MX2008008893A - Cyclohexyl piperazinyl methanone derivatives and their use as histamine h3 receptor modulators - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein s, R1aand R1to R3are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

Description

CYLOHEXIL DERIVATIVES PIPERAZINIL METANONE AND ITS USE AS MODULATORS OF THE H3 RECEPTOR HISTAMINE DESCRIPTION OF THE INVENTION The present invention relates to new derivatives of cyclohexyl piperazinyl methanone, their preparation, the 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 present invention relates to the compounds of the general formula where s is 1 or 2; R1 is selected from the group consisting of lower alkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, alkylsulfonylalkyl, and tetrahydropyranyl; Rla is hydrogen or lower alkyl; R2 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl, and lower cyanoalkyl; Ref .: 194377 - - R3 is selected from the group consisting of - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with r one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, ~ (CH2) n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl , lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, indanyl, 1-oxo-indanyl, -CO- (C3-C8) -alkyl, -CO- (CH2) p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is unsubstituted or is substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, -CO- (CH2) q-heteroaryl, wherein q is 0, 1 or 2 and in that the heteroaryl ring is unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, and lower hydroxyalkyl, and -CO-NR4R5; or R2 and R3 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring which is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three independently selected groups from lower alkyl, lower alkoxy and halogen; R 4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of - - lower alkyl, aryl unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and lower arylalkyl, in wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, and lower hydroxyalkyl; or R5 together with the nitrogen atom to which they are attached form a 4, 5, 6 or 7 membered heterocyclic ring, optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, the The heterocyclic ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, haloalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; and the pharmaceutically acceptable salts thereof.

The compounds of formula I are antagonists and / or inverse agonists of the histamine 3 receptor (receptor H3). Histamine (2- (4-imidazolyl) ethylamine) is one of the aminergic neurotransmitters that are widely distributed throughout the body, for example, the gastrointestinal tract (Burks 1994 in Johnson L.R. ed., Physiology of the Gastrointestinal Tract, Raven Press, NY, pp. 211-242). Histamine regulates a series of pathophysiological digestive events, such as gastric acid secretion, intestinal motility (Leurs et al., Br J. Pharmacol., 1991, 102, pp. 179-185), vasomotor responses, inflammatory bowel responses and allergic reactions (Raithel et al., Int. Arch. Allergy Immunol., 1995, 108, 127-133). In the mammalian brain, histamine is synthesized in the histaminergic cell bodies that are centrally located in the tuberomamilar nucleus of the posterior basal hypothalamus. From there, the histaminergic cell bodies are projected towards several regions of the brain (Panula et al., Proc. Nati, Acad. Sci. USA 1984, 81, 2572-2576; Inagaki et al., J. Comp.Neurol 1988, 273, 283-300). According to current knowledge, histamine mediates all its actions both in the CNS and in the peripheral through four different histamine receptors, the histamine receptors H1, H2, H3 and H4. The H3 receptors are located predominantly in the central nervous system (CNS). As autoreceptors, the H3 receptors constitutively inhibit the synthesis and secretion of histamine in histaminergic neurons (Arrang et al., Nature 1983, 302, 832-837, Arrang et al., Neuroscience 1987, 23, 149-157). . As heteroreceptors, the H3 receptors also modulate the release of other neurotransmitters such as acetylcholine, dopamine, serotonin and norepinephrine, among others, both in the central nervous system and in peripheral organs, such as the lungs, the cardiovascular system and the gastrointestinal tract ( Clapham and Kilpatrik, Br. J. Pharmacol., 1982, 107, 919-923; Blandina et al., In "The Histamine H3 Receptor" (Leurs RL and Timmermann H. eds., 1998, pp. 27-40, Elsevier, Amsterdam, The H3 receptors are constitutively active, indicating that even without exogenous histamine, the receptor is activated tonic.In the case of an inhibitory receptor such as the H3 receptor, this inherent activity causes tonic inhibition of neurotransmitter release. Therefore, it will be important that an H3R antagonist also possess a reverse agonist activity, to block the effects of exogenous histamine and to change the receptor from its constitutively active (inhibitory) state to a neutral state. The wide distribution of H3 receptors in the CNS of mammals indicates the physiological role of this receptor. Therefore, its therapeutic potential has been proposed in several indications as a new target for the development of drugs. Administration of H3R ligands - as antagonists, inverse agonists, agonists or partial agonists - can influence histamine levels or the secretion of neurotransmitters in the brain and periphery, and thus may be useful in the treatment of various disorders. Such 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, and attacks or seizures, sleep disorders, narcolepsy, pain, gastrointestinal disorders, vestibular dysfunction such as 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 antagonists, and in addition, selective inverse agonists that act directly on the H3 receptor. Such antagonists / inverse agonists are useful as therapeutically active substances, in particular in the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors. In the present description the term "alkyl", alone or in combination with other groups, refers to a chain of an aliphatic, saturated, monovalent, single or branched hydrocarbon radical, of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably from one to ten carbon atoms. The term "lower alkyl" or "C alquilo-C8 alkyl", alone or in combination, means a straight or branched chain alkyl group of 1 to 8 carbon atoms, preferably a straight or branched chain alkyl group of 1 to 6. carbon atoms and particularly preferably a straight or branched chain alkyl group of 1 to 4 carbon atoms. Examples of straight and branched chain C?-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric pentyls, hexyl. isomers, isomeric heptyls and isomeric octyls, preferably methyl and ethyl, and most preferred methyl. The term "cycloalkyl" or "C3-C7 cycloalkyl" denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Especially preferred is cyclopentyl. The term "cycloalkyl-lower alkyl" or "C-C7-cycloalkyl-C-C8-alkyl" refers to lower alkyl groups, as defined above, in which at least one of the hydrogen atoms of the lower alkyl group is substituted by a cycloalkyl group. A preferred lower cycloalkylalkyl group is cyclopropylmethyl. The term "alkoxy" refers to the group R'-O-, wherein R 'is a lower alkyl, and the term "lower alkyl" has the meaning given previously. 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, and most preferred methoxy. The term "lower alkoxyalkyl" or "C?-C8 alkoxy-C C-C8 alkyl" refers to lower alkyl groups, as defined above, wherein at least one of the hydrogen atoms of the lower alkyl groups is substituted by an alkoxy group, preferably methoxy or ethoxy. Between the Preferred lower alkoxyalkyl groups are 2-methoxyethyl or 3-methoxypropyl. The term "cycloalkylalkoxy lower" or "cycloalkyl C? -C7-alkoxy? C? -C8" refers to lower alkoxy groups, as defined above, in which at least one of the hydrogen atoms of the lower alkoxy groups it is replaced by a cycloalkyl group. A preferred lower cycloalkylalkoxy group is cyclopropylmethoxy. The term "lower cyanoalkyl" or "C?-C8 cyanoalkyl" refers to lower alkyl groups, as defined above, wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a cyano group. Preferred cyanoalkyl lower groups include cyanomethyl or cyanoethyl. The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred. The term "lower halogenoalkyl" or "haloalkyl Ci-Cs" refers to lower alkyl groups, as defined above, wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a halogen atom, preferably fluorine or chlorine, more preferably fluorine. Among the preferred halogenated lower alkyl groups are trifluoromethyl, difluoromethyl, trifluoroethyl, fluoromethyl and chloromethyl, with trifluoromethyl being especially preferred.

The term "lower halogenoalkoxy" or "haloalkoxy Ci-Cß" refers to lower alkoxy groups, as defined above, wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by a halogen atom, preferably fluorine or chlorine, more preferably fluorine. Among the preferred halogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy, fluoromethoxy and chloromethoxy, with trifluoromethoxy being especially preferred. The term "lower hydroxyalkyl" or "C? -C8 hydroxyalkyl" refers to lower alkyl groups, as defined above, in which at least one of the hydrogen atoms of the lower alkyl group is replaced by a hydroxy group. Examples of lower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl. The term "alkylsulfonyl" or "lower alkylsulfañilo" refers to the group R'-S (0) 2-, in which R 'is a lower alkyl and the term "lower alkyl" has the previously given meaning. Examples of alkylsulfonyl groups are, for example, methylsulfonyl or ethylsulfonyl. The term "lower alkylsulfonylalkyl" or "C 8 alkylsulfonyl-8-C 8 alkyl" refers to lower alkyl groups, as defined above, wherein at least one of the hydrogen atoms of the lower alkyl groups is - substituted by an alkylsulfonyl group, preferably methylsulfonyl. An example for a preferred lower alkylsulfonylalkyl group is 2-methylsulfonylethyl. The term "halogenoalkylsulfonyl" or "lower halogenoalkylsulfanyl" refers to the group R '-S (0) 2-, wherein R' is a lower halogenalkyl and the term "lower halogenalkyl" has the previously given meaning. An example of a halogenoalkylsulfonyl group is trifluoromethylsulfonyl. The term "lower alkanoyl" refers to the group -CO-R ', wherein R' is a lower alkyl and the term "lower alkyl" has the meaning given previously. A -CO-R 'group is preferred, where R' is methyl, which means an acetyl group. The term "benzoyl" refers to the group -CO-phenyl, wherein the phenyl ring may be optionally substituted by one, two or three groups independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, lower halogenoalkyl, halogenoalkoxy inferior and cyano. The term "carbamoyl" refers to the group -CO-NH2. The term "aryl" refers to a monovalent aromatic carbocyclic radical consisting of a single ring, or one or more fused rings, in which at least one ring It is aromatic in nature. Preferred "aryl" groups are the phenyl group or the naphthyl group, and more preferably "aryl" refers to the phenyl group. The term "heteroaryl" refers to a 5- or 6-membered aromatic ring comprising one, two or three atoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups are furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl and pyrrolyl. Especially preferred are pyridyl, thiazolyl and oxazolyl. The term "heterocyclyl" refers to a saturated or partially unsaturated ring of 5 or 6 members which may comprise one, two or three atoms selected from nitrogen, oxygen and / or sulfur. Examples of heterocyclyl rings include piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, and thiomorpholinyl. A preferred heterocyclyl group is piperidinyl or tetrahydropyranyl. The term "forms a 4, 5, 6 or 7 membered heterocyclic ring optionally containing another heteroatom selected from nitrogen, oxygen or sulfur" refers to to a N-heterocyclic ring, which may optionally contain another nitrogen atom, oxygen or sulfur, such as azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or azepanyl. A "4-, 5-, 6- or 7-membered heterocyclic ring containing a sulfinyl group or a sulfonyl group" denotes an N-heterocyclic ring containing a -S (0) - or a -S02- group, for example 1 -oxothiomorpholinyl or 1,1-dioxothiomorpholinyl. The heterocyclic ring may be unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, haloalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl. The heterocyclic ring can also be fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. Examples of such fused heterocyclic rings are 3,4-dihydro-lH-isoquinoline or 1,3-dihydroisoindole. The term "oxo" indicates that a C atom of the heterocyclic ring may be substituted by = 0, thus indicating that the heterocyclic ring may contain one or more carbonyl groups (-C0-).

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological etiveness and properties of the free bases or free acids, which are neither biologically nor otherwise undesirable. The salts are formed with 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, oxylic 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. In addition, these salts can be prepared in the form of addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amine salts, substituted amines including naturally 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 compound of formula I may also be present in the form of z-tterions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are the hydrochloride salts. The compounds of formula I can also be solvated, for example, hydrated. The solvation can be carried out during the course of the manufacturing process or can take place, for example, as a consequence of the hygroscopic properties of an initially anhydrous compound of formula I (hydration). The term "pharmaceutically acceptable salts" also includes physiologically acceptable solvates. "Isomers" are compounds that have identical molecular formula but that di in the nature or sequence of union of their atoms or in the arrangement of their atoms in space. The isomers that di in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of the other are termed "diastereomers," and stereoisomers that are non-superimposable mirror images are termed "enantiomers," or sometimes optical isomers. A carbon atom attached to four non-identical substituents is termed a "chiral center". In detail, the present invention is related to compounds of the general formula where s is 1 or 2; R1 is selected from the group consisting of lower alkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, alkylsulfonylalkyl, and tetrahydropyranyl; Rla is hydrogen or lower alkyl; R is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl, and lower cyanoalkyl; R is selected from the group consisting of - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or is substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, - (CH2) n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two independently selected groups between lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, indanyl, 1-oxo-indanyl, -CO- (C3-C8) -alkyl, -CO- (CH2) p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, haloalkoxy lower and hydroxyalkyl lower, -CO- (CH2) q-heteroaryl, wherein q is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or is substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and -CO-NR4R5; or R2 and R3 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring which is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three independently selected groups from lower alkyl, lower alkoxy and halogen; R 4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, aryl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl , Y lower arylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower haloalkoxy, and lower hydroxyalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4, 5, 6 or 7 members optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, and the heterocyclic ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenoalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; and the pharmaceutically acceptable salts thereof. Preferred are the compounds of formula I, according to with the present invention, wherein R3 is selected from the group consisting of ~ (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, ~ (CH2) n-heteroaryl , wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl , carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, indanyl and 1-oxo-indanyl. More preferred are the compounds of formula I according to the invention, wherein R3 is - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, alkylsulfonyl lower, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl. Also preferred are compounds of formula I wherein R3 is - (CH2) n -heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or is substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl. More preferred are the compounds of formula I, wherein R3 is - (CH2) n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is pyridyl or isoxazolyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy, and lower hydroxyalkyl. In addition, the compounds of formula I of the present invention with the formula are preferable wherein R1 is lower alkyl or cycloalkyl; R2 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl, and lower cyanoalkyl; R3 is selected from the group consisting of _ (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or is substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, - (CH2) n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is not is substituted or is substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, indanyl, -CO- (C3-C8 alkyl) -, -CO- (CH2) p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three independently selected groups from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, -CO- (CH2) q-heteroaryl, wherein q is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or is substituted by one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and -CO-NRR5; or R2 and R3 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring which is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three independently selected groups from lower alkyl, lower alkoxy and halogen; R4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, aryl unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl , and lower arylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower haloalkoxy, and lower hydroxyalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, and the heterocyclic ring is unsubstituted or is substituted by one, two or three groups independently selected from alkyl lower, halogen, halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; and the pharmaceutically acceptable salts thereof. Preferred compounds of formula I of the present invention are compounds of formula IA, wherein R3 is selected from the group consisting of - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, - (CH2) n- heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and indanyl.

Especially preferred are those compounds of formula IA, wherein R3 is - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is phenyl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, and lower hydroxyalkyl. Also preferred are compounds of formula IA, wherein R 3 is - (CH 2) n -heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or is substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, and lower hydroxyalkyl, with those compounds in which the heteroaryl ring is pyridyl unsubstituted or substituted with one or two groups being especially preferred. independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy, and lower hydroxyalkyl. Another group of preferred compounds of the present invention is that of the compounds of formula I, wherein R3 is selected from the group consisting of -CO- (C3-C8) -alkyl, -CO- (CH2) p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and -CO- (CH2) q-heteroaryl, wherein q is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower haloalkoxy, and lower hydroxyalkyl. In case R3 is -CO- (C3-C8 alkyl) -, those compounds of formula I in which (C3-C8 alkyl) means isopropyl are more preferable. The most preferred compounds are those compounds of formula I of the present invention in which R3 is -CO- (CH2) p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is unsubstituted phenyl or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, haloalkoxy lower and lower hydroxyalkyl. Preferably, the phenyl ring is substituted with one, two or three groups independently selected from halogen or lower alkoxy. Also preferred are compounds of formula I of the present invention, wherein R3 is -CO- (CH2) q-heteroaryl, wherein q is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or is substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl. Another group of preferred compounds of formula I according to the present invention are those compounds of formula I wherein R 3 is -CO-NR 4 R 5 and wherein R 4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenoalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, aryl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl , Y lower arylalkyl in which the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower haloalkoxy and lower hydroxyalkyl; or wherein R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4, 5, 6 or 7 members optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, the heterocyclic ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.

More preferred are the compounds of formula I wherein -CO-NR4R5 and wherein - -.

R 4 is hydrogen or lower alkyl; and R5 is selected from the group consisting of lower alkyl, phenyl unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and hydroxyalkyl lower, and phenylalkyl lower wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower haloalkoxy, and lower hydroxyalkyl. Especially preferred with this group are those compounds of formula I, wherein R5 is phenyl unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl , lower halogenoalkoxy and lower hydroxyalkyl, or wherein R5 is lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl. In addition, the compounds of formula I according to the invention are preferred, wherein R3 is -CO-NRR5 and wherein R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4.5. 6 or 7 members optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, and the heterocyclic ring is unsubstituted or is substituted by one, two or three groups independently selected from alkyl lower, halogen, halogenoalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. More preferred are the compounds of formula I according to the invention, wherein R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, pyrrolidine, azepam, piperazine, azetidine and thiomorpholine, and the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenoalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. Especially preferred are the compounds of formula I of the invention, wherein R4 and R5 together with the nitrogen atom to which they are attached form a group selected from 2-methylpyrrolidine, piperidine, 4-methoxypiperidine, 4, 4-difluoropiperidine, morpholine, 4-phenylpiperazine, 1,3-dihydro-isoindol and 3,4-dihydro-2H-quinoline. The most preferred compounds of formula I according to the invention are those in which R1 is a lower alkyl, with those compounds in which R1 is isopropyl being especially preferred. Also preferred are compounds of formula I, wherein R 1 is cycloalkyl, with those compounds wherein R 1 is cyclopentyl being especially preferred. More preferred are compounds of formula I according to the invention, wherein R 2 is hydrogen or lower alkyl. In addition, compounds of formula are also preferred I according to the present invention, wherein R2 and R3 together with the nitrogen atom to which they are attached form a - 5- or 6-membered heterocyclic ring which is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. Especially preferred are those compounds of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a 1,3-dihydro-isoindole group or a 3,4-dihydro-lH-isoquinoline group. The preferred compounds of formula I of the present invention are the following: (-isopropyl-piperazin-1-yl) - (4-p-tolylamino-cyclohexyl) -methanone, [4- (4-fluoro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (1,3-dihydro-isoindol-2-yl) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, ( -isopropy1-piperazin-1-yl) - [4- (6-methoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, [4- (3, -dihydro-lH-isoquinolin-2-yl) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (indane-1-ylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, (4-isopropyl-piperazine- l-il) - [4- (1-pheny1-propylamino) -cyclohexyl] -methanone, (4-isopropyl-piperazin-1-yl) -. { 4- [2- (3-methoxy-phenyl) -ethylamino] -cyclohexyl} -metanone, [4- (-difluoromethoxy-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, N- [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] ] -isobutyramide, N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-methoxy-benzamide, 2, -difluoro-N- [trans-4- (4-isopropyl-piperazine -l-carbonyl) -cyclohexyl] -benzamide, 2,4-dichloro-N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzamide, 1-benzyl-1-isopropyl-3 - [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea, 1,1-diethyl-3- [cis-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea, [4-phenyl-piperazine-1-carboxylic acid [cis-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide, 1- (4-chloro-phenyl) -3- [cis] -4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -1-methyl-urea, l-benzyl-l-ethyl-3- [cis-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -urea, [3- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 3,4-dihydro-2H-quinol ina-l-carboxylic, 1- (3-fluoro-phenyl) -3- [cis-4- (4-isopropyl-piperazine-l- carbonyl) -cyclohexyl] -1-methyl-urea, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 2-methyl-pyrrolidine-l-carboxylic acid, l-benzyl-l -isopropyl-3- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea, 1, l-diethyl-3- [trans-4- (4-isopropyl-piperazine-l-carbonyl ) -cyclohexyl] -urea, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of piperidine-1-carboxylic acid, [trans-4- (4-isopropyl-piperazine-l- carbonyl) -cyclohexyl] -amide of morpholine-4-carboxylic acid, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 4-methoxy-piperidine-l-carboxylic acid, [trans] -4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 4-phenyl-piperazine-l-carboxylic acid, 1- (4-chloro-phenyl) -3- [trans -4- (4-isopropyl-piperazine-l-oarbonyl) -cyclohexyl] -1-methyl-urea, l-benzyl-l-ethyl-3- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea, 3- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -1-phenyl-1-propyl- urea, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 3,4-dihydro-2H-quinoline-1 -amide - carboxylic, 1- (3-fluoro-phenyl) -3- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -1-methyl-urea, [trans-4- (4-isopropyl 4,4-difluoro-piperidine-1-carboxylic acid, [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -amide of the acid 1-cyclohexyl] -amide of 4, 4-difluoro-piperidine-1-carboxylic acid , 3-dihydro-isoindol-2-carboxylic acid, (4-cyclopentyl-piperazin-1-yl) - [4- (2-fluoro-phenylamino) -cyclohexyl] -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (3-Fluoro-phenylamino) -cyclohexyl] -metanone(4-cyclopentyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone (4-cyclopentyl-piperazin-1-yl) - [4- (2,4-difluoro phenylamino) -cyclohexyl] -methanone, 3- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexylamino] -benzonitrile, (4-cyclopentyl-piperazin-1-yl) - [4- (2-methoxy phenylamino) -cyclohexyl] -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (4-methoxy-phenylamino) -cyclohexyl] -methanone, 1-. { 4- [4- (4-Cyclopenti-1-piperazine-1-carbonyl) -cyclohexylamino] -phenyl} -etanone, [4- (4-benzoyl-phenylamino) -cyclohexyl] - (4-cyclopentyl-piperazin-1-yl) -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (pyrazin-2-ylamino) -cyclohexyl] -methanone, (4-cyclopenti1-piperazin-1-yl) -. { - [(3-fluoro-phenyl) -methyl-amino] -cyclohexyl} -metanone, (4-cyclopenti1-piperazin-1-yl) -. { 4- [(4-fluoro-phenyl) -methyl-amino] -cyclohexyl} -methanone, [4- (2-fluoro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (2,4-difluoro-phenylamino) -cyclohexyl] - (4- isopropyl-piperazin-1-yl) -methanone, 3- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -benzonitrile, (4-isopropyl-piperazin-1-yl) - [4- (4 -methoxy-phenylamino) -cyclohexyl] -methanone, l-. { 4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -phenyl} -etanone, [4- (4-benzoyl-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, 2- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexylamino] -benzonitrile, cis- [4- (4-difluoromethoxy-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (4-difluoromethoxy-phenylamino) -cyclohexyl] - (4- isopropyl-piperazin-1-yl) -methanone, trans-l-. { 4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -phenyl} -etanone, cis-l-. { 4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -phenyl} -ethanone, trans- (4-isopropyl-piperazin-1-yl) - [4- (6-methoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, cis- (4-isopropyl-piperazin-1-yl) - [4- (6-methoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, trans- [4- (4-fluoro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone , cis- [4- (4-fluoro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, trans- (4-cyclobutyl-piperazin-1-yl) - [4- (6 -methoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, cis- (4-cyclobutyl-piperazin-1-yl) - [4- (6-methoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, trans - [4- (4-Fluoro-phenylamino) -cyclohexyl] - (4-isopropyl-3-methyl-1-piperazin-1-yl) -methanone, trans- (4-tert-butyl-piperazin-1-yl) - [ 4- (4-fluoro-phenylamino) -cyclohexyl] -methanone, trans- (4-sec-butyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone, trans- ( 4-cyclohexyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone, trans- [4- (4-Fluoro-phenylamino) -cyclohexyl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, trans- [4- (4-fluoro-phenylamino) -cyclohexyl] ] - (4-propyl-piperazin-1-yl) -methanone, trans- [4- (4-fluoro-phenylamino) -cyclohexyl] - (4-methyl- [1,4] diazepan-1-yl) -methanone , trans- (4-cyclopropylmethyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone, trans -3. { 4- [4- (4-fluoro-phenylamino) -cyclohexanecarbonyl] -piperazin-1-yl} -propionitrile, 3-chloro-4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -benzonitrile, trans- [4- (3-fluoro-4-trifluoromethyl-phenylamino) -cyclohexyl] - ( 4-isopropyl-piperazin-1-yl) -methanone, cis- [4- (3-fluoro-4-trifluoromethyl-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, trans-2 -chloro-4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -benzonitrile, cis-2-chloro-4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -benzonitrile, trans- (4-isopropyl-piperazin-1-yl) - [4- (4-trifluoromethanesulfonyl-phenylamino) -cyclohexyl] -methanone, cis- (4-isopropyl-piperazin-1-yl) - [4- (4-trifluoromethanesulfonyl-phenylamino) -cyclohexyl] -methanone, trans-5- [4- (4-isopropyl-piperazine-1-carbonyl) - cyclohexylamino] -indan-1-one, cis-5- [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexylamino] -indan-1-one, trans-4- [4- (4-isopropyl-piperazine -l-carbonyl) -cyclohexylamino] -benzamide, cis-4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -benzamide, trans- (4-cyclobutyl-piperazin-1-yl) - [ 4- (4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, cis- (4-cyclobutyl-piperazin-1-yl) - [4- (4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, [4- (3 -chloro-4-methyl-phenylamino) -cyclohexyl] - (4-cyclobutyl-piperazin-1-yl) -methanone, trans- (4-cyclopentyl-piperazin-1-yl) - [4- (3-fluoro-4 -trifluoromethyl-phenylamino) -cyclohexyl] -metanone, cis- (4-cyclopentyl-piperazin-1-yl) - [4- (3-fluoro-4-trifluoromethyl-phenylamino) -cyclohexyl] -methanone, trans- (4-cyclopentyl-piperazin-1-yl) - [ 4- (4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, cis- (4-cyclopentyl-piperazin-1-yl) - [4- (4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, [4- (3 -chloro-4-methyl-phenylamino) -cyclohexyl] - (4-cyclopenty1-piperazin-1-yl) -methanone, [4- (3-chloro-4-methyl-phenylamino) -cyclohexyl] - (4-cyclopropyl- piperazin-1-yl) -metanone, - - trans- [4- (3-fluoro-4-trifluoromethyl-phenylamino) -cyclohexyl] - (4-isopropyl-3-methyl-piperazin-1-yl) -methanone, cis- [4- (3-fluoro- 4-trifluoromethyl-phenylamino) -cyclohexyl] - (4-isopropyl-3-methyl-piperazin-1-yl) -methanone, trans- (4-isopropyl-3-methyl-piperazin-1-yl) - [4- ( 4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, cis- (4-isopropyl-3-methylpiperazin-l-yl) - [4- (4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, trans- (4 -isopropyl-piperazin-1-yl) - [4- (6-trifluoromethyl-pyridin-3-ylamino) -cyclohexyl] -methanone trans- (4-isopropyl-piperazin-1-yl) - [4- (4-trifluoromethyl) phenylamino) -cyclohexyl] -methanone, trans- (4-isopropyl-piperazin-l-yl) - [4- (4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, trans- [4- (4-chloro-phenylamino ) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, trans- [4- (3-chloro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, trans - [4- (3-Chloro-4-methyl-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -me tanone, cis- (4-isopropyl-piperazin-1-yl) - [4- (6-trifluoromethyl-1-pyridin-3-ylamino) -cyclohexyl] -methanone, cis- (4-isopropyl-piperazin-1-yl) - [4- (4-trifluoromethyl-phenylamino) -cyclohexyl] -methanone, cis- (4-isopropyl-piperazin-1-yl) - [4- (4-trifluoromethoxy- phenylamino) -cyclohexyl] -methanone, cis- [4- (4-chloro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, cis- [4- (3-chloro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, cis- [4- (3-chloro-4-methyl-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) - methanone, trans- [4- (5-fluoro-2,3-dihydro-indol-l-yl) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, cis- [4- (5- fluoro-2, 3-dihydro-indol-l-yl) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (3,5-dimethyl-isoxazol-4-ylamino) -cyclohexyl] ] - (4-isopropyl-piperazin-1-yl) -methanone, trans- (4-cyclobutyl-piperazin-1-yl) - [4- (3-fluoro-4-trifluoromethyl-phenylamino) -cyclohexyl] -methanone, trans- (4-cyclobutyl-piperazin-1-yl) - [4- (6-trifluoromethyl-pyridin-3-ylamino) -cyclohexyl] -methanone, trans- (4-cyclobutyl-piperazin-1-yl) - [4 - (4-trifluoromethyl-phenylamino) -cyclohexyl] -methanone, trans- [4- (4-chloro-phenylamino) -cyclohexyl] - (4-cyclobutyl-piperazin-1-yl) -methanone, tr ans- [4- (3-chloro-phenylamino) -cyclohexyl] - (4-cyclobutyl-piperazin-1-yl) -methanone, trans- [4- (3-chloro-4-methyl-phenylamino) -cyclohexyl] - (4-cyclobutyl-piperazin-1-yl) -methanone, cis- (4-cyclobutyl-piperazin-1-yl) - [4- (3-fluoro-4-trifluoromethyl-phenylamino) -cyclohexyl] -methanone, cis- (4-cyclobutyl-piperazin-1-yl) - [4 - (6-trifluoromethyl-pyridin-3-ylamino) -cyclohexyl] -methanone, cis- (4-cyclobutyl-piperazin-l-yl) - [4- (4-trifluoromethyl-phenylamino) -cyclohexyl] -methanone, cis- [4- (4-chloro-phenylamino) -cyclohexyl] - (4-cyclobutyl-piperazin-1-yl) -methanone, cis- [4- (3-chloro-phenylamino) -cyclohexyl] - (4-cyclobutyl-piperazine -1-yl) -metanone, cis- [4- (3-chloro-4-methyl-phenylamino) -cyclohexyl] - (4-cyclobutyl-piperazin-1-yl) -methanone, trans- (4-cyclobutyl-piperazine) -l-il) - [4- (5-fluoro-2, 3-dihydro-indol-1-yl) -cyclohexyl] -methanone, cis- (4-cyclobutyl-piperazin-1-yl) - [4- ( 5-fluoro-2, 3-dihydro-indol-1-yl) -cyclohexyl] -methanone, (4-cyclobutyl-piperazin-1-yl) - [4- (3, 5-dimethyl-isoxazol-4-ylamino) -cyclohexyl] -metanone, trans- [4- (4-chloro-phenylamino) -cyclohexyl] - (4-cyclopentyl-piperazin-1-yl) -methanone, trans- [4- (3-chloro-phenylamino) -cycline ohexyl] - (4-cyclopenty1-piperazin-1-yl) -methanone, trans- [4- (3-chloro-4-methyl-phenylamino) -cyclohexyl] - (4-cyclopenty1-piperazin-1-yl) -methanone , cis- (4-cyclopentyl-piperazin-1-yl) - [4- (4-trifluoromethyl- phenylamino) -cyclohexyl] -methanone, cis- [4- (3-chloro-phenylamino) -cyclohexyl] - (4-cyclopentyl-piperazin-1-yl) -methanone, trans- (4-cyclopentyl-piperazin-l-yl ) - [4- (5-fluoro-2, 3-dihydro-indol-1-yl) -cyclohexyl] -methanone, cis- (4-cyclopentyl-piperazin-1-yl) - [4- (5-fluoro- 2,3-dihydro-indol-1-yl) -cyclohexyl] -methanone, trans- [4- (4-chloro-phenylamino) -cyclohexyl] - (4-isopropyl-3-methy1-pipe azin-1-yl) -metanone, trans- [4- (3-Chloro-phenylamino) -cyclohexyl] - (4-isopropyl-3-methyl-1-piperazin-1-yl) -methanone, cis- [4- (4-chloro-phenylamino) -cyclohexyl] - (4-isopropyl-3-methyl-piperazin-1-yl) -methanone, cis- [4- (3-chloro-phenylamino) -cyclohexyl] - (4-isopropyl-3-methyl-piperazin-1-yl) -methanone, cis- [4- (3-chloro-4-methyl-phenylamino) -cyclohexyl] - (4-isopropy1-3-methyl-1-piperazin-1-yl) -methanone, [4- (3,5-dimethyl) -isoxazol-4-ylamino) -cyclohexyl] - (4-isopropy1-3-methy1-piperazin-1-yl) -methanone, cis- [4- (4-chloro-phenylamino) -cyclohexyl] - (4-cyclopropylmethyl- piperazin-1-yl) -methanone, cis- [4- (3-chloro-phenylamino) -cyclohexyl] - (4-cyclopropylmethyl-piperazin-1-yl) -methanone, trans- (4-sec-butyl-piperazine- 1-yl) - [4- (3-fluoro-4-trifluoromethyl-phenylamino) -cyclohexyl] -methanone, trans- (4-sec-butyl-piperazin-1-yl) - [4- (4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, cis- (4-sec-butyl-piperazin-1-yl) - [4 - (3-fluoro-4-trifluoromethyl-phenylamino) -cyclohexyl] -methanone, cis- (4-sec-butyl-piperazin-1-yl) - [4- (4-trifluoromethoxy-phenylamino) -cyclohexyl] -methanone, cis- (4-sec-butyl-piperazin-1-yl) - [4- (3-chloro-phenylamino) -cyclohexyl] -methanone, trans- (4-cycloheptyl-piperazin-1-yl) - [4- ( 4-fluoro-phenylamino) -cyclohexyl] -methanone, trans- [4- (4-fluoro-phenylamino) -cyclohexyl] - [4- (tetrahydro-pyran-4-yl) -piperazin-1-yl] -methanone, trans- [4- (1-ethyl-propyl) -piperazin-1-yl] - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone, (4-cyclobutyl-piperazin-1-yl) - [4 - (6-isopropoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, (4-cyclobutyl-piperazin-1-yl) - [4- (6-cyclopropylmethoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, (4-cyclobutyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone, (4-cyclobutyl-piperazin-1-yl) - [4- (4-fl uoro-phenylamino) -cyclohexyl] -methanone, [4- (2, -dichloro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (6-chloro-pyridin-3 -ylamino) -cyclohexyl] - (4-isopropyl- piperazin-1-yl) -methanone, 6- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -nicotinonitrile, (4-isopropyl-piperazin-1-yl) - [4- (5-methanesulfonyl -pyridin-2-ylamino) -cyclohexyl] -methanone, and the pharmaceutically acceptable salts thereof.

Especially preferred are the following compounds: [4- (1,3-dihydro-isoindol-2-yl) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, (4-isopropyl-piperazine-1- il) - [4- (6-methoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, [4- (indane-1-ylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone , (4-isopropyl-piperazin-1-yl) - [4- (1-pheny1-propylamino) -cyclohexyl] -methanone, (4-isopropyl-piperazin-1-yl) -. { 4- [2- (3-methoxy-phenyl) -ethylamino] -cyclohexyl} -methanone, [4- (4-difluoromethoxy-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (4-fluoro phenylamino) -cyclohexyl] -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (2, 4-difluoro-phenylamino) -cyclohexyl] -methanone, 3- [4- (4-cyclopentyl-piperazine -l-carbonyl) -cyclohexylamino] -benzonitrile, - - [4- (4-benzoyl-phenylamino) -cyclohexyl] - (4-cyclopentyl-piperazin-1-yl) -methanone, (4-isopropyl-piperazin-1-yl) - [4- (4-methoxy-f-enylamino ) -cyclohexyl] -methanone, [4- (4-benzoyl-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, and the pharmaceutically acceptable salts thereof.

More especially preferred are the following compounds of formula I: trans- (4-cyclobutyl-piperazin-1-yl) - [4- (4-f luoro-phenylamino) -cyclohexyl] -methanone, trans- [4- (6- chloro-pyridin-3-ylamino) -cyclohexyl] - (4-i-sopro-pyl-pipera zin-1-yl) -methanone, trans-6- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] - nicotinonitrile, trans- (4-isopropyl-piperazin-1-yl) - [4- (5-methanesulfonyl-pyridin-2-ylamino) -cyclohexyl] -methanone, and the pharmaceutically acceptable salts thereof. In addition, the pharmaceutically acceptable salts of the compounds of formula I and the pharmaceutically acceptable esters of the compounds of formula I individually constitute preferred embodiments of the present invention.

The compounds of formula I can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulfate, pyruvate, citrate, lactate, mandelate, tartarate and anosul fonato. The hydrochloride salts are preferred. Solvates and hydrates of compounds of formula I and their salts also form part of the present invention. The compounds of formula I may have 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, diastereomeric racemates or mixtures of diastereomeric racemates. The optically active forms can be obtained, for example, by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with an adsorbent or chiral eluent). The invention encompasses all these forms. It can be appreciated that the compounds of the general formula I of this invention can be modified in the functional groups to provide derivatives that are capable of being reconverted into the parent compound in vivo. The physiologically acceptable and metabolically labile derivatives that are capable of producing the parent compounds of the formula General I in vivo are also within the scope of this invention. Another aspect of the present invention is the process of making the compounds of formula I as defined above, which process comprises a) coupling a compound of formula II wherein s, Rla and R1 are as defined above, with an amine of formula III H-NR2R3 III in which R2 and R3 are as defined above, with the proviso that R3 does not contain a carbonyl group, in the presence of a coupling reagent under basic conditions to obtain a compound of formula IB wherein s, Rla, R1 and R2 are as defined above and R3 is a group as defined herein, different from those groups containing a carbonyl group, and if desired, the conversion of the compound obtained into a pharmaceutically acceptable acid addition salt, or - - b) the reaction of a compound of formula IV wherein s, Rla and R1 are as defined above, with an acid chloride of formula V O Cl wherein R6 is selected from the group consisting of (C3-C8 alkyl), - (CH2) p-aryl and - (CH2) q-heteroaryl, in the presence of a base to obtain a compound of formula I-C wherein R is hydrogen and R3 is selected from the group consisting of -CO- (C3-C8 alkyl) -, -CO- (CH2) p-aryl and -CO- (CH2) q-heteroaryl, and if desired , the conversion of the compound obtained in a pharmaceutically acceptable acid addition salt, or c) the coupling of a compound of formula IV wherein s, Rla and R1 are as defined above, after activation with phenyl chloroformate with an amine of formula VI H-NRR5 III wherein R4 and R5 are as defined above, to obtain a compound of formula ID wherein s, Rla, R1, R2, R4 and R5 are as defined above, and if desired, the conversion of the compound obtained into a pharmaceutically acceptable acid addition salt. The preparation of compounds of formula I of the present invention can be carried out in sequential or convergent synthetic routes. The syntheses of the invention are shown in the following scheme. The skills necessary to carry out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the procedures possess the meaning given above, unless otherwise indicated. In more detail, the compounds of formula I can be made by the methods given below, by the methods given in the examples or by analogous methods. The appropriate reaction conditions for the individual reaction steps are known to one skilled in the art. The starting materials are commercially available or can be prepared by methods analogous to the methods given below, by the methods described in the references cited in the description or in the examples, or by methods known in the art. The compounds of formula IB, wherein R3 is selected from - (CH2) m-aryl, - (CH2) n-het eroaryl and indanyl, or wherein R2 and R3 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring that is fused with a phenyl ring, and the phenyl ring is unsubstituted or is substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen, can be prepared following the procedure as described in the reaction scheme 1.

Reaction scheme 1 Ethyl 4-oxo-cyclohexanecarboxylate VII is commercially available, the ketone function can be modified according to the methods described in the literature and the methods are known to those skilled in the art (for the reaction conditions described in the literature that affect to such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley &Sons, New York, NY, 1999). However, it has been found convenient to convert the ketone function to VII through reductive amination with amines III (commercially available or obtainable by the methods described in the references or by the methods known in the art; as appropriate) under reducing conditions. The reaction can be carried out in the presence or absence of a solvent and an acid. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents involved and that it can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: THF, methanol and the like. There is no particular restriction on the nature of the acid used in this step, and any acid commonly used in this type of reaction can likewise be employed here. Examples of such acids include acetic acid and the like. There is no particular restriction on the nature of the reducing agent used in this step, and any reducing agent commonly used in this type of reaction can also be used here. Examples of such reducing agents include sodium triacetoxyborohydride, sodium borohydride and the like. The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction with refluxing heat from room temperature. The time required for the reaction can vary widely, depending on many factors, especially the reaction temperature and the nature of the reactants. However, a period of 0.5 h up to several days is usually necessary to provide the intermediately constructed esters that can be saponified by different methods known in the literature. However, it is convenient to excise the ester function under basic conditions. The reaction can be carried out in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents involved and that it can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: THF, methanol, water and the like. There is no particular restriction on the nature of the base used in this step, and any acid commonly used in this type of reaction can equally be employed here. Examples of such bases include lithium hydroxide, sodium hydroxide and the like. The liberated acid function can be modified according to the methods described in the literature and the methods are known to those skilled in the art. However, it is convenient to transform the acid function via a coupled amide with substituted or unsubstituted piperazine (s) VIII (commercially available or obtainable by the methods described in the references or by methods known in the art; - as appropriate) using a coupling reagent. The reaction can be carried out in the presence or absence of a solvent and a base. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents involved and that it can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: DMF, THF, dioxane and the like. There is no particular restriction on the nature of the base used in this step, and any base commonly used in this type of reaction can equally be employed here. Examples of such bases include NEt3, diisopropylethylamide (DIPEA) and the like. There is no particular restriction on the nature of the coupling reagent used in this step, and any coupling reagent commonly used in this type of reaction can also be employed here. Examples of such reducing agents include 1- [bis (dimethylamino) methylene] -lH-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. The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heat at reflux from room temperature. The time required for the reaction can vary widely, depending on many factors, especially the reaction temperature and the nature of the reactants. However, a period of between about 0.5 h and several days will normally be sufficient to provide I-B compounds. In the case where the unsubstituted piperazine VII has been coupled, further functions can be added to the resulting compounds IA in the free NH of the piperazine moiety, by reductive amination with ketones or aldehydes respectively to give the compounds I-B. The conditions described above for reductive amination apply to this reaction step in a similar manner. An alternate alternative approach to this procedure can be chosen by reversing the order of the steps, ie, by cleaving the ester function as described above in the ethyl 4-oxo-cyclohexanecarboxylate VII (commercially available), coupling the amide with suitable piperazines as it has been described above and with the subsequent reductive amination as described above providing the desired compounds of formula IB. The respective diastereoisomers are obtained by separation techniques as described in the literature. It is convenient to separate the cis or trans isomers respectively from the diastereomeric mixture at through chromatography on silica gel or reverse phase HPLC techniques. The solvents for the elution are chosen appropriately. Compounds of formula IC, wherein R3 is selected from the group consisting of -CO- (C3-C8 alkyl) -, -CO- (CH2) p-aryl and -CO- (CH2) q-heteroaryl, can be prepared following the procedure described in the reaction scheme 2. Reaction scheme 2 I-C The 4-tert-butoxycarbonylamino-cyclohexane-carboxylic acid IX (cis or trans) is commercially available and can be subsequently modified in the acid function according to the methods described in the literature and the methods known to those skilled in the art (for the reaction conditions described in the literature that affect such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999) . However, it is convenient to transform the acid function to IX through an amide coupling with substituted piperazines VIII (commercially available or obtainable by the methods described in the references or by methods known in the art, as appropriate) using a coupling reagent. The reaction can be carried out in the presence or absence of a solvent and a base. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents involved and that it can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: DMF, THF, dioxane and the like. There is no particular restriction on the nature of the base used in this step, and any base commonly used in this type of reaction can equally be employed here. Examples of such bases include NEt3, DIPEA and the like. There is no particular restriction on the nature of the coupling reagent used in this step, and any coupling reagent commonly used in this type of reaction can also be employed here. Examples of such agents Reducers include TBTU, HATU, HOBT and the like. The reaction can take place within a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction with refluxing heat from room temperature. The time required for the reaction can vary widely, depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of between about 0.5 h and several days will normally be sufficient to provide compounds X. The removal of the protective group in X can be carried out under various conditions according to the methods described in the literature and the procedures are known to the experts in the field (for the reaction conditions described in the literature that affect such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley &; Sons, New York, NY. 1999) . However, it is convenient to cleave the Boc protecting group under acidic conditions in the presence or absence of a solvent to give the intermediate amine. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents - - involved and can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: dioxane, THF, water and the like. There is no particular restriction on the nature of the acid used in this step, and any acid commonly used in this type of reaction can likewise be employed here. Examples of such acids include HCl, acetic acid and the like. The reaction can take place within a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction with refluxing heat from room temperature. The time required for the reaction can vary widely, depending on many factors, especially the reaction temperature and the nature of the reactants. However, a period of between about 0.5 h and several days will normally be sufficient to provide the intermediate amine. The coupling of the intermediate amines with acid chlorides is widely described in the literature and the methods are known to those skilled in the art (for the reaction conditions described in the literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley &Sons, New York, NY, 1999). The respective amines IV can be converted conveniently into the respective amides I-C through coupling with acidic chlorides V (commercially available or obtainable by the methods described in the references or by methods known in the art, as appropriate). It is convenient to carry out the reaction in a solvent such as DCM and in the presence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents involved and that it can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: dichloromethane (DCM), dioxane, THF and the like. There is no particular restriction on the nature of the base used in this step, and any base commonly used in this type of reaction can equally be employed here. Examples of such bases include triethylamine, diisopropylethylamine and the like. The reaction can take place within a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction with refluxing heat from room temperature. The time required for the reaction can vary widely, depending on many factors, especially the reaction temperature and the nature of the reactants. However, a period of between about 0.5 h and several days will normally be sufficient to provide the amide derivatives I-C (R2 = H). However, the resulting compound of formula I-C (R2 = H) is a compound of the present invention and may be the desired product; alternatively it may be subjected to consecutive reactions such as the alkylation of the amide under suitable conditions. There are several reaction conditions known in the literature that affect these transformations, however, it is convenient to convert amides IC (R2 = H) to IE amides (R2 = alkyl) by the reaction of IC (R2 = H) with alcohols suitable in the presence of a coupling reagent such as phosphorane (adapted from: THL 2002, 43, 2187-2190). The reaction can be carried out in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents involved and that it can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: toluene and the like. There is no particular restriction on the nature of the phosphorane used in this step with the proviso that it affects the reaction. The reaction can take place within a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction with refluxing heat from room temperature. The time required for the reaction may vary Widely, depending on many factors, especially the reaction temperature and the nature of the reactants. However, a period of between about 0.5 h and several days will normally be sufficient to provide I-E amides (R2 = alkyl). Urea derivatives of formula ID can be prepared (compounds in which R3 means -CO-NR4R5) according to the following procedure: The coupling of the amine intermediates (obtaining these intermediates as described above) with amines after activation and the introduction of the Cl fragment, is widely described in the literature and the methods are known to those skilled in the art (for the reaction conditions described in the literature that affect such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley &Sons, New York, NY, 1999). The respective amine intermediates can be conveniently transformed into the respective ureas through activation with phenylchloroformate to obtain the intermediate-built phenyl carbamate and subsequent reaction with amines (commercially available or obtainable by the methods described in the references or by methods known in the art, as appropriate). It's found - it is convenient to carry out the reaction with phenyl chloroformate in a solvent such as DCM and in the presence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents involved and that it can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: dichloromethane (DCM), dioxane, THF and the like. There is no particular restriction on the nature of the base used in this step, and any base commonly used in this type of reaction can equally be employed here. Examples of such bases include triethylamine, diisopropylethylamine and the like. An amine (commercially available or obtainable by the methods described in the references or by methods known in the art, as appropriate) is then added (in a vessel or after the respective isolation of the carbamate formed in a separate reaction). The reaction can take place within a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction with refluxing heat from room temperature. The time required for the reaction can vary widely, depending on many factors, especially the reaction temperature and the - - nature of the reagents. However, a period of between about 0.5 h and several days will normally be sufficient to provide urea derivative I-D (R2 = H). In the case that R2 is to be alkyl, the intermediate X can be alkylated in free NH under the appropriate reaction conditions known to those skilled in the art preferably with suitable alkylating reagents under basic conditions. The reaction sequence will subsequently follow the route described above. The resulting compound of formula I-F is a compound of the present invention and may be the desired product; alternatively it can be subjected to consecutive reactions such as alkylation of urea under suitable conditions. There are several reaction conditions known in the literature that affect such transformations, however, it is convenient to convert the ureas IF (R4 = H) in ureas IG (R4 = alkyl) by the reaction of IF (R4 = H) with suitable alcohols in the presence of a coupling reagent such as a phosphorane (adapted from: THL 2002, 43, 2187-2190). The reaction can be carried out in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it does not cause adverse effects in the reaction or in the reagents involved and that it can dissolve the reagents, at least in a certain amount. Examples of suitable solvents include: toluene and the like. There is no particular restriction on the nature of the phosphorane used in this step with the proviso that it affects the reaction. The reaction can take place within a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction with refluxing heat from room temperature. The time required for the reaction can vary widely, depending on many factors, especially the reaction temperature and the nature of the reactants. However, a period of between about 0.5 h and several days will normally be sufficient to provide urea I-G derivatives (R4 = alkyl). As described above, the compounds of formula I of the present invention can be used as medicaments for the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors. In this context, the expression "diseases associated with the modulation of H3 receptors" indicates diseases that can be treated and / or prevented by modulation of H3 receptors. Such diseases include, but are not limited to, obesity, metabolic syndrome (syndrome X), neurological diseases including Alzheimer's disease, dementia, memory dysfunction related to aging, mild cognitive impairment, cognitive deficit, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and disorders of sleep including narcolepsy, and other diseases including asthma, allergy, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders. In a preferable aspect, the term "diseases associated with modulation of H3 receptors" is related to obesity, metabolic syndrome (syndrome X), and other eating disorders, with obesity being especially preferable. The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and / or adjuvant. In addition, the invention relates to compounds, as defined above, for use as therapeutically active substances, particularly as therapeutically active substances for the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors.

In another embodiment, the invention relates to a method for the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors, and the method comprises administering a therapeutically active amount of a compound of formula I to a human or animal A method for the treatment and / or prevention of obesity is preferred. The invention is also related to the use of compounds of formula I as defined above for the treatment and / or prevention of diseases that are associated with the modulation of H3 receptors. In addition, the 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 that are associated with the modulation of H3 receptors. The use of compounds of formula I as defined above for the preparation of medicaments for the treatment and / or prevention of obesity is preferable. In addition, the present invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving treatment with a lipase inhibitor and particularly, wherein the lipase inhibitor is orlistat.

- - It is a more preferable object of the present invention to provide a method for the treatment or prevention of obesity and disorders related to obesity, comprising the administration of a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of other drugs for the treatment of obesity or eating disorders, so that together they provide effective relief. Other suitable drugs include, but are not limited to, anorectic agents, lipase inhibitors, selective serotonin reuptake inhibitors (SSRIs), and agents that stimulate the metabolism of body fats. The combinations or associations of the above agents may encompass separate, sequential or simultaneous administration. The term "lipase inhibitor" refers to compounds that are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases. For example, orlistat and lipstatin as described in U.S. Pat. No. 4,598,089 are potent lipase inhibitors. Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin. Other lipase inhibitors include a class of compound commonly referred to as panclicins. Panclicins are analogous to orlistat (Mutoh et al, 1994). The term - - "lipase inhibitor" also refers, for example, to the polymer-bound lipase inhibitors described in the international patent application WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized by being substituted with one or more groups that inhibit lipases. The term "lipase inhibitor" also comprises the pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" preferably refers to tetrahydrolipstatin. The administration of a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of tetrahydrolipstatin is especially preferred. Tetrahydrolipstatin (orlistat) is a known compound useful for the control or prevention of obesity and hyperlipidemia. See U.S. Patent No. 4,598,089, filed July 1, 1986, which also describes processes for making orlistat and U.S. Patent No. 6,004,996, which discloses suitable pharmaceutical compositions. The most suitable pharmaceutical compositions are described, for example, in international patent applications WO 00/09122 and WO 00/09123. European Patent Application Publication Nos. 0185359, 0.189.577, 0.443.449, and 0.524.495 describe additional procedures for the preparation of orlistat.

Suitable anorexic agents for use in combination with a compound of the present invention include, but are not limited to, APD356, aminorex, amfechloram, amphetamine, axoquine, benzfetamine, bupropion, chlorphentermine, clobenzorex, cloforex, clominorex, clortermin, CP945598, cyclexedrine, CYT009-GhrQb, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-etilamfetamina, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, metreleptin, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex, rimonabant, sibutramine, SLV319, SNAP 7941, SR147778 (Surinabant), steroid plant extract (for example, P57) and TM30338, and the pharmaceutically acceptable salts thereof. The most preferred anorexic agents are sibutramine, rimonabant and phentermine. Selective serotonin reuptake inhibitors suitable for use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine, sertraline and the pharmaceutically acceptable salts thereof. The right agents to stimulate the metabolism of Body fat includes, but is not limited to, a growth hormone agonist (eg, AOD-9604). The use of a compound of formula I in the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving treatment with a compound selected from the group consisting of a lipase inhibitor, an anorectic agent , a selective inhibitor of serotonin reuptake and an agent that stimulates the metabolism of body fat, is also an object of the present invention. It is also an object of the present invention to use a compound of formula I in the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving a treatment with a lipase inhibitor, preferably with tetrahydrolipstatin. It is a more preferable object of the present invention to provide a method of treating or preventing type II diabetes (non-insulin dependent diabetes mellitus (NIDDM)) in a human, which comprises administering a therapeutically effective amount of a compound of according to formula I in combination or association with a therapeutically effective amount of a lipase inhibitor, particularly, wherein the inhibitor of lipase is tetrahydrolipstatin. Also an object of the present invention is the method as described above for the simultaneous, separate or sequential administration of a compound according to formula I and a lipase inhibitor, particularly tetrahydrolipstatin.

It is a more preferable object to provide a method of treatment or prevention of type II diabetes (non-insulin dependent diabetes mellitus (NIDDM)) in a human, which comprises administering a therapeutically effective amount of a compound according to the formula I in combination or association with a therapeutically effective amount of an anti-diabetic agent. The term "anti-diabetic agent" refers to a compound selected from the group consisting of 1) PPAR agonists? such as pioglitazone (acts) or rosiglitazone (avandia), and the like; 2) biguanides such as metformin (glucophage), and the like; 3) sulfonylureas such as glibenclamide, glimepiride (amaryl), glipizide (glucotrol), glyburide (DiaBeta) and the like; 4) no sulfonylureas such as nateglinide (starlix), repaglimide (prandin) and the like; 5) PPARa agonists /? such as GW-2331 and similar 6) DPP-IV inhibitors such as LAF-237 (vildagliptin), MK-0431, BMS-477118 (saxagliptin) or GSK23A and the like; 7) glucokinase activators such as the compounds described in for example, WO 00/58293 Al, and Similar; 8) D-glucosidase inhibitors such as acarbose (precose) or miglitol (glyset), and the like. Also an object of the present invention is the method as described above for the simultaneous, separate or sequential administration of a compound according to formula I and a therapeutically effective amount of an anti-diabetic agent. It is also an object of the present invention to use a compound of formula I in the manufacture of a medicament for the treatment and prevention of type II diabetes in a patient who is also receiving treatment with an anti-diabetic agent. It is a more preferable object to provide a method of treating or preventing dyslipidemias in a human, which comprises administering a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of an agent that decreases lipids. The term "lipid lowering agent" refers to compounds selected from the group consisting of 1) bile acid sequestrants such as cholestyramine (questran), colestipol (colestid) and the like; 2) HMG-CoA reductase inhibitors such as atorvastatin (lipitor), cerivastatin (baycol), fluvastatin (lescol), pravastatin (pravachol), simvastatin (zocor) and the like; 3) cholesterol absorption inhibitors such as ezetimibe and the like; 4) CETP inhibitors such as torcetrapib, JTT 705 and the like; 5) PPARa agonists such as beclofibrate, gemfibrozil (lopid), fenofibrate (lipidil), bezafibrate (bezalip) and the like; 6) inhibitors of lipoprotein synthesis such as niacin and the like; and 7) niacin receptor agonists such as nicotinic acid and the like. Also an object of the present invention is the method as described above for the simultaneous, separate or sequential administration of a compound according to formula I and a therapeutically effective amount of a lipid lowering agent. It is also an object of the present invention, the use of a compound of formula I in the manufacture of a medicament for the treatment and prevention of dyslipidemias in a patient who is also receiving a treatment with a lipid lowering agent. It is a more preferable object to provide a method for the treatment or prevention of hypertension in a human, which comprises the administration of a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of an agent antihypertensive The term "antihypertensive agent" or "agent that - - lowers blood pressure "refers to a compound selected from the group consisting of 1) angiotensin-converting enzyme (ACE) inhibitors including benazepril (lotensin), captopril (capoten), enalapril ( vasotec), fosinopril (monopril), lisinopril (prinivil, zestril), moexipril (univasc), perindopril (coversum), quinapril (accupril), ramipril (altace), trandolapril (mavik) and the like; 2) angiotensin receptor antagonists II, which includes candesartan (atacand), eprosartan (teveten), irbesartan (avapro), losartan (cozaar), telmisartan (micadisc), valsartan (diovan) and the like; 3) adrenergic (peripheral or central) blockers such as blockers beta-adrenergics, including acebutolol (sectrol), atenolol (tenormin), betaxolol (kerlone), bisoprolol (zebeta), carteolol (cartrol), metoprolol (lopressor, toprol-XL), nadolol (corgard), penbutolol (levatol) ), pindolol (visken), propranolol (inderal), timolol (blockadren) and the like; alpha / beta adrenergic blockers, including carvedilol (coreg), labetalol (normodyne) and the like; alpha-1 adrenergic blockers, including prazosin (minipress), doxazosin (cardura), terazosin (hytrin), phenoxybenzamine (dibencyline) and the like; Peripheral neuronal adrenergic blockers, including guanadrel (hilorel), guanethidine (ismelin), reserpine (serpasil) and the like; alpha-2 adrenergic blockers, including a-methyldopa (aldomet), clonidine (catapres), guanabenzo (wytensin), guanfacine (tenex) and the like; 4) blood vessel dilators (vasodilators), including hydralazine (apresolin), minoxidil (lonitren), clonidine (catapres) and the like; 5) calcium channel blockers, including amlodipine (norvasc), felodipine (plendil), isradipine (dynacirc), nicardipine (cardine sr), nifedipine (procardia, adalat), nisoldipine (sular), diltiazem (cardizem) , verapamil (isoptil) and the like; 6) diuretics such as thiazides and thiazide-like agents, including hydrochlorothiazide (hydrodiuril, microzide), chlorothiazide (diuril), chlorthalidone (hygroton), indapamide (lozol), metolazone (mykrox) and the like; loop diuretics, such as bumetanide (bumex) and furosemide (lasix), ethacrynic acid (edecrin), torsemide (demadex) and the like; Potassium-sparing diuretics, including amiloride (midamor), triamterene (dyrenium), spironolactone (aldactone), thiamenidine (symcor) and the like; 7) tyrosine hydroxylase inhibitors, including methirosine (demser) and the like; 8) neutral endopeptidase inhibitors, including BMS-186716 (omapatrilat), UK-79300 (candoxatril), ecadotril (sinorphan), BP-1137 (fasidotril), UK-79300 (sampatrilat) and the like; and 9) endothelin antagonists, which includes tezosentan (RO0610612), A308165 and the like. Also an object of the present invention is the method as described above for the simultaneous, separate or sequential administration of a compound according to formula I and a therapeutically effective amount of an antihypertensive agent. It is also an object of the present invention to use a compound of formula I in the manufacture of a medicament for the treatment and prevention of hypertension in a patient who is also receiving treatment with an antihypertensive agent. As described above, the compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good antagonists and / or inverse agonists of the histamine 3 receptor (H3R). The following tests were carried out to determine the activity of the compounds of formula (I). Binding assay with 3H- (R) α-methylhistamine Saturation binding experiments were performed using HR3-CH0 membranes prepared as described in Takahashi, K., Tokita, S., Kotani, H. (2003) J Pharmacol.

Exp. Therapeutics 307, 213-218. An appropriate amount of membranes (60 to 80 μg protein / well) was incubated with increasing concentrations of 3H (R) a-methylhistamine dihydrochloride (from 0.10 to 10 nM). The non-specific binding was determined using a 200-fold excess of (R) D-methylhistamine dibromhydrate (final concentration 500 nM). Incubation was carried out at room temperature (in shallow well plates shaken for three hours). The final volume in each well was 250 μl. After incubation, rapid filtration was carried out on GF / B filters (pre-wetted with 100 μl of 0.5% PEI in 50 mM Tris and stirred at 200 rpm for two hours). Filtration was performed using a cell harvester and the filter plates were then washed five times with ice-cold washing buffer, containing 0.5 M NaCl. After collection the plates were dried at 55 ° C for 60 min. added scintillation reagent (Microscint 40, 40 μl in each well) and, after shaking the plates for two hours at 200 rpm at room temperature, the level of radioactivity in the filter was determined with a Packard counter. Binding buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl2 x 6H20 pH 7.4. Wash Buffer: 50 mM Tris-HCl pH 7.4, 5 mM MgCl2 x 6H20 and 0.5 M NaCl pH 7.4. Indirect measurement of the affinity of H3R inverse agonists: twelve increasing concentrations (ranging from 10 μM to 0.3 nM) were always tested. 1 - . 1 - compounds selected in competitive binding experiments using membranes of the human cell line HR3-CH0. An appropriate amount of protein, eg, about 500 cpm of binding of RAMH to Kd, was incubated for 1 hour at room temperature in 250 μl of final volume in 96-well plates in the presence of 3H (R) α-methylhistamine ( final concentration 1 nM = Kd). The non-specific binding was determined using cold (R) a-methylhistamine dibromhydrate in a 200-fold excess. All the compounds were tested at a single concentration in duplicate. The compounds that showed an inhibition of [3 H] -RAMH of more than 50% were analyzed again to determine the IC 50 in a serial dilution experiment. The Ki were calculated from the IC50 based on the Cheng-Prusoff equation (Cheng, Y, Prusoff, WH (1973) Biochem Pharmacol 22, 3099-3108). The compounds of the present invention show Ki values in a range from about 1 nM to about 1000 nM, preferably from about 1 nM to about 100 nM, and more preferably from about 1 nM to about 30 nM. The following table shows the values found for several selected compounds of the present invention.

The demonstration of additional biological activities of the compounds of the present invention can be performed by in vitro assays, ex vivo and in vivo that are well known in the art. For example, to demonstrate the efficacy of a pharmacological agent in the treatment of obesity-related disorders such as diabetes, syndrome X or atherosclerotic disease, and related disorders such as hypertriglyceridemia and hypercholesterolemia, the following assays may be used. METHOD FOR MEASUREMENT OF GLUCOSE LEVELS IN BLOOD Blood (from the ocular vein or tail) was extracted from db / db mice (obtained from Jackson Laboratories, Bar Harbor, ME) and grouped based on average levels of blood glucose equivalents. They were administered orally (by forced feeding in a pharmaceutically acceptable vehicle) the test compound once a day for between 7 and 14 days. At that time, the animals were bled again from the eye or tail vein and the glucose levels were determined. Method for Measuring Triglyceride Levels Blood (from the ocular vein or tail) was extracted from hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) and grouped based on average levels of 14 -. 14 - equivalent serum triglycerides. They were administered orally (by forced feeding in a pharmaceutically acceptable vehicle) the test compound once a day for between 7 and 14 days. The animals were then bled again from the eye or tail vein and serum triglyceride levels were determined. Method for the Measurement of HDL Cholesterol Levels To determine plasma HDL-cholesterol levels, blood was extracted from hApoAl mice and pooled based on equivalent plasma HDL-cholesterol levels. The mice were orally administered once a day, vehicle or test compound for 7 to 14 days, and then the blood was collected the next day. The presence of HDL-cholesterol in plasma was analyzed. The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments, for example in the form of pharmaceutical preparations for enteral, parenteral or topical administration. These can be administered, for example, perorally, for example in the form of tablets, coated tablets, dragees, rigid and soft gelatine capsules, solutions, emulsions or suspensions; rectally, for example in the form of suppositories; parenterally, for example in the form of solutions for injection or solutions for infusion; or topically, for example in the form of - ointments, creams or oils. The production of the pharmaceutical preparations can be carried out by methods which will be familiar to any person skilled in the art, who provide the compounds of formula (I) described, and their pharmaceutically acceptable derivatives, in a galenic administration form together with solid or liquid carrier materials suitable, non-toxic, inert, therapeutically compatible and, if desired, the usual pharmaceutical adjuvants. The suitable conveyor materials are not only the inorganic carrier materials, but they can also be organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials in tablets, coated tablets, dragees and rigid gelatine capsules. Suitable carrier materials in soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient, no carriers are necessary in the case of soft capsules of jelly) . Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. The Suitable transporting materials in the solutions for injection are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials in suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials in topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives. Stabilizing agents, preservatives, humectants and emulsifiers, consistency-improving agents, flavor-improving agents, salts to alter osmotic pressure, buffer substances, solubilizing, coloring and masking agents, and the usual antioxidants are considered pharmaceutical adjuvants. The dosage of the compounds of formula (I) can vary within wide limits depending on the disease to be treated, the age and individual condition of the patient and the manner of administration, and of course, will be adjusted to the individual needs in each case in particular. In adult patients a daily dose of about 1 mg to about 1000 mg is considered, especially around 1 - . 1 - 1 mg to about 100 mg. Depending on the dose, it is convenient to administer the daily dose in several dosage units. The pharmaceutical preparations conveniently contain about 0.1-500 mg, preferably 0.5-100 mg, of a compound of formula (I). The following examples serve to illustrate the present invention in more detail. They do not intend, however, to limit their scope in any way. EXAMPLES Example 1 (4-isopropyl-piperazin-1-yl) - (4-p-tolylamino-cyclohexyl) -methanone a) Step 1: 4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexanone (Intermediate 1) A mixture of 882 mg (6.2 mmol) of 4-oxo-cyclohexanecarboxylic acid (commercially available), 875 mg (6.8 mmol) of 1 - (2 -propi 1) -piperazine, 2.98 g (9.3 mmol) of TBTU and 3.2 g (24.8 mmol) of DIPEA in 25 ml of DMF was stirred for 3 h at room temperature. After the elimination of volatiles, the The residue was extracted with ethyl acetate and evaporated. The residue was purified by column chromatography with silica, eluting with a gradient formed by n-heptane and ethyl acetate (0.1% NEt3) and methanol. Evaporation of the combined product fractions gave 830 mg (53%) of the title compound as a light brown oil. MS (m / e): 253.3 (MH +). b) Step 2: (4-isopropyl-piperazin-1-yl) - (4-p-tolyl-amino-cyclohexyl) -methanone A mixture of 25 mg (0.1 mmol) of 4- (4-isopropyl-piperazine-1) -carbonyl) -cyclohexanone, 27 mg (0.25 mmol) of p-tolylamine, 60 mg of acetic acid and 42 mg (0.2 mmol) of sodium triacetoxyborohydride in 2 ml of THF was stirred for 16 h at 70 ° C. After evaporation methanol and DMF were added, and the mixture was subjected to a purification by preparative reverse phase HPLC eluting with a gradient of acetonitrile / water (0.1% NEt3). The combined product fractions were evaporated to dryness to provide 5.1 mg (15%) of the title compound. MS (m / e): 344.3 (MH +). In accordance with the procedure described for Example 1, other piperazinyl-carbonyl-cyclohexyl derivatives have been synthesized from their respective starting materials, which are indicated in Table 1. Table 1 includes example 2 to example 9. Table 1 EXAMPLE 10 N- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -isobutyramide a) Step l [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -tert-butyl carbamate A mixture of 3 g (12 mmol) of 4-tert-butoxy-carbonylamino-trans-cyclohexane carboxylic acid (commercially available), 1.74 g (14 mmol) of 1- (2-propyl) -piperazine (commercially available), 4.75 g (15 mmol) of TBTU and 3.64 g (36 mmol) of NEt3 in 10 mL of DMF were stirred for 3 h at room temperature. After evaporation the residue was washed with a solution of 1N NaHCO 3, extracted with DCM, the combined organic phases were dried with MgSO 4 and evaporated to dryness to provide 4.56 g (94%, purity 90%) of the title compound and it was used in the next step without further purification. MS (m / e): 354.3 (MH +). b) Step 2 trans- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride (Intermediate 2) .

A mixture of 4.56 g (12 mmol) of [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -carbamic acid tert-butyl ester and 29 mL of 4N HCl in dioxane was stirred for 6 h at 50 ° C. C, it evaporated to dryness and was used in the next step without further purification. MS (m / e): 254.1 (MH +). c) Step 3 N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -isobutyramide A mixture of 32 mg (0.1 mmol) of trans- (4-amino-cyclohexyl) - ( 4-isopropyl-piperazin-1-yl) -methanone, 21 mg (0.2 mmol) of isobutyryl chloride and 101 mg (1 mmol) of NEt 3 in 2 mL of dichloromethane was stirred for 16 h at 40 ° C. After evaporation methanol and DMF were added, and the mixture was subjected to a purification by preparative reverse phase HPLC eluting with a gradient of acetonitrile / water (0.1% NEt3). The combined product fractions were evaporated to dryness to provide 3.6 mg (11%) of the title compound. MS (m / e): 324.4 (MH +). Cis- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride (Intermediate 3) a) Step 1: [cis-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -carbamic acid tert-butyl ester In accordance with the procedure described for the synthesis of [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -carbamic acid tert -butyl ester, the Title compound from 4-tert-butoxycarbonylamino-cis-cyclohexanecarboxylic acid (commercially available) and 1- (2-propyl) -piperazine (commercially available). MS (m / e): 354.3 (MH +). b) Step 2: cis- (4-amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone dihydrochloride According to the procedure described for the synthesis of trans- (4-amino-) dihydrochloride cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone, the title compound was synthesized from [cis-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -carbamic acid ester. butyl. MS (m / e): 254.4 (MH +). According to the procedure described for example 10, other piperazinyl-carbonyl-cyclohexyl derivatives have been synthesized from their respective starting materials, which are indicated in table 2. Table 2 includes from example 11 to example 13. Table 2 Example 14 l-Benzyl-l-isopropyl-3- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea A mixture of 23 mg (0.07 mmol) of cis- (4-) dihydrochloride amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone, 13 mg (0.08 mmol) of phenyl chloroformate and 36 mg (0.35 mmol) of NEt3 in 1.5 mL of DCM was stirred for 2 h at room temperature. Then 31 mg (0.21 mmol) of benzyl isopropylamine was added and the mixture was stirred for 16 h at room temperature. After evaporation methanol and DMF were added, and the mixture was subjected to a purification by preparative reverse phase HPLC eluting with a gradient of acetonitrile / water (0.1% NEt3). The fractions of the combined product were evaporated to dryness to provide 19 mg (62%) of the title compound. MS (m / e): 429.5 (MH +). In accordance with the procedure described in example 14, other piperazinyl-carbonyl-cyclohexyl derivatives (examples 15 to 34) have been synthesized from their respective starting materials, which are indicated in table 3. Table 3 Example 35 (4-cyclopentyl-piperazin-1-yl) - [4- (2-fluoro-phenylamino) -cyclohexyl] -methanone A mixture of 86 mg (0.5 mmol) of ethyl 4-oxo-cyclohexanecarboxylate (commercially available) , 100 mg (0.6 mmol) of 2-fluoro-phenylamine and 300 mg (5 mmol) of acetic acid in 5 mL of THF were stirred for 1 h at 60 ° C. Then, 159 mg (0.75 mmol) of sodium triacetoxyborohydride was added and the mixture was heated to 65 ° C for 16 h. After evaporation of the volatiles, 10 mL of aq. NaHCO 3 was added. 1 N, and the mixture was extracted with DCM. The combined organic phases were evaporated, methanol and DMF were added, and the mixture was subjected to purification by preparative reverse phase HPLC eluting with an acetonitrile / water gradient (0.1% NEt3). The combined product fractions were evaporated to dryness to provide the ethyl 3- (2-fluoro-phenylamino) -cyclohexanecarboxylate intermediate. MS (m / e): 266.2 (MH +). A mixture of 21 mg (0.08 mmol) of ethyl 4- (2-fluoro-phenylamino) -cyclohexanecarboxylate, 17 mg (0.4 mmol) of LiOH'H20 in a mixture of 2 mL of THF / methanol / water was heated to 45 °. C for 2 h and subsequently evaporated. The acid obtained as an intermediate was dissolved in 2 mL of DMF and treated with 30 mg (0.096 mmol) of TBTU, 24 mg (0.24) of NEt3 and 13.5 mg (0.88 mmol) of 1-cyclopentyl-piperazine (commercially available ) and stirred for 16 h at room temperature. The mixture was subjected directly to a purification by preparative reverse phase HPLC eluting with a gradient of acetonitrile / water (0.1% NEt3). The combined product fractions were evaporated to dryness to provide 6.4 mg (21%) of the title compound. MS (m / e): 374.4 (MH +). According to the procedure described for example 35, other pipera zini 1-carbonyl-cyclohexyl derivatives have been synthesized from their respective starting materials indicated in table 4. The cis and trans isomers have been obtained by separating the diastereomeric reaction mixture by column chromatography with silica or preparative reverse phase HPLC as appropriate. Table 4 comprises from Example 36 to Example 146. Table 4 - - - - - - - - - - - - - - - - EXAMPLE 147 Trans- (4-cycloheptyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone a) Step 1: trans- [4- (4-fluoro-phenylamino) -cyclohexyl ] -piperazin-1-yl-methanone In analogy to the procedure described for the synthesis of 4-cyclopentyl-piperazin-1-yl) - [4- (2-fluoro-phenylamino) -cyclohexyl] -methanone (Example 35), the The title compound was prepared from ethyl 4-oxo-cyclohexanecarboxylate (commercially available), 2-fluoro-phenylamine (commercially available) and piperazine. The trans-4- (4-fluoro- phenylamino) -cyclohexanecarboxylic acid that is produced as an intermediate was obtained from the racemic reaction mixture by separation by reverse phase preparative HPLC. MS (m / e): 306.1 (MH +). b) Step 2: trans- (4-cycloheptyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone A mixture of 76.3 mg (0.25 mmol) of (trans) - [4 - (4-Fluoro-phenylamino) -cyclohexyl] -piperazin-1-yl-methanone, 36.4 mg (0.325 mmol) of cycloheptanone and 79.5 mg (0.375 mmol) of sodium triacetoxyborohydride and 150 mg (2.5 mmol) of acetic acid in 3 mL of methanol was heated to 70 ° C for 16 h. The mixture was evaporated and NaHCO3 (aq) was added. The mixture was extracted with DCM and after evaporation was purified by preparative reverse phase HPLC eluting with a gradient formed with acetonitrile, water and NEt3. Evaporation of the product fraction gave 7.8 mg (8%) of the title compound. MS (m / e): 402.5 (MH +). Example 148 Trans- [4- (4-Fluoro-phenylamino) -cyclohexyl] - [4- (tetrahydro-pyran-4-yl) -piperazin-1-yl] -methanone In analogy to the procedure described for the synthesis of trans- [4- (4-Fluoro-phenylamino) -cyclohexyl] -piperazin-1-yl-methanone (example 147), the title compound was prepared at from trans- [4- (4-fluoro-phenylamino) -cyclohexyl] -piperazin-1-yl-methanone and tetrahydro-pyran-4-one (commercially available). MS (m / e): 390.4 (MH +). Example 149 trans- [4- (1-ethyl-propyl) -piperazin-1-yl] - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone In analogy to the procedure described for the synthesis of trans- [4] - (4-fluoro-phenylamino) -cyclohexyl] -piperazin-1-yl-methanone (example 147), the title compound was prepared from trans- [4- (4-fluoro-phenylamino) -cyclohexyl] -piperazine -1-yl-methanone and pentan-3-one (commercially available). MS (m / e): 376.4 (MH +). Example 150 (4-cyclobutyl-piperazin-1-yl) - [4- (6-isopropoxy-pyridin-3-ylamino) -cyclohexyl] -methanone a) Step l (4-cyclobutyl-piperazin-1-yl) - [ 4- (6-hydroxy-pyridin-3-ylamino) -cyclohexyl] -methanone In analogy to the procedure described for the synthesis of 4-cyclopentyl-piperazin-1-yl) - [4- (2-fluoro-phenylamino) -cyclohexyl ] -metanone (Example 35), the title compound was prepared from ethyl 4-oxo-cyclohexanecarboxylate (commercially available), 5-amino-pyridin-2-ol (commercially available) and 1-cyclobutyl-piperazine (available commercially). MS (m / e): 359.2 (MH +). b) Step 2 (4-cyclobutyl-piperazin-1-yl) - [4- (6-isopropoxy-pyridin-3-ylamino) -cyclohexyl] -methanone A mixture of 21 mg (0.058 mmol) of (4-cyclobutyl) piperazin-1-yl) - [4- (6-hydroxy-pyridin-3-ylamino) -cyclohexyl] -methanone, 17.4 mg (0.29 mmol) of isopropanol and 28 mg (0.11 mmol) of cyanomethylene tri-N-butylphosphorane in 2 mL of THF was heated to 80 ° C for 2 h. The mixture was concentrated and purified by preparative reverse phase HPLC eluting with a gradient formed with acetonitrile., water and NEt3. Evaporation of the product fraction gave 6.6 mg (28%) of the title compound. MS (m / e): 401.4 (MH +). Example 151 (4-cyclobutyl-piperazin-1-yl) - [4- (6-cyclopropylmethoxy-pyridin-3-ylamino) -cyclohexyl] -methanone In analogy to the procedure described for the synthesis of 4-cyclobutyl-piperazine-1- il) - [4- (6-isopropoxy-pyridin-3-ylamino) -cyclohexyl] -methanone (example 150), the title compound was prepared from (4-cyclobutyl-piperazin-1-yl) - [4 - (6-hydroxy-pyridin-3-ylamino) -cyclohexyl] -methanone and cyclopropylmethanol (commercially available). MS (m / e): 413.5 (MH +).

- - Example 152 trans- (4-cyclobutyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone a) Step 1: A mixture of 500 mg (2.9 mmol) of 4-oxo- ethyl cyclohexanecarboxylate (commercially available), 359 mg (0.6 mmol) of 4-fluoro-phenylamine and 1.76 g (29 mmol) of acetic acid in 5 mL of THF was stirred for 1 h at room temperature. Then, 809 mg (3.8 mmol) of sodium triacetoxyborohydride was added and the mixture was heated to 60 ° C for 2 h. To the mixture, aq. NaHCO 3 was added. Saturated and the mixture was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and evaporated. The mixture was purified with flash column chromatography (c-heptane-AcOEt from 100: 0 to 15:85). The combined product fractions were evaporated to dryness to provide the ethyl 3- (4-fluoro-phenylamino) -cyclohexanecarboxylate intermediate (679 mg, 87%). A mixture of 679 mg (2.6 mmol) of ethyl 4- (4-fluoro-phenylamino) -cyclohexanecarboxylate, 430 mg (10.5 mmol) of LiOH "H20 in a mixture of THF (5 mL) / methanol (1 mL) / water (1 mL) was stirred at room temperature for 72 h.The mixture was filtered and the filtrate was evaporated.The mixture was subjected to a purification by preparative reversed-phase HPLC eluting with a gradient of acetonitrile / water (HCOOH).

- - %) . The combined product fractions were evaporated to dryness to provide 122 mg of trans-4- (4-fluoro-phenylamino) -cyclohexanecarboxylic acid (20%) and 178 mg of cis-4- (4-f luoro-phenylamino) acid. -cyclohexane-carboxylic acid (29%). Trans derivative: MS (m / e): 238. 1 (MH +); Derived cis: S (m / e): 238. 1 (MH +). b) Step 2: 44 mg (0.185 mmol) of trans-4- (4-fluoro-phenylamino) -cyclohexanecarboxylic acid were dissolved in 0.3 mL of DMF and treated with 71 mg (0.223 mmol) of TBTU (0-Benzo-triazol-1-yl-N, N, NJN '-tetramethyl-uronium tetrafluoroborate), 94 mg (0.927 mmol) of NEt3 and 43 mg (0.204 mmol) of 1-cyclobutyl-piperazine and stirred for 12 at room temperature. To the mixture was added aq. NaHCO 3. Saturated and the mixture was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and evaporated. The mixture was purified by flash column chromatography (CH2Cl2-MeOH 9: 1). The combined product fractions were evaporated to dryness to give 45 mg (67%) of the title compound. MS (m / e): 360.3 (MH +). Example 153 cis- (4-cyclobutyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone According to the procedure described in step 2 of Example 152, cis- (4-cyclobutyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone was synthesized from cis-4- (4-fluoro-phenylamino) ) -cyclohexanecarboxylic acid. MS (m / e): 360.3 (MH +). Example 154 [4- (2,4-dichloro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone According to the procedure described in step 2 of example 1, it has been synthesized [4 - (2,4-dichloro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone from 2,4-dichloroaniline and 4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexanone. MS (m / e): 398.2 (MH +). Example 155 trans- [4- (6-Chloro-pyridin-3-ylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone A mixture of 50 mg (0.197 mmol) of trans- (4- amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone, 47 mg (0.197 mmol) of 2-chloro-5-iodopyridine, 4 mg (0.02 mmol) of Cul, 84 mg (0.395 mmol) of K3P0, 24 mg (0.395 mmol) of ethylene glycol and 0.5 mL of 2-propanol was stirred at 160 ° C for 30 min. under microwave radiation. NaHC03 aq. saturated, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and they evaporated. The mixture was purified by preparative TLC (CH2Cl2-Me0H 20: 1). The combined product fractions were evaporated to dryness to provide 14 mg (19%) of the title compound. MS (m / e): 365.2 (MH +). Example 156 trans-6- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -nicotinonitrile A mixture of 214 mg (0.84 mmol) of trans- (4-amino-cyclohexyl) - (4-isopropyl- piperazin-1-yl) -metanone, 200 mg (1.44 mmol) of 6-chloronicotinonitrile (commercially available), 932 mg (7.22 mmol) of diisopropylethylamine and 5 mL of 1,4-dioxane was stirred at 170 ° C for 20 min. under microwave radiation. The mixture was evaporated. The mixture was purified by column elution chromatography (CH2Cl2-MeOH 95: 5). The combined product fractions were evaporated to dryness to provide 26 mg (9%) of the title compound. MS (m / e): 356.1 (MH +). Example 157 trans- (4-isopropyl-piperazin-1-yl) - [4- (5-methanesulfonyl-pyridin-2-ylamino) -cyclohexyl] -methanone A mixture of 215 mg (0.85 mmol) of trans- (4- amino-cyclohexyl) - (4-isopropyl-piperazin-1-yl) -methanone, 200 mg (0.85 mmol) of 2-bromo-5-methanesulfonyl-pyridine (Bioorg, Med. Chem. Lett., 16, 2076 (2006) ), 547 mg (4.24 mmol) of diisopropylethylamine and 5 mL of 1,4-dioxane was stirred at 170 ° C for 1 h under microwave irradiation. The mixture was evaporated. The mixture was purified by column elution chromatography (CH2Cl2-MeOH 95: 5). The combined product fractions were evaporated to dryness to provide the title compound. MS (m / e): 409.1 (MH +). Example A Film-coated tablets containing the following ingredients can be made in conventional manner: Ingredients Per tablet Core: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Hydrated lactose 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Core weight) 120.0 mg 350.0 mg Coating film: Hydroxypropylmethylcellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron Oxide (yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg The active ingredient is screened and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate, and compressed to provide cores of 120 or 350 mg respectively. The cores are lacquered with an aqueous solution / suspension of the aforementioned coating film. Example B Capsules containing the following ingredients can be manufactured in conventional manner: Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Corn starch 20.0 mg Talcum 5.0 mg The components are sieved, mixed and filled into size 2 capsules. Example C The solutions for injection can have the following composition: Compound of formula (I) 3.0 mg Gelatin 150.0 mg Phenol 4.7 mg Sodium carbonate to obtain a final pH of 7 Water for injectable solutions up to 1.0 ml EXAMPLE D Soft gelatine capsules containing the following ingredients can be prepared in conventional manner: Capsule Content Compound of formula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated soybean oil 8.0 mg Partially hydrogenated vegetable oils 34.0 mg Soybean Seed 110.0 mg Weight of capsule content 165.0 mg Gelatin capsule Gelatin 75.0 mg 85% glycerol 32-0 mg Karion 83 8.0 mg (dry material) Titanium dioxide 0.4 mg Yellow Iron Oxide 1.1 mg The active ingredient is dissolved in a fusion mixture of the other hot ingredients, and the mixture is filled into soft gelatine capsules of the appropriate size. The filled soft gelatine capsules are treated according to the usual procedures. Example E The sachets containing the following ingredients can be prepared in a conventional manner: Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 1400.0 mg 102) Sodium carboxymethylcellulose 14.0 mg Polyvinylpyrrolidone K30 10.0 mg Magnesium stearate 10.0 mg Flavoring additives 1.0 mg The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose, and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives, and introduced into the envelopes. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (30)

1. -
2. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the general formula characterized because s is 1 or 2; R1 is selected from the group consisting of lower alkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, alkylsulfonylalkyl, and tetrahydropyranyl; Rla is hydrogen or lower alkyl; R2 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl, and lower cyanoalkyl; R3 is selected from the group consisting of - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, - (CH2) n-heteroaryl, wherein is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, indanyl, 1-oxo-indanyl, -CO- (C3-C8 alkyl) -, -CO- (CH2) p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, iano, lower alkoxy, lower alkanoyl, benzoyl, haloalkoxy lower and hydroxyalkyl lower, -CO- (CH2) q-heteroaryl, wherein q is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen , lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and -CO-NRR5; or R2 and R3 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring which is fused with a phenyl ring, and the phenyl ring is unsubstituted or substituted by one, two or three groups independently selected from between lower alkyl, lower alkoxy and halogen; R 4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, aryl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, alkanoyl lower, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and lower arylalkyl wherein the phenyl ring may be unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, and the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, haloalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, and the phenyl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; - - and the pharmaceutically acceptable salts thereof. 2. Compounds of formula I according to claim 1 with the formula characterized in that R1 is lower alkyl or cycloalkyl; R2 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl, and lower cyanoalkyl; R3 is selected from the group consisting of - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from alkyl lower, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, - (CH2) n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is not substituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, indanyl, -CO- (C3-C8 alkyl) -, -CO- (CH2) p-aryl, wherein p is 0.1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, - CO- (CH2) q-heteroaryl, wherein q is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted by one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and -CO-NRR5; O 3 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring which is fused with a phenyl ring, and the phenyl ring is unsubstituted or substituted by one, two or three groups independently - - selected from lower alkyl, lower alkoxy and halogen; R 4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, aryl unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl , and lower arylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower haloalkoxy, and lower hydroxyalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, and the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, haloalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl , benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, and the phenyl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; and the pharmaceutically acceptable salts thereof. 3. Compounds of formula I according to claim 1, characterized in that R3 is selected from the group consisting of - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is not substituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl,
3. -
4. - (CH2) n-heteroaryl, wherein n is O, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, alkoxy lower, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl, indanyl and 1-oxo-indanyl. 4. Compounds of formula I according to claim 1 or 3, characterized in that R3 is - (CH2) m-aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl.
5. 5. Compounds of formula I according to claims 1 or 3, characterized in that R3 is - (CH2) n-heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two - groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy and lower hydroxyalkyl and wherein the heteroaryl group is selected from furyl , pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoxazolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl and pyrrolyl.
6. 6. Compounds of formula I according to any of claims 1, 3 or 5, characterized in that R3 is - (CH2) n -heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is pyridyl or isoxazolyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, carbamoyl, lower alkylsulfonyl, lower halogenoalkylsulfonyl, lower halogenoalkoxy, lower cycloalkylalkoxy, and lower hydroxyalkyl.
7. 7. Compounds of formula I according to claim 1, characterized in that R3 is selected from the group consisting of -CO- (C3-C8 alkyl) -, -CO- (CH2) p-aryl, wherein p is 0 , 1 or 2 and in the < 5 the - - aryl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, and -CO- (CH2 ) q-heteroaryl, wherein q is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, alkanoyl lower, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl.
8. 8. Compounds of formula I according to claim 1 or 7, characterized in that R3 is -CO- (CH2) p-aryl, wherein p is 0, 1 or 2 and wherein the aryl ring is unsubstituted phenyl or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl.
9. 9. Compounds of formula I according to claim 1, characterized in that R3 is -CO-NRR5 and wherein R4 is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; R5 is selected from the group consisting of lower alkyl, aryl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl , and lower arylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower haloalkoxy and lower hydroxyalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4, 5, 6 or 7 members optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, and the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, and the phenyl ring is unsubstituted or substituted by one , two or three groups independently selected from lower alkyl, lower alkoxy and halogen.
10. 10. Compounds of formula I according to claims 1 or 9, characterized in that R3 is -CO-NR4R5 and wherein R4 is hydrogen or lower alkyl; and R5 is selected from the group consisting of lower alkyl, phenyl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower haloalkoxy and hydroxyalkyl lower, and phenylalkyl lower wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, alkanoyl - - lower, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl.
11. 11. Compounds of formula I according to any of claims 1, 9 or 10, characterized in that R5 is phenyl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, alkoxy lower, lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl, or lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy , lower alkanoyl, benzoyl, lower halogenoalkoxy and lower hydroxyalkyl.
12. 12. Compounds of formula I according to claim 1, characterized in that R3 is -CO-NR4R5 and in which R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-, 5-, 6 or 7 members optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, and the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, hydroxyalkyl lower, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is fused with a phenyl ring, and the phenyl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen .
13. 13. Compounds of formula I according to claims 1 or 12, characterized in that R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, pyrrolidine, azepine, piperazine, azetidine and thiomorpholine, the heterocyclic ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, haloalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or is condensed with a phenyl ring, the phenyl ring is unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.
14. 14. Compounds of formula I according to any of claims 1, 12 or 13, characterized in that R4 and R5 together with the nitrogen atom to which they are attached form a group selected from 2-methylpyrrolidine, piperidine, 4-methoxypiperidine, 4,4-difluoropiperidine, morpholine, 4-phenylpiperazine, 1,3- dihydro-isoindol and 3,4-dihydro-2H- < quinoline
15. 15. Compounds of formula I according to any of claims 1 to 14, characterized in that R1 is a lower alkyl.
16. 16. Compounds of formula I according to any of claims 1 to 14, characterized in that R1 is a cycloalkyl.
17. 17. Compounds of formula I according to any of claims 1 to 16, characterized in that R2 is a hydrogen or lower alkyl.
18. 18. Compounds of formula I according to claim 1, characterized in that they are selected from the group consisting of (4-isopropyl-piperazin-1-yl) - (4-p-tolylamino-cyclohexyl) -methanone, [4 - (4-Fluoro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (1,3-dihydro-isoindol-2-yl) -cyclohexyl] - (4-isopropyl) -piperazin-1-yl) -methanone, (4-isopropyl-piperazin-1-yl) - [4- (6-methoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, [4- (3, 4- dihydro-lH-isoquinolin-2-yl) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (indane-1-ylamino) -cyclohexyl] - (4-isopropyl-piperazine-1) -il) -metanone, - (4-isopropyl-piperazin-1-yl) - [4- (1-phenyl-propylamino) -cyclohexyl] -methanone, (4-isopropyl-piperazin-1-yl) -. { 4- [2- (3-methoxy-phenyl) -ethylamino] -cyclohexyl} -methanone, [4- (4-difluoromethoxy-phenylamino) -cyclohexyl] - (4-isopropyl-1-piperazin-1-yl) -methanone, N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) - cyclohexyl] -isobutyramide, N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -4-methoxy-benzamide, 2,4-difluoro-N- [trans-4- (4-isopropyl -piperazine-1-carbonyl) -cyclohexyl] -benzamide, 2,4-dichloro-N- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -benzamide, 1-benzyl-1-isopropyl -3- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea, 1, l-diethyl-3- [cis-4- (4-isopropyl-piperazine-1-carbonyl) - cyclohexyl] -urea, [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -amide of 4-phenyl-piperazine-1-carboalicylic acid, 1- (4-chloro-phenyl) - 3- [cis-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -1-methyl-urea, l-benzyl-l-ethyl-3- [cis-4- (4-isopropyl-piperazine- l-carbonyl) -cyclohexyl] -urea, [cis-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] - 3, 4-dihydro-2H-quinoline-l-carboxylic acid amide, 1- (3-fluoro-phenyl) -3- [cis-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -1 -methyl-urea, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 2-methyl-pyrrolidine-l-carboxylic acid, l-benzyl-l-isopropyl-3- [trans] -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea, 1,1-diethyl-3- [trans -4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of piperidine-1-carboxylic acid, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of morpholine-4-carboxylic acid, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 4-methoxy-piperidine-l-carboxylic acid, [trans-4- (4-isopropyl 4-phenyl-piperazine-1-carboxylic acid-piperazine-1-carbonyl) -cyclohexyl] -amide, 1- (4-chloro-phenyl) -3- [trans-4- (4-isopropyl-piperazine-1-carboxylic acid) carbonyl) -cyclohexyl] -1-methyl-urea, l-benzyl-l-ethyl-3- [ trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -urea, 3- [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -1-phenyl-1-propyl -urea, - [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 3,4-dihydro-2H-quinoline-l-carboxylic acid, 1- (3-fluoro-phenyl) -3- [ trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -1-methyl-urea, [trans-4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexyl] -amide of acid 4, 4-difluoro-piperidine-1-carboxylic acid, [trans-4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexyl] -amide of 1,3-dihydro-isoindol-2-carboxylic acid, (4-cyclopentyl- piperazin-1-yl) - [4- (2-fluoro-phenylamino) -cyclohexyl] -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (3-fluoro-phenylamino) -cyclohexyl] -methanone (4-cyclopentyl-piperazin-1-yl) - [4- (4-fluoro-phenylamino) -cyclohexyl] -methanone (4-cyclopentyl-piperazin-1-yl) - [4- (2,4-difluoro phenylamino) -cyclohexyl] -methanone, 3- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexylamino] -benzonitrile, (4-cyclopentyl-piperazin-1-yl) - [4- (2-methoxy phenylamino) -cyclohexyl] -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (4 -methoxy-phenylamino) -cyclohexyl] -methanone, l-. { 4- [4- (4-cyclopentyl-piperazine-1-carbonyl) -cyclohexylamino] -phenyl} -etanone, [4- (4-benzoyl-phenylamino) -cyclohexyl] - (4-cyclopentyl-piperazin-1-yl) -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (pyrazin-2 -ylamino) -cyclohexyl] -methanone, (4-cyclopentyl-piperazin-1-yl) -. { 4- [(3-fluoro-phenyl) -methyl-amino] -cyclohexyl} -metanone, (4-cyclopenti1-piperazin-1-yl) -. { 4- [(4-fluoro-phenyl) -methyl-amino] -cyclohexyl} -methanone, [4- (2-fluoro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, [4- (2,4-difluoro-phenylamino) -cyclohexyl] - (4- isopropyl-piperazin-1-yl) -methanone, 3- [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexylamino] -benzonitrile, (4-isopropyl-piperazin-l-yl) - [4- (4 -methoxy-phenylamino) -cyclohexyl] -methanone, l-. { 4- [4- (4-isopropyl-piperazine-1-carbonyl) -cyclohexylamino] -phenyl} ethanone, [4- (4-benzoyl-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, 2- [4- (4-cyclopentyl-piperazine-l-carbonyl) -cyclohexylamino] -benzonitrile, and the pharmaceutically acceptable salts thereof - -
19. 19. Compounds of formula I according to claim 1, characterized in that they are selected from the group consisting of [4- (1,3-dihydro-isoindol-2-yl) -cyclohexyl] - (4-isopropyl-piperazine-1) -yl) -metanone, (4-isopropyl-piperazin-1-yl) - [4- (6-methoxy-pyridin-3-ylamino) -cyclohexyl] -methanone, [4- (indane-1-ylamino) -cyclohexyl ] - (4-isopropyl-piperazin-1-yl) -methanone, (4-isopropyl-piperazin-l-yl) - [4- (1-phenyl-propylamino) -cyclohexyl] -methanone, (4-isopropyl-piperazin -l-il) -. { 4- [2- (3-methoxy-phenyl) -ethylamino] -cyclohexyl} -methanone, [4- (4-difluoromethoxy-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, (4-cyclopentyl-piperazin-1-yl) - [4- (4-fluoro phenylamino) -cyclohexyl] -methanone, (4-ciclopenti1 piperazin-1-yl) - [4- (2, 4-difluoro-phenylamino) -cyclohexyl] -methanone, 3- [4- (4-cyclopentyl-piperazine l-carbonyl) -cyclohexylamino] -benzonitrile, [4- (4-benzoyl-phenylamino) -cyclohexyl] - (4-cyclopentyl-piperazin-1-yl) -methanone, (4-isopropyl-piperazin-l-yl) - [4- (4-methoxy-phenylamino) -cyclohexyl] -methanone, - [4- (4-benzoyl-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, trans- (4-cyclobutyl-piperazin-1-yl) - [4- (4-fluoro- phenylamino) -cyclohexyl] -methanone, [4- (2,4-dichloro-phenylamino) -cyclohexyl] - (4-isopropyl-piperazin-1-yl) -methanone, trans- [4- (6-chloro-pyridin- 3-ylamino) -cyclohexyl] - (4-isopropi1-piperazine-1-yl) -methanone, trans-6- [4- (4-isopropyl-piperazine-l-carbonyl) -cyclohexylamino] -nicotinonitrile, trans- (4 -isopropyl-piperazin-1-yl) - [4- (5-methanesulfonyl-pyridin-2-ylamino) -cyclohexyl] -methanone, and the pharmaceutically acceptable salts thereof.
20. 20. Process for the preparation of compounds according to any of claims 1 to 20, characterized in that it comprises a) the coupling of a compound of formula II wherein s, Rla and R1 are as defined in claim 1, with an amine of formula III H-NR2R3 III wherein R and R3 are as defined in claim 1, with the proviso that R3 does not contain a carbonyl group, in the presence of a coupling reagent under basic conditions to obtain a compound of formula I-B wherein s, Rla, R1 and R2 are as defined in claim 1 and R3 is a group as defined in claim 1, different from those groups containing a carbonyl group, and if desired, the conversion of the compound obtained in a pharmaceutically acceptable acid addition salt, or b) the reaction of a compound of formula IV wherein s, Rla and R1 are as defined in claim 1, with an acid chloride of formula V .0 tf < V Cl where R6 is selected from the group consisting of - (C3-C8 alkyl), - (CH2) p-aryl and - (CH2) q-heteroaryl, in the presence of a base to obtain a compound of formula I-C wherein R2 is hydrogen and R3 is selected from the group consisting of -CO- (C3-C8 alkyl) -, -CO- (CH2) p-aryl and
21. -CO- (CH2) q-heteroaryl, and if desired, the conversion of the compound obtained to a pharmaceutically acceptable acid addition salt, or c) the coupling of a compound of formula IV wherein s, Rla and R1 are as defined in claim 1, after activation with phenyl chloroformate, with an amine of formula VI H-NRR5 III wherein R4 and R5 are as defined in the claim 1, to obtain a compound of formula ID wherein s, Rla, R1, R2, R4 and R5 are as defined in claim 1, and if desired, the conversion of the compound obtained in a pharmaceutically acceptable acid addition salt. 21. Compounds according to any of claims 1 to 19, characterized in that they are made by a process according to claim 20.
22. 22. Pharmaceutical compositions characterized in that they comprise a compound according to any of claims 1 to 19 as well as a pharmaceutically acceptable carrier and / or adjuvant.
23. 23. Pharmaceutical compositions according to claim 22, characterized in that they are for the treatment and / or prevention of diseases that are associated with the modulation of the H3 receptors.
24. 24. Compounds according to any of claims 1 to 19, characterized in that they are used as therapeutically active substances.
25. 25. Compounds according to any of claims 1 to 19, characterized in that they are used as therapeutically active substances for the treatment and / or prevention of diseases that are associated with the modulation of the H3 receptors.
26. 26. Use of compounds according to any of claims 1 to 19 for the preparation of medicaments for the treatment and / or prevention of diseases that are associated with the modulation of - H3 receptors.
27. 27. Use according to claim 28 for the treatment and / or prevention of obesity.
28. 28. Use of a compound of formula I according to any of claims 1 to 20 in the manufacture of a medicament for the treatment or prevention of obesity in a patient who is also receiving a treatment with a lipase inhibitor.
29. 29. Use of a compound of formula I according to any of claims 1 to 19 in the manufacture of a medicament for the treatment or prevention of type II diabetes in a patient who is also receiving a treatment with an antidiabetic agent.
30. 30. Use of a compound of formula I according to any of claims 1 to 19 in the manufacture of a medicament for the treatment or prevention of dyslipidemia in a patient who is also receiving a treatment with a lipid lowering agent.