343.5		344.1
22		357.5		358.4	23	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropylamide	341.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and cyclopropylamine (commercially available)	342.3
24	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl-methyl-amide	343.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and ethyl-methyl-amine (commercially available)	344.3	23		341.5		342.3
24		343.5		344.3	25	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid propionamide	343.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and propylamine (commercially available)	344.4
26	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl-propyl-amide	357.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and methyl-propyl-amine (commercially available)	358.4	25		343.5		344.4

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	27	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid allylamide	341.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and allylamine (commercially available)	342.1
28	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid prop-2-ynylamide	339.4	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and prop-2-ynylamine (commercially available)	340.4	27		341.5		342.1
28		339.4		340.4	29	(2, 6-dimethyl-morpholin-4-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	399.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2, 6-dimethyl-morpholine (commercially available)	400.6
30	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl-phenethyl-amide	419.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and methyl-phenethyl-amine (commercially available)	420.4	29		399.5		400.6
30		419.6		420.4	31	(2, 5-dihydro-pyrrol-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	353.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2, 5-dihydro-pyrrole (commercially available)	354.3
32	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclohexyl-methyl-amide	397.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and cyclohexyl-methyl-amine (commercially available)	398.5	31		353.5		354.3
32		397.6		398.5	33	(3-hydroxy-pyrrolidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	371.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 3-hydroxy-pyrrolidine (commercially available)	372.4

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	34	Azepan-1-yl- [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	383.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and azepane (commercially available)	384.5
35	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl- (2-methoxy-ethyl) -amide	387.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2-methoxy-ethyl-amine (commercially available)	388.5	34		383.5		384.5
35		387.5		388.5	36	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (4-methyl-piperidin-1-yl) -methanones	383.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 4-methyl-piperidine (commercially available)	384.4
37	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid isopropyl-methyl-amide	357.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and isopropyl-methyl-amine (commercially available)	358.3	36		383.5		384.4
37		357.5		358.3	38	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid isobutyl-amide	357.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and isobutyl-amine (commercially available)	358.4
39	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (2-methyl-piperidin-1-yl) -methanones	383.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2-methyl-piperidine (commercially available)	384.5	38		357.5		358.4
39		383.5		384.5	40	(4-benzyl-piperazin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	460.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 4-benzyl-piperazine (commercially available)	461.5

Example No. 2	System naming	MW	Raw material	Experiment MW(M+H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW(M+H)⁺	41	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid cyclopropylmethyl-propyl-amide	383.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and cyclopropylmethyl-propyl-amine (commercially available)	384.5
42	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid diethylamide	343.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and diethylamine (commercially available)	344.0	41		383.5		384.5
42		343.5		344.0	43	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid isopropylamide	329.4	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and isopropylamine (commercially available)	330.4
44	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid tert-butanamide	343.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and tert-butylamine (commercially available)	344.4	43		329.4		330.4
44		343.5		344.4	45	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid ethyl-methyl-amide	329.4	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and ethyl-methyl-amine (commercially available)	330.4
46	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid methyl-propyl-amide	343.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and methyl-propyl-amine (commercially available)	344.3	45		329.4		330.4
46		343.5		344.3	47	(2, 6-dimethyl-morpholin-4-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	385.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 2, 6-dimethyl-morpholine (commercially available)	386.5

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	48	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid methyl-phenethyl-amide	405.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and methyl-phenethyl-amine (commercially available)	406.5
49	(2, 5-dihydro-pyrrol-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } methanone	339.4	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 2, 5-dihydro-pyrrole (commercially available)	340.3	48		405.5		406.5
49		339.4		340.3	50	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid cyclohexyl-carboxamide	383.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and cyclohexyl-methylamine (commercially available)	384.5
51	(3-hydroxy-pyrrolidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	357.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 3-hydroxy-pyrrolidine (commercially available)	358.3	50		383.5		384.5
51		357.5		358.3	52	Azepan-1-yl- (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl) -methanones	369.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and azepane (commercially available)	370.3
53	(4-methyl-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	369.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 4-methyl-piperidine (commercially available)	370.3	52		369.5		370.3
53		369.5		370.3	54	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid isopropyl-methyl-amide	343.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and isopropyl-methyl-amine (commercially available)	344.3

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	55	(2-methyl-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanones	369.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 2-methyl-piperidine (commercially available)	370.3
56	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid methyl- (2-pyridin-2-yl-ethyl) -amide	406.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 2-pyridin-2-yl-ethyl-amide (commercially available)	407.5	55		369.5		370.3
56		406.5		407.5	57	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclohexanamide	369.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and cyclohexylamine (commercially available)	370.3
58	5- (1-isopropyl-pyrrole)Alk-3-yloxy) -1H-indole-2-carboxylic acid (2-piperidin-1-yl-ethyl) -amide	398.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 2-piperidin-1-yl-ethyl-amine (commercially available)	399.5	57		369.5		370.3
58		398.5		399.5	59	Azetidin-1-yl- [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	327.4	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and azetidine (commercially available)	328.3
60	(4-isopropyl-piperazin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	398.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 4-isopropyl-piperazine (commercially available)	399.5	59		327.4		328.3
60		398.5		399.5	61	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]- (2-methyl-pyrrolidin-1-yl) -methanones	355.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 2-methyl-pyrrolidine (commercially available)	356.4

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	62	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-pyrrolidin-1-yl-methanones	341.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and pyrrolidine (commercially available)	342.2
63	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-piperidin-1-yl-methanones	355.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and piperidine (commercially available)	356.4	62		341.5		342.2
63		355.5		356.4	64	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-thiomorpholin-4-yl-methanones	373.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and thiomorpholine (commercially available)	374.4
65	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]- (4-methoxy-piperidin-1-yl) -methanones	385.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 4-methoxy-piperidine (commercially available)	386.4	64		373.5		374.4
65		385.5		386.4	66	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]- (4-methyl-piperazin-1-yl) -methanone	370.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 4-methyl-piperazine (commercially available)	371.3
67	(4-benzyl-piperidin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	445.6	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 4-benzyl-piperidine (commercially available)	446.3	66		370.5		371.3
67		445.6		446.3	68	(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	391.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 4, 4-difluoro-piperidine (commercially available)	392.2

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	69	(3, 6-dihydro-2H-pyridin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	353.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 3, 6-dihydro-2H-pyri-dinePyridine (commercially available)	354.3
70	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]- (3-methyl-piperidin-1-yl) -methanones	369.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 3-methyl-piperidine (commercially available)	370.3	69		353.5		354.3
70		369.5		370.3	71	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid methyl-pyridin-3-ylmethyl-amide	392.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and methyl-pyridin-3-ylmethyl-amine (commercially available)	393.2
72	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid [2- (2-methyl-piperidin-1-yl) -ethyl]-amides of	412.6	5- (1-isopropyl-pyrrolidin-3-yloxy)) -1H-indole-2-carboxylic acid (example 5/step 2) and 2- (2-methyl-piperidin-1-yl) -ethyl-amine (commercially available)	413.5	71		392.5		393.2
72		412.6		413.5	73	(4-hydroxymethyl-piperidin-1-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	385.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 4-hydroxymethyl-piperidine (commercially available)	386.4
74	(1, 3-dihydro-isoindol-2-yl) - [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	389.5	5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid (example 5/step 2) and 1, 3-dihydro-isoindole (commercially available)	390.3	73		385.5		386.4

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	75	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl- (2-pyridin-2-yl-ethyl) -amide	420.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2-pyridin-2-yl-ethyl-amine (commercially available)	421.4
76	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl-pyridin-4-ylmethyl-amide	420.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and ethyl-pyridin-4-ylmethyl-amine (commercially available)	421.4	75		420.6		421.4
76		420.6		421.4	77	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- ((S) -2-trifluoromethyl-pyrrolidin-1-yl) -methanone	423.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and (S) -2-trifluoromethyl-pyrrolidine (commercially available)	424.4
78	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (furan-2-ylmethyl) -amide	381.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and furan-2-ylmethyl-amine (commercially available)	382.3	77		423.5		424.4
78		381.5		382.3	79	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (2-morpholin-4-yl-ethyl) -amide	414.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2-morpholin-4-yl-ethyl-amine (commercially available)	415.5
80	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (3-methoxy-propyl) -amide	373.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 3-methoxy-propyl-amine (commercially available)	374.5	79		414.5		415.5
80		373.5		374.5	81	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (3-dimethylamino-propyl) -amide	386.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 3-dimethylamino-propyl-amine (commercially available)	387.4

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	82	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopentylamide	369.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and cyclopentylamine (commercially available)	370.4
83	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclohexanamide	383.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and cyclohexylamine (commercially available)	384.4	82		369.5		370.4
83		383.5		384.4	84	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (2-piperidin-1-yl-ethyl) -amide	412.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2-piperidin-1-yl-ethyl-amine (commercially available)	413.5
85	Azetidin-1-yl- [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-a ketone; hydrochloride salt	341.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and azetidine (commercially available)	342.3	84		412.6		413.5
85		341.5		342.3	86	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (3-pyridin-2-yl-pyrrolidin-1-yl) -methanones	432.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 3-pyridin-2-yl-pyrrolidine (commercially available)	433.4
87	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (1-ethyl-piperidin-3-yl) -amide	412.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 1-ethyl-piperidin-3-yl-amine (commercially available)	413.5	86		432.6		433.4
87		412.6		413.5	88	(4-isopropyl-piperazin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	412.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 4-isopropyl-piperazine (commercially available)	413.5

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	89	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (2-methyl-pyrrolidin-1-yl) -methanones	369.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2-methyl-pyrrolidine (commercially available)	370.4
90	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-pyrrolidin-1-yl-methanones	355.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and pyrrolidine (commercially available)	356.4	89		369.5		370.4
90		355.5		356.4	91	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-piperidin-1-yl-methanones	369.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and piperidine (commercially available)	370.4
92	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones	371.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and morpholine (commercially available)	372.3	91		369.5		370.4
92		371.5		372.3	93	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-thiomorpholin-4-yl-methanones	387.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and thiomorpholine (commercially available)	388.3
95	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-amide	355.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and cyclopropylmethyl-amine (commercially available)	356.4	93		387.5		388.3
95		355.5		356.4	96	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (4-methoxy-piperidin-1-yl) -methanones	399.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 4-methoxy-piperidine (commercially available)	400.5

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	97	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (4-methyl-piperazin-1-yl) -methanone	384.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 4-methyl-piperazine (commercially available)	385.4
98	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (3-methoxy-piperidin-1-yl) -methanones	399.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 3-methoxy-piperidine (commercially available)	400.5	97		384.5		385.4
98		399.5		400.5	99	(4-benzyl-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	459.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 4-benzylBase-piperidine (commercially available)	460.6
100	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (2-methylsulfanyl-ethyl) -amide	375.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2-methylsulfanyl-ethyl-amine (commercially available)	376.4	99		459.6		460.6
100		375.5		376.4	101	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (1-phenyl-propyl) -amide	419.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 1-phenyl-propyl-amine (commercially available)	420.4
102	(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	405.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid(intermediate 1) and 4, 4-difluoro-piperidine (commercially available)	406.5	101		419.6		420.4
102		405.5		406.5	103	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl- (2-fluoro-benzyl) -amide	437.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and ethyl- (2-fluoro-benzyl) -amine (commercially available)	438.4

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	104	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid 4-methyl-benzylamide	405.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 4-methyl-benzyl-amine (commercially available)	406.5
105	1- [5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carbonyl]-piperidine-4-carboxylic acid amide	412.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and piperidine-4-carboxylic acid amide (commercially available)	413.4	104		405.5		406.5
105		412.5		413.4	106	(3, 6-dihydro-2H-pyridin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	367.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 3, 6-dihydro-2H-pyridine (commercially available)	368.3
107	[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (3-methyl-piperidin-1-yl) -methanones	383.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 3-methyl-piperidine (commercially available)	384.3	106		367.5		368.3
107		383.5		384.3	108	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl-pyridin-3-ylmethyl-amide	406.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and methyl-pyridin-3-ylmethyl-amine (commercially available)	407.4
109	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid [2- (2-methyl-piperidin-1-yl) -ethyl]-amides of	426.6	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 2- (2-methyl-piperidin-1-yl) -ethyl-amine (commercially available)	427.5	108		406.5		407.4
109		426.6		427.5	110	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid dimethylcarbamoylmethyl-methyl-amide	400.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and dimethylcarbamoylmethyl-methyl-amine (commercially available)	401.6

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	111	(4-hydroxy)Ylmethyl-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	399.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 4-hydroxymethyl-piperidine (commercially available)	400.5
112	(1, 3-dihydro-isoindol-2-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	403.5	5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (intermediate 1) and 1, 3-dihydro-isoindole (commercially available)	404.5	111		399.5		400.5
112		403.5		404.5	113	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid cyclopentylamide	355.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and cyclopentylamide (commercially available)	356.3
114	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (2-piperidin-1-yl-ethyl) -amide	398.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and (2-piperidin-1-yl-ethyl) -amine (commercially available)	399.5	113		355.5		356.3
114		398.5		399.5	115	Azetidin-1-yl- (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl) -methanones	327.4	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and azetidine (commercially available)	328.2
116	{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } - (3-pyridin-2-yl-pyrrolidin-1-yl) -methanone	418.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 3-pyridin-2-yl-pyrrolidine (commercially available)	419.4	115		327.4		328.2
116		418.5		419.4	117	(4-isopropyl-piperazin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	398.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 4-isopropyl-piperazine (commercially available)	399.5

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	118	(2-methyl-pyrrolidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	355.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 2-methyl-pyrrolidine (commercially available)	356.4
119	{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -pyrrolidin-1-yl-methanone	341.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and pyrrolidine (commercially available)	342.2	118		355.5		356.4
119		341.5		342.2	120	{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -piperidin-1-yl-methanone	355.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and piperidine (commercially available)	356.4
121	{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -morpholin-4-yl-methanones	357.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and morpholine (commercially available)	358.3	120		355.5		356.4
121		357.5		358.3	122	{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -thiomorpholin-4-yl-methanone	373.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and thiomorpholine (commercially available)	374.4
123	(4-methoxy-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	385.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 4-methoxy-piperidine (commercially available)	386.4	122		373.5		374.4
123		385.5		386.4	124	(4-methyl-piperazin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indoleIndole-2-yl-methanones	370.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 4-methyl-piperazine (commercially available)	371.3

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	125	(3-methoxy-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	385.5	5-[2-(1-Methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 3-methoxy-piperidine (commercially available)	386.4
126	(4-benzyl-piperidin-1-yl) - (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl) -methanones	445.6	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 4-benzyl-piperidine (commercially available)	446.3	125		385.5		386.4
126		445.6		446.3	127	(4-hydroxy-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	371.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 4-hydroxy-piperidine (commercially available)	372.3
128	(4, 4-difluoro-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	391.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 4, 4-difluoro-piperidine (commercially available)	392.2	127		371.5		372.3
128		391.5		392.2	129	(3, 6-dihydro-2H-pyridin-1-yl) - (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl) -methanones	353.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 3, 6-dihydro-2H-pyridin-1-yl (commercially available)	354.3
130	(3-methyl-piperidin-1-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	369.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 3-methyl-piperidine (commercially available)	370.4	129		353.5		354.3
130		369.5		370.4	131	(4-hydroxymethyl-piperidin-1-yl) - (5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl) -methanones	385.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and 4-hydroxymethyl-piperidine (commercially available)	386.4

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	132	(1, 3-dihydro-isoindol-2-yl) - {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	389.5	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2Carboxylic acid (intermediate 2) and 1, 3-dihydro-isoindole (commercially available)	390.3
133	[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]- ((S) -2-trifluoromethyl-pyrrolidin-1-yl) -methanone	409.4	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and (S) -2-trifluoromethyl-pyrrolidine (commercially available)	410.5	132		389.5		390.3
133		409.4		410.5	134	{5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } - ((S) -2-trifluoromethyl-pyrrolidin-1-yl) -methanone	409.4	5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid (intermediate 2) and (S) -2-trifluoromethyl-pyrrolidine (commercially available)	410.5

Example 135

[5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

a) Step 1: 5- ((S) -1-benzyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester

A mixture of 20.5g (0.1mol) ethyl-5-hydroxyindole-2-carboxylate, 23g (0.13mol) of (R) -1-benzyl-pyrrolidine, 58ml (0.2mol) of tri-n-butylphosphine and 50g (0.2mol) of 1, 1' -azobiscarbonyldipiperidine in 600ml of THF is stirred at room temperature for 17 hours. The suspension was filtered and the filtrate was evaporated to dryness. The residue was taken up in 100ml of heptane/DCM 1/1, the precipitate was filtered off and washed with 100ml of heptane/DCM 1/1. The filtrate was evaporated to dryness and the residue taken up in 100ml of DCM and purified by flash column chromatography on silica eluting with a gradient of ethyl acetate/heptane 1/3 to 2/1. The product-containing fractions were enriched, evaporated to dryness, purified again on silica gel, 2N NH in DCM/MeOH₃A gradient from 99/1 to 19/1. Enrichment and evaporation of the pure fractions gave 6.2g of pure product. This was recrystallized from diethyl ether and heptane, washing with diethyl ether/heptane to yield 3.5g of pure product. MS (m/e): 365.1(MH +, 100%). Enrichment and evaporation of the respective fractions gave 26g of impure product. This was recrystallized from diethyl ether and heptane, washing with diethyl ether/heptane to yield 9.0g of pure product. All filtrates were enriched and evaporated to dryness to give 14g of slightly impure product, which was used in the continuous step without further purification.

b) Step 2: [5- ((S) -1-benzyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone

A mixture of 14g of ethyl 5- ((S) -1-benzyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylate and 1.45g (0.035mol) lithium hydroxide monohydrate in 100ml of THF/MeOH 1/1 and 25ml of water was heated to reflux for 2 hours, after which all organic volatiles were removed under reduced pressure. 100ml of water (0 ℃ C.) were added and the mixture was extracted with 2X 100ml of diethyl ether. The aqueous phase was adjusted to pH 2 with 4N HCl and the water decanted from the precipitate formed. The mixture was dried under vacuum at 50 ℃ to give 8.5g of a brownish foam. This was taken up in 100ml of DMF and treated at 0 ℃ with 9.6g (0.03mol) of 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, 2.6g (0.03mol) of morpholine and 25.8ml (0.15mol) of N-ethyldiisopropylamine and stirred at room temperature for 1 hour. The mixture is evaporated to dryness and 200ml of ethyl acetate, 200ml of water and 200ml of 10% Na₂CO₃An aqueous solution. The aqueous phase is extracted with 200ml of ethyl acetate. The combined organic phases were washed with 200ml of saturated aqueous NaCl solution. Through Na₂SO₄Dried, filtered and evaporated to dryness. The residue was suspended in 100ml of diethyl ether/methanol 9/1, filtered, washed with 30ml of diethyl ether/methanol 9/1 and dried under vacuum at 30 ℃ to obtain 6g (0.014mmol) of the title compound as a white solid. MS (m/e): 406.5 (MH)⁺，100％)。

c) And step 3: morpholin-4-yl- [5- ((S) -pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone

4.6(0.016mol) [5- ((S) -1-benzyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] are reacted over a period of 4 hours]A mixture of-morpholin-4-yl-methanone and 480mg of 10% palladium on charcoal in 250ml of ethyl acetate/acetic acid 9/1 was hydrogenated at room temperature. After filtration the filtrate was evaporated to dryness and the residue taken up in 250ml DCM and 150ml 10% Na₂CO₃. The aqueous phase was extracted with 2X 100ml DCM, Na₂SO₄The combined organic phases were dried and evaporated to dryness to yield 2.77g (77% title compound as off-white solid MS (m/e): 316.1 (MH)⁺，100％)。

d) And 4, step 4: [5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl methanone

315mg (1mmol) of morpholin-4-yl- [5- ((S) -pyrrolidin-3-yloxy) -1H-indol-2-yl]Methanone, 615mg (5mmol) 2-bromopropane and 173mg (1.25mmol) K₂CO₃The mixture in 3ml DMF was heated to 50 ℃ for 16 h. The mixture is evaporated to dryness and taken up in 50ml of ethyl acetate and 50ml of water. The aqueous phase is extracted with 50ml of ethyl acetate and the combined organic phases are washed with 50ml of saturated aqueous NaCl solution and passed over Na₂SO₄Dried, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography using 2N NH in DCM/methanol₃19/1 to 85/15. The fractions containing the product were enriched and evaporated to dryness and treated with diethyl ether. The precipitate was filtered off and washed with a small portion of diethyl ether. The title compound was dried under vacuum at 30 ℃ to obtain 172mg (48%) as a white solid。MS(m/e)：358.3(MH⁺，100％)。

As above for [5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]Synthesis of (E) -morpholin-4-yl-methanone the procedure described, starting in an analogous manner from ethyl-5-hydroxyindole-2-carboxylate and (S) -1-benzyl-pyrrolidine, synthesizes the respective enantiomer [5- ((R) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone. MS (m/e): 358.3 (MH)⁺，100％)。

Example 136

[5- ((S) -1-Cyclopropylmethyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

According to the procedure for the synthesis of [5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone from morpholin-4-yl- [5- ((S) -pyrrolidin-3-yloxy) -1H-indol-2-yl]Methanone and bromomethyl-cyclopropane the title compound was synthesized. The title compound was obtained as a pale yellow solid. MS (m/e): 370.3 (MH)⁺，100％)。

Example 137

Morpholin-4-yl- [5- ((S) -1-propyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones

According to the procedure for the synthesis of [5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone from morpholin-4-yl- [5- ((S) -pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanone and 1-iodopropane. The title compound was obtained as a white solid. MS (m/e): 358.4 (MH)⁺，100％)。

Example 138

[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

a) Step 1: 6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester

A mixture of 1g (4.8mmol) of ethyl-6-hydroxyindole-2-carboxylate (Journal of the American chemical Society (1967), 89(13), 3349-50), 0.81g (6.3mmol) of 1-isopropyl-3-pyrrolidinol, 2.83ml (11mmol) of tri-n-butylphosphine and 2.56g (9.75mmol) of 1, 1' -azobiscarbonyl-dipiperidine in 50ml of THF is stirred at room temperature for 16 hours. The suspension was filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using DCM/2 NNH in MeOH₃99/1 to 19/1. The fractions containing the product were combined, evaporated to dryness to give a brown oil which was crystallized from diethyl ether and heptane to give 0.5g of brownish crystals (MS (m/e): 317.1 (MH)⁺100%)). The filtrate was evaporated and 0.6g of slightly impure product was used in the continuous step without further purification.

b) Step 2: [6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone

A mixture of 0.6g of ethyl 6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylate and 0.088g (2.1mmol) of lithium hydroxide monohydrate in 20ml of THF/MeOH 1/1 and 5ml of water was heated to reflux for 1 hour, after which all organic volatiles were removed under reduced pressure. 10ml of water (0 ℃) were added and the pH was adjusted to 2 with 4N HCl. All volatiles were removed under reduced pressure to give 680mg of a brownish foam. This was taken up in 5ml of DMF and treated with 0.61g (1.9mmol) of 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, 165mg (1.9mmol) of morpholine and 1.63ml (9.5mmol) of N-ethyldiisopropylamine and stirred at room temperature for 16H. The mixture was evaporated to dryness and 50ml ethyl acetate, 50ml water and 50ml 10% Na were added₂CO₃An aqueous solution. The aqueous phase is extracted with 50ml of ethyl acetate. The combined organic phases were washed with 50ml of saturated aqueous NaCl solution and Na₂SO₄Dried, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel with DCM/2N NH in MeOH₃19/1 to 85/15. The fractions containing the product were enriched and evaporated to dryness. The residue is taken up in 5ml of diethyl ether, filtered and washed again with 5ml of diethyl ether. The title compound (165mg) was obtained as a white solid after drying in vacuo at 50 ℃. MS (m/e): 358.4 (MH)⁺，100％)。

Intermediate 3

6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester

Ethyl 6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylate was synthesized from ethyl 6-hydroxy-1H-indole-2-carboxylate and 1-isopropyl-piperidin-4-ol (commercially available) according to the procedure for the synthesis of example 138/step 1. The title compound was 15% yield as a light brown solid. MS (m/e): 331.1 (MH)⁺，100％)。

Intermediate 4

6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid ethyl ester

6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid ethyl ester was synthesized from 6-hydroxy-1H-indole-2-carboxylic acid ethyl ester and 2- (1-methyl-pyrrolidin-2-yl) -ethanol (commercially available) according to the procedure described for the synthesis of example 138/step 1. The title compound was obtained in 77% yield as a pale brown oil. MS (m/e): 317.3(MH +, 100%).

Intermediate 5

6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid ethyl ester

Following the procedure described for the synthesis of example 138/step 1, starting from 6-hydroxy-1H-indole-2-carboxylic acid ethyl ester and 3-piperidine-1-Yl-propan-1-ol (commercially available) Synthesis of 6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid ethyl ester. The title compound was obtained in 77% yield as a pale brown oil. MS (m/e): 317.3 (MH)⁺，100％)。

Following the procedure described for the synthesis of example 138/step 2, from 6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy ] -1H-indole-2-carboxylic acid ethyl ester, 6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester, more indole derivatives have been synthesized from 6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester or 6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid ethyl ester and the respective amines mentioned in table 2. The results are shown in table 2 and include example 139 through example 162.

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	139	[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl-4-morpholin-4-yl-methanone	371.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and morpholine (commercially available)	372.4
140	[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-thiomorpholin-4-yl-methanones	387.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and thiomorpholine (commercially available)	388.5	139		371.5		372.4
140		387.5		388.5	141	[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-piperidin-1-yl-methanones	369.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and piperidine (commercially available)	370.3
142	[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (4-methyl-piperidin-1-yl) -methanones	383.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and 4-methyl-piperidine (commercially available)	384.5	141		369.5		370.3
142		383.5		384.5	143	[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (4-methoxy-piperidin-1-yl) -methanones	399.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and 4-methoxy-piperidine (commercially available)	400.6

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	144	[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-pyrrolidin-1-yl-methanones	355.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and pyrrolidine (commercially available)	356.5
145	[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (2-methyl-pyrrolidin-1-yl) -methanones	369.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and 2-methyl-pyrrolidine (commercially available)	370.1	144		355.5		356.5
145		369.5		370.1	146	Azepan-1-yl- [6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	383.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and azepane (commercially available)	384.1
147	(2, 6-dimethyl-morpholin-4-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones	399.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and 2, 6-dimethyl-morpholine (commercially available)	400.0	146		383.5		384.1
147		399.5		400.0	148	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-amide	355.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and cyclopropylmethyl-amine (commercially available)	356.5
149	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid 4-fluoro-benzamide	409.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and 4-fluoro-benzylamine (commercially available)	410.3	148		355.5		356.5

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	150	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid (furan-2-ylmethyl) -amide	381.5	6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 3) and furan-2-ylmethyl-amine (commercially available)	382.4
151	Azepan-1-yl- {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -methanone	369.5	6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid ethyl ester (intermediate 4) and azepane (commercially available)	370.3	150		381.5		382.4
151		369.5		370.3	152	{6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indol-2-yl } -pyrrolidin-1-yl-methanone	341.5	6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy]-1H-indole-2-carboxylic acid ethyl ester (intermediate 4) and pyrrolidine (commercially available)	342.1
153	[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-thiomorpholin-4-yl-methanones	373.5	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester (example 138/step 1) and thiomorpholine (commercially available)	374.5	152		341.5		342.1
153		373.5		374.5	154	[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-piperidin-1-yl-methanones	355.5	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester (example 138/step 1) and piperidine (commercially available)	356.5

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	155	[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]- (4-methyl-piperidin-1-yl) -methanones	369.5	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester (example 138/step 1) and 4-methyl-piperidine (commercially available)	370.3
156	[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]- (4-methoxy-piperidin-1-yl) -methanones	385.5	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester (example 138/step 1) and 4-methoxy-piperidine (commercially available)	386.5	155		369.5		370.3
156		385.5		386.5	157	[6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-pyrrolidin-1-yl-methanones	341.5	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester (example 138/step 1) and pyrrolidine (commercially available)	342.1
158	Azepan-1-yl- [6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	369.5	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester (example 138/step 1) and azepane (commercially available)	370.3	157		341.5		342.1
158		369.5		370.3	159	(2, 6-dimethyl-morpholin-4-yl) - [6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanones	385.5	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester (example 138/step 1) and 2, 6-dimethyl-morpholine (commercially available)	386.5

Example No. 2	System naming	MW	Original sourceMaterial	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Original sourceMaterial	Experiment MW (M + H)⁺	160	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-amide	341.5	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester (example 138/step 1) and cyclopropylmethyl-amine (commercially available)	342.3
161	(4, 4-difluoro-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl]-methanones	371.5	6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 5) and 4, 4' -difluoropiperidine (commercially available)	371.6	160		341.5		342.3
161		371.5		371.6	162	6- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid cyclopropylmethyl-amide	341.5	6- (3-piperidin-1-yl-propane)Oxy) -1H-indole-2-carboxylic acid ethyl ester (intermediate 5) and morpholine (commercially available)	342.3

Example 163

[5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methylthioone

0.1g (0.28mmol) of [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]A mixture of-morpholin-4-yl-methanone and 141mg (0.47mmol) of Lawson's reagent in 10ml of THF is stirred at room temperature for 68 hours. The mixture was evaporated to dryness and the residue was purified by silica gel column chromatography using 2N NH in DCM/methanol₃97/3 to 19/1 to yield 56mg (54%) of the title compound as a yellow foam. MS (m/e): 374.4 (MH)⁺，100％)。

Example 164

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

a) Step 1: 4-benzyloxy-3-fluoro-benzaldehyde

18.6g (0.133mol) of 3-fluoro-4-hydroxy-benzaldehyde, 24.9g (0.146mol) of benzyl bromide and 22g (0.159mol) of K₂CO₃The mixture in 150ml DMF was heated to 55 ℃ for 2 hours. After filtration and washing of the residue with 30ml DMF, all volatiles were removed in vacuo. The residue was partitioned between water and ethyl acetate and brine, extracted with ethyl acetate. The combined organic layers were washed with brine, over Na₂SO₄Dry, filter, evaporate, recrystallize the residue from ethyl acetate/heptane, and use without further purification. MS (m/e): 231.1 (MH)⁺，100％)。

b) Step 2: 6-benzyloxy-5-fluoro-1H-indole-2-carboxylic acid methyl ester

2-azidoA mixture of methyl acetate, 4-benzyloxy-3-fluoro-benzaldehyde and sodium methoxide (in methanol) in toluene was reacted at 0 ℃ for 3 hours. The residue after filtration of the suspension was washed with methanol, partitioned between ethyl acetate and ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were passed over Na₂SO₄Dried and evaporated to dryness and the residue taken up in p-xylene and allowed to stand at reflux temperature for 2 hours. After concentration the mixture is left to crystallize, and the crystals formed are filtered off and washed with toluene. After drying at 40 ℃ in vacuo, the title compound was obtained as yellow crystals. MS (m/e): 300.3 (MH)⁺，100％)。

c) And step 3: 5-fluoro-6-hydroxy-1H-indole-2-carboxylic acid methyl ester

A solution of 20.2g (0.067mol) of methyl 6-benzyloxy-5-fluoro-1H-indole-2-carboxylate in 800ml of ethyl acetate was treated with 2g (10%) Pd/C and hydrogenated at 1 bar for 2H. After filtration and evaporation, the residue was recrystallized from ethyl acetate. The crystals were filtered off, washed with diethyl ether and dried in vacuo at 40 ℃ to yield 10.9g (74%) of the title compound as white crystals. MS (m/e): 208.1 (MH)^-，100％)。

d) And 4, step 4: 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl ester

The title compound was synthesized in 48% yield as white crystals from 5-fluoro-6-hydroxy-1H-indole-2-carboxylic acid methyl ester and 1-isopropyl-piperidin-4-ol (commercially available) according to the method described for the synthesis of example 5 (step 2). MS (m/e): 335.4 (MH)⁺，100％)。

e) And 5: 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid

The title compound was synthesized from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl ester and lithium hydroxide according to the procedure described for the synthesis of example 5 (step 3) and was used in the successive steps without further purification. MS (m/e): 321.4 (MH)⁺，100％)。

f) Step 6: [ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone

The title compound was synthesized in 68% yield from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and morpholine (commercially available) according to the procedure described for the synthesis of example 5 (step 3). MS (m/e): 390.4 (MH)⁺，100％)。

Example 165

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-thiomorpholin-4-yl-methanones

Synthesis of [ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone (example 164) the title compound was synthesized from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and thiomorpholine (commercially available). MS (m/e): 406.3 (MH)⁺，100％)。

Example 166

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-piperidin-1-yl-methanones

Synthesis of [ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone (example 164) the title compound was synthesized from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and piperidine (commercially available). MS (m/e): 388.0 (MH)⁺，100％)。

Example 167

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yly-l) -1H-indol-2-yl]- (4-methyl-piperidin-1-yl) -methanones

Synthesis of [ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone (example 164) the title compound was synthesized from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and 4-methyl-piperidine (commercially available). MS (m/e): 402.3 (MH)⁺，100％)。

Example 168

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- (4-methoxy-piperidin-1-yl) -methyl Ketones

Synthesis of [ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone (example 164) the title compound was synthesized from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and 4-methoxy-piperidine (commercially available). MS (m/e): 418.1 (MH)⁺，100％)。

Example 169

[ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Pyrrolidin-1-yl-methanones

Synthesis of [ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone (example 164) the title compound was synthesized from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and pyrrolidine (commercially available). MS (m/e): 374.0 (MH)⁺，100％)。

Example 170

Azepan-1-yl- [ 5-fluoro-6- (1-isopropyl-1-piperidin-4-yloxy) -1H-indol-2-yl]-methanones

Synthesis of [ 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone (example 164) the title compound was synthesized from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and azepane (commercially available). MS (m/e): 402.1 (MH)⁺，100％)。

Example 171

5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid cyclopropyl-methyl-amide

Synthesis of [ 5-fluoro-6- (1-iso) as described abovePropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanone (example 164) the title compound was synthesized from 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and cyclopropylmethylamine (commercially available). MS (m/e): 374.0 (MH)⁺，100％)。

Example 172

[ 1-Ethyl-5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

0.179g (0.5mmol) of [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]A mixture of-morpholin-4-yl-methanone, 0.094g (0.6mmol) iodoethane and 0.022g (0.5mmol) NaH (as a 55% suspension in oil) in 2ml N, N-dimethylacetamide was heated to 60 ℃ for 1 hour. After evaporation of all volatiles, the residue was taken up in 50ml of ethyl acetate and 50ml of water and extracted with ethyl acetate. The combined organic layers were washed with brine, over Na₂SO₄Dried and evaporated to dryness. Purify the residue by flash column chromatography on silica gel with DCM/2N NH in MeOH₃Elution gave a yellow oil after evaporation of the product fractions, which crystallized from diethyl ether. The title compound was obtained, (0.051g (26%)) as a white solid. MS (m/e): 386.5 (MH)⁺，100％)。

Example 173

[ 1-isopropyl-5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

Synthesis of [ 1-ethyl-5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl as described above]-morpholin-4-yl-methanone (example 172) from [5- (1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]Morpholin-4-yl-methanone and 2-iodopropane (commercially available) the title compound was synthesized. MS (m/e): 400.5 (MH)⁺，100％)。

Example 174

(3, 3-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-methanones

The title compound was synthesized from [5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid and 3, 3' -difluoropiperidine (commercially available) according to the procedure described for the synthesis of example 5/step 3. MS (m/e): 406.6 (MH)⁺，100％)。

Example 175

(4, 4-difluoro-piperidin-1-yl) - (5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]First of all Ketones

a) Step 1: [5- ((S) -1-benzyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] - (4, 4-difluoro-piperidin-1-yl) -methanone

The title compound was synthesized from ethyl 5- ((S) -1-benzyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylate and 4, 4-difluoropiperidine according to the procedure described for example 135. MS (m/e): 440.4 (MH)⁺，100％)。

b) Step 2: (4, 4-difluoro-piperidin-1-yl) - [5- ((S) -pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone

The title compound was obtained from [5- ((S) -1-benzyl-pyrrolidin-3-yloxy) -1H-indol-2-yl) - (4, 4-difluoro-piperidin-1-yl) -methanone by hydrogenation according to the method described for example 135. MS (m/e): 350.5 (MH)⁺，100％)。

c) And step 3: (4, 4-difluoro-piperidin-1-yl) - [5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -methanone

By the method described for example 135, starting from (4, 4-difluoro-piperidin-1-yl) - [5- ((S) -pyrrolidin-3-yloxy) -1H-indol-2-yl]-methanone and 2-iodopropane. MS (m/e): 392.3 (MH)⁺，100％)。

Example 176

(4, 4-difluoro-piperidin-1-yl) - [5- ((R) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-first of all Ketones

Synthesis of (4, 4-difluoro-piperidin-1-yl) - [5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]The procedure described for the synthesis of the respective enantiomer (4, 4-difluoro-piperidin-1-yl) - [5- ((R) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl) - [ from ethyl-5-hydroxyindole-2-carboxylic acid and (R) -1-benzyl-pyrrolidine in an analogous manner to that described for methanone (example 75)]-a ketone. MS (m/e): 392.4 (MH)⁺，100％)。

Example 177

[5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl]-pyrrolidin-1-yl-methanonesa) Step 1: 5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester

18g (49mmol) of ethyl 5- ((S) -1-benzyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylate, 28.3ml of acetic acid and 2g of Pd/C10% are reacted with H in a 16-hour period₂Hydrogenation at room temperature. The mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in 500ml of DMF and 34.1g (247mmol) of K₂CO₃42g (247mmol) of 2-iodopropane were added and the mixture was stirred at 50 ℃ for 4 hours. After filtration and evaporation, the residue was purified on silica gel with DCM/MeOH (2N NH)₃)98/2 to 92/8, obtained 60% of the title compound as a light brown solid after evaporation of the product fractions. MS (m/e): 317.3 (MH)⁺，100％)。

b) Step 2: 5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid 1: 1 hydrochloride

A mixture of 8.9g (28mmol) of ethyl 5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylate and 1.3g (31mmol) of LiOH monohydrate in 100ml of THF, 50ml of water and 10ml of methanol is heated to reflux for 2 hours and the organic solvent is removed under reduced pressure. After addition of 4N aqueous HCl, the mixture was evaporated to dryness and used in the next step without further purification. MS (m/e): 289.3 (MH)⁺，100％)。

c) And step 3: [5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indol-2-yl ] -pyrrolidin-1-yl-methanone

The title compound was synthesized from 5- ((S) -1-isopropyl-pyrrolidin-3-yloxy) -1H-indole-2-carboxylic acid 1: 1 hydrochloride and pyrrolidine following the procedure described for the synthesis of example 1, using TBTU and DIPEA in DMF under coupling conditions. The crude product was purified by silica gel eluting with DCM/MeOH (2N NH)₃)98/2 to 94/6. The product fractions were evaporated to give the title compound as an off-white solid. (m/e): 342.3 (MH)⁺，100％)。

Example 178

(4, 4-difluoro-piperidin-1-yl) - [ 5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl]-methanonesa) Step 1: 5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid methyl ester

The title compound was synthesized from 5-fluoro-6-hydroxy-1H-indole-2-carboxylic acid methyl ester and 3-piperidin-1-yl-propan-1-ol (commercially available) according to the method described above for the synthesis of 5-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-carboxylic acid methyl ester (example 164/step 4). MS (m/e): 335.4 (MH)⁺，100％)。

b) Step 2: 5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid

The title compound was synthesized following the procedure described for the synthesis of example 5 (step 3), starting from 5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid methyl ester and lithium hydroxide and used in the successive steps without further purification. MS (m/e): 321.4 (MH)⁺，100％)。

c) And step 3: (4, 4-difluoro-piperidin-1-yl) - (5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone

The title compound was synthesized from 5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid and 4, 4' -difluoropiperidine (commercially available) according to the procedure described for the synthesis of example 5 (step 3). MS (m/e): 424.5 (MH)⁺，100％)。

Example 179

[ 5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

The title compound was synthesized following the procedure described for the synthesis of example 5 (step 3), starting from 5-fluoro-6- (3-piperidin-1-yl-propoxy) -1H-indole-2-carboxylic acid and morpholine (commercially available). MS (m/e): 390.5 (MH)⁺，100％)。

Example 180

(4, 4-difluoro-piperidin-1-yl) - [ 1-isopropyl-5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2- Base of]-methanones

Following the procedure described for the synthesis of example 172, from (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from methanone (example 102) and 2-bromopropane (commercially available), the title compound was synthesized. MS (m/e): 448.5 (MH)⁺，100％)。

Example 181

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1- (2-methoxy-ethyl) -1H- Indol-2-yl]-methanones

Following the procedure described for the synthesis of example 172, from (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from methanone (example 102) and 2-bromoethyl methyl ether (commercially available), the title compound was synthesized. MS (m/e): 464.6 (MH)⁺，100％)。

Example 182

(4, 4-difluoro-piperidin-1-yl) - [ 1-ethyl-5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]- Ketone

Following the procedure described for the synthesis of example 172, from (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Methanone (example 102) and bromoethane (may)Commercial) the title compound was synthesized. MS (m/e): 434.5 (MH)⁺，100％)。

Example 183

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1- (2, 2, 2-trifluoroethyl) -1H- Indol-2-yl]-methanones

Following the procedure described for the synthesis of example 172, from (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from methanone (example 102) and 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (commercially available), the title compound is obtained. MS (m/e): 434.5 (MH)⁺，100％)。

Example 184

[ 1-Cyclopropylmethyl-5- (1-isopropyl-piperidin-4-yly-l) -1H-indol-2-yl]- (4, 4-difluoro-piperidine) -1-yl) -methanones

Following the procedure described for the synthesis of example 172, from (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from methanone (example 102) and bromomethylcyclopropane (commercially available), the title compound was synthesized. MS (m/e): 434.5 (MH)⁺，100％)。

Example 185

[5- (1-isopropyl-piperidin-4-yloxy) -1- (2, 2, 2-trifluoro-ethyl) -1H-indol-2-yl]Pyrrolidine-1- Alkyl-ketones

Following the procedure described for the synthesis of example 172, from [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from-pyrrolidin-1-yl-methanone (example 90) and 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (commercially available) the title compound was synthesized. MS (m/e): 437.5 (MH)⁺，100％)。

Example 186

[5- (1-isopropyl-piperidin-4-yloxy) -1- (2, 2, 2-trifluoro-ethaneRadical) -1H-indol-2-yl]-morpholin-4-yl -methanones

Following the procedure described for the synthesis of example 172, from [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from-morpholin-4-yl-methanone (example 92) and 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (commercially available), the title compound was synthesized. MS (m/e): 454.5 (MH)⁺，100％)。

Example 187

(3, 3-difluoro-piperidin-1-yl) - (5- (1-isopropyl-piperidin-4-yloxy) -1- (2, 2, 2-trifluoroethyl) -1H- Indol-2-yl]-methanones

Following the procedure described for the synthesis of example 172, from (3, 3-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from methanone (example 174) and 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (commercially available), the title compound was synthesized. MS (m/e): 488.5 (MH)⁺，100％)。

Example 188

(4, 4-difluoro-piperidin-1-yl) - [1- (2-hydroxy-ethyl) -5- (1-isopropyl-piperidin-4-yloxy) -1H-indole Indole-2-yl]-methanones

Following the procedure described for the synthesis of example 172, from (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from ketone (example 102) and 1, 3, 2-dioxathiolane-2, 2-dioxide (commercially available), the title compound is synthesized. MS (m/e): 488.5 (MH)⁺，100％)。

Example 189

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1-methanesulfonyl-1H-indol-2- Base of]-methanones

Following the procedure described for the synthesis of example 172, from (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indole-2-radical]Starting from methanone (example 102) and methanesulfonyl chloride (commercially available), the title compound was synthesized. MS (m/e): 484.5 (MH)⁺，100％)。

Example 190

1- [2- (4, 4-difluoro-piperidine-1-carbonyl) -5- (1-isopropyl-piperidin-4-yloxy) -indol-1-yl]-ethanones

Following the procedure described for the synthesis of example 172, from (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]Starting from methanone (example 102) and acetyl chloride (commercially available), the title compound was synthesized. MS (m/e): 448.5 (MH)⁺，100％)。

Example 191

(4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1-methyl-1H-indol-2-yl]- Ketone

a) Step 1: 4- [2- (4, 4-difluoro-piperidine-1-carbonyl) -1-methyl-1H-indol-5-yloxy ] -1-isopropyl-1-methyl-pyridinium as monomethyl sulfate salt

Mixing (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl]A mixture of methanone (example 102, 400mg, 0.99mmol, 1.0eq.), cesium carbonate (1.26g, 3.85mmol, 3.9eq.) and dimethyl sulfate (0.744g, 5.72mmol, 5.8eq.) in acetone (16mL) was stirred at room temperature for 6 hours. The resulting suspension was filtered and the solid was washed with acetone. The filtrate was concentrated in vacuo to give 926mg (quant.) of the title compound as an orange oil, which was used in the next step without further purification. MS (m/e): 434.3 (M)⁺，100％)。

b) Step 2: (4, 4-difluoro-piperidin-1-yl) - [5- (1-isopropyl-piperidin-4-yloxy) -1-methyl-1H-indol-2-yl ] -methanone

To 4- [2- (4, 4-difluoro-piperidine-1-carbonyl) -1-methyl-1H-indol-5-yloxy as methyl sulfate salt]-1-isopropyl-1-methyl-pyridinium (120mg, 0.2mmol, 1.0eq.), lithium hydroxide(5mg, 0.5mmol, 2.5eq.) in N, N-dimethylformamide (0.5mL) ethanethiol (0.05mL, 0.6mmol, 2.7eq.) was added. The reaction mixture was stirred at 100 ℃ for 1 hour, cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, then filtered and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography using 2N NH in DCM/methanol₃19/1 to yield 89mg (96%) of the title compound as a white foam. MS (m/e): 420.5 (MH)⁺，100％)。

Example 192

[5- (1-Cyclopropylmethyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

a) Step 1: 1-cyclopropylmethyl-piperidin-4-one

To a suspension of (bromomethyl) cyclopropane (500mg, 4mmol, 1.0eq.) and 4-piperidone hydrate hydrochloride (579mg, 4mmol, 1.0eq.) in acetonitrile (30mL) was added sodium carbonate (1.148g, 11mmol, 3. eq.). The reaction mixture was heated at 85 ℃ for 16 hours. The resulting suspension was filtered and the solid was washed with acetonitrile. The filtrate was concentrated in vacuo and purified by silica gel column chromatography using 2N NH in DCM/methanol₃97: 3 to yield 339mg (62%) of the title compound as a yellow oil. MS (m/e): 154.2 (MH)⁺，100％)。

b) Step 2: 1-cyclopropylmethyl-piperidin-4-ol

To a cold (0 ℃) solution of 1-cyclopropylmethyl-piperidin-4-one (314mg, 2mmol, 1.0eq.) in ethanol (4mL) was added sodium borohydride (61mg, 2mmol, 0.75 eq.). The reaction mixture was stirred at room temperature for 16 hours. Water, sodium hydroxide and dichloromethane were added and the reaction mixture was stirred at room temperature for 2 hours. The aqueous layer was extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give 160mg (50%) of the title compound as a colourless oil, which was used in the next step without further purification. MS (m/e): 156.3 (MH)⁺，100％)。

c) And step 3: [5- (1-Cyclopropylmethyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone

The title compound was synthesized from (5-hydroxy-1H-indol-2-yl) -morpholin-4-yl-methanone (example 1, step 1) and 1-cyclopropylmethyl-piperidin-4-ol (example 192, step 2) according to the method described for the synthesis of example 1/step 2. (m/e): 384.4 (MH)⁺，100％)。

Example 193

[5- (1-benzyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

The title compound was synthesized from (5-hydroxy-1H-indol-2-yl) -morpholin-4-yl-methanone (example 1, step 1) and 1-benzyl-4-hydroxy-piperidine (commercially available) according to the method described for the synthesis of example 1/step 2. (m/e): 419.52 (MH)⁺，100％)。

Example 194

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (methyl-propyl-amino) -propoxy]-1H-indol-2-yl } methanone, is formate salt

a) Step 1: 5- (3-chloro-propoxy) -1H-indole-2-carboxylic acid ethyl ester

To a solution of ethyl 5-hydroxyindole-2-carboxylate (15g, 73mmol, 1.0eq.) and 1-bromo-3-chloropropane (8.8mL, 88mmol, 1.2eq.) in 2-butanone (200mL) was added potassium carbonate (12.1g, 88mmol, 1.2 eq.). The reaction mixture was stirred at 80 ℃ for 160 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography on silica gel eluting with cyclohexane/ethyl acetate 9: 1 to give 15.3mg (74%) of the title compound as a pale yellow solid. MS (m/e): 282.7 (MH)⁺，100％)。

b) Step 2: 5- (3-chloro-propoxy) -1H-indole-2-carboxylic acid

[5- (3-chloro-propoxy) -1H-indole-2-carboxylic acid was synthesized from ethyl 5- (3-chloro-propoxy) -1H-indole-2-carboxylate according to the method described for the synthesis of example 5/step 2. The title compound was 98% yield as an off-white solid. MS (m/e): 253.1(M, 100%).

c) And step 3: [5- (3-chloro-propoxy) -1H-indol-2-yl ] - (4, 4-difluoro-piperidin-1-yl) -methanone

5- (3-chloro-propoxy) -1H-indole-2-carboxylic acid and 4, 4 '-difluoropiperidine (commercially available) were synthesized from 5- (3-chloro-propoxy) -1H-indole-2-carboxylic acid and 4, 4' -difluoropiperidine (commercially available) according to the method described for the synthesis of example 5/step 3. The title compound was 76% yield as an off-white solid. MS (m/e): 357.8 (MH)⁺，100％)。

d) And 4, step 4: (4, 4-difluoro-piperidin-1-yl) - {5- [3- (methyl-propyl-amino) -propoxy ] -1H-indol-2-yl } methanone as formate salt

To [5- (3-chloro-propoxy) -1H-indol-2-yl]A mixture of (4, 4-difluoro-piperidin-1-yl) -methanone (42mg, 0.12mmol, 1.0eq.) and potassium carbonate (50mg, 0.35mmol, 3.0eq.) in N, N-dimethylformamide (1mL) was added N-methyl-N-propylamine (13mg, 0.18mmol, 1.5 eq.). The reaction mixture was stirred at 80 ℃ for 40 hours, cooled and then subjected to HPLC on YMC Combiprep^TMThe crude mixture was purified directly on the column, eluting with water/acetonitrile/formic acid 90: 10: 0.1, to give 2.1mg (4%) of the title compound as a pale yellow solid. MS (m/e): 440.5 (MH)⁺，100％)。

Further indole derivatives have been synthesized from [5- (3-chloro-propoxy) -1H-indol-2-yl ] - (4, 4-difluoro-piperidin-1-yl) -methanone and the respective amines mentioned in table 3 according to the method described for the synthesis of example 194/step 4. The results are shown in table 3 and include example 195 through example 208.

TABLE 3

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	195	(4, 4-difluoro-piperidin-1-yl) - {5- [3- (ethyl-propyl-amino) -propoxy]-1H-indol-2-yl } -methanone as formate salt	407.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and N-ethyl-N-propylamine (commercially available)	408.5
196	(4, 4-difluoro-piperidin-1-yl) - {5- [3- (isopropyl-methyl-amino) -propoxy]-1H-indol-2-yl } -methanone as formate salt	393.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and N-methyl-N-isopropylamine (commercially available)	394.5	195		407.5		408.5
196		393.5		394.5	197	(4, 4-difluoro-piperidin-1-yl) - [5- (3-pyrrolidin-1-yl-propoxy) -1H-indol-2-yl]Methanone, as formate salt	391.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and pyrrolidine (commercially available)	392.5
198	[5- (3-azepan-1-yl-propoxy) -1H indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone, as formate salt	419.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and hexamethyleneimine (commercially available)	420.6	197		391.5		392.5
198		419.5		420.6	199	(4, 4-difluoro-piperidin-1-yl) - {5- [3- (3-methyl-piperidin-1-yl) -propoxy]-1H-indol-2-yl } -methanone, is AAcid salts	419.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and (rac) -3-methylpiperidine (commercially available)	420.5

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	200	(4, 4-difluoro-piperidin-1-yl) - (5- [3- (2, 6-cis-dimethyl-piperidin-1-yl) -propoxy]-1H-indol-2-yl) -methanone as formate salt	433.5	[5- (3-chloro-propoxy)Radical) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and cis-2, 6-dimethyl-piperidine (commercially available)	434.5
201	(4, 4-difluoro-piperidin-1-yl) - [5- (3-thiomorpholin-4-yl-propoxy) -1H-indol-2-yl]Methanone, as formate salt	423.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and thiomorpholine (commercially available)	424.5	200		433.5		434.5
201		423.5		424.5	202	(4, 4-difluoro-piperidin-1-yl) - (5- [3- (2, 5-dihydro-pyrrol-1-yl) -propoxy]-1H-indol-2-yl) -methanone as formate salt	389.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and 3-pyrroline (commercially available)	390.4
203	(4, 4-difluoro-piperidin-1-yl) - (5- [3- (2-methyl-pyrrolidin-1-yl) -propoxy)]-1H-indol-2-yl) -methanone as formate salt	405.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and rac-2-methyl-pyrrolidine (commercially available)	405.6	202		389.5		390.4
203		405.5		405.6	204	(4, 4-difluoro-piperidin-1-yl) - {5- [3- (2, 5-cis/trans-dimethyl-pyrrolidin-1-yl) -propoxy]-1H-indol-2-yl } -methanone as formate salt	419.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and cis/trans-2, 5-dimethyl-pyrrolidine (commercially available)	420.6
205	(4, 4-difluoro-piperidin-1-yl) - {5- [3- (3S-hydroxy-pyrrolidin-1-yl) -propoxy]-1H-indol-2-yl } -methanone as formate salt	407.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and 3S-hydroxy-pyrrolidine (commercially available)	408.6	204		419.5		420.6

Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺
Example No. 2	System naming	MW	Raw material	Experiment MW (M + H)⁺	206	(4, 4-difluoro-piperidin-1-yl) - {5- [3- (3-dimethylamino-pyrrolidin-1-yl) -propoxy]-1H-indol-2-yl } -methanone as formate salt	434.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and rac-2-N, N-dimethylamino-pyrrolidine (commercially available)	435.6
207	(4, 4-difluoro-piperidin-1-yl) - [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl]-methanones	405.5	[5- (3-chloro-propoxy)Radical) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and piperidine (commercially available)	406.5	206		434.5		435.6
207		405.5		406.5	208	(4, 4-difluoro-piperidin-1-yl) - [5- (3-morpholin-4-yl-propoxy) -1H-indol-2-yl]-methanones	407.5	[5- (3-chloro-propoxy) -1H-indol-2-yl]- (4, 4-difluoro-piperidin-1-yl) -methanone and morpholine (commercially available)	408.5

Example 209

{5- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy]-1H-indol-2-yl } -morpholin-4-yl-methanones

a) Step 1: [5- (3-chloro-propoxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone

[5- (3-chloro-propoxy) -1H-indol-2-yl was synthesized from 5- (3-chloro-propoxy) -1H-indole-2-carboxylic acid and morpholine (commercially available) according to the method described for the synthesis of example 5/step 3]-morpholin-4-yl-methanone. The title compound was 92% yield as an off-white solid. MS (m/e): 323.9 (MH)⁺，100％)。

b) Step 2: {5- [3- (4, 4-difluoro-piperidin-1-yl) -propoxy ] -1H-indol-2-yl } -morpholin-4-yl-methanone

Following the procedure described for the synthesis of example 194/step 4, starting from [5- (3-chloro-propoxy) -1H-indol-2-yl]Synthesis of [3- (4, 4-bis-di-methyl) -methanone and 4, 4' -difluoropiperidine hydrochloride (commercially available)Fluoro-piperidin-1-yl) -propoxy]-1H-indol-2-yl } -morpholin-4-yl-methanone. The title compound was 54% yield as a brown solid. MS (m/e): 408.5 (MH)⁺，100％)。

Example 210

[5- (1-cyclopropyl-piperidin-4-yloxy) -1H-indol-2-yl]-morpholin-4-yl-methanones

a) Step 1: 3- [ cyclopropyl- (2-ethoxycarbonyl-ethyl) -amino ] -propionic acid ethyl ester

A mixture of ethyl acrylate (30.0g, 300mmol, 2.0eq.) and cyclopropylamine (8.5mL, 149mmol, 1.0eq.) in anhydrous ethanol (45mL) was stirred at room temperature for 24 hours. The crude mixture was purified by fractional distillation under vacuum (20 mBar). One fraction (boiling point: 135 ℃ C. at 20mBar) was collected to obtain 20.58g (54%) of the desired product as colorless oil. MS (m/e): 274.3 (MH)⁺，100％)。

b) Step 2: 1-cyclopropyl-piperidin-4-one

A solution of 3- [ cyclopropyl- (2-ethoxycarbonyl-ethyl) -amino ] -propionic acid ethyl ester (10.0g, 39mmol, 1.0eq.) in anhydrous tetrahydrofuran (65mL) was added dropwise to a solution of sodium hydride (60% oil dispersion, 2.33g, 58mmol, 1.5eq.) in anhydrous tetrahydrofuran (65 mL). Absolute ethanol (1.79g, 39mmol, 1.0eq.) was then added. The resulting mixture was heated at reflux for 24 hours. The resulting solution was neutralized with dilute acetic acid (pH: 7) and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed in vacuo to yield 10.2g of a reddish oil.

The crude oil was then heated in 18% w/w hydrochloric acid (130mL) at reflux for 5 hours. After basification with sodium hydroxide (about 31g, pH: about 12), the crude mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed in vacuo. The crude mixture was purified by fractional distillation under vacuum (20 mbar). One fraction (boiling point: 75 ℃ C. at 20mBar) was collected to obtain 3.6g (67%) of the target product as colorless oil. MS (m/e): 140.0 (MH)⁺，100％)。

c) And step 3: 1-cyclopropyl-piperidin-4-ol

To a cold (0 ℃) solution of 1-cyclopropyl-piperidin-4-one (1.5g, 11mmol, 1.0eq.) in anhydrous ethanol was added sodium borohydride (306mg, 8mmol, 0.75 eq.). The reaction mixture was stirred at room temperature for 65 hours. The mixture was concentrated in vacuo. Glacial acetic acid (10mL) was added, followed by aqueous sodium hydroxide (28% w/w, ca. 10mL) and dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours. After phase separation, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude mixture was purified on silica gel with 2N NH in DCM/methanol₃93/7 to yield 1.44g (95%) of the title product as a colorless oil. MS (m/e): 423.1 (MH)⁺，100％)

d) And 4, step 4: [5- (1-cyclopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone

[5- (1-cyclopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] was synthesized from (5-hydroxy-1H-indol-2-yl) -morpholin-4-yl-methanone (example 1, step 1) and 1-cyclopropyl-piperidin-4-ol (example 201, step 3) according to the method described for the synthesis of example 1/step 2]-morpholin-4-yl-methanone. The title compound was 14% yield as a white solid. MS (m/e): 370.5 (MH)⁺，100％)。

Example A

Film-coated tablets containing the following ingredients may be prepared in a conventional manner:

composition (I) Each sheet is

The core is as follows:

10.0mg 200.0mg of compound of formula (I)

Microcrystalline cellulose 23.5mg 43.5mg

Lactose Anhydrous 60.0mg 70.0mg

Polyvinylpyrrolidone K3012.5mg 15.0mg

Sodium starch glycolate 12.5mg 17.0mg

Magnesium stearate 1.5mg 4.5mg

(nuclear weight) 120.0mg 350.0mg

Film coating

Hydroxypropyl methylcellulose 3.5mg 7.0mg

Polyethylene glycol 60000.8 mg 1.6mg

Talc 1.3mg 2.6mg

Iron oxide (Iron oxide) (yellow) 0.8mg 1.6mg

Titanium dioxide 0.8mg 1.6mg

The active ingredient is sieved, mixed with microcrystalline cellulose and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules were mixed with sodium starch glycolate and magnesium stearate and compressed to obtain 120 or 350mg cores, respectively. The cores were coated with the aqueous solution/suspension of the film coating described above.

Example B

Capsules containing the following ingredients can be prepared in a conventional manner:

composition (I) Per capsule

25.0mg of the Compound of formula (I)

Lactose 150.0mg

Corn starch 20.0mg

Talc 5.0mg

The components were sieved and mixed and filled into # 2 capsules.

Example C

The injection solution may have the following composition:

3.0mg of a Compound of formula (I)

Gelatin 150.0mg

Phenol 4.7mg

Sodium carbonate to obtain a final pH of 7

Adding water for injection to 1.0ml

Example D

Soft gelatin capsules containing the following ingredients may be prepared in a conventional manner:

capsule content

5.0mg of a Compound of formula (I)

Yellow wax 8.0mg

Hydrogenated Soybean oil 8.0mg

Partially hydrogenated vegetable oil 34.0mg

Soybean oil 110.0mg

The weight of the capsule content was 165.0mg

Gelatin capsule

Gelatin 75.0mg

Glycerol 85% 32.0mg

Karion 838.0 mg (dry matter)

Titanium dioxide 0.4mg

Iron oxide yellow 1.1mg

The active ingredient is dissolved in a warm melt of the other ingredients and the mixture is filled into suitably sized soft gelatin capsules. The filled soft gelatin capsules are processed according to conventional methods.

Example E

Sachets containing the following ingredients may be prepared in a conventional manner:

50.0mg of a compound of formula (I)

Lactose, fine powder 1015.0mg

Microcrystalline cellulose (AVICEL PH 102) 1400.0mg

Sodium carboxymethylcellulose 14.0mg

Polyvinylpyrrolidone K3010.0mg

Magnesium stearate 10.0mg

Flavoring additive 1.0mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and flavouring additives and filled into sachets.

Claims

1. A compound of the general formula,

wherein

X is O or S;

R¹selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

a lower hydroxyalkyl group,

a lower alkoxyalkyl group,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

R²selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

R¹And R²Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered saturated or partially unsaturated heterocyclic ring, optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated heterocyclic ring being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, halogen, haloalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or

R⁴is-O-Het and R⁵Is hydrogen, or

R⁴Is hydrogen or fluorine and R⁵is-O-Het;

het is selected from

Or

Wherein

m is 0, 1 or 2;

n is 0, 1 or 2;

R⁷is a lower alkyl group;

p is 0, 1 or 2;

q is 0, 1 or 2;

x is selected from CR¹⁰R^10′O and S;

R⁸，R^8′，R⁹，R^9′，R¹⁰，R^10′，R¹¹and R^11′Independently of each other selected from the group consisting of: hydrogen, lower alkyl, hydroxy, halogen and dialkylamino, or R⁹And R¹⁰Together form a double bond;

R¹²is a lower alkyl group;

R¹³is C₃-C₆-an alkyl group;

and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein

X is O or S;

R¹selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

a lower hydroxyalkyl group,

a lower alkoxyalkyl group,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

R²selected from the group consisting of:

the presence of hydrogen in the presence of hydrogen,

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

a lower alkyl sulfanyl alkyl group,

a lower dialkylaminoalkyl group,

a lower dialkylcarbamoylalkyl group,

R¹And R²Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered saturated or partially unsaturated heterocyclic ring, optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated heterocyclic ring being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, halogen, haloalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or fused to a phenyl ring which is unsubstituted or substituted by one, two or three groups independently selected from: lower alkyl, lower alkoxy and halogen;

R³is hydrogen or lower alkyl;

R⁴is-O-Het and R⁵Is hydrogen, or

R⁴Is hydrogen or fluorine and R⁵is-O-Het;

het is selected from

Or

Wherein

m is 0, 1 or 2;

R⁶is a lower alkyl group;

n is 0, 1 or 2;

R⁷is a lower alkyl group;

p is 0, 1 or 2;

q is 0, 1 or 2;

R⁸is hydrogen or lower alkyl;

and pharmaceutically acceptable salts thereof.

3. Compounds of formula I according to claims 1 or 2, wherein R¹Selected from the group consisting of:

lower alkyl, lower alkenyl, lower alkynyl,

cycloalkyl, lower cycloalkylalkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

a lower alkyl sulfanyl alkyl group,

lower dialkylaminoalkyl,

R²is hydrogen or lower alkyl.

4. Compounds of formula I according to any one of claims 1 to 3, wherein R¹Selected from the group consisting of:

lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower alkoxyalkyl,

a lower phenylalkyl group,

lower heteroarylalkyl, and

R²is hydrogen or lower alkyl.

5. Compounds of formula I according to any one of claims 1 to 4, wherein R¹And R²Is a lower alkyl group.

6. Compounds of formula I according to claims 1 or 2, wherein R¹And R²Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered saturated or partially unsaturated heterocyclic ring, optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated heterocyclic ring being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, halogen, haloalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or fused to a phenyl ring which is unsubstituted or substituted by one, two or three groups independently selected from: lower alkyl, lower alkoxy and halogen.

7. Compounds of formula I according to claim 6, wherein R¹And R²Together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of: morpholine, piperidine, 2, 5-dihydropyrrole, pyrrolidine, azepane, piperazine, azetidine, thiomorpholine and 3, 6-dihydro-2H-pyridine, said saturated heterocycle being unsubstituted or substituted with one, two or three groups independently selected from: lower alkyl, halogen, haloalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or fused to a phenyl ring which is unsubstituted or substituted by one, two or three groups independently selected from: lower alkyl, lower alkoxy and halogen.

8. Compounds of formula I according to claim 7, wherein R¹And R²Together with the nitrogen atom to which they are attached form a heterocyclic ring selected from morpholinyl, 2, 6-dimethylmorpholinyl, azepanyl, piperidinyl, 2-methylpiperidinyl, 4-methylpiperidinyl, pyrrolidinyl, 2-methylpyrrolidinyl, and azetidinyl.

9. Compounds of formula I according to any one of claims 1 to 8, wherein R³Is hydrogen or lower alkyl.

10. Compounds of formula I according to any one of claims 1 to 9, wherein R⁴is-O-Het and R⁵Is hydrogen.

11. Compounds of formula I according to any one of claims 1 to 9, wherein R⁴Is hydrogen or fluorine and R⁵is-O-Het.

12. A compound of formula I according to claim 1, wherein Het represents

Wherein m is 0, 1 or 2, and R⁶Selected from the group consisting of lower alkyl, cycloalkyl, lower cycloalkylalkyl and lower phenylalkyl.

13. Compounds of formula I according to claim 12, wherein R⁶Is a lower alkyl group.

14. Compounds of formula I according to claims 12 or 13, wherein m is 0.

15. Compounds of formula I according to claims 12 or 13, wherein m is 1.

16. A compound of formula I according to claim 1, wherein Het represents

Wherein n is 0, 1 or 2; and R is⁷Is a lower alkyl group.

17. Compounds of formula I according to claim 16, wherein n is 0.

18. Compounds of formula I according to claim 16, wherein n is 1.

19. A compound of formula I according to claim 1, wherein Het represents

R⁹And R¹⁰Together form a double bond.

20. Compounds of formula I according to claim 19, wherein p is 0, 1 or 2, q is 0, 1 or 2, X is CR¹⁰R^10′And R is⁸、R^8′、R⁹、R^9′、R¹⁰、R^10′、R¹¹And R^11′Is hydrogen or lower alkyl.

21. Compounds of formula I according to claim 19 or 20, wherein p is 1.

22. A compound of formula I according to claim 1, wherein Het represents

23. A compound of formula I according to claim 1, selected from the group consisting of:

morpholin-4-yl- [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

(4, 4-difluoro-piperidin-1-yl) - [ 5-1-isopropyl-piperidin-4-yloxy ] -1- (2, 2, 2-trifluoro-ethyl) -1H-indol-2-yl ] -methanone,

1- [2- (4, 4-difluoro-piperidine-1-carbonyl) -5- (1-isopropyl-piperidin-4-yloxy) -indol-1-yl ] ethanone,

(4, 4-difluoro-piperidin-1-yl) - {5- [3- (2-methyl-pyrrolidin-1-yl) -propoxy ] -1H-indol-2-yl } methanone as a formate salt,

and pharmaceutically acceptable salts thereof.

24. A compound of formula I according to claim 1, selected from the group consisting of:

morpholin-4-yl- [5- (3-piperidin-1-yl-propoxy) -1H-indol-2-yl ] -methanone,

[5- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

[6- (1-isopropyl-piperidin-4-yloxy) -1H-indol-2-yl ] -morpholin-4-yl-methanone,

and pharmaceutically acceptable salts thereof.

25. A process for the preparation of a compound according to any one of claims 1 to 24, which process comprises

a) The compound of the formula II is reacted with a compound of the formula II,

wherein X, R¹And R²As defined in claim 1, and

R⁴and R⁵One of which is-OH and the other is H,

HO-Het III

wherein Het is as defined in claim 1,

to obtain the compound of formula Ia,

wherein R is³Is a hydrogen atom, and is,

and optionally alkylating the compound to obtain a compound of formula Ia',

wherein R is³Is a lower alkyl group, and is,

or in the alternative,

b) the compound of the formula IV is reacted with a compound of the formula IV,

wherein R is⁴And R⁵One is-O-Het as defined in claim 1 and the other is H,

coupled with an amine of formula V under basic conditions,

H-NR¹R² V

wherein R is¹And R²As defined in claim 1, wherein the first and second substrates are,

to obtain the compound of the formula Ib,

wherein R is³Is a hydrogen atom, and is,

and optionally alkylating the compound to obtain a compound of formula Ib',

wherein R is³Is a lower alkyl group, and is,

and if so desired, the user can then,

26. Compounds according to any of claims 1-24, when manufactured by a process according to claim 25.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 together with a pharmaceutically acceptable carrier and/or adjuvant.

28. Pharmaceutical compositions according to claim 27 for the treatment and/or prevention of diseases which are associated with the modulation of the H3 receptor.

29. Compounds according to any of claims 1-24 for use as therapeutically active substances.

30. Compounds according to any of claims 1-24 for use as therapeutic active substances for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

31. A method for the treatment and/or prophylaxis of diseases which are associated with the modulation of H3 receptors, which method comprises administering a compound according to any one of claims 1 to 24 to a human being or animal.

32. The use of compounds according to any of claims 1-24 for the preparation of medicaments for the treatment and/or prevention of diseases which are associated with the modulation of the H3 receptor.

33. Use according to claim 32 for the treatment and/or prevention of obesity.

34. The novel compounds, processes and methods as well as the use of such compounds substantially as described herein before.