HK1191235A - Novel benzofurane-piperidine compounds - Google Patents

Description

Novel benzofuran-piperidine compounds

The present invention relates to 5-HT_2AAnd D₃Dual modulators of receptors, their manufacture, pharmaceutical compositions containing them and their use as medicaments.

In particular, the invention relates to compounds of formula (I)

Wherein R is¹、R²、R³N and Y are as defined herein, and pharmaceutically acceptable salts and esters thereof.

The compound and its medicinal salt of the invention are dopamine D₃And serotonin 5-HT_2ABoth receptors have high affinity and selectivity and are effective in therapy or prophylaxis, alone or in combination with other drugsPsychotic disorders, as well as other diseases such as depression, anxiety, drug addiction, attention deficit hyperactivity disorder, dementia and memory impairment, while exhibiting fewer associated side effects. Psychotic disorders encompass a wide range of diseases including schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disorder, mania, psychotic depression, and other psychoses involving paranoia and delusions.

In particular, schizophrenia is characterized by a complex of symptoms, including positive symptoms (i.e., delusions and hallucinations), and negative symptoms (i.e., loss of interest, restricted fluency and efficiency of thinking and speaking). In addition, it is now well recognized that cognitive impairment is the third major diagnostic category of schizophrenia, characterized by loss of working memory and other deficits. Other symptoms include aggressiveness, depression and anxiety (Stahl, s.m., Essential psychopharmacologic biology. neuroscientific basic and practical Applications) (2000), 2nd edition, Cambridge University Press, Cambridge, UK).

Dopamine, a major catecholamine neurotransmitter, is involved in the regulation of a wide variety of functions, including mood, cognition, motor function, and positive reinforcement. The biological activity of dopamine is mediated through G-protein coupled receptors (GPCRs), and in humans, five different dopamine receptors D have been identified₁-D₅Wherein D is₂-like receptors (D)₂，D₃And D₄) Coupled to G-protein G_αI。D₃Dopamine receptors are most highly expressed in the nucleus accumbens and are thought to regulate the limbic pathway consisting of neuronal projections from the ventral tegmental area, hippocampus and amygdala to the nucleus accumbens, which project to the prefrontal and cingulate cortex and individual thalamic nuclei. This edge loop is considered important for emotional behavior and thus D₃Receptor antagonists are proposed for the modulation of psychotic disorders such as hallucinations, delusions and thought disorders (Joyce J.N., Millan M.J., Drug Discovery Today (2005) 10: 917-925). In addition, it has been reported that first-time-administered schizophrenic patients exhibit altered D₃Receptor expression levels (Gurevich E.V. et al, Arch.Gen.Psychiatry (1997)54, 225-232) and dopamine release levels (Laruell M., Presentation at institute de Receches Intern a mechanisms Servier work on Schizophrania: Pathological Bases and mechanisms of antipathological Action, Chicago, IL, 2000), indicate that disturbed dopamine homeostasis plays an important role in the etiology of Schizophrenia symptoms.

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is involved in a variety of psychiatric disorders, including schizophrenia (Kandel E.R. et al (eds.), Principles of neuroscience (2000)3 rd edition, Appleton & Lange, Norwalk, CT). Serotonin has been implicated in psychotic disorders in a number of studies including treatment in humans with the psychotropic agent lysergic acid (LSD; a serotonin agonist) which induces schizophrenia-like symptoms such as hallucinations (Leikin J.B., et al, Med. Toxicol. Adverse Drug Exp (1989) 4: 324-350). In addition, altered serotonergic tone, as well as altered serotonergic brain distribution, has been detected in schizophrenic patients (Harrison P.J., Br.J.Psychiatry Suppl (1999) 38: 12-22).

In mammals, serotonin exerts its biological activity through a family of 14 5-HT GPCRs. 5-HT_2AThe receptor is most significantly expressed in the prefrontal cortex of the human brain and is expressed at lower levels in the basal ganglia and hippocampus, and is primarily coupled to the G-protein, ga q. 5-HT_2AThe genetic linkage studies of polymorphs with schizophrenia (Spurlock G. et al, mol. Psychiatry (1998) 3: 42-49), as well as their reactivity to antipsychotics (Arranz, M.J. et al, Lancet (2000) 355: 1615-1616), further suggest 5-HT_2AThe role of the receptor in the treatment and pathology of psychosis. In addition, dopaminergic neurotransmission appears to be at 5-HT_2AUnder the afferent regulation of receptors (Porras G. et al, Neuropsychopharmacology (2002) 26: 311-324).All 5-HT_2AReceptor antagonists are proposed to be useful in the treatment of conditions associated with dysfunction of the dopaminergic system. Furthermore, 5-HT_2AReceptor antagonism has been considered beneficial for the treatment of psychosis (deAngelis l., curr. opin. investig. drugs (2002) 3: 106-.

In addition to the psychotic disorders mentioned, D₃And 5-HT_2AReceptors have further been reported to be associated with other psychiatric disorders including paranoia and delusions (Reavill C. et al, JPET (2000) 294: 1154-1165; Harrison P.J., Br.J.Psychiatry Suppl (1999) 38: 12-22), drug-dependent, drug abuse and withdrawal (Vorel S.R. et al, J.Neurosci (2002) 22: 9595-9603; Campos A.C. et al, Soc.Neurosci.Abstract, (2003) 322: 8; Ashby C.R. et al, Synapse (2003) 48: 154-156), Attention Deficit Hyperactivity Disorder (ADHD) (Retz W. et al, J.Neurol.Transm. (2003) 110: 531-572; Levitan R.D. et al, J.Affjorty (229) 229; J.2002) 71: 2000-2000, and depression (PET 1164: 294; PET 1164: 1155; Ser. 233: 26-11).

The drugs currently used to treat schizophrenia, bipolar mania and other psychoses, including classical (D)₂／D₃Preferred) or more recently atypical drugs that exhibit multidrug interactions (e.g., D) at multiple receptors₁，D₂，D₃，D₄，5-HT_1A，5-HT_2A，5-HT_2c，H₁，M₁，M₂，M₄Etc.) (Roth b.l. et al, nat. rev. drug Discov. (2004) 3: 353-359). Although relatively successful in treating the positive symptoms of schizophrenia (some patients exhibit treatment resistance), these antipsychotics are not very effective in treating negative symptoms, cognitive deficits and associated depression and anxiety, all of which lead to reduced patient quality of life and socioeconomic problems. In addition, patient compliance is impaired by commonly occurring side effects such as weight gain, extrapyramidal symptoms (EPS) and cardiovascular effects (Lieberman J.A., et al, N.Engl.J.Med. (2005) 353: 1209-.

In the present invention, the pair D is described₃And 5-HT_2AThe receptors have high affinity and improved selectivity compounds and are proposed for the treatment of psychosis and other diseases with fewer associated side effects. The compound of the invention is 5-HT_2AAnd D₃Dual modulators of receptors and in₂Is selective at the receptor.

Antipsychotic treatment is often due to extensive D₂The serious side effects of antagonism are complicated by extrapyramidal ensemble or parkinsonism caused by antagonism of dopaminergic projection from the substantia nigra to the striatum. D₂Receptor blockade induces catalepsy and is associated with negative effects on cognition. And D₃Relative to D₂Preferential blockade of receptors preserves and/or enhances cognitive function and increases frontal cortical cholinergic transmission. (Journal J.N., Millan M.J., drug discovery Today (2005) 10: 917 925, Moore N.A., et al, European Journal of pharmacy (1993) 237: 1-7; Barth V.N., typing and typing landification science: translation science in vivo therapy D (2) registration of usage LC/MS and change in neurology and specificity (Typical and atypical antipsychotics: relationship between dopamine D (2) receptor occupancy and neurochemical changes and syncope in rats evaluated using LC/MS) specificity index (2006: University M.J. et al, Journal M.J. Journal of therapy, J.2009, et al, Experimental society (324: V.p. 204, et al, J.P. J. 3: J.P. 3, J.P. J. 3, et al, European Journal of pharmacy, 237: 7; Bar J.P.N., J. 265, et al, correlation).

Typical antipsychotic drug display on the market today D₂Antagonism, and most have extrapyramidal side Effects (EPS) such as pseudoparkinsonism (pseudoparkinsonism) and tardive dyskinesia (Howard h.r., seger t.f., Annual Reports in Medicinal Chemistry (1993) 28: 39). It has been shown by selective binding experiments that D is relative to the edge region responsible for the thought process₂The receptors are more responsible for exerciseIn the striated regions of the controlled brain. Relative to striatal area, D₃Receptors are more concentrated in the border area. Thus D considered selective₃The ligand can relieve the symptoms of schizophrenia without causing D₂Receptor blockade associated EPS (gackenheimer s.l., et al, j. pharmacol. exp. ther. (i995) 274: 1558, Belliotti t. r., bioorg. med. chem. lett. (1997) 7: 2403).

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, suitable methods and materials are described below.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

Unless otherwise mentioned, any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the formulae herein indicates the presence of hydrogen.

The definitions described herein apply regardless of whether the terms in question appear alone or in combination. It is contemplated that the definitions described herein may be superimposed to form chemically related combinations, such as "heterocycloalkyl-aryl," haloalkyl-heteroaryl, "" aryl-alkyl-heterocycloalkyl, "or" alkoxy-alkyl. The last member of the combination is a group that is substituted in reverse order by the other members of the combination.

The term "one or more" when referring to the number of substituents refers to substitution from one substituent up to the highest possible number, i.e., the range of substitution of one hydrogen by a substituent up to the substitution of all hydrogens.

The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "substituent" refers to an atom or group of atoms replacing a hydrogen atom on a parent molecule.

The term "substituted" means that the specified group bears one or more substituents. Where any group may carry multiple substituents and multiple possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When the number of substituents is given, the term "one or more" means one substituent up to the highest possible number of substituents, i.e. one hydrogen is substituted by a substituent up to the substitution of all hydrogens by substituents.

The terms "one or more compounds of this invention" and "one or more compounds of the invention" refer to compounds of formula (I) and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

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

The term "pharmaceutically acceptable ester" refers to derivatives of the compounds of the present invention wherein the carboxyl group is converted to an ester, wherein the carboxyl group means-C (O) O-. Methyl-, ethyl-, methoxymethyl-, methylthiomethyl-and pivaloyloxymethyl esters are examples of such suitable esters. The term "pharmaceutically acceptable esters" also includes derivatives of the compounds of the invention wherein the hydroxyl group has been converted to the corresponding ester with the following inorganic or organic acids: such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, or p-toluenesulfonic acid, which are non-toxic to living tissue.

The term "pharmaceutically acceptable salt" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and base addition salts.

The term "pharmaceutically acceptable acid addition salts" refers to those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from: aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

The term "pharmaceutically acceptable base addition salts" refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of the following organic bases: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine (hydrabamine), choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine (theobromamine), purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

The stereochemical definitions and conventions used herein generally follow the McGraw-Hill Dictionary of Chemical Terms (1984), edited by s.p. parker, McGraw-Hill book company, new york; and Eliel, E. and Wilen, S., "Stereochemistry of organic Compounds", John Wiley & Sons, Inc., New York, 1994. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. Substituents attached to the chiral center under consideration are ordered according to the order rule of Cahn, Ingold and Prelog. (Cahn et al, Angew. chem. Inter. Edit.1966, 5, 385; reconnaissance 511). The prefixes D and L or (+) and (-) are used to refer to symbols in which plane polarized light is rotated by the compound, where (-) or L means that the compound is left-handed. Compounds prefixed with (+) or D are dextrorotatory.

The term "trans configuration" refers to a configuration within a molecule in which a pair of substituents are attached on opposite sides of a stereoisomeric group.

The term "protecting group" means a group that selectively blocks a reactive site in a polyfunctional compound in its conventional meaning in relation to its use in synthetic chemistry such that a chemical reaction can proceed selectively at another unprotected reactive site. The protecting group may be removed at a suitable point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups.

The term "amino protecting group" refers to a group that protects an amino group and includes benzyl, benzyloxycarbonyl (carbonylbenzyloxy, CBZ), Fmoc (9-fluorenylmethyloxycarbonyl), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-Butoxycarbonyl (BOC) and trifluoroacetyl. Further examples of such Groups are found in t.w.greene and p.g.m.wuts, "Protective Groups in organic Synthesis", 2nd edition, John Wiley & Sons, inc., New York, NY, 1991, chapter 7; haslam, "Protective Groups in Organic chemistry", edited by J.G.W.McOmie, plenum Press, New York, NY, 1973, Chapter 5, and T.W.Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected amino" refers to an amino group substituted with an amino protecting group.

The term "deprotection" or "deprotection" refers to a process of removing a protecting group after completion of a selective reaction. Deprotecting agents include acids, bases or hydrogen, especially potassium or sodium carbonate, lithium hydroxide in alcoholic solution, zinc in methanol, acetic acid, trifluoroacetic acid, palladium catalyst, or boron tribromide.

The terms "halo", "halogen" and "halide" are used interchangeably herein and refer to fluorine, chlorine, bromine, or iodine. Examples of particular halogens are fluorine and chlorine.

The term "alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms, especially 1 to 7 carbon atoms, more especially 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Examples of particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, most particularly methyl, ethyl, isopropyl, isobutyl and tert-butyl.

The term "alkenyl" refers to a monovalent straight or branched chain hydrocarbon group of 2 to 7 carbon atoms, especially 2 to 4 carbon atoms, having at least one double bond. Examples of alkenyl groups include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, iso-butenyl, and tert-butenyl. Examples of particular alkenes are n-propenyl and isobutenyl, in particular prop-2-enyl and isobutenyl.

The term "alkynyl" refers to monovalent straight or branched chain saturated hydrocarbon radicals of 2 to 7 carbon atoms, especially 2 to 4 carbon atoms, and containing one, two or three triple bonds. Examples of alkynyl include ethynyl, propynyl, prop-2-ynyl, isopropynyl, n-butynyl and iso-butynyl. A particular example of alkynyl is propynyl, most particularly prop-1-ynyl.

The term "alkoxy" refers to a group of the formula-O-R ', wherein R' is alkyl. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy. Examples of particular alkoxy groups are methoxy and tert-butoxy.

The term "haloalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by the same or different halogen atom, especially a fluorine atom. Examples of haloalkyl include mono-, difluoro-or trifluoro-methyl, -ethyl or-propyl, such as 3, 3, 3-trifluoropropyl, 2-fluoroethyl, 2, 2, 2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term "perhaloalkyl" refers to an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced with the same or different halogen atoms. Particular examples of haloalkyl are trifluoromethyl and trifluoroethyl, most particularly trifluoromethyl.

The term "haloalkoxy" denotes an alkoxy group wherein at least one hydrogen atom of the alkoxy group has been replaced by the same or different halogen atom, especially a fluorine atom. Examples of haloalkoxy include mono-, difluoro-or trifluoro-methoxy, -ethoxy or-propoxy, such as 3, 3, 3-trifluoropropoxy, 2-fluoroethoxy, 2, 2, 2-trifluoroethoxy, fluoromethoxy or trifluoromethoxy. The term "perhaloalkoxy" denotes an alkoxy group wherein all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms.

The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 10 ring carbon atoms, especially 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more common carbon atoms. Particular cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutaneyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicycloalkyl are bicyclo [2.2.1] heptanyl or bicyclo [2.2.2] octanyl. Particular cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, most particularly cyclopropyl and cyclohexyl.

The term "cycloalkylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced with a cycloalkyl group. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylpropyl and cyclopentylbutyl.

The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or partially unsaturated ring of 4 to 9 ring atomsBicyclic ring system comprising 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. By bicyclic is meant consisting of two rings having two ring atoms in common, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl groups are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, azepinyl, diazepanyl, homopiperazinyl, or oxepinyl. An example of a bicyclic saturated heterocycloalkyl is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl, 3-oxa-9-aza-bicyclo [3.3.1]Nonyl, or 3-thia-9-aza-bicyclo [3.3.1]Nonyl radical. Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, dihydro-Oxazolyl, tetrahydro-pyridyl, or dihydropyranyl. Examples of particular heterocycloalkyl groups are oxetanyl, tetrahydrofuryl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl and dimorpholinylAn alkyl group. Most particular examples of heterocycloalkyl groups are piperidinyl, tetrahydropyranyl, morpholinyl and diAn alkyl group.

The term "heterocycloalkylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced with a heterocycloalkyl group.

The term "aromaticity" denotes the conventional concept of aromaticity as defined in the literature, in particular as described in IUPAC-Complex of Chemical technology, 2nd, A.D.McNaught & A.Wilkinson (eds.), Blackwell Scientific Publications, Oxford (1997).

The term "aryl" refers to a monovalent aromatic carbocyclic mono-or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl, most particularly phenyl.

The term "heterocycloalkyl-fused aryl" refers to an aryl group as defined herein and a heterocycloalkyl group as defined herein fused together to share two adjacent ring atoms. Examples of aryl groups fused to heterocycloalkyl groups include optionally substituted benzodioxolyl groups.

The term "heteroaryl" refers to a monovalent aromatic heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl,an azole group, a thiazole group, a triazole group,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azaRadical, diazaBasic group, heteroAzolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, iso-thiazolylIndolyl, isobenzofuranyl, benzimidazolyl, benzoAzolyl, benzisoylAzolyl, benzothiazolyl, benzisothiazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl. Particular examples of heteroaryl are pyrrolyl, pyrazolyl, isoThe group of azolyl groups,oxadiazolyl, thienyl, pyridyl, pyrazinyl, quinolinyl and benzisoxazolylAzolyl radical, most particularlyA diazolyl group.

The term "oxo" refers to a divalent oxygen atom = O.

The term "alkylsulfonyl" refers to the group-SO₂-R ', wherein R' is alkyl. Examples of alkylsulfonyl include methylsulfonyl, and ethylsulfonyl, particularly methylsulfonyl.

The term "active pharmaceutical ingredient" (or "API") refers to a compound in a pharmaceutical composition that has a particular biological activity.

The term "pharmaceutically acceptable" refers to the properties of materials that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable and that are acceptable for veterinary as well as human pharmaceutical use.

The term "pharmaceutically acceptable excipient" refers to any ingredient used in formulating pharmaceutical products that is not therapeutically active and is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, osmotic agents, stabilizers, antioxidants, surfactants or lubricants.

The term "pharmaceutical composition" (or "composition") refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with a pharmaceutically acceptable excipient to be administered to a mammal, such as a human, in need thereof.

The term "modulator" refers to a molecule that interacts with a target. Interactions include, for example, agonism, antagonism, or inverse agonism.

The term "antagonist" refers to a compound that reduces or prevents The action of another compound or receptor site, as defined, for example, in Goodman and Gilman, "The pharmacological basis of Therapeutics, 7 th edition," page 35, Macmillan Publ. In particular, an anti-caking agent refers to a compound that impairs the effect of an agonist. A "competitive antagonist" binds to the same site as an agonist but does not activate it, thereby blocking the action of the agonist. A "non-competitive antagonist" binds to an allosteric (non-agonistic) site on the receptor to prevent activation of the receptor. The "reversible antagonist" binds non-covalently to the receptor and can thus be "eluted". An "irreversible antagonist" covalently binds to a receptor and cannot be displaced by competing ligands or elution.

The term "inhibition constant" (Ki) refers to the absolute binding affinity of a particular inhibitor for a receptor. It is measured using a competitive binding assay and is equal to the concentration at which a particular inhibitor would occupy 50% of the receptors if no competing ligand (e.g., radioligand) were present. Ki values can be converted logarithmically to pKi values (-1og Ki), with higher values indicating exponentially greater potency.

The term "therapeutically effective amount" refers to the amount of such a compound of the invention: when administered to a subject, (i) treat or prevent a particular disease, health problem or disorder described herein, (ii) attenuate, ameliorate or eliminate one or more symptoms of a particular disease, health problem or disorder described herein, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, health problem or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state to be treated, the severity or disease to be treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

The terms "treat" or "treating" of a disease state includes (1) preventing the disease state, i.e., causing clinical symptoms of the disease state not to be exhibited in a subject that may be exposed to or predisposed to developing the disease state, but that has not yet experienced or exhibited symptoms of the disease state, (2) inhibiting the disease state, i.e., preventing the manifestation of the disease state or clinical symptoms thereof, or (3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or clinical symptoms thereof.

The term "subject" refers to a vertebrate. In a particular embodiment, the vertebrate is a mammal. Mammals include humans, non-human primates such as chimpanzees and other apes and monkey species, farm animals such as cows, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats, and laboratory animals including rodents such as rats, mice and guinea pigs. In a particular embodiment, the mammal is a human. The term subject does not denote a particular age or gender.

In particular, the invention relates to compounds of formula (I)

Wherein

n is 0, 1, 2, 3 or 4;

y is-C (O) -or-S (O)₂-；

R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, adamantyl, heterocycloalkyl, aryl fused with heterocycloalkyl, heteroaryl, -NR⁶R⁷Hydroxy, alkoxy, or haloalkoxy; and is

Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkoxy and haloalkoxy are optionally substituted with one, two or three independent R⁴Substitution; and is

Wherein cycloalkyl, adamantyl, heterocycloalkyl, aryl, heterocycloalkyl-fused aryl and heteroaryl are optionally substituted with one, two or three independent R⁵Substitution;

R²，R³independently hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy;

R⁴is cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C (O) NR⁶R⁷，-NR⁶R⁷-NH (CO) -alkyl, hydroxy, alkoxy, haloalkoxy, oxo, or-S (O)₂R⁶；

And is

Wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three independent R⁵Substitution;

R⁵is halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C (O) NR⁶R⁷，-NR⁶R⁷-NH (CO) -alkyl, hydroxy, alkoxy, haloalkoxy, oxo, or-S (O)₂R⁶(ii) a And is

Wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from: halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy and oxo;

R⁶，R⁷independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, or heteroaryl;

and pharmaceutically acceptable salts and esters thereof.

Particular embodiments of the present invention are compounds of formula (I) and pharmaceutically acceptable salts and pharmaceutically acceptable esters thereof.

Furthermore, it will be appreciated that reference to specific residues n, Y, R as disclosed herein is made¹、R²、R³、R⁴、R⁵、R⁶Or R⁷May be related to another residue n, Y, R as disclosed herein¹、R²、R³、R⁴、R⁵、R⁶Or R⁷Any other embodiment of (a) or (b) in combination.

A particular embodiment of the invention relates to compounds of formula (I) wherein the two opposite substituents, the amide residue and the piperidinyl-ethyl residue, at the central cyclohexyl portion of the molecular backbone, are oriented in the trans configuration.

A particular embodiment of the present invention relates to compounds of the formula (I

Wherein n and R¹、R²And R³As defined herein.

A particular embodiment of the present invention relates to compounds of formula (I ″)

Wherein n and R¹、R²And R³As defined herein.

In a particular embodiment of the compounds of formula (I), n is 0.

In a particular embodiment of the compounds of formula (I), n is 1.

In a particular embodiment of the compounds of formula (I), n is 2.

In a particular embodiment of the compounds of formula (I), n is 3.

In a particular embodiment of the compounds of formula (I), n is 4.

In a particular embodiment of the compounds of formula (I), n is 0, 1 or 2.

In a particular embodiment of the compounds of formula (I), Y is-C (o) -.

In a particular embodiment of the compounds of formula (I), Y is-S (O)₂-。

In a particular embodiment of the compounds of formula (I), R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, adamantyl, heterocycloalkyl, aryl fused with heterocycloalkyl, heteroaryl, -NR⁶R⁷Hydroxy, alkoxy or haloalkoxy; and wherein alkyl and haloalkyl are optionally substituted with one, two or three independent R⁴Substitution; and wherein cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three independent R⁵And (4) substitution.

In a particular embodiment of the compounds of formula (I), R¹Is hydrogen, methyl substituted by methoxy, n-propyl substituted by hydroxy, isopropyl substituted by hydroxy, n-butyl, tert-butyl, n-propenyl, isobutenyl, propynyl, trifluoromethyl, trifluoroethyl substituted by hydroxy, cyclopropyl substituted by fluorine,cyclopropyl substituted by hydroxy, cyclobutyl, cyclohexyl substituted by tert-butyl, cyclohexyl substituted by trifluoromethyl, cyclohexyl substituted by methoxy, adamantyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanylAlkyl, phenyl, by R⁸Substituted phenyl, benzodioxolyl, isobenzoylAzolyl, methyl-substituted iso-phenylOxazolyl, thienyl substituted by methyl-sulfonyl, pyridyl substituted by methyl, pyridyl substituted by morpholinyl, pyrazinyl substituted by morpholinyl, quinolyl, benzisoxazolylAzolyl, -N (methyl)₂Hydroxy, or methoxy;

and wherein R⁸Selected from the group consisting of fluoro, chloro, cyano, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclohexyl, piperidinyl, methyl-piperazinyl, morpholinyl, dioxo-thiomorpholinyl, phenyl, pyrrolyl, pyrazolyl, methyl-Oxadiazolyl, pyridinyl, tert-butoxy or methyl-sulfonyl.

In a particular embodiment of the compounds of formula (I), R¹Is cyclohexyl, cyclohexyl substituted by tert-butyl, tetrahydropyranyl, diAlkyl, methoxy, phenyl, or phenyl substituted with a substituent selected from the list consisting of: ethyl radicalIsopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, piperidinyl, morpholinyl, methyl-Oxadiazolyl and tert-butoxy.

In a particular embodiment of the compounds of formula (I), R²Is hydrogen.

In a particular embodiment of the compounds of formula (I), R³Is hydrogen.

In a particular embodiment of the compounds of formula (I), R²And R³Is hydrogen.

In a particular embodiment of the compounds of formula (I), R⁴Is cyano, -C (O) -NR⁶R⁷Hydroxy, alkoxy, or-S (O)₂R⁶。

In a particular embodiment of the compounds of formula (I), R⁴Is cyano, -C (O) N (methyl)₂Hydroxy, methoxy, or methyl-sulfonyl.

In a particular embodiment of the compounds of formula (I), R⁵Is halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, or alkylsulfonyl; and wherein heterocycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from alkyl and oxo.

In a particular embodiment of the compounds of formula (I), R⁵Is fluorine, chlorine, cyano, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclohexyl, piperidinyl, methyl-piperazinyl, morpholinyl, dioxo-thiomorpholinyl, phenyl, pyrrolyl, pyrazolyl, methyl-Oxadiazolyl, pyridinyl, hydroxy, methoxy, tert-butoxy, or methyl-sulfoAnd (4) acyl.

In a particular embodiment of the compounds of formula (I), R⁵Is ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, piperidinyl, morpholinyl, methyl-Oxadiazolyl, or tert-butoxy.

In a particular embodiment of the compounds of formula (I), R⁶And R⁷Independently selected from alkyl groups.

In a particular embodiment of the compounds of formula (I), R⁶And R⁷Is methyl.

A particular embodiment of the present invention relates to compounds of formula (I) described in the examples as single compounds, as well as pharmaceutically acceptable salts thereof, and pharmaceutically acceptable esters thereof. Furthermore, the substituents found in the specific examples described below each constitute a separate particular embodiment of the invention.

Particular compounds of formula (I) of the present invention are those selected from the group consisting of:

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-methoxy-propionamide;

tetrahydro-pyran-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2- (tetrahydro-pyran-4-yl) -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-methoxy-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-methanesulfonyl-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } - (RS) -2- [1, 4]IIAlk-2-yl-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -2- (3-methyl-iso-propyl) -benzeneOxazol-5-yl) -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-hydroxy-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3, 3-trifluoro-propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-morpholin-4-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -isobutyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-methyl-butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-hydroxy-2-methyl-propionamide;

(RS) -tetrahydro-furan-3-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

(RS) -tetrahydro-furan-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

quinoline-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

cyclobutanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-hydroxy-propionamide;

1-hydroxy-cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyano-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-fluoro-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyclopropyl-acetamide;

tetrahydro-pyran-3-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide; trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 2-dimethyl-propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2- (tetrahydro-furan-2-yl) -acetamide;

2, 2-difluoro-cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (RS) -2-methyl-butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (RS) -3, 3, 3-trifluoro-2-hydroxy-propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-hydroxy-3-methyl-butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (R) -4, 4, 4-trifluoro-3-hydroxy-butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -methanesulfonamide;

ethanesulfonic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-methyl-benzenesulfonamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 2, 2-trifluoro-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3-dimethyl-butyramide;

3-methyl-isoAzole-5-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -N ', N' -dimethyl-succinamide;

n' - (trans-4- {2- [4- (benzofuran-3-yl) -piperidin-1-yl ] -ethyl } -cyclohexyl) -N, N-dime thylsulfonamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4, 4, 4-trifluoro-butyramide;

4-methyl-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide; (R) -3-hydroxy-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

(S) -3-hydroxy-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyclobutyl-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-chloro-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-trifluoromethyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-piperidin-1-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3-dimethoxy-propionamide;

3-methyl-but-2-enoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

(E) -pent-3-enoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

but-2-ynoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -carboxamide;

pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

benzo [1, 3] dioxole-5-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyrazol-1-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4- (4-methyl-piperazin-1-yl) -benzamide;

biphenyl-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide; trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyridin-3-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -6-morpholin-4-yl-nicotinamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4- (1, 1-dioxo-1 λ 6-thiomorpholin-4-yl) -benzamide;

5-morpholin-4-yl-pyrazine-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyrrol-1-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -6-methyl-nicotinamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyano-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butoxy-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-trans- (4-methoxy-cyclohexyl) -acetamide;

quinoline-6-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-2-benzo [1, 3] dioxol-5-yl-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -acetamide;

5-methanesulfonyl-thiophene-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-oxetan-3-yl-acetamide;

4-tert-butyl-cyclohexanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

adamantane-1-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

4-trifluoromethyl-cyclohexanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isobutyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-ethyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyclohexyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isopropyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyclopropyl-benzamide;

trans-2-benzo [ d ]]Different from each otherAzol-3-yl-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-methanesulfonyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 4-dichloro-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butyl-benzenesulfonamide; and

pharmaceutically acceptable salts and esters thereof.

Particular compounds of formula (I) of the present invention are those selected from the group consisting of: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-methoxy-propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2- (tetrahydro-pyran-4-yl) -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-methoxy-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } - (RS) -2- [1, 4]IIAlk-2-yl-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-morpholin-4-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-trifluoromethyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-piperidin-1-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butoxy-benzamide;

4-tert-butyl-cyclohexanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isobutyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-ethyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isopropyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyclopropyl-benzamide;

and pharmaceutically acceptable salts and esters thereof.

The present invention also relates to a process for the preparation of a compound of formula (I) as defined above, said process comprising:

a) a compound of formula (V)

And formula R¹(CH₂)_nC(O)OH、R¹(CH₂)_nC (O) OR OR R¹(CH₂)_nS(O)₂Reaction of compounds of Cl, wherein n, R¹、R²And R³As defined above, and R is alkyl; or

b) A compound of formula (II)

Reaction with a Compound of formula (VI)

Wherein n, Y, R¹、R²And R³As defined above.

In particular, the compounds of formula (I) may be prepared according to standard methods according to scheme 1 or 2.

According to scheme 1, in a first step, a compound of formula (II) is reacted with an aldehyde of formula (III) under reductive amination conditions, such as for example using sodium triacetoxyborohydride (Na (AcO)₃BH) in a solvent such as 1, 2-dichloroethane in the presence of methanol (MeOH) or an acid such as acetic acid (AcOH) to give the compound of formula (IV). The amino moiety of aldehyde (III) is protected with an amino protecting group such as Boc moiety. In a second step, the compound of formula (IV) is deprotected to give the compound of formula (V). In such cases where the amino protecting group is a Boc functional group, the compound of formula (IV) may be reacted with an acid such as HCl in a suitable solvent mixture such as ethyl acetate (AcOEt) and MeOH to give the primary amine (V) which is isolated as an HCl salt.

The compounds of the formula (V) can be reacted in a third step with a large number of different nucleophilic reagentsThe reagents are reacted to obtain the compound of formula (I). For example, compounds of formula (V) and general structure R¹(CH₂)_nCarboxylic acids of C (O) OH in coupling agents such as O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylureaTetrafluoroborate (TBTU) and a base such as Hunig's base (N, N-diisopropylethylamine, DIPEA) in the presence of a solvent such as Dimethylformamide (DMF) to give the compound of formula (I'). In some cases, the general structure R¹(CH₂)_nThe carboxylic acid of C (O) OH or a salt thereof can be prepared by the following steps: formula R¹(CH₂)_nC (O) esters of OR (where R is alkyl) with e.g. a base such as LiOH OR a mild agent such as potassium trimethylsilanolate (KOSiMe)₃) Such a reagent is saponified in a solvent such as Dichloromethane (DCM), followed by complete evaporation of all the solvent and direct use of the crude product from the amide coupling step described above to obtain the compound of formula (I').

Scheme 1Wherein n, R¹，R²And R³As defined above, Z is an amino-protecting group and R is an alkyl group.

In yet another case, the compound of formula (V) may be reacted with the appropriate general structure R¹(CH₂)_nS(O)₂Reagent of Cl in base such as triethylamine (Et)₃N) in a solvent such as DCM to obtain the compound of formula (I ").

Derivatization at the primary amine does not have to be carried out in the last step, but can already take place before the reductive amination step, thereby avoiding the use of amino-protecting groups. According to scheme 2, reductive amination of a compound of formula (II) with an aldehyde of formula (VI) under conditions well known to those skilled in the art will directly result in the production of an amide of formula (I). Is used for the stepAn example of suitable conditions for the process is the use of Na (AcO) in a solvent such as 1, 2-dichloroethane with or without MeOH or an acid such as AcOH₃BH. Methods for producing compounds of formula (VI) have been described (e.g. WO 2007/093540).

Scheme 2Wherein n, Y, R¹，R²And R³As defined above.

According to scheme 3, compounds of formula (II) can be prepared from the corresponding 3-bromobenzofuran compounds of formula (VII) and the commercially available tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate of formula (VIII) or similar boron derivatives by cross-coupling reaction to tert-butyl 4- (benzofuran-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (IX), followed by deprotection and hydrogenation, wherein Z is an amino-protecting group, in particular Boc.

According to scheme 3, the compound of formula (II) can be obtained from the compound of formula (VII) by cross-coupling with a compound of formula (VIII) or a similar boron derivative, wherein Z is an amino-protecting group, in particular Boc. The most particular compound of formula (VIII) is commercially available tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate. The coupling between the compound of formula (VII) and the compound of formula (VIII) is carried out under conditions known to the person skilled in the art to obtain the compound of formula (IX), in particular to obtain 4- (benzofuran-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester, for example under Suzuki conditions using a catalyst such as palladium (II) acetate in the presence of a ligand, in particular triphenylphosphine, in the presence of a base, in particular potassium bicarbonate, in a solvent, in particular 1, 2-dimethoxyethane. Other coupling conditions are well known to those skilled in the art. Compounds of formula (IX) wherein Z is an amino-protecting group, particularly Boc, can be treated with an acid, particularly BocHCl in a suitable solvent mixture, in particular bisDeprotection in alkane and MeOH, followed by hydrogenation of the double bond using Pd/C to obtain the desired benzofuranpiperidine of formula (II).

Scheme 3Wherein R is²And R³As defined above, and Z is an amino-protecting group.

The corresponding acid salts of the compounds of formula (I) may be obtained by standard methods known to those skilled in the art, for example by dissolving a compound of formula (I) in a suitable solvent such as a di-alcoholAlkane or Tetrahydrofuran (THF) and the appropriate amount of the corresponding acid was added. The product can usually be isolated by filtration or by chromatography.

The compounds of formula (I) may be converted into pharmaceutically acceptable esters, for example, by using, for example, condensation reagents (condensing reagents) such as benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), N, N-Dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDCI) or O- (1, 2-dihydro-2-oxo-1-pyridinyl) -N, N, N, N-tetra-methylureaTetrafluoroborates (TPTU), carried out by treating the appropriate hydroxyl groups present in the molecule with an appropriate carboxylic acid.

In the case that their preparation is not described in the examples, the compounds of formula (I) as well as all intermediates can be prepared according to analogous methods or according to the methods set forth above. Starting materials are commercially available, are known in the art or can be prepared by methods known in the art or similar methods.

The invention also relates to compounds of formula (I) as defined above, prepared by the above process.

Another embodiment provides pharmaceutical compositions or medicaments comprising a compound of the invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.

The compositions may be formulated, metered, and administered in a manner consistent with good medical practice. Factors considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the etiology of the condition, the site of drug delivery, the method of administration, the timing of administration, and other factors known to the practitioner.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the invention may be administered in any convenient form for administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH adjusting agents, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents, antioxidants, and additional active agents. They may also contain other therapeutically valuable substances.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c. et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philiadelphia; gennaro a.r. et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C, Handbook of Pharmaceutical Excipients (Handbook of Pharmaceutical Excipients) (2005) Pharmaceutical Press, Chicago. The formulations may also include one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents (opaquing agents), glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents and other known additives to provide an excellent appearance to the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or to aid in the preparation of the pharmaceutical product (i.e., medicament).

The doses at which the compounds of the invention can be administered may vary within wide ranges and will of course be adapted to the individual requirements of each particular case. In general, in the case of oral administration, a daily dosage of about 0.1 to 1000 mg/person of a compound of formula (I) will be appropriate, but the above upper limit may also be exceeded if desired.

An example of a suitable oral dosage form is a tablet comprising about 100mg to 500mg of a compound of the invention complexed with about 30 to 90mg of anhydrous lactose, about 5 to 40mg of croscarmellose sodium, about 5 to 30mg polyvinylpyrrolidone (PVP) K30 and about 1 to 10mg of magnesium stearate. These powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment.

An example of an aerosol formulation may be prepared by dissolving, for example, 10 to 100mg of a compound of the invention in a suitable buffer solution, for example phosphate buffer, and, if desired, adding a tonicity agent (tonifier), for example a salt such as sodium chloride. The solution may be filtered, for example using a 0.2 μm filter, to remove impurities and contaminants.

As mentioned above, the novel compounds of the present invention and their pharmaceutically acceptable salts and esters have valuable pharmacological properties and have been found to be 5-HT_2AAnd D₃Dual modulators of receptors. The compounds of the invention may therefore be used, alone or in combination with other drugs, for the treatment or prevention of the disorders mediated by 5-HT_2AOr D₃A ligand-modulated disease of a receptor. These include, but are not limited to, psychotic disorders including schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions, depression, anxiety, drug addiction, attention deficit hyperactivity disorder, dementia, and memory impairment.

The invention therefore also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable excipient.

The invention likewise covers the compounds as described above for use as therapeutically active substances, especially as medicaments for the treatment or prevention of diseases involving 5-HT_2AOr D₃Therapeutically active substances for the treatment or prevention of diseases of the receptor, in particular for the treatment or prevention of the following diseases: psychotic disorders, depression, anxiety disorders, drug addiction, attention deficit hyperactivity disorder, dementia and memory deficits, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

In another embodiment, the invention relates to a method for the treatment or prevention of a condition involving 5-HT_2AOr D₃A method for the treatment or prevention of a disease of a receptor, in particular a method for the treatment or prevention of: psychotic disorders, depression, anxiety, drug addiction, attention deficit hyperactivity disorder, dementia and memory impairment, wherein psychotic disorders compriseSchizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions, which method comprises administering a compound as defined above to a human or animal.

The invention also encompasses the use of a compound as defined above for the treatment or prevention of a condition involving 5-HT_2AOr D₃Use of a receptor for a disease, in particular for the treatment or prevention of: psychotic disorders, depression, anxiety disorders, drug addiction, attention deficit hyperactivity disorder, dementia and memory deficits, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

The invention also relates to the use of a compound as described above for the preparation of a medicament for the treatment or prevention of a condition involving 5-HT_2AOr D₃A disease of the receptor, in particular for the treatment or prevention of psychotic disorders, depression, anxiety, drug addiction, attention deficit hyperactivity disorder, dementia and memory deficits, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions. Such drugs include compounds as described above.

In particular, the compounds of the present invention may be used for the treatment or prevention of psychotic disorders comprising schizophrenia and positive, negative and/or cognitive symptoms associated with schizophrenia.

The invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the invention.

Intermediates

An intermediate A: trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexylamine dihydrochloride

Step A

A mixture of commercially available 3-bromobenzofuran (2.50g, 12.7mmol) and commercially available tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (4.32g, 14.0mmol) in 1, 2-dimethoxyethane (85ml) and 2M sodium carbonate solution (21.1ml, 42.3mmol) was purged with argon in an ultrasonic bath for 5 minutes. Triphenylphosphine (666mg, 2.54mmol) and palladium (II) acetate (285mg, 1.27mmol) were then added and the reaction stirred at 85 ℃ for 17 h. The reaction mixture was cooled to room temperature, poured into water (30ml) and extracted with diethyl ether (2 × 120 ml). The combined organic layers were washed with brine (60ml), dried (MgSO4) and evaporated. The crude product (5.78g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 4: 1) to yield 4- (benzofuran-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester as a yellow oil (2.06g, 54%), ms (isp) M/z =300.2[ (M + H)⁺]。

Step B

To a stirred solution of 4- (benzofuran-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.06g, 6.88mmol) in dichloromethane (50ml) was added hydrochloric acid solution (bis4M in alkane, 25.8ml, 103mmol) and the reaction mixture was stirred for 2 h. The reaction mixture is treated withDiluted with alkane (25ml), the precipitate was collected by filtration and washed with dichloromethaneThe alkane was washed and dried to give 4- (benzofuran-3-yl) -1, 2, 3, 6-tetrahydropyridine hydrochloride as an off-white solid (1.37g, 85%), ms (isp) M/z =200.2[ (M + H)⁺]，mp276℃。

Step C

A stirred mixture of 4- (benzofuran-3-yl) -1, 2, 3, 6-tetrahydropyridine hydrochloride (1.57g, 6.66mmo1), palladium on carbon (10%, 0.35g, 0.33mmol), ammonium formate (2.1g, 33.3mmol) and MeOH (61ml) was heated at reflux for 1h, cooled to RT, filtered and evaporated. The residue was diluted with ice water (20ml) and 3M NaOH (10ml) and extracted with dichloromethane/methanol 9: 1(4X50 ml). The combined organic layers were washed with brine (1 × 25ml), dried (MgSO4) and evaporated. The crude product (1.37g) was purified by flash chromatography on silica gel (dichloromethane/methanol/NH 4OH 65: 10: 1) to give 4- (benzofuran-3-yl) -piperidine as a pale yellow oil (1.1g, 82%), ms (isp) M/z =202.3[ (M + H)⁺]。

Step D

To a stirred solution of 4- (benzofuran-3-yl) -piperidine (1.1g, 5.47mmol) in dichloromethane (31ml) was added commercially available tert-butyl trans-4- (2-oxoethyl) -cyclohexylcarbamate (1.86g, 6.56mmol) and triethylamine (1.11g, 1.52ml, 10.9mmol) at room temperature and the solution was stirred for 30 min. Sodium triacetoxyborohydride (2.09g, 9.84mmo1) was added stepwise and the mixture was stirred at room temperature for 16 h. The solution was poured into saturated sodium bicarbonate solution (20ml) and extracted with dichloromethane (2 × 40 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (20ml), dried (MgSO4) and evaporated. The crude material (3.05g) was purified by flash chromatography on silica gel (dichloromethane/MeOH 2-6%) to give trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -ethyl]-cyclohexyl } -carbamic acid tert-butyl ester, as a white semisolid (2.31g, 99%), ms (isp) M/z =427.4[ (M + H)⁺]。

Step E

To trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]To a mixture of tert-butyl (2.3g, 5.39mmol) cyclohexyl } -carbamate in dichloromethane (40ml) was added a hydrochloric acid solution (di @) at room temperature4M in alkane, 20.2ml, 80.9mmol) and the mixture stirred for 2h, diethyl ether (50ml) was added and the mixture stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white solid (1.89g, 88%), ms (isp) M/z =327.4[ (M + H)⁺]，mp339℃。

Examples

Example 1: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -acetyl

To trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]To a stirred mixture of cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) in DMF (3ml) were added N, N-diisopropylethylamine (113mg, 150. mu.l, 0.88mmol), acetic acid (22.6mg, 21.5. mu.l, 376. mu. mol) and TBTU (121mg, 376. mu. mol). The mixture was stirred at room temperature for 16h, poured onto ice/water (5ml) and 1N NaOH (5ml) and extracted with dichloromethane (2 × 20 ml). The combined organic layers were washed with brine (10ml), dried (MgSO4) and evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH 4OH 150: 10: 1) and triturated from dichloromethane (1ml) and heptane (5ml) for 30 min. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound as a white solid (39mg, 42%), ms (isp) M/z =369.3[ (M + H)⁺]，mp162℃。

Example 2: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-methoxy-propionamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 3-methoxy-propionic acid the title compound was prepared as a white solid (51mg, 50%), ms (isp) M/z =413.5[ (M + H)⁺]，mp136℃。

Example 3: tetrahydro-pyran-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and tetrahydro-pyran-4-carboxylic acid the title compound was prepared as a white solid (66mg, 60%), ms (isp) M/z =439.4[ (M + H)⁺]，mp175℃。

Example 4: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2- (tetrahydro-pyran-4-yl) -acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Preparation of (R) -cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and 2- (tetrahydro-pyran-4-yl) -acetamide the title compound was prepared as whiteColoured solid (58mg, 51%), ms (isp) M/z =453.4[ (M + H)⁺]，mp175℃。

Example 5: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -propionamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and propionic acid the title compound was prepared as a yellow solid (61mg, 64%), ms (isp) M/z =383.4[ (M + H)⁺]，mp162℃。

Example 6: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-methoxy-acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2-methoxy-acetic acid the title compound was prepared as a white solid (59mg, 59%), ms (isp) M/z =399.3[ (M + H)⁺]，mp115℃。

Example 7: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-methanesulfonyl-acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100 m)g, 0.25mmol) and 2-methanesulfonyl-acetic acid the title compound was prepared as a white solid (79mg, 71%), ms (isp) M/z =447.3[ (M + H)⁺]，mp187℃。

Example 8: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } - (RS) -2- [1, 4]IIAlk-2-yl-acetamides

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and (RS) -2- [1, 4]IIAlk-2-yl-acetic acid the title compound was prepared as a white solid (60mg, 53%), ms (isp) M/z =455.3[ (M + H)⁺]，mp172℃。

Example 9: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and benzoic acid the title compound was prepared as a pale yellow solid (65mg, 60%), ms (isp) M/z =431.5[ (M + H)⁺]，mp189℃。

Example 10: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -2- (3-methyl-iso-propyl) -benzeneAzol-5-yl) -acetamides

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and 2- (3-methyl-iso-p-phenylenediamineOxazol-5-yl) -acetic acid the title compound was prepared as an off-white solid (84mg, 74%), ms (isp) M/z =450.3[ (M + H)⁺]，mp165℃。

Example 11: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-hydroxy-acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2-hydroxy-acetic acid the title compound was prepared as an off-white solid (70mg, 73%), ms (isp) M/z =385.4[ (M + H)⁺]，mp161℃。

Example 12: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3, 3-trifluoro-propionamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl radicalAmine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 3, 3, 3-trifluoro-propionic acid the title compound was prepared as an off-white solid (84mg, 77%), ms (isp) M/z =437.3[ (M + H)⁺]，mp182℃。

Example 13: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-morpholin-4-yl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-morpholin-4-yl-benzoic acid the title compound was prepared as a pale yellow solid (103mg, 80%), ms (isp) M/z =516.3[ (M + H)⁺]，mp249℃。

Example 14: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -isobutyramide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Preparation of the title compound as an off-white solid (70mg, 70%), ms (isp) M/z =397.3[ (M + H)⁺]，mp173℃。

Example 15: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-methyl-butyramide

According toExample 1 general procedure is carried out using trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 3-methyl-butyric acid the title compound was prepared as an off-white solid (74mg, 72%), ms (isp) M/z =411.5[ (M + H)⁺]，mp182℃。

Example 16: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-hydroxy-2-methyl-propionamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2-hydroxy-2-methyl-propionamide the title compound was prepared as a white solid (65mg, 63%), ms (isp) M/z =413.4[ (M + H)⁺]，mp169℃。

Example 17: (RS) -tetrahydro-furan-3-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and (RS) -tetrahydro-furan-3-carboxylic acid the title compound was prepared as a light yellow solid (79mg, 75%), ms (isp) M/z =425.2[ (M + H)⁺]，mp183℃。

Example 18: (RS) -tetrahydro-furan-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and (RS) -tetrahydro-furan-2-carboxylic acid the title compound was prepared as an off-white solid (74mg, 70%), ms (isp) M/z =425.3[ (M + H)⁺]，mp132℃。

Example 19: quinoline-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and quinoline-4-carboxylic acid the title compound was prepared as a yellow solid (106mg, 88%), ms (isp) M/z =482.3[ (M + H)⁺]，mp169℃。

Example 20: cyclobutanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and cyclobutanecarboxylic acid the title compound was prepared as an off-white solid (70mg, 69%), ms (isp) M/z =409.4[ (M + H)⁺]，mp180℃。

Example 21: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-hydroxy-propionamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 3-hydroxy-propionic acid the title compound was prepared as an off-white solid (20mg, 20%), ms (isp) M/z =399.3[ (M + H)⁺]，mp148℃。

Example 22: 1-hydroxy-cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 1-hydroxy-cyclopropanecarboxylic acid the title compound was prepared as a white solid (67mg, 65%), ms (isp) M/z =411.3[ (M + H)⁺]，mp200℃。

Example 23: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyano-acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2-cyano-acetic acid the title compound was prepared as an off-white solid (50mg, 51%), ms (isp) M/z =394.3[ (M + H)⁺]，mp186℃。

Example 24: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-fluoro-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-fluoro-benzoic acid the title compound was prepared as a pale yellow solid (92mg, 82%), ms (isp) M/z =449.3[ (M + H)⁺]，mp193℃。

Example 25: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyclopropyl-acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2-cyclopropyl-acetic acid the title compound was prepared as a light yellow solid (74mg, 73%), ms (isp) M/z =409.4[ (M + H)⁺]，mp165℃。

Example 26: tetrahydro-pyran-3-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and (RS) -tetrahydro-pyran-3-carboxylic acid the title compound was prepared as a light yellow solid (78mg, 71%), ms (isp) M/z =439.3[ (M + H)⁺]，mp188℃。

Example 27: cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and cyclopropanecarboxylic acid the title compound was prepared as a white solid (73mg, 74%), ms (isp) M/z =395.3[ (M + H)⁺]，mp204℃。

Example 28: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 2-dimethyl-propionamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2, 2-dimethyl-propionic acid the title compound was prepared as a white solid (76mg, 74%), ms (isp) M/z =411.5[ (M + H)⁺]，mp157℃。

Example 29: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2- (tetrahydro-furan-2-yl) -acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and rac- (tetrahydro-furan-2-yl) -ethaneAcid preparation the title compound was prepared as an off-white solid (62mg, 56%), ms (isp) M/z =439.4[ (M + H)⁺]，mp149℃。

Example 30: 2, 2-difluoro-cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2, 2-difluoro-cyclopropane-carboxylic acid the title compound was prepared as a light brown solid (81mg, 75%), ms (isp) M/z =431.4[ (M + H)⁺]，mp189℃。

Example 31: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (RS) -2-methyl-butyramide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and (RS) -2-methyl-butyric acid the title compound was prepared as an off-white solid (77mg, 75%) with ms (isp) M/z =411.4[ (M + H)⁺]，mp172℃。

Example 32: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (RS) -3, 3, 3-trifluoro-2-hydroxy-propionamide

According to one of embodiment 1The general process consists of trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and (RS) -3, 3, 3-trifluoro-2-hydroxy-propionic acid the title compound was prepared as a light yellow solid (91mg, 81%), ms (isp) M/z =453.3[ (M + H)⁺]，mp206℃。

Example 33: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -butyramide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and butyric acid the title compound was prepared as an off-white solid (60mg, 60%), ms (isp) M/z =397.3[ (M + H)⁺]，mp155℃。

Example 34: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-hydroxy-3-methyl-butyramide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 3-hydroxy-3-methyl-butyric acid the title compound was prepared as a light yellow solid (59mg, 55%), ms (isp) M/z =427.3[ (M + H)⁺]，mp150℃。

Example 35: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (R) -4, 4, 4-trifluoro-3-hydroxy-butyramide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and (R) -4, 4, 4-trifluoro-3-hydroxy-butyric acid the title compound was prepared as an off-white solid (79mg, 68%), ms (isp) M/z =467.2[ (M + H)⁺]，mp166℃。

Example 36: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -methanesulfonamide

To trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]To a stirred mixture of cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) in dichloromethane (1.5ml) was added triethylamine (88.7mg, 122. mu.l, 0.876mmol) and methanesulfonyl chloride (43mg, 29.2. mu.l, 376. mu. mol) at room temperature. The mixture was stirred at room temperature for 18h, and then evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH 40H 150: 10: 1) and triturated with dichloromethane (1mL) and heptane (5mL) for 30 minutes to give the title compound as a white solid (62mg, 61%), ms (isp) M/z =405.4[ (M + H)⁺]，mp142℃。

Example 37: ethanesulfonic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 36 is carried out from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and ethanesulfonyl chloride the title compound was prepared as a white solid (54mg, 51%)，MS(ISP)m／z=419.3[(M+H)⁺]，mp153℃。

Example 38: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-methyl-benzenesulfonamide

The general procedure according to example 36 is carried out from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and p-toluenesulfonyl chloride the title compound was prepared as a light brown solid (79mg, 66%), ms (isp) M/z =481.3[ (M + H)⁺]，mp149℃。

Example 39: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 2, 2-trifluoro-acetamide

The general procedure according to example 36 is carried out from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2, 2, 2-trifluoroacetic anhydride preparation the title compound as an off-white solid (41mg, 39%), ms (isp) M/z =423.2[ (M + H)⁺]，mp152℃。

Example 40: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3-dimethyl-butyramide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexylamineDihydrochloride (intermediate a) (100mg, 0.25mmol) and 3, 3-dimethyl-butyric acid the title compound was prepared as an off-white solid (83mg, 78%), ms (isp) M/z =425.3[ (M + H)⁺]，mp174℃。

Example 41: 3-methyl-isoAzole-5-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and 3-methyl-iso-Oxazole-5-carboxylic acid the title compound was prepared as an off-white solid (89mg, 82%), ms (isp) M/z =436.3[ (M + H)⁺]，mp178℃。

Example 42: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -N ', N' -dimethyl-succinamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4- (dimethylamino) -4-oxobutanoic acid the title compound was prepared as an off-white solid (55mg, 48%), ms (isp) M/z =454.4[ (M + H)⁺]，mp167℃。

Example 43: n' - (trans-4- {2- [4- (benzofuran-3-yl) -piperidin-1-yl ] -ethyl } -cyclohexyl) -N, N-dimethylsulfonamide

The general procedure according to example 36 is carried out from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and dimethylsulfamoyl chloride the title compound was prepared as a pale yellow solid (50mg, 46%), ms (isp) M/z =434.4[ (M + H)⁺]，mp229℃。

Example 44: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4, 4, 4-trifluoro-butyramide

The general procedure of example 1 was followed starting from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4, 4, 4-trifluoro-butyric acid the title compound was prepared as a light brown solid (80mg, 71%), ms (isp) M/z =451.2[ (M + H)⁺]，mp192℃。

Example 45: 4-methyl-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-methyl-pentanoic acid the title compound was prepared as an off-white solid (72mg, 68%), ms (isp) M/z =425.3[ (M + H)⁺]，mp179℃。

Example 46: (R) -3-hydroxy-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

To a solution of (R) -3-hydroxypentanoic acid methyl ester (49.6mg, 48.2. mu.l) in dichloromethaneTo a stirred solution in silane (3ml) was added potassium trimethylsilanolate (64.2mg, 0.5mmol) at room temperature and the mixture was stirred for an additional 18 h. Then N, N-diisopropylethyl-amine (178mg, 1.38mmol), trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl-l-is added]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and TBTU (121mg, 0.376mmol), and the mixture was stirred at rt for 3 h. The reaction mixture was poured into saturated NaHCO3 solution (20ml) and extracted with dichloromethane (2 × 40 ml). The combined organic layers were washed with brine (20ml), dried (MgSO4) and evaporated. The crude material (130mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH 4OH 150: 10: 1) to give the title compound as a white solid (95mg, 89%), ms (isp) M/z =427.3[ (M + H)⁺]，mp142℃。

Example 47: (S) -3-hydroxy-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 46 is followed from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and methyl (S) -3-hydroxypentanoate the title compound was prepared as a white solid (99mg, 93%), ms (isp) M/z =427.3[ (M + H)⁺]，mp140℃。

Example 48: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyclobutyl-acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2-cyclobutyl-acetamide the title compound was prepared as an off-white solid (68mg, 64%), ms (isp) M/z =423.3[ (M + H)⁺]，mp173℃。

Example 49: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-chloro-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-chloro-benzoic acid the title compound was prepared as a light brown solid (95mg, 82%), ms (isp) M/z =465.2[ (M + H)⁺]，mp203℃。

Example 50: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-trifluoromethyl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and 4-trifluoromethylBenzoic acid preparation of the title compound as a light brown solid (98mg, 78%), ms (isp) M/z =499.4[ (M + H)⁺]，mp218℃。

Example 51: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-piperidin-1-yl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-piperidin-1-yl-benzoic acid the title compound was prepared as an off-white solid (95mg, 72%), ms (isp) M/z =514.4[ (M + H)⁺]，mp221℃。

Example 52: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3-dimethoxy-propionamide

The general procedure according to example 46 is followed from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and methyl 3, 3-dimethoxy-propionate the title compound was prepared as a white solid (71mg, 64%), ms (isp) M/z =443.4[ (M + H)⁺]，mp148℃。

Example 53: 3-methyl-but-2-enoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

General according to example 1The process is carried out by reacting trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 3-methyl-but-2-enoic acid the title compound was prepared as an off-white solid (83mg, 81%), ms (isp) M/z =409.4[ (M + H)⁺]，mp147℃。

Example 54: (E) -pent-3-enoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and (E) -pent-3-enoic acid the title compound was prepared as a white solid (71mg, 70%), ms (isp) M/z =409.4[ (M + H)⁺]，mp165℃。

Example 55: but-2-ynoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and but-2-ynoic acid the title compound was prepared as a light brown solid (71mg, 72%), ms (isp) M/z =393.3[ (M + H)⁺]，mp161℃。

Example 56: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -carboxamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and formic acid the title compound was prepared as an off-white solid (20mg, 23%), ms (isp) M/z =355.2[ (M + H)⁺]，mp155℃。

Example 57: pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and pentanoic acid to prepare the title compound as an off-white solid (77mg, 75%), ms (isp) M/z =411.5[ (M + H)⁺]，mp167℃。

Example 58: benzo [1, 3] dioxole-5-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and benzo [1, 3]]Dioxole-5-carboxylic acid the title compound was prepared as an off-white solid (97mg, 82%), ms (isp) M/z =475.3[ (M + H)⁺]，mp198℃。

Example 59: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyrazol-1-yl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-pyrazol-1-yl-benzoic acid the title compound was prepared as a light yellow solid (93mg, 75%), ms (isp) M/z =497.4[ (M + H)⁺]，mp205℃。

Example 60: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butyl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-tert-butyl-benzoic acid the title compound was prepared as a yellow solid (110mg, 90%), ms (isp) M/z =487.5[ (M + H)⁺]，mp180℃。

Example 61: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -benzamides

One method according to example 1 consists of trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and 4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -benzoic acid the title compound was prepared as a yellow solid (111mg, 87%), ms (isp) M/z =513.3[ (M + H)⁺]，mp194℃。

Example 62: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4- (4-methyl-piperazin-1-yl) -benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4- (4-methyl-piperazin-1-yl) -benzoic acid the title compound was prepared as an off-white solid (56mg, 42%), ms (isp) M/z =529.4[ (M + H)⁺]，mp242℃。

Example 63: biphenyl-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and biphenyl-4-carboxylic acid the title compound was prepared as a yellow solid (119mg, 94%), ms (isp) M/z =507.3[ (M + H)⁺]，mp235℃。

Example 64: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyridin-3-yl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-pyridin-3-yl-benzoic acid the title compound was prepared as an off-white solid (98mg, 77%), ms (isp) M/z =508.4[ (M + H)⁺]，mp224℃。

Example 65: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -6-morpholin-4-yl-nicotinamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 6-morpholin-4-yl-nicotinic acid the title compound was prepared as a light yellow solid (81mg, 63%), ms (isp) M/z =517.3[ (M + H)⁺]，mp215℃。

Example 66: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4- (1, 1-dioxo-1. lamda.6-thiomorpholin-4-yl) -benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4- (1, 1-dioxo-1 λ 6-thiomorpholin-4-yl) -benzoic acid the title compound was prepared as a light yellow solid (116mg, 82%), ms (isp) M/z =564.4[ (M + H)⁺]，mp269℃。

Example 67: 5-morpholin-4-yl-pyrazine-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 5-morpholin-4-yl-pyrazine-2-carboxylic acid the title compound was prepared as an off-white solid (95mg, 73%), ms (isp) M/z =518.4[ (M + H)⁺]，mp202℃。

Example 68: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyrrol-1-yl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-pyrrol-1-yl-benzoic acid the title compound was prepared as an off-white solid (77mg, 62%), ms (isp) M/z =496.4[ (M + H)⁺]，mp212℃。

Example 69: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -6-methyl-nicotinamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 6-methyl-nicotinic acid the title compound was prepared as a yellow solid (66mg, 59%), ms (isp) M/z =446.4[ (M + H)⁺]，mp203℃。

Example 70: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyano-benzamides

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-cyano-benzoic acid the title compound was prepared as a yellow solid (54mg, 47%), ms (isp) M/z =456.5[ (M + H)⁺]，mp195℃。

Example 71: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butoxy-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-tert-butoxy-benzoic acid the title compound was prepared as a white solid (82mg, 65%), ms (isp) M/z =503.3[ (M + H)⁺]，mp186℃。

Example 72: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-trans- (4-methoxy-cyclohexyl) -acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and trans- (4-methoxy-cyclohexyl) -acetic acid the title compound was prepared as an off-white solid (70mg, 58%), ms (isp) M/z =481.4[ (M + H)⁺]，mp179℃。

Example 73: quinoline-6-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and quinoline-6-carboxylic acid the title compound was prepared as a yellow solid (106mg, 88%), ms (isp) M/z =482.4[ (M + H)⁺]，

Example 74: trans-2-benzo [1, 3] dioxol-5-yl-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and 2- (benzo [1, 3] amine]Dioxol-5-yl) -acetic acid the title compound was prepared as an off-white solid (79mg, 65%), ms (isp) M/z =489.3[ (M + H)⁺]，mp177℃。

Example 75: 5-methanesulfonyl-thiophene-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexylamine dihydrochlorideSalt (intermediate a) (100mg, 0.25mmol) and 5-methanesulfonyl-thiophene-2-carboxylic acid the title compound was prepared as a yellow solid (101mg, 78%), ms (isp) M/z =515.3[ (M + H)⁺]，mp214℃。

Example 76: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-oxetan-3-yl-acetamide

The general procedure according to example 46 is followed from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and methyl 2- (oxetan-3-yl) acetate the title compound was prepared as a white solid (99mg, 93%), ms (isp) M/z =425.4[ (M + H)⁺]，mp197℃。

Example 77: 4-tert-butyl-cyclohexanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-tert-butyl-cyclohexanecarboxylic acid the title compound was prepared as an off-white solid (77mg, 63%), ms (isp) M/z =493.4[ (M + H)⁺]，mp199℃。

Example 78: adamantane-1-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and adamantane-1-carboxylic acid the title compound was prepared as a light yellow solid (94mg, 77%), ms (isp) M/z =489.4[ (M + H)⁺]，mp200℃。

Example 79: 4-trifluoromethyl-cyclohexanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-trifluoromethyl-cyclohexanecarboxylic acid the title compound was prepared as a white solid (42mg, 33%), ms (isp) M/z =505.3[ (M + H)⁺]，mp190℃。

Example 80: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isobutyl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Preparation of cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-isobutyl-benzoic acid the title compound was prepared as an off-white solid (89mg, 73%), ms (isp) M/z =487.4[ (M + H)⁺]，mp190℃。

Example 81: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-ethyl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-ethyl-benzoic acid the title compound was prepared as a white solid (94mg, 82%), ms (isp) M/z =459.5[ (M + H)⁺]，mp192℃。

Example 82: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyclohexyl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-cyclohexyl-benzoic acid the title compound was prepared as a white solid (114mg, 89%), ms (isp) M/z =513.6[ (M + H)⁺]，mp230℃。

Example 83: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isopropyl-benzamide

One method according to example 1 consists of trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-isopropyl-benzoic acid the title compound was prepared as a light yellow solid (42mg, 36%), ms (isp) M/z =473.4[ (M + H)⁺]，mp188℃。

Example 84: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyclopropyl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-cyclopropyl-benzoic acid the title compound was prepared as a light yellow solid (85mg, 72%), ms (isp) M/z =471.4[ (M + H)⁺]，mp199℃。

Example 85: trans-2-benzo [ d ]]Different from each otherAzol-3-yl-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -acetamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100mg, 0.25mmol) and 2-benzo [ d ]]Different from each otherOxazole-acetic acid the title compound was prepared as a white solid (93mg, 76%), ms (isp) M/z =486.4[ (M + H)⁺]，mp175℃。

Example 86: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-methanesulfonyl-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuro)Pyran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-methanesulfonyl-benzoic acid the title compound was prepared as an off-white solid (95mg, 75%), ms (isp) M/z =509.3[ (M + H)⁺]，mp224℃。

Example 87: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 4-dichloro-benzamide

The general procedure according to example 1 was followed to synthesize trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 2, 4-dichloro-benzoic acid the title compound was prepared as a light yellow solid (88mg, 70%), ms (isp) M/z =499.3[ (M + H)⁺]，mp187℃。

Example 88: trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butyl-benzenesulfonamide

The general procedure according to example 36 is carried out from trans-4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]Cyclohexylamine dihydrochloride (intermediate a) (100mg, 0.25mmol) and 4-tert-butyl-benzenesulfonyl chloride the title compound was prepared as a white solid (92mg, 70%), ms (isp) M/z =523.6[ (M + H)⁺]，mp171℃。

Biochemical assay

The compounds bind to 5-HT_2A、D₃And D₂Receptor capacity was determined using radioligands that bound to cloned receptors selectively expressed in HEK-293EBNA cells.

Film preparation

HEK293EBNA cells encoding human D₂Or D₃Or encode human 5-HT_2AExpression plasmids for the receptor were transiently transfected. Cells were harvested 48h post transfection, washed three times with cold PBS and stored at-80 ℃ prior to use. The pellet was suspended in cold 50mM Tris-HCl buffer (pH7.4) containing 10mM EDTA and homogenized with Polytron (Kinematica AG, Basel, Switzerland) at 12.000rpm for 20-30 seconds. After centrifugation at 48.000X g for 30min at 4 ℃, the pellet was resuspended in cold 10mM Tris-HCl buffer (pH7.4) containing 0.1mM EDTA, homogenized, and centrifuged as above. This pellet was further resuspended in a smaller volume of ice-cold 10mM Tris-HCl buffer (pH7.4) containing 0.1mM EDTA and homogenized with Polytron at 12.000rpm for 20-30 seconds. The Protein content of this homogenate was determined using gamma globulin as standard using Bio-Rad (Bradford) Protein Assay (Biorad Laboratories GmbH, Munich, Germany) according to the manufacturer's instructions. This homogenate was stored in aliquots at-80 ℃ and thawed immediately prior to use.

Radioligand binding assays

Aliquots of membrane preparations were thawed at room temperature and resuspended in assay buffer (D)₂，D₃：50mMTris-HCl，120mM NaCl，5mM MgCl₂，1mM EDTA，5mM KCl，1.5mMCaCl₂，pH=7.4；5-HT_2A：50mM Tris-HCl，10mM MgCl₂1mM EGTA, pH =7.4), homogenized with Polytron at 12.000rpm for 20-30 seconds and adjusted to approximately 7.5. mu.g protein/well (D), respectively₂，D₃) And 15. mu.g protein/well (5-HT)_2A) To the final concentration of (c).

Binding affinity (K) of said compound_i) Determined using radioligand binding. Membranes were treated with a fixed concentration of radioligand (for D) in a total volume of 200. mu.l₂A final concentration of about 0.7nM³H]Spiperone for D₃Is 0.5nM [ 2]³H]-spiperone, and for 5-HT_2AIs 1.1nM [ 2]³H]Ketanserin) and ten concentrations of test compound ranging from 10 μ M to 0.1nM were incubated for 1h at room temperature. At the end of the incubation, the reaction mixture was filtered onto a unifilter 96-well white microplate with an adhesive GF/C filter (Packard BioScience, Z rich, Switzerland; preincubated for 1h in 0.1% Polyethyleneimine (PEI) in assay buffer), with a Filtermate196 harvester (Packard BioScience) and washed 3 times with cold assay buffer. Non-specific binding was determined with the same composition of the reaction mixture in the presence of 10. mu.M unlabeled spiperone. Add 45. mu.l of Microscint40(Perkin Elmer, Schwerzenbach, Switzerland) per well, plate for sealing, shake for 20min and count for 3min on a Topcount Microplate Scintillation Counter (Topcount Microplate Scintillation Counter) (Canberra PackardSA, Z rich, Switzerland) with quenching correction.

Data computation

CPM values were averaged for each replicate of the concentration of the competing compound (y1), and% specific binding was then calculated according to the following formula: ((y 1-nonspecific)/(total binding-nonspecific)) x 100). Curves were plotted with% specific binding using XLfit (a curve fitting program that plots data iteratively using the Levenberg-Marquardt algorithm). The single site competition assay formula used was y = a + ((B-a)/(1 + ((x/C) D))), where y is% specific binding, a is the smallest y, B is the largest y, and C is IC₅₀X is the log10 of the concentration of the competing compound and D is the slope of the curve (Hill coefficient). From these curves, the IC was determined₅₀(inhibitory concentration at which 50% of the specific binding of the radioligand is replaced) and Hill coefficient. Affinity constant (K)_i) Using Cheng-Prusoff equation K_i=(IC₅₀／1+([L]／K_d) Calculation of where [ L]Is the concentration of the radioligand_dIs the dissociation constant of the radioligand at the receptor as determined by saturation isotherm.

The compound of the invention is 5-HT_2AAnd D₃Selective dual modulators of the receptor, as shown in table 1 below. Examples the aboveThe assay is performed in a medium and is measured to have a K of about 0.1nM to about 1 μ M_i5-HT_2AValues and K of about 0.1nM to about 1. mu.M_i D₃The value is obtained. The specific compound of formula (I) is measured to have a K of about 0.1nM to about 100nM_i5-HT_2AValues and Ks of about 0.1nM to about 200nM_i D₃The value is obtained. More particular compounds of formula (I) were determined to have Ks of about 1nM to about 50nM_i5-HT_2AValues and Ks of about 0.1nM to about 50nM_i D₃The value is obtained. More particular compounds of formula (I) were determined to have Ks of about 1nM to about 10nM_i5-HT_2AValues and Ks of about 0.1nM to about 10nM_i D₃The value is obtained.

Measuring the specific compound of formula (I) and D₂Receptors bind to 5-HT more selectively than to factors of 5-fold or more, more particularly 10-fold or more, and most particularly 15-fold or more_2AA receptor. Measuring the specific compound of formula (I) and D₂Receptors bind to D more selectively than by factors of 5-fold or more, more particularly 10-fold or more, and most particularly 15-fold or more₃A receptor.

A particular embodiment of the invention relates to the ratio D₂Receptors bind 5-HT more selectively with 14-fold or more factors_2AAcceptor, and ratio D₂Receptors bind to D with greater than 15-fold selectivity₃A compound of formula (I) or pharmaceutically acceptable salts and esters thereof.

Table 1: binding affinity to HEK293EBNA cells expressing human (h) receptor of representative examples.

Claims (26)

1. A compound of formula (I)

Wherein

n is 0, 1, 2, 3 or 4;

y is-C (O) -or-S (O)₂-；

R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, adamantyl, heterocycloalkyl,aryl, aryl condensed with heterocycloalkyl, heteroaryl, -NR⁶R⁷Hydroxy, alkoxy, or haloalkoxy; and is

Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkoxy and haloalkoxy are optionally substituted with one, two or three independent R⁴Substitution; and is

Wherein cycloalkyl, adamantyl, heterocycloalkyl, aryl, heterocycloalkyl-fused aryl and heteroaryl are optionally substituted with one, two or three independent R⁵Substitution;

R²，R³independently hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy;

R⁴is cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C (O) NR⁶R⁷，-NR⁶R⁷-NH (CO) -alkyl, hydroxy, alkoxy, haloalkoxy, oxo, or-S (O)₂R⁶；

And is

Wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three independent R⁵Substitution;

R⁵is halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C (O) NR⁶R⁷，-NR⁶R⁷-NH (CO) -alkyl, hydroxy, alkoxy, haloalkoxy, oxo, or-S (O)₂R⁶(ii) a And is

Wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from: halogen, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy and oxo;

R⁶，R⁷independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl or heteroaryl;

and pharmaceutically acceptable salts and esters thereof.

2. The compound of claim 1, wherein n is 0, 1 or 2.

3. The compound of any one of claims 1-2, wherein Y is-c (o) -.

4. The compound of any one of claims 1-3, wherein R¹Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, adamantyl, heterocycloalkyl, aryl fused with heterocycloalkyl, heteroaryl, -NR⁶R⁷Hydroxy, alkoxy, or haloalkoxy; and wherein alkyl and haloalkyl are optionally substituted with one, two or three independent R⁴Substitution; and wherein cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three independent R⁵Substitution; and wherein R⁴，R⁵，R⁶And R⁷As claimed in claim 1.

5. The compound of any one of claims 1-4, wherein R¹Is hydrogen, methyl substituted by methoxy, n-propyl substituted by hydroxy, isopropyl substituted by hydroxy, n-butyl, tert-butyl, n-propenyl, isobutenyl, propynyl, trifluoromethyl, trifluoroethyl substituted by hydroxy, cyclopropyl substituted by fluorine, cyclopropyl substituted by hydroxy, cyclobutyl, cyclohexyl substituted by tert-butyl, cyclohexyl substituted by trifluoromethyl, cyclohexyl substituted by methoxy, adamantyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, di-n-propyl, cyclopropyl substituted by hydroxy, cyclopropyl substituted by fluoro, cyclopropyl substituted by hydroxy, cyclobutyl, cyclohexyl substituted by tert-butyl, cyclohexyl substituted by trifluoromethyl, cyclohexyl substituted by methoxy, adamantyl, oxetanyl, tetrahydrofuranyl, di-n-propyl, trifluoromethylAlkyl, phenyl, by R⁸Substituted phenyl, benzodioxolyl, isobenzoylAzolyl, methyl-substituted iso-phenylOxazolyl, thienyl substituted by methyl-sulfonyl, pyridyl substituted by methyl, pyridyl substituted by morpholinyl, pyrazinyl substituted by morpholinyl, quinolyl, benzisoxazolylAzolyl, -N (methyl)₂Hydroxy, or methoxy;

and wherein R⁸Selected from the group consisting of fluoro, chloro, cyano, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclohexyl, piperidinyl, methyl-piperazinyl, morpholinyl, dioxo-thiomorpholinyl, phenyl, pyrrolyl, pyrazolyl, methyl-Oxadiazolyl, pyridinyl, tert-butoxy, or methyl-sulfonyl.

6. The compound of any one of claims 1-5, wherein R¹Is cyclohexyl, cyclohexyl substituted by tert-butyl, tetrahydropyranyl, diAlkyl, methoxy, phenyl, or phenyl substituted with a substituent selected from the list of: ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, piperidinyl, morpholinyl, methyl-Oxadiazolyl and tert-butoxy.

7. According to claim1-6, wherein R²And R³Is hydrogen.

8. The compound of any one of claims 1-7, wherein R⁴Is cyano, -C (O) -NR⁶R⁷Hydroxy, alkoxy, or-S (O)₂R⁶。

9. The compound of any one of claims 1-8, wherein R⁴Is cyano, -C (O) N (methyl)₂Hydroxy, methoxy, or methyl-sulfonyl.

10. The compound of any one of claims 1-9, wherein R⁵Is halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, or alkylsulfonyl; and wherein heterocycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from alkyl and oxo.

11. The compound of any one of claims 1-10, wherein R⁵Is fluorine, chlorine, cyano, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclohexyl, piperidinyl, methyl-piperazinyl, morpholinyl, dioxo-thiomorpholinyl, phenyl, pyrrolyl, pyrazolyl, methyl-Oxadiazolyl, pyridinyl, hydroxy, methoxy, t-butoxy, or methyl-sulfonyl.

12. The compound of any one of claims 1-11, wherein R⁵Is ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, piperidinyl, morpholinyl, methyl-Oxadiazolyl, or tert-butoxy.

13. The compound of any one of claims 1-12, wherein R⁶And R⁷Independently selected from alkyl groups.

14. The compound of any one of claims 1-13, wherein R⁶And R⁷Is methyl.

15. The compound of any one of claims 1-14, selected from the group consisting of:

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-methoxy-propionamide;

tetrahydro-pyran-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2- (tetrahydro-pyran-4-yl) -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-methoxy-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-methanesulfonyl-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } - (RS) -2- [1, 4]IIAlk-2-yl-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -2- (3-methyl-iso-propyl) -benzeneOxazol-5-yl) -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-hydroxy-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3, 3-trifluoro-propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-morpholin-4-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -isobutyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-methyl-butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-hydroxy-2-methyl-propionamide;

(RS) -tetrahydro-furan-3-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

(RS) -tetrahydro-furan-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

quinoline-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

cyclobutanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-hydroxy-propionamide;

1-hydroxy-cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyano-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-fluoro-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyclopropyl-acetamide;

tetrahydro-pyran-3-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 2-dimethyl-propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2- (tetrahydro-furan-2-yl) -acetamide;

2, 2-difluoro-cyclopropanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (RS) -2-methyl-butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (RS) -3, 3, 3-trifluoro-2-hydroxy-propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-hydroxy-3-methyl-butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } - (R) -4, 4, 4-trifluoro-3-hydroxy-butyramide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -methanesulfonamide;

ethanesulfonic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-methyl-benzenesulfonamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 2, 2-trifluoro-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3-dimethyl-butyramide;

3-methyl-isoAzole-5-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -N ', N' -dimethyl-succinamide;

n' - (trans-4- {2- [4- (benzofuran-3-yl) -piperidin-1-yl ] -ethyl } -cyclohexyl) -N, N-dime thylsulfonamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4, 4, 4-trifluoro-butyramide;

4-methyl-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

(R) -3-hydroxy-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

(S) -3-hydroxy-pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-cyclobutyl-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-chloro-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-trifluoromethyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-piperidin-1-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3, 3-dimethoxy-propionamide;

3-methyl-but-2-enoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

(E) -pent-3-enoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

but-2-ynoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -carboxamide;

pentanoic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

benzo [1, 3] dioxole-5-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyrazol-1-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4- (4-methyl-piperazin-1-yl) -benzamide;

biphenyl-4-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyridin-3-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -6-morpholin-4-yl-nicotinamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4- (1, 1-dioxo-1 λ 6-thiomorpholin-4-yl) -benzamide;

5-morpholin-4-yl-pyrazine-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-pyrrol-1-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -6-methyl-nicotinamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyano-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butoxy-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-trans- (4-methoxy-cyclohexyl) -acetamide;

quinoline-6-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-2-benzo [1, 3] dioxol-5-yl-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -acetamide;

5-methanesulfonyl-thiophene-2-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-oxetan-3-yl-acetamide;

4-tert-butyl-cyclohexanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

adamantane-1-carboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

4-trifluoromethyl-cyclohexanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isobutyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-ethyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyclohexyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isopropyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyclopropyl-benzamide;

trans-2-benzo [ d ]]Different from each otherAzol-3-yl-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-methanesulfonyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2, 4-dichloro-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butyl-benzenesulfonamide; and

pharmaceutically acceptable salts and esters thereof.

16. The compound of any one of claims 1-15, selected from the group consisting of:

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -3-methoxy-propionamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2- (tetrahydro-pyran-4-yl) -acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -2-methoxy-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } - (RS)-2-[1，4]IIAlk-2-yl-acetamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-morpholin-4-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-trifluoromethyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-piperidin-1-yl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl]-cyclohexyl } -4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-tert-butoxy-benzamide;

4-tert-butyl-cyclohexanecarboxylic acid trans- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -amide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isobutyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-ethyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-isopropyl-benzamide;

trans-N- {4- [2- (4-benzofuran-3-yl-piperidin-1-yl) -ethyl ] -cyclohexyl } -4-cyclopropyl-benzamide; and

pharmaceutically acceptable salts and esters thereof.

17. A process for preparing a compound according to any one of claims 1-16, the process comprising:

a) a compound of formula (V)

And formula R¹(CH₂)_nC(O)OH，R¹(CH₂)_nC (O) OR OR R¹(CH₂)_nS(O)₂Reaction of a compound of Cl; or

b) A compound of formula (II)

Reaction with a Compound of formula (VI)

Wherein n, Y, R¹，R²And R³As defined in any one of claims 1 to 16 and R is alkyl.

18. A compound according to any one of claims 1 to 16, obtainable by the process of claim 17.

19. A pharmaceutical composition comprising a compound according to any one of claims 1-16 and a pharmaceutically acceptable excipient.

20. A compound according to any one of claims 1-16 for use as therapeutically active substance.

21. A compound according to any one of claims 1-16 for use in the treatment or prevention of: psychotic disorders, depression, anxiety disorders, drug addiction, attention deficit hyperactivity disorder, dementia and memory deficits, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

22. A method for treating or preventing the following diseases: psychotic disorders, depression, anxiety disorders, drug addiction, attention deficit hyperactivity disorder, dementia and memory deficits, wherein psychotic disorders comprise schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions, which method comprises administering a compound according to any of claims 1-16 to a human being or animal.

23. Use of a compound according to any one of claims 1-16 for the manufacture of a medicament.

24. The use of a compound according to any one of claims 1-16 for the preparation of a medicament for the treatment or prevention of psychotic disorders, depression, anxiety, drug addiction, attention deficit hyperactivity disorder, dementia and memory impairment, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

25. Use of a compound according to any one of claims 1-16 for the treatment or prevention of: psychotic disorders, depression, anxiety disorders, drug addiction, attention deficit hyperactivity disorder, dementia and memory deficits, wherein psychotic disorders include schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions.

26. The invention as hereinbefore described.