New derivatives of cyclic amide

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

 

The technical field

The present invention relates to new compounds, which act as ligand Sigma receptor/binding site, and medicines containing these compounds as the active ingredient.

Prior art

Recently identified Sigma receptor/binding site brain is an important target in the development of antipsychotic (neuroleptic) funds, which are devoid of side effects inherent in the currently available antipsychotic means, having antagonistic activity towards dopamine D2 receptor (J.M.Walker and W.D.Bowen, F.O.Walker and R.R.Matsumoto, B. de Costa and K.C.Rice, Pharmacological Reviews, 42, pp.355-402, 1990; G. Debonnel, J. Psychiatr. Neurosci., 18, 4, pp.157-172, 1993; G.Debonnel and C. de Montigny, Life Sciences, 58, 9, pp.721-734, 1996). In addition, it was reported some evidence of the regulation of signal transmission Sigma ligand (also referred to in the description of the ligand of the Sigma receptor”) and its receptor by controlling the level of calcium uptake (P.J.Brent, H.Saunders and P.R.Dunkley, Neurosci. Lett., 211, pp.138-142, 1996).

Used herein, the term "receptor" refers to the type of receptor, to bind to the membrane and other binding sites. It was found the existence of at least two subtypes of Sigma receptors, ie, Sigma 1 and Sigma 2, and was proposed CL is suficate Sigma binding sites (R.Quirion, W.D.Bowen, Y.Itzhak, J.L.Junien, J.M.Musacchio, R.B.Rothman, T.P.Su, W.Tam and D.P.Taylor, TiPS, 13, pp.85-86, 1992). Sigma-1 binding site is characterized by the fact that it has high affinity for haloperidol, di-o-tolylguanidine (DTG) and (+)-benzomorphan, such as (+)-pentazocine, while Sigma 2 binding site is characterized by the fact that it has high affinity for haloperidol and DTG, but has a low affinity for (+)-benzomorphan.

Sigma-1 ligand has an effect on the gastrointestinal tract, and it is possible that Sigma 1 website can mediashout suppression of acetylcholine receptor-like muscarine/phosphoinositide response Sigma ligands. Sigma-1 binding site is present not only in the brain but in cells of the spleen (Y.Lin, B.B.Whitlock, J.A.Pultz and S.A.Wolfe Jr, J.Neuroimmunol, 58, pp.143-154, 1995), and such Sigma ligands can suppress the immune system (H.H.Garza, S.Mayo, W.D.Bowen, B.R.DeCosta and D.J.J.Carr, J. of Immunology, 151, 9, pp.4672-4680, 1993).

Sigma 2 binding site is present in excess in the liver (A.E.Bruce, S.B.Hellewell and W.D.Bowen, Neurosci. Abstr., 16, 370, 1990; A.S.Basile, I.A.Paul and B.DeCosta, Eur. J.Pharmacol. Mol. Pharm. Sect., 227, pp.95-98, 1992; C.Torrence-Campbell and W.D.Bowen, Eur. J. Pharmacol., 304, pp.201-210, 1996), kidney (W.D.Bowen, G.Feinstein and J.S.Orringer, Soc. Neurosci. Abstr., 18, 456, abstract HKD 195.8, 1992), and heart (M. Dumont and S. Lemaire, Eur. J. Pharmacol., 209, pp.245-248, 1991).

Sigma 2 binding site in the brain exists in the hypothalamus, cerebellum, bridge brain (the part of the brain stem) and the medulla. In the hippocampus, lobn the second lobe and the occipital lobe of rat brain, it exists in greater abundance than Sigma 1 binding site (D.J.McCann, and A.D.Weissmann T.P.Su Soc. Neurosci. abstr. 18, 22, abstract 16.5, 1992). The uptake in the hippocampus of the Guinea pig also has Sigma 2 binding site, which can be selectively labeled radioactive label [3H] BIMU (D.W.Bonhaus, D.N.Loury, L.B.Jakeman, To Z., A. DeSouza, R.M.Eglen E.H.F. and Wong, J. Pharmacol. Exp. Ther., 267, 2, pp.961-970, 1993). The relationship between Sigma 2 binding site and the cortex of the cerebral hemispheres, as well as the limbic system of the brain confirms the usefulness of the compounds used for the treatment of diseases associated with mental disorders (D.C.Mash and C.P.Zabetian, Synapse, 12, pp.195-205, 1992).

Believed that Sigma 2 binding site involved in motor function, particularly dystonia (R.R.Matsumoto, M.K.Hemstreet, N.L.Lai and A.Thurkauf, B.R.DeCosta, K.C.Rice, S.B.Hellewell, W.D.Bowen and J.M.Walker, Pharmacol. Biochem. Behav., 36, pp.151-155, 1990). However, in models of primates with functional disorders of extrapyramidal path found no evidence supporting such action (L.T.Meltzer, C.L.Christoffersen, K.A.Serpa, T.A.Pugsley, A.Razmpour and T.G.Heffner, Neuropharmacology, 31, 9, pp.961-967, 1992).

Haloperidol, which is clinically effective dopaminergic antiserotonin tool that shows a high affinity to these two Sigma subtypes. However, the reduced metabolite of haloperidol, which acts on the Central nervous system, has a higher affinity selectively in relation to Sigma 2 receptor, than dopamine D2, compared with haloperidol (J.C.Jaen., B.W.Caprathe, T.A.Pugsley, L.D.Wise and H.Akunne, J.Med. Chem., 36, pp.3929-3936, 1993). Because selective means does not exist, there is no relevant studies that explain the pharmacological significance, distribution and function of Sigma 2 binding site. On the other hand, recent studies have shown that Sigma 2 website plays a role in the regulation of the ileum (G.G.Kinney, E.W.Haris, R.Ray and T.J.Hudzik, Europ. J.Pharmacol, 294, pp.547-553, 1995). These data confirm that the selective Sigma-2 ligand are useful for the treatment of irritable bowel syndrome.

Such Sigma ligands are disclosed in open display patent application Japan No.9-302607, open display of patent applications filed in Japan under the PCT, No.10-508826, etc. However, in these publications are not described derivatives of cyclic amide, such as isoindoline-1-he, as a typical example.

As compounds which have a structure similar to the compounds of General formula (I) of the present invention, in an open display of patent applications filed in Japan under the PCT, No.7-506107 disclosed 4-aminomethyl-1-[2'-phenyl-2'-oxoethyl]piperidine, such as:

and hydrochloride and the like. However, these compounds have been described as antagonists of serotonin 2, and was not yet known whether they will or no action is SQL as Sigma ligands. In addition, these compounds having phthalimido group, it may be possible to have the issue of lack of security.

The invention

The aim of the present invention is the provision of a new connection, which has a high degree of affinity for the Sigma binding site. Another objective of the present invention is the provision of medicines, including a connection with the above properties, as an active ingredient useful for the treatment of diseases that can be treated therapeutically and/or prophylactically through regulatory actions on nerve Sigma ligand.

The authors of the present invention have conducted a thorough investigation aimed at achieving the above goals. In the result it was found that the compounds represented by formula (I) below, have a high affinity for the binding site of the Sigma ligand and low inhibition constant Ki for Sigma 1 and/or Sigma 2. In addition, it was found that these compounds have a profile of selective binding, completely different from the profiles of known compounds, and are useful for treating diseases that can be treated therapeutically and/or prophylactically through regulatory actions on nerve Sigma legend. The present invention is based on the s data.

The present invention relates to compounds represented by the following formula (I)or their salts or hydrates, or solvate:

where:

X represents alkyl group, substituted cycloalkyl alkyl group, a substituted aryl alkyl group, substituted aryl alkenylphenol group, substituted aryl alkylamino group, monocyclic or polycyclic cycloalkyl group which may be substituted by an alkyl group, aryl group, heterocyclic group, or a substituted or an unsubstituted amino group;

Q represents a group represented by-CH2-, -CO-, -O-, -S-, -CH(OR7)-, -C(=CH2)- or-C(=NR8)- (where R7represents a hydrogen atom, alkyl group, hydroxyalkyl group, or acyl group, and R8represents a hydroxyl group, CNS group, aralkylated, alloctype, alluminare or alkoxycarbonylmethyl);

n represents an integer from 0 to 5;

R1and R2each independently represents a hydrogen atom or alkyl group, or R1and R2connect with education alkalinous group;

B represents any of the following groups:

,

(where R3, R4, R5and R6each, independently researched the performance is Deputy, selected from the group consisting of hydrogen atom, halogen atom, nitro group, alkyl group, halogenated alkyl group, hydroxyl group, CNS group, halogenated CNS group and cyanopropyl);

m is 1 or 2; and

ring:

represents 5 - or 6-membered aromatic heterocyclic ring containing one or two heteroatoms, which may be substituted.

In accordance with another aspect of the present invention relates to medicines, which comprise as an active ingredient a substance selected from the group consisting of the aforementioned compounds and their salts and hydrate and solvate. In a preferred variant embodiment of the invention relates to the aforementioned drugs are used to treat diseases that can be treated therapeutically and/or prophylactically through regulatory actions on nerve Sigma ligand (for example, diseases of the Central nervous system, gastro-intestinal tract, diseases associated with disorders of the heart and the like). In addition, the present invention relates to a Sigma ligand, which comprises a substance selected from the group consisting of the aforementioned compounds and their salts and hydrate and solvate.

In accordance with other aspects, the present invention relates to the use of a substance selected from the group consisting of the aforementioned compounds and their salts, hydrate and solvate to obtain the above-mentioned drugs, preferably in the form of pharmaceutical compositions, and method of therapeutic and/or prophylactic treatment of diseases by means of regulatory actions on nerve Sigma ligands, which include the introduction of a mammal, including humans, an effective amount of a substance selected from the group consisting of the aforementioned compounds and their salts, hydrate and solvate.

The preferred embodiment of the invention

In the above formula (I), X represents alkyl group, substituted cycloalkyl alkyl group, a substituted aryl alkyl group, substituted aryl alkenylphenol group, substituted aryl alkylamino group, monocyclic or polycyclic cycloalkyl group which may be substituted by an alkyl group, aryl group, heterocyclic group, or a substituted or an unsubstituted amino group.

Used herein, the term "alkyl group" and the term "alkyl" group-containing alkyl group as part covers, for example, straight or branched alkyl group having from 1 to 6 of plastics technology : turning & is-breaking atoms, preferably from 1 to 4 carbon atoms. In particular, as the alkyl groups can be used methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, isopentyl group, neopentyl group, tert-pencilina group, n-exilda group, etc.

In the description, the term "alkyl group" includes groups, having one or more substituents, unless otherwise stated. Examples of the substituent include a halogen atom, a nitro-group, cycloalkyl group, aryl group, alloctype, heteroaryl group, hydroxyl group, CNS group, halogenated CNS group, carboxyl group, alkoxycarbonyl group, a substituted or an unsubstituted amino group, acyl group, or cyano. As these substituents, preferably you can use the groups described below.

Used herein, the term "cycloalkyl group" and the term "cycloalkyl for a group containing cycloalkyl group as part covers, for example, 3-8-membered cycloalkyl group, preferably approximately 3-6-membered cycloalkyl group (monocyclic cycloalkyl group, unless otherwise stated). These cycloalkyl group can do is be one or more alkyl groups on their rings. In particular, for example, as cycloalkyl groups can be used cyclopropyl group, methylcyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, methylcyclohexyl group, dimethylcyclohexyl group, etc. as polycyclic cycloalkyl you can use the group 5-12-membered polycyclohexylene group, such as norbornylene group or adamantly group, and preferably can be used adamantly group.

Examples of substituted cycloalkyl alkyl groups include, for example, cyclopropylmethyl group, methylcyclopentadienyl group, cyclopropylethyl group, cyclopropylamino group, cyclobutylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, dimethylcyclohexylamine group, etc.

Used herein, the term "aryl group" and the term "aryl" group, aryl group as part covers, for example, monocyclic, bicyclic or tricyclic aryl group containing from about 6 to 14 atoms. For example, it is possible to use phenyl group, 1-naftalina group and 2-naftalina group, and phenanthroline group, antarctilyne group, etc. in Addition, the term "aryl group" includes bicyclic what if tricyclic aryl group, the ring or rings which are partially gidrirovanny, 5,6,7,8-tetrahydronaphthalene group.

Used herein, the term "Alchemilla group" includes straight or branched alkeneamine group having from 2 to 6 carbon atoms, preferably from 3 to 6 carbon atoms, and containing one or more double bonds, preferably one double bond. For example, as alkenylphenol groups can be used 1-protanilla group, allyl group, Isopropenyl group, 1-bucinellina group, 3-bucinellina group, 1-penttila group, 2-penttila group, 3-penttila group, 4-penttila group, 1-examilia group, 2-examilia group, etc. of the Double bond contained in alkenylphenol group may be either CIS-or TRANS-configuration.

The term "Alchemilla group" includes straight or branched alkyline group having from 2 to 6 carbon atoms, preferably from 3 to 6 carbon atoms, for example, 2-proponila group, 3-Butyrina group, 4-penicilina group, 5-hexylamine group, etc.

As the heterocyclic group may use 5-10-membered monocyclic-tricyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, as atoms constituting the ring. E.g. the measures acceptable groups include follow group (furan ring), benzofuranyl group (ring benzofuran), isobenzofuranyl group (ring isobenzofuran), thienyl group (thiophene ring), benzothiophene group (ring benzothiophene), pyrrolidinyl group (pyrrole ring), imidazolidinyl group (imidazole ring), pyrazolidine group (ring of pyrazole), thiazolidine group (thiazole ring), benzothiazolyl group (the ring of the benzothiazole), isothiazoline group (ring isothiazole), benzisothiazolinone group (ring benzisothiazole), triazolyl group (triazole ring), tetrazolyl group (ring tetrazole), pyridyloxy group (pyridine ring), personilnya group (ring pyrazine), pyrimidinyl group (pyrimidine ring), pyridazinyl group (ring pyridazine), indolenine group (indole ring), isoindolyl group (ring, isoindole), benzimidazolyl group (ring of benzimidazole), parinello group (purine ring), pinolillo group (quinoline ring), izohinolinove group (the ring of the isoquinoline), dihydroisoquinolyl group (ring-dihydroisoquinoline), talinolol group (ring phthalazine), naphthylidine group (ring naphthylidine), khinoksalinona group (ring finokalia), indolinyl group (ring cinnoline), pteridinyl group (ring FR is Regina), oxazolidinyl group (ring oxazole), isoxazolyl group (ring isoxazol), benzoxazolyl group (ring benzoxazole), benzisoxazole group (ring benzisoxazole), foratenolol group (ring of furazan), oxazinyl group (ring oxazine), etc. in Addition, you can use the heterocyclic group, the ring or rings which are partially gidrirovanny, including pyrrolidinyloxy group (ring pyrrolidine), imidazolidinyl group (ring of imidazolidine), piperidinyloxy group (piperidine ring), piperazinilnom group (piperazine ring), morpholinyl group (ring research), etc. Among those listed in as the heterocyclic group in accordance with the present invention preferably use a 5-7-membered monocyclic heterocyclic group containing 1 or 2 heteroatom, or an 8-10-membered bicyclic heteroaryl group containing 1 or 2 heteroatoms.

In the description, when referred to the terms "cycloalkyl group", "aryl group", "heterocyclic group" or "heteroaryl group", they cover cycloalkyl group, aryl group, heterocyclic group or heteroaryl group having one or more substituents on the ring, unless otherwise stated. Examples of the substituent include a halogen atom, a nitro-group, Alki is inuu group, cycloalkyl group, alkenylphenol group, alkylamino group, halogenated alkyl group, hydroxyl group, CNS group, halogenated CNS group, carboxyl group, alkoxycarbonyl group, phenyl group, fenoxaprop, a substituted or an unsubstituted amino group, acyl group, cyano, etc. as these substituents, preferable substituents mentioned above, or the substituents disclosed below.

Examples of the substituted or unsubstituted amino group include, for example, an amino group, alkylamino such as monoalkylamines and dialkylamines, alluminare such as alkanolamines and arylcarboxamide, aralkylamines, alkylsulfonamides, etc. In particular, examples include alkylamines such as monomethylamine, dimethylaminopropyl, atramentaria, diethylaminopropyl, methylaminopropyl, propylamino, dipropylamino, butylamino, intellimorph and hexylamine; alluminare such as acetylamino, triptoreline, Propionaldehyde, benzoylamino and p-methoxybenzylamine; aralkylamines such as benzylamine and p-methoxybenzylamine; and alkylsulfonamides, such as methylsulfonylamino the Agrippa, ethylsulfonylimidazo, n-propylsulfonyl and n-hexylaniline.

When the description mentions the term "halogen atom" or "halogenated", as the halogen atom may be fluorine atom, chlorine atom, bromine atom and iodine atom. The term "halogenated alkyl group"used in the description, covers, for example, monitoramento group, deformational group, triptorelin group, triptorelin group, panafcortelone group, monochloromethyl group, dichloromethylene group, trichlorethylene group and the like, and preferred examples of such groups include triptorelin group.

Used herein, the term "CNS group" and the term "alkoxy" group containing CNS group as part covers, for example, straight or branched CNS group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. In particular, as alkoxygroup can be used a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, tert-butoxypropan, n-pentyloxy, n-hexyloxy etc. Such as halogenated alkoxygroup you can use cryptometer, triptracker, monochloroacetate, trichlormethiazide the etc.

As alkoxycarbonyl group can be used, for example, alkoxycarbonyl group formed of the above-mentioned CNS groups, and, in particular, can be used methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, etc.

Examples of acyl groups include alkanoyloxy group (for example, alkylcarboxylic group, halogenated alkylcarboxylic group and the like), arylcarbamoyl group, heteroarylboronic group and the like, In particular, can be used formyl group, acetyl group, propylaniline group, triftormetilfullerenov group, pentaftorosilikata group, benzoline group, p-methoxybenzoyl group, 3-pyridylcarbonyl group, etc.

As X, in the present invention preferably can be used alkyl group, a substituted aryl alkyl group, substituted aryl alkenylphenol group, substituted aryl alkylamino group, aryl group, monocyclic cycloalkyl group, a monocyclic heterocyclic group, an 8-10 membered bicyclic heteroaryl group containing 1 or 2 heteroatom, or an amino group which is substituted by an alkyl or aryl group. More preferably, can be used substituted or illegal is asenna phenyl group (examples of the substituent include one or more substituents, selected from the group consisting of, for example, halogen atom, alkyl group, halogenated alkyl group, CNS group, halogenated CNS group, aranceles group, aralkylated, phenyl group, fenoxaprop, shriley group, acyl group, amino group, alkylamino, alluminare, nitro and ceanography), 5 - or 6-membered monocyclic heterocyclic group, or an 8-10 membered bicyclic heteroaryl group containing one or two heteroatoms.

More preferred examples of X in the present invention include substituted or unsubstituted phenyl group (Deputy represents one or more substituents selected from the group consisting of halogen atom, alkyl group, halogenated alkyl group, CNS group, halogenated CNS group and ceanography, and more preferably one or more substituents selected from the group consisting of a halogen atom and CNS group). The most preferred n-Fortunella group.

In the above formula (I), Q represents a group represented by-CH2-, -CO-, -O-, -S-, -CH(OR7)-, -C(=CH2)- or-C(=NR8)-. R7represents a hydrogen atom, alkyl group, hydroxyalkyl group, or acyl group, more preferably an atom in Dorada, lower alkyl group or acetyl group, and most preferably a hydrogen atom or acetyl group. R8represents a hydroxyl group, CNS group, aralkylated, alloctype, alluminare or alkoxycarbonylmethyl, and more preferably a hydroxyl group, CNS group, or alluminare. Most preferably, when R8represents a hydroxy-group or acetylamino.

As Q in the present invention, it may be preferable group represented by-CH2-, -CO-, -O-, -C(=NOH)- or-CH(=NR7)is preferably a group represented by-CH2-, -CO-, -O - or-CH(OH)-. The most preferred-CO - group.

In the above formula (I), n represents an integer from 0 to 5, preferably from 0 to 4, more preferably from 1 to 3 and most preferably 1.

In the above formula (I), R1and R2each independently represents a hydrogen atom or alkyl group, or R1and R2joined together, forming alkylenes group. Among them, preferably R1and R2represent independently a hydrogen atom or alkyl group, and most preferably, when both R1and R2represent hydrogen atoms.

For B in the above formula (I), R3, R4, R5and R6, each of the first, independently represents a Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro group, alkyl group, halogenated alkyl group, hydroxyl group, CNS group, halogenated CNS group and ceanography. Among them, preferably, R3, R4, R5and R6each independently represents a Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro group, alkyl group, hydroxyl group, CNS group and ceanography. More preferably, three of R3, R4, R5and R6are hydrogen atoms, and one remaining is the Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro group, alkyl group, hydroxyl group, CNS group and ceanography. More preferably, three of R3, R4, R5and R6are hydrogen atoms, and one remaining is the Deputy selected from the group consisting of hydrogen atom, halogen atom, CNS group and ceanography. Most preferably, three of R3, R4, R5and R6are hydrogen atoms, and the remaining represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methoxy group or a cyano, m is an integer of 1 Il is 2 and preferably equal to 1. In the group represented by B, the ring:

represents 5 - or 6-membered aromatic heterocyclic ring containing one or two heteroatoms, which may be substituted. Among them, preferably an aromatic heterocyclic ring selected from the group consisting of a furan ring, a thiophene ring and a pyridine ring, and more preferred is unsubstituted thiophene ring or furan ring.

Examples of preferred classes of compounds belonging to the above formula (I)include:

(1) classes of compounds, where X represents an alkyl group, a substituted aryl alkyl group, substituted aryl alkenylphenol group, substituted aryl alkylamino group, aryl group, monocyclic cycloalkyl group, a monocyclic heterocyclic group, an 8-10 membered bicyclic heteroaryl group containing 1 or 2 heteroatoms, or a substituted or an unsubstituted amino group; Q represents a group represented by-CH2-, -CO-, -O-, -S-, -CH(OR7)- or-C(=NR8)- (where R7represents a hydrogen atom, alkyl group or acyl group, and R8represents a hydroxyl group, CNS group, or alluminare); n represents an integer from 0 to 4; R1and R2each, independently presented yet a hydrogen atom or alkyl group; R3, R4, R5and R6each independently represents a Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro group, alkyl group, halogenated alkyl group, hydroxyl group, CNS group, halogenated CNS group and cyanopropyl; m is 1 or 2; and ring:

represents a heterocyclic ring selected from the group consisting of a furan ring, a thiophene ring and a pyridine ring which may be substituted.

Examples of preferred classes of compounds include:

(2) compounds according to (1), where X represents an alkyl group, a substituted aryl alkyl group, substituted aryl alkenylphenol group, substituted aryl alkylamino group, aryl group, monocyclic cycloalkyl group, a monocyclic heterocyclic group, an 8-10 membered bicyclic heteroaryl group containing 1 or 2 heteroatom, or an amino group which is substituted by an alkyl or aryl group, both, R1and R2are hydrogen atoms, R3, R4, R5and R6each independently represents a Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro group, alkyl group, hydroxyl group, alkoxyl the Noah group and ceanography, m is 1 or 2, and the ring:

represents a furan ring, a thiophene ring or a pyridine ring which may be substituted;

(3) compounds according to (1), where X represents a substituted or unsubstituted phenyl group with substituents on the ring may be one or more selected from the group consisting of halogen atom, alkyl group, halogenated alkyl group, CNS group, halogenated CNS group and ceanography), 5 - or 6-membered monocyclic heterocyclic group, or an 8-10 membered bicyclic heteroaryl group containing one or two heteroatoms, both, R1and R2are hydrogen atoms, three of R3, R4, R5and R6are hydrogen atoms, and one remaining is the Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro group, alkyl group, halogenated alkyl group, hydroxyl group, CNS group, halogenated CNS group and ceanography, m is 1 or 2, and the ring:

represents a heterocyclic ring selected from the group consisting of a furan ring, a thiophene ring and a pyridine ring, each of which may be substituted;

(4) connection vishey the above (2) or (3), where Q is-CH2-, -CO-, -O-. -C(=NOH)- or-CH(OR7)- (where R7represents a hydrogen atom, alkyl group or acyl group), B is represented by the following formula:

(where three of R3, R4, R5and R6are hydrogen atoms and one remaining is the Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro group, alkyl group, hydroxyl group, CNS group and ceanography), and n is 1; and

(5) compounds where X represents substituted or unsubstituted phenyl group (Deputy represents one or more substituents selected from the group consisting of a halogen atom and CNS group), Q is-CH2-, -CO-, -O-, or-CH(OH)-, n is an integer from 1 to 3, both, R1and R2are hydrogen atoms, three of R3, R4, R5and R6are hydrogen atoms, and the remaining represents a hydrogen atom, halogen atom or CNS group, m is 1 or 2, and the following ring:

is thiophene or furan ring.

Examples of particularly preferred classes of compounds include:

(6) compounds where X represents substituted or unsubstituted phenyl group, naftalina group, tert-b is a stylish group, tsiklogeksilnogo group, substituted or unsubstituted pyrrolidinyl group, piperidinyl group, benzisoxazole group, benzodioxolyl group, tetrahydropyridine group, indolenine group or a substituted or unsubstituted phenylaminopropyl, Q is-CH2-, -CO-, -O-, -S-, -CH(OH)- or-C(=NHO)-, n represents an integer 1 or 2; each of R1and R2represents a hydrogen atom, three of R3, R4, R5and R6represent hydrogen atoms and one remaining is the Deputy selected from the group consisting of hydrogen atom, fluorine atom, chlorine atom, bromine atom and metoxygroup, m is 1 or 2, and the ring:

represents a furan or thiophene ring;

(7) compounds where X is n-florfenicol group, Q represents-CH2-, -CO-, -O - or-CH(OH)-, n is 1, both, R1and R2are hydrogen atoms, three of R3, R4, R5and R6are hydrogen atoms, and the remaining represents a hydrogen atom, halogen atom or methoxy group, and m is 1;

(8) compounds according to (7), where Q is-CO-;

(9) compounds according to (8), where all R3, R4, R5and R6are hydrogen atoms;

(10) compounds according to (8), where three of R3, R4, R5and R6are hydrogen atoms and one ostavi the Xia represents a halogen atom; and

(11) compounds according to (6), where X is p-florfenicol group, Q represents-CO-, n is 1, and the ring:

represents a furan or thiophene ring.

The tables below show the specific examples of especially preferred compounds of the present invention. However, compounds of the present invention is not limited to these examples. In the compounds mentioned below, both, and R1and R2are hydrogen atoms. In the tables, for example, the description "p-F-Ph" for X means that X is p-florfenicol group. Other descriptions indicated similar ways. In addition, "Bu" represents butyl, or butylene group, "Pr" represents a propyl or propylene group, "Et" represents ethyl or ethylene group, "Ac" represents an acetyl group, and "” represents the same group as the group shown in the top row.

Table 1 shows the compounds where b is a group represented by the following formula:

and table 2 illustrates the connections, where B is a group represented by the following formula:

In accordance with the present invention the compounds specifically disclosed in the examples, are also pre is respectful, as the compounds described below.

Methods for obtaining compounds of the present invention represented by the formula (I)is not particularly limited. For example, the compounds can be obtained by any of the methods outlined below. Obtain preferred compounds related to the compounds of the present invention will be described in more detail in the examples. Accordingly, experts in the Noi area can get any of the compounds of the present invention, falling under formula (I), based on General explanations that follow below, and specific methods of examples, and, if necessary, modifying or changing properly the ingredients, reaction conditions, reagents, etc.

The way to obtain

Scheme:

The compound of formula (II) (in the formula, Z represents a halogen atom such as chlorine atom, bromine atom or iodine atom, or toilet or mesilate or similar, Q' is-CH2-, -CO-, -O - or-S-, and X is the same as described above) may be subjected to interaction with nucleophilic amino derivative represented by the formula (III) (R1, R2and B have the same meanings as described above) to obtain the corresponding compounds of formula (I). This reaction is usually carried out in a polar solvent such as dimethylformamide, N-organic, ethanol or acetonitrile, in the presence of a base such as triethylamine, strigidaemon or potassium carbonate.

In the case where Q' represents-CO-, amino-keto-derivative of formula (I) can be restored by receiving hydroxy-derivative of the formula (I’), where A represents A hydroxyl group and Y represents a hydrogen atom. In General, recovery can be accomplished at room temperature in an organic solvent, such as ethanol, methanol or tetrahydrofuran, IP is by using natrojarosite. In addition, the amino-keto-derivative of formula (I) may be subjected to interaction with the ORGANOMETALLIC reagent, such as Y-MgBr, to obtain the compound of formula (I’), where a is a hydroxyl group.

Acyloxy - and alkoxy-compounds can be obtained by conventional means, on the basis of a derivative that does not contain free hydroxy-group. O-Alkyl-derivative can be obtained by solvolysis intermediate sulfonylurea of ester [Advanced Organic Chemistry, J. March., John Wiley & Sons, New York, pp.264-317, 1985]. In addition, chiral ester can be obtained by solvolysis of chiral derivative sulfonylurea of ester, such as camphorsulfonic. The oxime o-substituted derivative of formula (I), where Q' represents-CO-, can be obtained according to the method of producing oxime described in Organic Functional Group Preparation Vol. III, S.R. Sandler and W. Karo, Academic Press, London, pp.430-481, 1989.

As the compounds of formula (II), shown in Scheme A, where Q' is-CH2- or-CO-, you can use commercially available compounds, or these compounds can be obtained by halogenoalkanes, using as the starting material compound, a substituted alkyl group or alkylthio group, or in any similar way. In the case when Q' is-O - or-S-, you can use commercially available compounds, or compounds can be obtained interaction is m connection substituted hydroxyl group or Tilney group as the starting material, with Z(CH2)nZ' (where Z and Z' represent a halogen atom, tosylate, mesilate or similar) or any similar method.

In the case of syntheses derived benzisoxazoles and derived benzisothiazolin, examples include the methods described in known references [H.Uno, M.Kurokawa, K.Natsuka, Y.Yamato and H.Nishimura, Chem. Pharm. Bull., 24 (4), pp.632-643, 1976; H.Uno and M.Kurokawa, Chem. Pharm. Bull., 26 (12), pp.3888-3891, 1978].

Scheme B:

The compound of formula (III)as the starting material in the above scheme A, where m is 1, can be obtained, as shown in the above diagram, by way P.D.Leeson et al., (J.Med. Chem., 35, 1954-1968, 1992). The compound of formula (IV) (where R9represents an alkyl group, and R3, R4, R5and R6such as defined above) are galogenirovannyie in a solvent such as carbon tetrachloride, using, for example, N-bromosuccinimide, to obtain the compounds of formula (V) (where Z' represents a halogen atom), which is then subjected to interaction with the compound of the formula (VI).

Deputy P compounds shown in the diagram, represents a protective group for amino groups, such as the groups described in Protective Groups in Organic Synthesis [T.W.Greene and P.G.M.Wuts, John Wiley & Sons, New York, 1991], and to obtain a connection is piperidine formula (III), the specified protective group can be easily removed.

Alternatively, the compounds of formula (VII) can be synthesized by methods described in the literature (I.Takahashi, T.Kawakami, E.Hirano, H.Yokota and H.Kitajima, Synlett, 4, 353-355, 1996; S.M.Allin, C.C.Hodkinson and N.Taj, Synlett. 8, 781-782, 1996).

The compounds used as starting substances in the above methods, can be in the form of the racemate or in the form of the desired optically active substances, and can be obtained from the corresponding racemate or optically active compound. In addition, the desired optically active substance can be obtained by optical separation in accordance with known standard methods. The main compounds of formula (I) can form acid additive salts, preferably pharmaceutically acceptable salts with various inorganic and organic acids. These salts can easily be obtained by treatment of the compound of formula (I) with a mineral acid or organic acid in a suitable organic solvent, such as methanol, ethanol, isopropanol or ethyl acetate.

Compounds of the present invention represented by the General formula (I)may have one or more asymmetric carbon atoms, and, therefore, these compounds can exist as optical isomers. Any racemate, optical isomers in optically pure form, and any who MESI optical isomers are included in the scope of the present invention. The racemates can be divided into optically pure enantiomers way, well known to specialists in this field.

In addition, the diastereomers formed on two or more asymmetric carbon atoms, and any of their mixtures are also included in the scope of the present invention. Acid additive salts, preferably pharmaceutically acceptable acid additive salts, hydrates, or any solvate of the compounds of the present invention represented by the General formula (I), also included in the scope of the present invention.

Examples of salts that can be formed by the compounds of the present invention include, for example, salts of inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, sulphates, nitrates and phosphates; organic acid salts such as succinate, the acetates, glycolate, methansulfonate and toluensulfonate; salts of alkaline metals such as sodium and potassium salts; salts of alkaline-earth metals such as magnesium salts and calcium salts; ammonium salts such as ammonium salts and salts of alkylamine etc.

Examples of solvents which are able to form a solvate with the compounds of the present invention include methanol, ethanol, isopropanol, acetone, ethyl acetate, etc. But the form of salts and solvate are not limited to forms and solvate, illustrated above.

With the unity of the present invention have a high affinity for the Sigma binding site (when describing a connection called “Sigma ligand”, this means that the compound has the above property). Therefore, compounds of the present invention are useful as medicines for the treatment of various diseases and symptoms that can be treated therapeutically and/or prophylactically through regulatory actions on nerve Sigma ligands in mammals, including humans, preferably in humans. Such diseases include, for example, diseases of the Central nervous system, gastrointestinal tract and cardiovascular system.

Diseases of the Central nervous system include, for example, anxiety, depression or emotional disorder, schizophrenia, drug intoxication or drug addiction, sharp pain, dyskinesia; a condition associated with impaired blood supply to the brain; epilepsy; dementia, including Alzheimer's disease; Parkinson's disease, brain tumors, and mental disorder associated with attention deficit. Diseases of the gastrointestinal tract include, for example, irritable bowel syndrome, irritable bowel syndrome, spastic condition of the colon, mucous colitis, enterocolitis, diverticulitis, and dysentery. Diseases of the cardiovascular system include, for example, hypertension, arrhythmia, angina. However, the disease being treated drug is suspended by means of the present invention, not limited to these specific diseases and/or symptoms, and medications can be used for the treatment and/or prophylaxis of diseases and/or symptoms, in which in vivo involved Sigma ligands.

Compounds according to the present invention have excellent anti-methamphetamine activity, and therefore, among the above-mentioned diseases and symptoms they are especially useful as drugs for therapeutic and/or prophylactic treatment of schizophrenia, drug intoxication or drug use.

As the active ingredient of the drug of the present invention can be used one or more substances selected from the group consisting of the aforementioned compounds and their salts, hydrate and solvate. The method of administering drugs of the present invention is not particularly limited, and can be administered orally or parenterally. As a drug of the present invention the above-mentioned substances can enter the patients as such. Preferably, the medicinal product should be introduced in the form of preparations in the form of pharmaceutical compositions containing the active ingredient and one or more pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmacist what Cesky acceptable additives include, for example, fillers, disintegrating agents or loosening additives, binders, lubricants, agents for coatings, paints, thinners, substance basis, dissolving means or solvent additive, isotonic agents, pH modifiers, stabilizers, propellant, adhesives and the like. Examples of pharmaceutical preparations suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, syrups and the like. Examples of pharmaceutical preparations suitable for parenteral administration include, for example, pharmaceutical forms for injections, drip infusions, ointments, creams, crosslisted drugs, eye drops, ear drops, pharmaceutical forms for inhalation, suppositories and the like. However, forms of drugs are not limited to these examples.

For preparations suitable for oral administration, as auxiliary additives can be used, for example, fillers, such as glucose, lactose, D-mannitol, starch and crystalline cellulose; loosening agents or loosening additives, such as carboxymethylcellulose, starch and calcixerollic; binders such as hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone and gelatin; lubricants such as magnesium stearate and talc; means for coating the hat, as hypromellose, sucrose, polyethylene glycol and titanium oxide; substance bases such as vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water and tallow. For preparations suitable for injection or drip infusion, as auxiliary additives for pharmaceutical preparations can be used, for example, dissolving agents or dissolving supplements that can be aqueous compositions for injection or compositions for injection, which is dissolved before use, for example, distilled water for injection, saline solution and polypropyleneglycol; isotonic agents, such as glucose, sodium chloride, D-mannitol and glycerol; pH modifiers such as inorganic acids, organic acids, inorganic bases and organic bases and the like.

The dose of the drug of the present invention should be appropriately determined depending on the type of disease to be treated, target prophylactic or therapeutic treatment, age, body weight and conditions of the patient, etc. Dose for an adult patient per day for oral administration can typically be in the range of from about 0.05 to 500 mg. In General, the above dose may be given once daily or in two is whether a larger number of separate parts during the day, or may be every few days.

Examples

This invention is further illustrated in more detail using the following examples. However, the scope of the present invention is not limited to these examples.

When specifying the physico-chemical characteristics NMR means spectrum of nuclear magnetic resonance, the values are represented as δ values that are commonly used to indicate chemical shifts, and unit of measure are expressed in ppm (million days). TMS (TMS, tetramethylsilane was) used as internal standard. In parentheses after the values δ, (s) denotes the singlet, d means doublet, t (t) denotes the triplet, (q) denotes quadruplet, m (m) denotes the multiplet, W (br) indicates a broad peak absorption, and the number before the letters represent the number of hydrogen atoms.

Example 1: the Hydrochloride of 2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 1 in Table 1)

a) Hydrochloride tert-butyl 4-aminomethylpyridine-1-carboxylate

Tert-Butyl-4-aminomethylpyridine-1-carboxylate prepared as in the method described in Synthetic Commun., 22(16), 2357-2360 (1992), using as the starting material 4-aminomethylpyridine (5.71 in). The compound obtained is dissolved in 80 ml of ethyl acetate and to the solution add a mixture of 4N hydrochloric acid-atilas the tat and mix. Precipitated precipitated solid is collected by filtration, getting mentioned in the title compound (10,27 g, yield: 82%).

Melting point: 236-240°

1H-NMR (DMSO-d6): 8,00 (3H, s)to 3.92 (2H, sh. d, J=12,6), 2,68 (4H, m), 1.77 in-of 1.65 (3H, m)of 1.39 (9H, s)of 1.02 (2H, m).

b) Ethyl ester of 2-bromoethylamine acid

Ethyl ester of 2-methylbenzoic acid (2,g, to 11.9 mmol) dissolved in carbon tetrachloride (60 ml) and the solution is added N-bromosuccinimide (2,56 g, 14.4 mmol) and a catalytic amount of benzoyl peroxide and then refluxed. After one hour, the reaction mixture is cooled to room temperature and add hexane (40 ml)to remove insoluble solids by filtration. The filtrate is evaporated under reduced pressure, receiving, and 3.16 g specified in the title compound as a yellow oil. The product is used in subsequent reactions without purification.

C) tert-Butyl 4-(1-occaisonaly-2-yl-methyl)piperidine-1-carboxylate

The compound obtained in Example 1b (3,15 g), and the compound obtained in Example 1A (3.00 g, 12,0 mmol), added in dimethylformamide (30 ml). To the mixture is added triethylamine (3.5 ml, 25 mmol) under stirring at room temperature and then at the same temperature and continue stirring for 17 hours. To the reaction mixture are added water and extracted with a mixed solvent e is elzett-hexane. The organic layer is washed with 10% aqueous citric acid solution, water, aqueous sodium bicarbonate solution and then with saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated PI reduced pressure. The resulting oil is purified column chromatography on silica gel (ethyl acetate-hexane), getting mentioned in the title compound as a yellow oil (yield: 41%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,4-7,6 (3H, m)to 4.41 (2H, s), 4,0-4,2 (2H, m), 3,4-3,6 (2H, m), 2,6-2,8 (2H, m), 1,8-2,0 (1H, m), of 1.5-1.7 (4H, m)of 1.45 (9H, s).

d) of the Hydrochloride of 2-(piperidine-4-yl-methyl)isoindoline-1-it

The compound obtained in Example 1C (1,61 g, to 4.87 mmol), dissolved in a mixed solvent of methylene chloride (5 ml)-ethanol (1 ml) and the solution was added 4N hydrochloric acid in ethyl acetate (5 ml, 20 mmol) at room temperature. The mixture was stirred at the same temperature for 1 hour and precipitated precipitated solid is collected by filtration. The obtained solid is washed with ethyl acetate and then dried under reduced pressure, obtaining mentioned in the title compound as a colourless solid (726 mg, yield: 56%).

1H-NMR (DMSO-d6): 8,83 (1H, s, C), 8,53 (1H, s, C), between 7.4 and 7.7 (4H, m), 4,50 (2H, s), 3,44 (2H, d, J=7,2), 3,2-3,3 (2H, m), 2,7-2,9 (2H, m), 1,9-2,1 (1H, m), 1,6-1,8 (2H, m), 1,3-1,5 (2H, m).

e) 2-[[1-[2-(4-FPO is phenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

To dimethylformamide (12 ml) is added the compound obtained in Example 1d (518 mg, 1.94 mmol)and 2-chloro-4-peracetate (358 mg, 2,07 mmol) and the solution is added triethylamine (575 μl, 4,13 mmol) under stirring at room temperature. Stirring is continued at the same temperature for 4 hours and then the reaction mixture was added water and extracted with ethyl acetate. The organic layer is washed with water and then with saturated salt solution and then dried over sodium sulfate. The insoluble solid is removed by filtration and the filtrate evaporated under reduced pressure, obtaining an orange oil (0,70 g). The oil obtained utverjdayut by adding hexane, and the solid is collected by filtration and dried under reduced pressure, obtaining mentioned in the title compound as a pale yellow solid (551 mg, yield: 77%).

1H-NMR (CDCl3): to 8.0 and 8.1 (2H, m), a 7.85 (1H, d, J=7,2), 7,4-of 7.55 (3H, m), 7,12 (2H, t)to 4.41 (2H, s), of 3.73 (2H, s), 3,51 (2H, d, J=7,5), of 2.9-3.0 (2H, m), 2.1 to a 2.2 (2H, m), 1,4-1,9 (5H, m).

f) of the Hydrochloride of 2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

The compound obtained in Example 1E (550 mg, 1.50 mmol), dissolved in ethanol (2 ml) and the solution was added 4N hydrochloric acid in ethyl acetate (2 ml, 8 mmol) at room temperature and continue stirring at the same temperature for 15 minutes. In the reactions is nnow the mixture was added ethyl acetate (10 ml) and precipitated precipitated solid is collected by filtration. The obtained solid is washed with ethyl acetate and then dried under reduced pressure, obtaining a white powder (364 mg). The product is recrystallized from a mixture of ethanol-ethyl acetate, getting mentioned in the title compound as a colourless solid (246 mg, yield: 41%).

Melting point: 182-188° C.

1H-NMR (DMSO-d6): to 9.93 (1H, sh. s), 8,0-8,2 (2H, m), of 7.4 to 7.7 (6H, m), 4,9-5,1 (2H, m), a 4.53 (2H, s), 2,9-3,6 (6H, m), 1,6-2,2 (5H, m)

Example 2: the Hydrochloride of 4-bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (compound 5 in Table 1)

a) Ethyl ester of 3-Bromo-2-methylbenzoic acid

Ethyl ester of 2-methylbenzoic acid (to 18.3 mmol) is added dropwise to aluminiumchlorid (of 45.7 mmol) and then added dropwise Br2(22,0 mmol). Stirring is continued at room temperature for 1 hour and then the reaction mixture was added ice and ethyl acetate to separate an organic layer. The organic layer is washed with water, aqueous sodium bicarbonate solution and then with saturated salt solution and dried over sodium sulfate. The desiccant is removed by filtration, layer concentrate and there are three product using column chromatography on silica gel (hexane-simple ester), i.e. ethyl ester of 3-bromo-2-methylbenzoic acid (yield: 14%), ethyl ester of 5-bromo-2-methylbenzoic acid (yield: 13%), ethyl EPE is 3,5-dibromo-2-methylbenzoic acid (yield: 10%).

ethyl ester of 3-bromo-2-methylbenzoic acid:

1H-NMR (CDCl3): δ 7,71 (DD, J=7,9, 1.0 Hz, 1H), 7,69 (DD, J=7,9, 1.0 Hz, 1H), 7,10 (t, J=7.9 Hz, 1H), 4,37 (K, J=7,0 Hz, 2H), 2.63 in (s, 3H), of 1.40 (t, J=7.0 Hz, 3H).

ethyl ester of 5-bromo-2-methylbenzoic acid:

1H-NMR (CDCl3): δ 8,03 (d, J=2.1 Hz, 1H), 7,50 (DD, J=8,4, and 2.1 Hz, 1H), 7,12 (d, J=8,4 Hz, 1H), 4,36 (K, J=6,9 Hz, 2H), 2,54 (s, 3H), of 1.40 (t, J=6.9 Hz, 3H).

ethyl ester of 3,5-dibromo-2-methylbenzoic acid:

1H-NMR (CDCl3): δ a 7.85 (d, J=2 Hz, 1H), to 7.84 (d, J=2 Hz, 1H), 4,37 (K, J=7,0 Hz, 2H), 2.57 m (s, 3H), of 1.40 (t, J=7,0 Hz, 3H).

b) tert-Butyl 4-(4-bromo-1-occaisonaly-2-ylmethyl)piperidine-1-carboxylate

Specified in the title compound is obtained by methods similar to the methods of Examples 1b and 1C, using the ethyl ester of 3-bromo-2-methylbenzoic acid obtained in Example 2A.

1H-NMR (CDCl3): δ 7,80 (d, J=9 Hz, 1H), 7,66 (d, J=6 Hz, 1H), 7,37 (DD, J=9, 6 Hz, 1H), 4,33 (s, 2H), 4,12 (m, 2H), 3,54 (SD, J=7 Hz, 2H), 2,70 (S.T., J=12 Hz, 2H), 1,95 (m, 1H), 1,66 (SD, J=12 Hz, 2H), 1,45 (s, 9H), 1,24 (DK, J=12, 4 Hz, 2H).

c) the hydrochloride of 4-bromo-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the header of the connection will receive the same manner as in Example 1d (yield: 62%), using the compound obtained in Example 2b.

1H-NMR (DSO-d6): δ 8,92 (sh. s, 1H), 8,64 (sh. s, 1H), 7,83 (d, J=9 Hz, 1H), 7,71 (d, J=6 Hz, 1H), of 7.48 (DD, J=9, 6 Hz, 1H), of 4.45 (s, 2H), 3.45 points (d, J=12 Hz, 2H), 3,24 (sh. d, J=12 Hz, 2H), 2,79 (sh. K, J=12 Hz, 2H), 2.06 to (m, 1H), 174 (sh. d, J=12 Hz, 2H), 1,37 (sh. K, J=12 Hz, 2H)

d) 4-Bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-on

Specified in the title compound is obtained by methods similar to the methods of Example 1E (yield: 57%), using the compound obtained in Example 2C.

1H-NMR (CDCl3): δ 8,07 (m, 2H), 7,79 (d, J=7.8 Hz, 1H), 7,65 (d, J=7.8 Hz, 1H), 7,37 (t, J=7.8 Hz, 1H), 7,11 (t, J=8.6 Hz, 2H), 4,32 (s, 2H), and 3.72 (s, 2H), 3,53 (d, J=7.2 Hz, 2H), 2,96 (sh. d, J=11,4 Hz, 2H), 2,16 (dt, J=11,4, 2.7 Hz, 2H), of 1.84 (m, 1H), 1.69 in (sh. d, J=12 Hz, 2H), 1,48 (DK, J=12, 4 Hz, 2H).

e) of the hydrochloride of 4-bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header of the connection receives a manner analogous to the method of Example 1f (yield: 66%), using the compound obtained in Example 2d.

Melting point: 152-154° C.

1H-NMR (DMSO-d6): δ 9,98 (sh. s, 1H), 8,06-8,16 (m, 2H), to 7.84 (d, J=8,1 Hz, 1H), 7,72 (d, J=7.5 Hz, 1H), 7,45-of 7.48 (m, 3H), 5,04-5,10 (m, 2H), 4,48 (s, 2H), 3.00 and of 3.56 (m, 6H), is 2.09 (m, 1H), 1,58 of-1.83 (m, 4H).

Example 3: Hydrochloride, 5-bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

a) methyl ester of 4-bromo-2-methylbenzoic acid

4-Bromo-2-methylbenzoic acid (4,06 g, 18.5 mmol) was dissolved in methanol (60 ml). To the solution was added concentrated sulfuric acid (1 ml) and then refluxed for 9 hours. The solvent is evaporated under reduced pressure and the residue diluted with ethyl shall FYROM (100 ml). Received the diluted mixture was washed with water, aqueous sodium bicarbonate solution and then with saturated salt solution and dried over magnesium sulfate. The insoluble solid is removed by filtration and the filtrate concentrated under reduced pressure, obtaining mentioned in the title compound as a yellow oil (a 3.87 g, yield: 91%).

1H-NMR (CDCl3): for 7.78 (1H, d, J=8,3), 7,42 (1H, d, J=1,9), 7,38 (1H, DD, J=1,9, 8,3), 3,88 (3H, s), 2,58 (3H, s).

b) methyl ester of 4-bromo-2-bromoethylamine acid

Specified in the header connection (5,70 g) are obtained by methods similar to Example 1b, using the compound obtained in Example 3A (a 3.83 g, and 16.7 mmol). The product is used in subsequent reactions without any processing.

C) tert-Butyl 4-(5-bromo-1-occaisonaly-2-ylmethyl)piperidine-1-carboxylate

Specified in the title compound obtained as white solid by methods similar to the methods of Example 1C (3.04 from g, yield: 44%), using the compound obtained in Example 3b (5,70 g).

1H-NMR (CDCl3): 7,69-7,73 (1H, m), to 7.59 to 7.62 (2H, m), 4,39 (2H, s), 4,0-4,2 (2H, m), 3,4-3,6 (2H, m), 2,5-2,7 (2H, m), 1,8-2,0 (1H, m), 1,5-1,7 (2H, m)of 1.45 (9H, s), 1,1-1,3 (2H, m).

d) of the hydrochloride of 5-bromo-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the title compound obtained as a white solid (1.86 g, yield: 73%)using the compound obtained in Example 3C (3.03 g, 7.40 mmol ways, similar to the methods of Example 1d.

1H-NMR (DMSO-d6): 8,96 (1H, sh. C)8,68 (1H, sh. C), 7,89 (1H, s), of 7.69 (1H, d, J=8,2), to 7.61 (1H, d, J=8,2), 4,50 (2H, s), 3,42 (2H, d, J=7,2), 3,1-3,3 (2H, m), 2,6-2,9 (2H, m), 1,9-2,1 (1H, m), 1,6-1,8 (2H, m), 1,2-1,4 (2H, m).

e) 5-Bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a pale yellow solid (727 mg, yield: 68%)using the compound obtained in Example 3d (834 mg, 2,41 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): to 8.0 and 8.1 (2H, m), 7.68 per-7,72 (1H, m), 7,58 to 7.62 (2H, m), 7,08-to 7.15 (2H, m), to 4.38 (2H, s), of 3.73 (2H, s), 3,49 (2H, d, J=7,2), of 2.8-3.0 (2H, m), of 2.0-2.2 (2H, m), 1,6-1,9 (3H, m), 1,35-1,5 (2H, m).

f) hydrochloride, 5-bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (704 mg, yield: 89%), using the compound obtained in Example 3E (727 mg, and 1.63 mmol), by methods similar to the methods of Example 1f.

Melting point: 205-222° C.

1H-NMR (DSO-d6): to 9.91 (1H, sh. s), 8,0-8,2 (2H, m), of 7.90 (1H, s), of 7.70 (1H, d, J=8,2), a 7.62 (1H, d, J=8,2), to 7.4 and 7.5 (2H, m), 5,0-5,2 (2H, m), a 4.53 (2H, s), i.e., 3.3 to 3.6 (4H, m), 2,9-3,1 (2H, m), of 2.0-2.2 (1H, m), of 1.5-1.9 (4H, m).

Example 4 the Hydrochloride of 6-bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 3 in Table 1).

a) tert-Butyl 4-(6-bromo-1-occaisonaly-2-ylmethyl)piperidine-1-carboxylate

The decree is Noah in the header connection receive (yield: 52%), using the ethyl ester of 5-bromo-2-methylbenzoic acid obtained in Example 2A, by methods similar to the methods of Examples 1b and 1C.

1H-NMR (CDCl3): δ 7,98 (d, J=1.8 Hz, 1H), 7,65 (DD, J=8,0, 1.8 Hz, 1H), 7,32 (d, J=8.0 Hz, 1H), 4,36 (s, 2H), 4,10 (m, 2H), 3,48 (m, 2H), 2,69 (sh. t, J=12 Hz, 2H), 1.93 and (m, 1H), 1,64 (sh. d, J=12 Hz, 2H), 1,45 (s, 9H), 1,24 (DK, J=12,3, 4,4 Hz, 2H).

(b) hydrochloride of 6-bromo-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the header connection receive (yield: 96%)using the compound obtained in Example 4A, by methods similar to the methods of Example 1d.

1H-NMR (DSO-d6): δ 8,90 (sh. s, 1H), 8,61 (sh. s, 1H), 7,78-7,81 (m, 2H), 7,60 (d, J=8,8 Hz, 1H), 4,48 (s, 2H), 3.43 points (d, J=7,4 Hz, 2H), 3,24 (sh. d, J=12 Hz, 2H), 2,80 (sh. K, J=12 Hz, 2H), 2,01 (m, 1H), 1,73 (sh. d, J=12 Hz, 2H), 1,37 (sh. K, J=12 Hz, 2H).

C) 6-bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the header connection receive (yield: 93%)by using the compound obtained in Example 4b, by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,07 (m, 2H), of 7.97 (d, J=1.8 Hz, 1H), 7,65 (DD, J=8,1, 1.8 Hz, 1H), 7,32 (d, J=8,1 Hz, 1H), 7,12 (t, J=8.7 Hz, 2H), 4,36 (s, 2H), and 3.72 (s, 2H), 3,50 (d, J=6,9 Hz, 2H), 2,96 (sh. d, J=12 Hz, 2H), and 2.14 (dt, J=11,6, 2.4 Hz, 2H), equal to 1.82 (m, 1H), 1,67 (sh. d, J=12 Hz, 2H), 1,46 (DK, J=11,7, 3.6 Hz, 2H),

d) of the Hydrochloride of 6-bromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 72%), using soy is inania, obtained in Example 4C, by methods similar to the methods of Example 1f.

1H-NMR (DSO-d6): δ 9,99 (sh. s, 1H), 8,05-8,16 (m, 2H), 7,62 for 7.78 (m, 2H), 7,60 (d, J=8.6 Hz, 1H), 7,47 (t, J=8.6 Hz, 2H), 5,03-5,09 (m, 2H), 4,51 (s, 2H), 3,01-3,55 (m, 6H), 2,03 (m, 1H), 1,62 is 1.86 (m, 4H),

Example 5: Hydrochloride 4,6-dibromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (compound 6 in Table 1)

a) tert-Butyl 4-(4,6-dibromo-1-occaisonaly-2-imethyl)piperidine-1-carboxylate

Specified in the header connection receive (yield: 64%), using ethyl ether, 3,5-dibromo-2-methylbenzoic acid obtained in Example 2A, by methods similar to the methods of Examples 1b and 1C.

1H-NMR (CDCl3): δ to 7.93 (d, J=1.5 Hz, 1H), 7,82 (d, J=1.5 Hz, 1H), 4,27 (s, 2H), 4,12 (m, 2H), 3,51 (d, J=6,7 Hz, 2H), 2.70 height (sh. t, J=12 Hz, 2H), was 1.94 (m, 1H), 1,64 (sh. d, J=12 Hz, 2H), 1,45 (s, 9H), 1,25 (DK, J=12, 4 Hz, 2H).

(b) hydrochloride of 4,6-dibromo-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the header connection receive (yield: 100%)using the compound obtained in Example 5A, by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6): δ 8,87 (sh. s, 1H), 8,60 (sh. s, 1H), 4,43 (s, 2H), 3,44 (d, J=7.5 Hz, 2H), 3,24 (sh. d, J=12 Hz, 2H), 2,79 (sh. K, J=12 Hz, 2H), 2.06 to (m, 1H), 1,74 (sh. d, J=12 Hz, 2H), 1,36 (sh. K, J=12 Hz, 2H).

(C) 4,6-dibromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the header connection receive (yield: 83%)using the connection, is received in Example 5b, by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,07 (m, 2H), 7,92 (d, J=1.4 Hz, 1H), 7,81 (d, J=1.4 Hz, 1H), 7,60 (t, J=8.6 Hz, 2H), 4,28 (s, 2H), of 3.73 (s, 2H), 3,51 (d, J=7,3 Hz, 2H), 2,97 (sh. d, J=12 Hz, 2H), 2,16 (sh. t, J=12 Hz, 2H)and 1.83 (m, 1H), 1,68 (sh. d, J=12 Hz, 2H), 1,47 (DK, J=12, 3 Hz, 2H).

d) hydrochloride 4,6-dibromo-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 77%), using the compound obtained in Example 5C, by methods similar to the methods of Example 1f.

Melting point: 186 to 190°

1H-NMR (DMSO-d6): δ there is a 10.03 (sh. s, 1H), 8,06-8,16 (m, 3H), 7,86 (s, 1H), 7,47 (t, J=8.7 Hz, 2H), 5,04-5,10 (m, 2H), 4,46 (s, 2H), 3,30 of 3.56 (m, 6H), of 2.08 (m, 1H), 1,58 is 1.91 (m, 4H).

Example 6: Hydrochloride 4-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 10, Table 1)

a) Ethyl ester of 3-fluoro-2-methylbenzoic acid

Specified in the title compound obtained as a colorless oil (1.31 g)using 3-fluoro-2-methylbenzoic acid (2.0 g, 12,98 mmol), by methods similar to the methods of Example 3A. The product is used in subsequent reactions without purification.

b) Ethyl ester of 2-methyl bromide-3-fermenting acid

Specified in the title compound obtained as a pale yellow oil (2,01 g)using the compound obtained in Example 6A (1.31 g), by methods similar to the methods of Example 1b. The product is used the subsequent reaction without purification.

C) tert-Butyl 4-[(4-horizontalis-1-he)-2-ylmethyl]piperidine-1-carboxylate

Specified in the title compound obtained as a colorless solid (1.68 g, yield: 63%), using the compound obtained in Example 6b (1,57 g), by methods similar to the methods of Example 1c.

1H-NMR (CDCl3): δ the 7.65 (d, 1H, J=7.5 Hz), 7,49-the 7.43 (DDD, 1H, J=7,8, and 7.8, 4.8 Hz), 7,22 (DD, 1H, J=8,6, 8.5 Hz), of 4.45 (s,2H), 4,11 (sh. d, 2H, J=11.7 Hz), 3,50 (sh. d, 2H, J=6.3 Hz), 2,70 (sh. DD, 2H, J=12,6, 6.3 Hz), 1,98 is 1.91 (m, 1H), 1,67-of 1.62 (m, 2H), 1,45 (s, 9H), 1,35-1,19 (m, 2H).

d) of the hydrochloride of 4-fluoro-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the title compound obtained as a colorless solid (1.27 g, yield: 93%)by using the compound obtained in Example 6C (1.68 g, 4,82 mmol), by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6): δ 8,91 (sh. s, 1H), 8,65 (sh. s, 1H), 7,60-7,42 (m, 3H), 4,60 (s, 2H), 3,44 (d, 2H, J=7.5 Hz), 3,24 (sh. d, 2H, J=12,6 Hz), 2,79 (sh. DD, 2H, J=23,3, 12,2 Hz), 2,08 of 1.99 (m, 1H), 1,74 (sh. d, 2H, J=12.3 Hz), 1,45 to 1.31 (m, 2H).

e) 4-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a pale brown solid (1.52 g, yield: 89%), using the compound obtained in Example 6d (1.27 g, of 4.46 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,10-with 8.05 (m, 2H), 7,65 (d, 1H, J=7,3 Hz), 7,46-7,44 (m, 1H), 7,21 (DD, 2H, J=8,8, 8,8 Hz), 7,11 (DD, 2H, J=7,6, 7,6 is C), of 4.45 (s, 2H), 3,71 (s, 2H),3,52 (d, 2H, J=7,2 Hz), 2,96 (sh. d, 2H, J=11,6 Hz), 2,19-of 2.08 (m, 2H), 1,71-to 1.67 (m, 2H), 1,54 of 1.46 (m, 2H).

f) of the hydrochloride of 4-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (484 mg, yield: 89%), using the compound obtained in Example 6E (500 mg, of 1.30 mmol), by methods similar to the methods of Example 1f.

Melting point: 177-196° C.

1H-NMR (DMSO-d6): δ 9,92 (sh. s, 1H), 8,16-of 8.06 (m, 2H), to 7.59-7,44 (m, 5H), 5,04-free 5.01 (m, 2H), 4,63 (s, 2H), 3,56-of 3.46 (m, 4H), to 3.02 (sh. d, 2H, J=10,8 Hz), 2,09-to 2.06 (m, 1H), 1.91 a tariff-1.62 (m, 4H).

Example 7: Hydrochloride of 6-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 8 in Table 1)

a) methyl ester of 5-fluoro-2-methylbenzoic acid

Specified in the title compound obtained as a colorless oil (1.01 g)using 5-fluoro-2-methylbenzoic acid (900 mg, 5,78 mmol), by methods similar to the methods of Example 3A. The product is used in subsequent reactions without purification.

b) methyl ester of 2-methyl bromide-5-fermenting acid

Specified in the header connection receive (1,57 g)using the compound obtained in Example 7a (957 mg), by methods similar to the methods of Example 1b. The product is used in subsequent reactions without purification.

c) tert-Butyl 4-(6-fluoro-1-occaisonaly-2-ylmethyl)piperidine-1-carboxylate

Listed is in the title compound obtained as a colorless solid (1.13 g, yield: 57%), using the compound obtained in Example 7b (1,57 g), by methods similar to the methods of Example 1C.

1H-NMR (CDCl3): 7,50-rate of 7.54 (1H, m), 7,38-the 7.43 (1H, m), 7,20-7,28 (1H, m), to 4.38 (2H, s), 4,0-4,2 (2H, m), 3,4-3,6 (2H, m), 2,6-2,8 (2H, m), 1,8-2,0 (1H, m), 1,5-1,7 (2H, m)of 1.45 (9H, s), 1,1-1,3 (2H, m).

d) of the hydrochloride of 6-fluoro-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the title compound obtained as a colorless solid (722 mg, yield: 81%), using the compound obtained in Example 7C (1,09 g of 3.13 mmol), by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6): 8,73 (1H, sh. C)8,46 (1H, sh. C), 7,63-of 7.69 (1H, m), 7,43-7,49 (2H, m), 4,48 (2H, s), 3,44 (2H, d, J=7,3), 3,1-3,3 (2H, m), 2,7-2,9 (2H, m), 1,9-2,1 (1H, m), 1,6-1,8 (2H, m), 1,2-1,4 (2H, m).

e) 6-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a pale yellow solid (762 mg, yield: 78%), using the compound obtained in Example 7d (721 mg, 2,53 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): 8,04-8,10 (2H, m), 7,49-7,53 (1H, m), 7,37-7,41 (1H, m), 7,22-7,26 (1H, m), 7,08-to 7.15 (2H, m), to 4.38 (2H, s), of 3.73 (2H, s), 3,50 (2H, d, J=7,3), of 2.9-3.0 (2H, m), of 2.0-2.2 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1,3-1,5 (2H, m).

f) of the hydrochloride of 6-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (762 mg, yield: 91%), ISOE is isua connection, obtained in Example 7E (762 mg, to 1.98 mmol), by methods similar to the methods of Example 1f.

Melting point: 193-205° C.

1H-NMR (DMSO-d6): 9,96 (1H, sh. s), 8,0-8,2 (2H, m), of 7.64-of 7.70 (1H, m), 7,3-7,5 (4H, m), 5,0-5,2 (2H, m)to 4.52 (2H, s), 3,4-3,6 (4H, m), 3,9-4,1 (2H, m), 1,9-2,1 (1H, m), of 1.5-1.9 (4H, m).

Example 8: Hydrochloride, 5-chloro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 13 in Table 1)

a) Ethyl 4-chloro-2-methylbenzoate

Specified in the title compound obtained as a colorless solid (347 mg), using 4-chloro-2-methylbenzoic acid (300 mg, of 1.76 mmol), by methods similar to the methods of Example 3A. The product is used in subsequent reactions without purification.

b) Ethyl 2-methyl bromide-4-chlorobenzoate

Specified in the title compound obtained as a pale brown oil (494 mg), using the compound obtained in Example 8A (347 mg), by methods similar to the methods of Example 1b. The product is used in subsequent reactions without purification.

c) tert-Butyl 4-[(5-horizontalis-1-he)-2-ylmethyl)]piperidine-1-carboxylate

Specified in the title compound obtained as a pale brown solid (375 mg, yield: 58%), using the compound obtained in Example 8b (490 mg), by methods similar to the methods of Example 1C.

1H-NMR (CDCl3): δ to 7.77 (d, 1H, J=8.7 Hz), of 7.48-7,44 (m, 2H), 4,39 (s, 2H), 4,11 (sh. s, 2H), 3,49 (sh. s, 2H), 2,69 (sh. DD, 2H, J=1,2, and 12.2 Hz), 1,97-1,89 (m, 1H), 1,66-of 1.62 (m, 2H), 1,45 (s, 9H), 1,31-of 1.18 (m, 2H).

d) hydrochloride, 5-chloro-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the title compound obtained as a colorless solid (211 mg, yield: quantitative)using the compound obtained in Example 8C (370 mg, 1.01 mmol), by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6): δ the remaining 9.08 (sh. s, 1H), 8,81 (sh. s, 1H), 7,80 (s, 1H), 7,74 (d, 1H, J=8.0 Hz), 7,60 (DD, 1H, J=8,1, 1,6 Hz), 4,56 (s, 2H), 3,48 (d, 2H, J=7.4 Hz), 3,29 (sh. d, 2H, J=12,6 Hz), 2,85 (sh. DD, 2H, J=23,0, 12.0 Hz), 2,10-2,02 (m, 1H), 1,78 (sh. d, 2H, J=12,8 Hz)and 1.51 to 1.37 (m, 2H).

e) 5-Chloro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a white solid (213 mg, yield: 78%), using the compound obtained in Example 8d (205 mg, of 0.68 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,07 (DD, 2H, J=8,9, and 5.6 Hz), 7,76 (d, 1H, J=9.0 Hz), 7,44 (d, 2H, J=8.1 Hz), 7,12 (DD, 2H, J=8,7, to 8.7 Hz), 4,39 (s, 2H), of 3.73 (s, 2H), 3,49 (d, 2H, J=7,2 Hz), 2,96 (sh. d, 2H, J=11,4 Hz), 2,19-2,11 (m, 2H), 1,84-to 1.77 (m, 1H), 1,68 (sh. d, 2H, J=12,6 Hz), 1,54-of 1.45 (m, 2H).

f) Hydrochloride, 5-chloro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (155 mg, yield: 48%), using the compound obtained in Example 8E (213 mg, of 0.53 mmol), by methods similar to the methods of Example 1.

Melting point: 209-221° C.

1H-NMR (DMSO-d6): δ 9,94 (sh. s, 1H), 8,19-of 8.06 (m, 2H), 7,76 (s, 1H), 7,69 (d, 1H, J=8.1 Hz), the 7.65 (d, 1H, J=9.3 Hz), of 7.48 (DD, 2H, J=8,7, to 8.7 Hz), 5,10-to 5.03 (m, 2H), of 4.54 (s, 2H), 3,55 is 3.40 (m, 4H), is 3.08 3.00 for (m, 2H), 2,09 of 1.99 (m, 1H), 1,86-to 1.61 (m, 4H).

Example 9: Hydrochloride 5-metiloksi-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 17 in Table 1)

a) Methyl ester of 4-metiloksi-2-methylbenzoic acid

Methyl 4-bromo-2-methylbenzoate (19.0 mmol) dissolved in dimethylformamide (2.7 ml) and methanol (1.1 ml) and the solution is heated at 80° and then added CuBr (1,09 mmol). After stirring for 2 hours while heating the mixture to cool to room temperature. Then the mixture was added diethyl ether (25 ml) and filtered. The filtrate is washed four times with water, aqueous sodium bicarbonate solution and then with saturated salt solution and dried over sodium sulfate. The desiccant is removed by filtration and the filtrate is concentrated and receiving specified in the header of the connection.

1H-NMR (CDCl3): δ to 7.93 (d, J=9,3 Hz, 1H), 6,72-6,76 (m, 2H), 3,86 (s, 3H), of 3.84 (s, 3H), 2,60 (s, 3H).

b) tert-Butyl 4-(5-metiloksi-1-occaisonaly-2-ylmethyl)-piperidine-1-carboxylate

Specified in the header connection receive (yield: 40%)using the compound obtained in Example 9a, by methods similar to the methods of Examples 1b and 1C.

1H-NMR (CDCl3): δ of 7.75 (d, J=8,4 Hz, 1H), 6,99 (DD, J=8,4, and 2.1 Hz, 1H), 6,93 (d, J=2.1 Hz, 1H), 4,35 (s, 2H), 4,11 (m, 2H), a 3.87 (s, 3H), 3,47 (m, 2H), 2,69 (sh. t, J=12 Hz, 2H), 1.93 and (m, 1H), 1,65 (sh. d, J=12 Hz, 2H), 1,45 (s, 9H), 1,24 (DK, J=12, 4 Hz, 2H).

c) Hydrochloride 5-metiloksi-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the header connection receive (yield: 100%)using the compound obtained in Example 9b, by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6): δ 9,13 (sh. s, 1H), 8,86 (sh. s, 1H), EUR 7.57 (d, J=8,4 Hz, 1H), 7,15 (d, J=2.2 Hz, 1H), 7,02 (DD, J=8,6, 2.2 Hz, 1H), 4,43 (s, 2H), 3,83 (s, 3H), 3,39 (d, J=7,4 Hz, 2H), 3,22 (sh. d, J=12 Hz, 2H), 2,78 (sh. K, J=12 Hz, 2H), up to 1.98 (m, 1H), 1,71 (sh. d, J=12 Hz, 2H), 1,43 (sh. K, J=12 Hz, 2H).

d) 5-Metiloksi-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the header connection receive (yield: 84%), using the compound obtained in Example 9c, by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,08 (m, 2H), of 7.75 (d, J=7.8 Hz, 1H), 7,11 (t, J=8,4 Hz, 2H), 6,98 (DD, J=8,4, 2.4 Hz, 1H), 6,77 (d, J=2.4 Hz, 1H), 4,34 (s, 2H), a 3.87 (s, 3H), 3,71 (s, 2H), 3,47 (d, J=7.2 Hz, 2H), 2.95 and (sh. d, J=12 Hz, 2H), 2,15 (dt, J=11,7, 2.4 Hz, 2H), 1,80 (m, 1H), 1,67 (sh. d, J=12 Hz, 2H), 1,46 (DK, J=12, 4 Hz, 2H).

e) hydrochloride 5-metiloksi-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 65%), using the compound obtained in Example 9d, by methods similar to the methods of Example 1f.

Melting point: 205-214° C.

1H-NMR (DMSO-d6): δ 10,07 (sh. s, 1H), 8,06-8,16 (m, 2H), to 7.59 (d, J=8,4 Hz, 1H), 7,47 (t, J=8,4 Hz, 2H), 7,17 (s, 1H), 7,03 (d, J=8,4 Hz, 1H), 5,06-5,12 (m, 2H), 4,47 (s, 2H), of 3.84 (s, 3H), 3,02-to 3.52 (m, 6H), for 2.01 (m, 1H), 1,63-1,84 (m, 4H).

Example 10: Hydrochloride 5-cyano-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 21 in Table 1)

a) methyl ester of 4-cyano-2-methylbenzoic acid

4-Bromo-2-benzoic acid (17.5 mmol) is dissolved in N-methyl-2-pyrrolidone (24 ml) and the solution was added CuCN (21,0 mmol) and heated at 180° C. After 5 hours the reaction mixture is cooled to room temperature and add 40 ml of water and filtered. The solid remaining on the filter is extracted with acetone and the extract was concentrated, obtaining mentioned in the title compound (yield: 45%).

1H-NMR (CDCl3): δ of 7.97 (d, J=8.6 Hz, 1H), 7,55 (s, 1H), 7,54 (d, J=8.6 Hz, 1H), 3,93 (s, 3H), 2,62 (s, 3H).

b) tert-Butyl 4-(5-cyano-1-occaisonaly-2-ylmethyl)piperidine-1-carboxylate

Specified in the header connection receive (yield: 40%)using the compound obtained in Example 10A, by methods similar to the methods of Examples 1b and 1C.

1H-NMR (CDCl3): δ of 7.96 (d, J=7.5 Hz, 1H), 7,78 (d, J=7.5 Hz, 1H), 7,76 (s, 1H), 4,48 (s, 2H), 4,11 (m, 2H), 3,53 (m, 2H), 2,69 (sh. t, J=12 Hz, 2H), 1,95 (m, 1H), 1,64 (sh. d, J=12 Hz, 2H), 1,45 (s, 9H), 1.26 in (DK, J=12, 4 Hz, 2H).

c) the hydrochloride of 5-cyano-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the header is Obedinenie get (yield: 100%), using the compound obtained in Example 10b, by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6): δ 9,06 (sh. s, 1H), 8,80 (sh. s, 1H), 8,16 (s, 1H), 7,95 (d, J=7,4 Hz, 1H), to 7.84 (d, J=7,4 Hz, 1H), 4,57 (s, 2H), 3.45 points (d, J=7,3 Hz, 2H), 3,22 (sh. d, J=12 Hz, 2H), 2,78 (sh. K, J=12 Hz, 2H), 2,02 (m, 1H), 1,73 (sh. d, J=12 Hz, 2H), 1.39 in (sh. K, J=12 Hz, 2H).

d) 5-Cyano-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the header connection receive (yield: 79%)using the compound obtained in Example 10C, by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,07 (m, 2H), 7,95 (d, J=7.8 Hz, 1H), to 7.77 (d, J=7.8 Hz, 1H), 7,76 (s, 1H), 7,12 (t, J=8,4 Hz, 2H), 4,48 (s, 2H), 3,74 (s, 2H), 3,54 (d, J=7.2 Hz, 2H), 2,97 (sh. d, J=12 Hz, 2H), 2,15 (dt, J=11,4, 2,1 Hz, 2H), of 1.84 (m, 1H), 1,66 (sh. d, J=12 Hz, 2H), 1,48 (DK, J=12, 4 Hz, 2H).

e) of the hydrochloride of 5-cyano-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 85%), using the compound obtained in Example 10d, by methods similar to the methods of Example 1f.

Melting point: 212-217° C.

1H-NMR (DMSO-d6): δ 10,00 (sh. s, 1H), 8,18 (s, 1H), 8,06-to 8.14 (m, 2H), of 7.97 (d, J=8 Hz, 1H), 7,86 (d, J=8 Hz, 1H), of 7.48 (t, J=8,8 Hz, 2H), 5,06-5,12 (m, 2H), br4.61 (s, 2H), 3,01-3,61 (m, 6H), to 2.06 (m, 1H), 1,59-to 1.87 (m, 4H).

Example 11: Hydrochloride 4-nitro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 25 in Table 1)

a) Methyl ester of 2-methyl-3-neath what obenteni acid

Specified in the title compound obtained as a colorless solid (1,74 g)using 2-methyl-3-nitrobenzoic acid (3.0 g, 16,56 mmol), by methods similar to the methods of Example 3A. The product is used in subsequent reactions without purification.

b) methyl ester of 2-methyl bromide-3-nitrobenzoic acid

Specified in the title compound obtained as a pale yellow oil (1,43 g)using the compound obtained in Example 11a (1,00 g), by methods similar to the methods of Example 1b. The product is used in subsequent reactions without purification.

C) tert-Butyl 4-[(4-nitroisoquinoline-1-he)-2-ylmethyl]piperidine-1-carboxylate

Specified in the title compound obtained as a pale brown solid (590 mg, yield: 56%), using the compound obtained in Example 11b (783 mg), by methods similar to the methods of Example 1C.

1H-NMR (CDCl3): δ to 8.40 (DD, 1H, J=8,2, 0.9 Hz), 8,19 (d, 1H, J=7,6 Hz), 7,71 (DD, 1H, J=7,9, 7.9 Hz), 4,88 (s, 2H), 4,11 (sh. s, 2H), 3,57 (sh. d, 2H, J=7,2 Hz), 2,71 (sh. DD, 2H, J=12,9, 12.9 Hz), 2,04 is 1.96 (m, 1H), 1,69 is 1.58 (m, 2H), 1,45 (s, 9H), 1,35-to 1.21 (m, 2H).

d) of the hydrochloride of 4-nitro-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the title compound obtained as a colorless solid (454 mg, yield: 93%)by using the compound obtained in Example 11C (590 mg, 1.57 mmol), by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6

e) 4-nitro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a pale yellow solid (344 mg, yield: 57%), using the compound obtained in Example 11d (454 mg, of 1.46 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ to 8.40 (d, 1H, J=8,2 Hz), 8,18 (d, 1H, J=7.4 Hz), 8,10-with 8.05 (m, 2H), of 7.70 (DD, 1H, J=7,8, and 7.8 Hz), to 7.09 (DD, 2H, J=8,6, 8.6 Hz), 4,88 (s, 2H), and 3.72 (s, 2H), 3,57 (d, 2H, J=7,2 Hz), 2,97 (sh. d, 2H, J=11.5 Hz), 2.21 are a 2.12 (m, 2H), 1,88 of-1.83 (m, 1H), 1,71 (sh. s, 2H), 1.56 to about 1.47 (m, 2H).

f) of the hydrochloride of 2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-4-nitroisoquinoline-1-it

Specified in the title compound obtained as a colorless solid (262 mg, yield: 75%)using the compound obtained in Example 11th (320 mg, 0.78 mmol), by methods similar to the methods of Example 1f.

Melting point: 177-181° C.

1H-NMR (DMSO-d6): δ 9,90 (sh. s, 1H), 8,46 (d, 1H, J=8,4 Hz), 8,16-of 8.09 (m, 3H), 7,83 (DD, 1H, J=7,8, and 7.8 Hz), of 7.48 (DD, 2H, J=8,7, to 8.7 Hz), equal to 4.97 (s, 4H), 3,53 (sh. s, 4H), to 3.02 (sh. s, 2H), 2,12 (sh. s, 1H), 1,83-to 1.61 (m, 4H).

Example 12: Fumarate 6-nitro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 23 in Table 1)

a) methyl ester of 2-methyl-5-n is trementina acid

Specified in the title compound obtained as a colorless solid (2.14 g)using 2-methyl-5-nitrobenzoic acid (2.0 g, 11,04 mmol), by methods similar to the methods of Example 3A. The product is used in subsequent reactions without purification.

b) methyl ester of 2-methyl bromide-5-nitrobenzoic acid

Specified in the title compound obtained as a pale brown oil (3,22 g)using the compound obtained in Example 12A (2.14 g), by methods similar to the methods of Example 1b. The product is used in subsequent reactions without purification.

C) tert-Butyl 4-[(6-nitroisoquinoline-1-he)-2-ylmethyl]piperidine-1-carboxylate

Specified in the title compound obtained as a pale brown solid (864 mg, yield: 21%), using the compound obtained in Example 12b (3,22 g), by methods similar to the methods of Example 1C.

1H-NMR (CDCl3): δ 8,68 (d, 1H, J=2.1 Hz), 8,43 (DD, 1H, J=8,4, 1.8 Hz), a 7.62 (d, 1H, J=8.1 Hz), a 4.53 (s, 2H), 4,11 (sh. s, 2H), 3,53 (sh. s, 2H), 2.70 height (sh. DD, 2H, J=12,0, 12.0 Hz), 2.00 in with 1.92 (m, 1H), 1,68-of 1.64 (m, 2H), 1,45 (s, 9H), 1,33-1,20 (m, 2H).

d) of the Hydrochloride of 6-nitro-2-(piperidine-4-ylmethyl)isoindoline-1-it

Specified in the title compound obtained as a colorless solid (732 mg, yield: quantitative)using the compound obtained in Example 12C (860 mg, to 2.29 mmol), by methods similar to the methods of Example 1d.

1H-NMR (DMSOd 6): δ 8,93 (sh. s, 1H), 8,67 (sh. s, 1H), of 8.47 (DD, 1H, J=8,3, 2.3 Hz), 8,35 (d, 1H, J=2.1 Hz), 7,92 (d, 1H, J=8,4 Hz), of 4.67 (s, 2H), 3.46 in (sh. s, 2H), 3,25 (sh. d, 2H, J=12.3 Hz), 2,80 (sh. DD, 2H, J=23,1, 12.0 Hz), 2,07 is 2.00 (m, 1H), 1,75 (sh. d, 2H, J=12.3 Hz), 1,46 is 1.34 (m, 2H).

e) 6-nitro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a pale yellow solid (637 mg, yield: 67%), using the compound obtained in Example 12d (725 mg, of 2.33 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,68 (d, 1H, J=2.1 Hz), 8,43 (DD, 1H, J=8,4, and 2.1 Hz), 8,09-8,02 (m, 2H), 7,63 (d, 1H, J=8,4 Hz), 7,16-was 7.08 (m, 2H), of 4.54 (s, 2H), 3,74 (s, 2H), 3,55 (d, 2H, J=7,2 Hz), 2,98 (sh. d, 2H, J=9.9 Hz), 2,20-2,19 (m, 2H), 1,87-of 1.81 (m, 1H), 1,70 (sh. d, 2H, J=12.9 Hz), 1.56 to about 1.47 (m, 2H).

f) Fumarate, 6-nitro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

The compound obtained in Example 12E (287 mg, 0.70 mmol), dissolved in dichloromethane (3 ml) and acetone (3 ml) and the solution was added fumaric acid (41 mg, 0.35 mmol) at room temperature and the mixture is stirred for 3 hours. Precipitated precipitated solid is collected by filtration, getting mentioned in the title compound as a colourless solid (148 mg, yield: 40%).

Melting point: 195-206° C.

1H-NMR (DMSO-d6): δ 8,46 (DD, 1H, J=8,3, 2.3 Hz), a 8.34 (d, 1H, J=2.4 Hz), 8,11-8,07 (m, 2H), 7,88 (d, 1H, J=8,4 Hz), 7,38-to 7.32 (m, 2H), is 6.61 (s, 2H), of 4.66 (s, 2H), 3,86 (s, 2H), 3,44 (d, H, J=7.5 Hz), 2,90 (sh. d, 2H, J=11,4 Hz), 2,16 (sh. t, 2H, J=10,8 Hz), 1,79-of 1.74 (m, 1H), 1,59 (sh. d, 2H, J=11.7 Hz), 1.30 and 1,19 (m, 2H).

Example 13: Hydrochloride 2-[[1-(2-phenyl-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 26 in Table 1)

a) 2-[[1-(2-phenyl-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

A solution of the compound obtained in Example 1d (400 mg, 1.50 mmol), 2-bromoacetophenone (299 mg, 1.50 mmol) and triethylamine (0,46 ml 3,30 mmol) in dimethylformamide (3 ml) was stirred at room temperature for 3 hours. The reaction mixture was added water (10 ml) and stirred at room temperature and then precipitated crystals are collected by filtration and washed with water, getting mentioned in the title compound (319 mg, yield: 61%).

1H-NMR (CDCl3): 8,01 (d, 2H), to 7.84 (d, 1H,), 7,56-7,42 (m,6H), to 4.41 (s, 2H), 3,79 (s, 1H), 3,51 (d, 2H), 3,00 W. d, 2H), 2,16 (dt, 2H), equal to 1.82 (m, 1H), 1,70 (m, 2H), 1,52 (dt, 2H).

(b) hydrochloride of 2-[[1-(2-phenyl-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

The compound obtained in Example 13A (319 mg), dissolved in a mixture of ethanol-ethyl acetate and the solution was added 4N hydrochloric acid in ethyl acetate. Precipitated precipitated crystals are collected by filtration, getting mentioned in the title compound as a white solid (299 mg, yield: 85%).

Melting point: 190-197° C.

1H-NMR (DMSO-d6): to 9.91 (sh. s, 1H), 8,03 (m, 2H), to 7.77 (m, 1H), 7,65 (m, 1H), 7,49 (m, 1H), is 5.06 (m, 2H), of 4.54 (s, 2H), 3,48 (who, 2H), 3,03 (m, 2H), 2,04 (m, 1H), 1,99-to 1.61 (m, 4H).

Example 14: Hydrochloride 2-[[1-[2-(4-chlorophenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 51 in Table 1)

a) 2-[[1-[2-(4-chlorophenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

A solution of the compound obtained in Example 1d (400 mg, 1.50 mmol), 2-bromo-4’-chloroacetophenone (350 mg, 1.50 mmol) and triethylamine (0,46 ml 3,30 mmol) in dimethylformamide (3 ml) was stirred at room temperature for 3 hours. The reaction mixture was added water and extracted with ethyl acetate. The extract is washed four times with water and dried over sodium sulfate. The solvent is evaporated and the residue crystallized from a mixture of ethyl acetate-hexane, obtaining mentioned in the title compound (318 mg, yield: 55%).

1H-NMR (CDCl3): to 7.99 (d, 2H), to 7.84 (d, 2H), 7,56-7,40 (m, 5H), to 4.41 (s, 2H), of 3.73 (s, 2H), 3,51 (d, 1H,), 2,95 (sh. d, 2H), 2,15 (dt, 2H), equal to 1.82 (m, 1H), 1,70 (m, 2H), 1,50 (dt, 2H).

(b) hydrochloride of 2-[[1-[2-(4-chlorophenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

The compound obtained in Example 14a (318 mg), dissolved in a mixture of ethanol-ethyl acetate and the solution was added 4N hydrochloric acid in ethyl acetate. Precipitated precipitated crystals are collected by filtration, getting mentioned in the title compound as a white solid (268 mg, yield: 77%).

Melting point: 188-196° C.

1H-NMR (DMSO-d6): becomes 9.97 (sh. s, 1H), 8,00 (m, 2H), 7,68 (m, 3H), EUR 7.57 (m, 2H), 7,47 (m, 1H), to 5.03 (m, 2H), 4,51 (s, 2H), 3,54-2,95 (m, 6H), of 1.97 (m, 1H), 1,80-to 1.60 (m, 4H).

Example 15: Hydrochloride 2-[[1-[2-(4-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 64 in Table 1)

a) 2-[[1-[2-(4-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

A solution of the compound obtained in Example 1d (400 mg, 1.50 mmol), 2-bromo-4’-methoxyacetophenone (344 mg, 1.50 mmol) and triethylamine (0,46 ml 3,30 mmol) in dimethylformamide (3 ml) was stirred at room temperature for 3 hours. The reaction mixture was added water (10 ml) and stirred at room temperature. Then precipitated precipitated crystals are collected by filtration and washed with water, getting mentioned in the title compound (537 mg, yield: 95%).

1H-NMR (CDCl3): 8,02 (d, 2H), a 7.85 (d, 1H,), 7,53-7,42 (m, 3H), 6,91 (d, 2H), to 4.41 (s, 2H), a 3.87 (s, 3H), of 3.73 (s, 2H), 3,51 (d, 2H), 2,98 (sh. d, 2H), 2,15 (dt, 2H), is 1.81 (m, 1H), 1,70 (m, 2H)and 1.51 (dt, 2H).

(b) hydrochloride of 2-[[1-[2-(4-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

The compound obtained in Example 15A (537 mg), dissolved in a mixture of ethanol-ethyl acetate and the solution was added 4N hydrochloric acid in ethyl acetate. Precipitated precipitated crystals are collected by filtration, getting mentioned in the title compound as a white solid (444 mg, yield: 75%).

Melting point: 163-168° C.

1H-NMR (DMSO-d6): 9,85 (sh. s, 1H), 7,95 (m, 2H), to 7.67 (d, 1H,),to 7.59 (d, 2H), 7,47 (m, 1H), 7,12 (d, 2H), 4.95 points (m, 2H), 4,51 (s, 2H), 3,86 (s, 3H), of 3.45 (m, 4H), 2,99 (m, 2H), 2,01 (m, 1H), 1,65 (m, 4H).

Example 16: Hydrochloride of (R,S)-2-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 77 in Table 1)

a) (R,S)-2-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 1f (403 mg, 1.0 mmol), treated with methylene chloride and 1N-sodium hydroxide solution.

The methylene chloride layer is dried over sodium sulfate and then the solvent is evaporated. The resulting residue is dissolved receiving ethanol solution (15 ml)and the solution add borohydride sodium (30 mg, 0.79, which mmol) and stirred at room temperature for 2 hours. The solvent is evaporated and to the residue water is added, receiving a suspension. The resulting crystals are collected by filtration, getting mentioned in the title compound as a white solid (331 mg, yield: 90%).

1H-NMR (CDCl3): 7,86 (d, 1H,), 7,55-the 7.43 (m, 3H), 7,32 (m, 2H), 7,02 (m, 2H), 4,69 (m, 1H), 4,42 (s, 2H), 3,53 (d, 2H), 3.15 in (m, 1H), 2,82 (m, 1H), 2.49 USD is 2.00 (m, 4H), of 1.84 (m, 1H), 1,70 (m, 2H), 1,40 (m, 2H).

(b) Hydrochloride of (R,S)-2-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]isoindoline-1-it

The compound obtained in Example 16A (331 mg), dissolved in a mixture of ethanol-ethyl acetate and the solution was added 4N hydrochloric acid in ethyl acetate. Precipitated precipitated crystals are collected by filtration, olucha specified in the title compound as a white solid (347 mg, yield: 95%).

Melting point: 223-228° C.

1H-NMR (DMSO-d6): 9,82 (sh. s, 1H), 7,68 (d, 1H,), to 7.61 (d, 2H), of 7.48 (m, 3H), 7,22 (m, 2H), of 6.26 (m, 1H), 5,15 (m, 1H), to 4.52 (s, 2H), 3,63 (m, 2H), 3.45 points (d, 2H), 3,18 (m, 2H), 2.95 and (m, 2H), 1,99 (m, 1H), 1,86-of 1.57 (m, 4H).

Example 17: Hydrochloride of (R,S)-5-bromo-2-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 79 in Table 1)

a) (R,S)-5-bromo-2-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a colorless solid (677 mg, yield: 99%), using the compound obtained in Example 3E (678 mg, of 1.52 mmol), by methods similar to the methods of Example 16A.

1H-NMR (CDCl3): 7,70-7,74 (1H, m), 7,60-7,63 (2H, m), 7,31 and 7.36 (2H, m), 6,99-7,06 (2H, m), 4,69 (1H, DD, J=3,6, 10,2), and 4.40 (2H, s), 3,51 (2H, d, J=6,9), 3,1-3,2 (1H, m), 2,7-2,8 (1H, m), 2,30 is 2.51 (2H, m), 2,2-2,3 (1H, m), 2,0-2,1 (1H, m), 1,3-1,9 (5H, m).

(b) Hydrochloride of (R,S)-5-bromo-2-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (317 mg, yield: 94%)using the compound obtained in Example 17A (313 mg, 0,700 mmol), by methods similar to the methods of Example 1f.

Melting point: 230-240° C.

1H-NMR (DMSO-d6): 9,81 (1H, sh. C)of 7.90 (1H, d, J=0,9), of 7.70 (1H, DD, J=0,9, 8,0), a 7.62 (1H, d, J=8,0), 7,43-7,53 (2H, m), 7,20-7,26 (2H, m), 6,29 of 6.31 (1H, m), 5,0-5,2 (1H, m)to 4.52 (2H, s), of 3.5-3.7 (2H, m), 2.8 to 3.5 (4H, m), 1,5 is 2.2 (5H, m).

Example 18: Emarat 2-[[1-[2-(4-forfinal)-2-(Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it (Z-isomer of Compound 90 in Table 1)

a) 2-[[1-[2-(4-forfinal)-2-(E,Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 1E (496 mg, 1.35 mmol), dissolved in a mixed solvent of ethanol (10 ml) - pyridine (10 ml). To the solution was added hydroxylamine hydrochloride (255 mg, to 3.67 mmol) at room temperature and continue stirring at the same temperature for 5 days. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and then with saturated salt solution and dried over sodium sulfate. The insoluble solid is removed by filtration and the solvent is evaporated under reduced pressure. The obtained solid is purified column chromatography on silica gel (eluent a mixture of methanol-dichloromethane), getting mentioned in the title compound (295 mg, yield: 57%) and E-isomer (216 mg, yield: 42%) as colorless solids.

(Z-isomer)

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,4), 7,42-to 7.64 (5H, m), 7,01-7,07 (2H, m)to 4.41 (2H, s), 3,74 (2H, s), 3,52 (2H, d, J=7,4), 3,0-3,1 (2H, m), 2,13-2,22 (2H, m), 1,8-2,0 (1H, m), 1,7-1,8 (2H, m), 1,3-1,5 (2H, m).

(E-isomer)

1H-NMR (CDCl3): to 7.84 (1H, d, J=6,9), to 7.61-to 7.67 (2H, m), 7,41-rate of 7.54 (3H, m), 7,05 for 7.12 (2H, m), to 4.38 (2H, s), 3,48 (2H, d, J=7,2), and 3.31 (2H, s), of 2.8-3.0 (2H, m), 1,9-of 2.05 (2H, m), 1.5 and 1.8 (3H, m), 1,3-1,4 (2H, m).

b) Fumarate, 2-[[1-[2-(4-forfinal)-2-(Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header of the connection of the floor is up in the form of a colorless solid (320 mg, yield: 85%), using the Z-isomer of the compound obtained in Example 18a (289 mg, 0,756 mmol), by methods similar to the methods of Example 36C.

Melting point: 178-180°

1H-NMR (DMSO-d6): 7,76-7,81 (2H, m), between 7.4 and 7.7 (4H, m), 7,16-of 7.23 (2H, m), 6,62 (2H, s, fumaric acid), of 4.45 (2H, s), 3,61 (2H, s), 3,2-3,4 (2H, m), 2,7-2,8 (2H, m), 1,9-2,1 (2H, m), of 1.6-1.8 (1H, m), 1,4-1,6 (2H, m), 1.0 to 1,2 (2H, m).

Example 19: Fumarate 2-[[1-[2-(4-forfinal)-2-(E)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it (E-isomer of Compound 90 in Table 1)

Specified in the title compound obtained as a colorless solid (225 mg, yield: 81%), using E-isomer of the compound obtained in Example 18a (214 mg, 0,560 mmol), by methods similar to the methods of Example 36C.

Melting point: 186-188° C.

1H-NMR (DMSO-d6): 11,03 (1H, sh. s, OH), between 7.4 and 7.7 (6H, m), 7,19-of 7.25 (2H, m), 6,62 (2H, s, fumaric acid), to 4.46 (2H, s), 3,2-3,4 (2H, m), 2,8-2,9 (2H, m), 1,9-of 2.05 (2H, m), of 1.6-1.8 (1H, m), 1,4-1,6 (2H, m), 1,0-1,2 (2H, m).

Example 20: Hydrochloride 2-[[1-[2-(2,4-differenl)-2-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-she (Compound 116 in Table 1)

a) Reaction of 2-Chloro-2’,4’-defloration

2-Chloro-2’,4’-defloration (3,09 g, 16.2 mmol) was dissolved in ethanol (30 ml). In the obtained solution under cooling with ice consistently add hydroxylamine hydrochloride (1.23 g of 17.7 mmol) and sodium acetate (1.45 g of 17.7 mmol) and the mixture allow to warm to whom atoi temperature and stirred for 20 hours. The solvent of the reaction mixture is evaporated under reduced pressure and the residue diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and then with saturated salt solution and dried over magnesium sulfate. The insoluble solid is removed by filtration and the solvent is evaporated under reduced pressure. The residue is suspended in hexane and dried, obtaining mentioned in the title compound as a colourless solid (to 2.29 g, yield: 69%).

1H-NMR (CDCl3): a total of 8.74 (1H, s)of 7.48-7,56 (1H, m), 6,85-6,99 (2H, m), 4,63 (2H, s).

b) 2-[[1-[2-(2,4-differenl)-2-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a colorless solid (1,38 g, yield: 100%)using the compound obtained in Example 20A (710 mg, of 3.45 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): 8,3 (1H, sh. C)to 7.84 (1H, d, J=7,5), 7,41-7,53 (3H, m), 7,25-7,31 (1H, m), for 6.81-6,92 (2H, m), to 4.38 (2H, s), of 3.46 (2H, d, J=7,2), to 3.33 (2H, s), 2,87-only 2.91 (2H, m), 1,96-of 2.05 (2H, m), of 1.5-1.9 (3H, m), 1,2-1,4 (2H, m,).

c) the Hydrochloride of 2-[[1-[2-(2,4-differenl)-2-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (168 mg, yield: 72%), using the compound obtained in Example 20b (213 mg, of 0.533 mmol), by methods similar to the methods of Example 1f.

Melting point: 152-157#x000B0; C.

1H-NMR (DMSO-d6): to 12.1 (1H, s), 9,92 (1H, sh. C)the 7.65 (1H, d, J=7,5), 7,45-to 7.59 (4H, m), 7,32-7,39 (1H, m), 7,17-of 7.23 (1H, m), 4,48 (2H, s), 4,20-to 4.38 (2H, m), i.e., 3.3 to 3.6 (4H, m), 2.8 to 3.0 (2H, m), 1,4-2,2 (5H, m).

Example 21: Hydrochloride of (R,S)-5-bromo-2-[[1-[2-(4-forfinal)-2-acetoxyethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 105 in Table 1)

a) (R,S)-5-bromo-2-[[1-[2-(4-forfinal)-2-acetoxyethyl]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 17A (360 mg, 0,805 mmol), and dimethylaminopyridine (139 mg, to 1.14 mmol) dissolved in dichloromethane (6 ml). To the solution was added acetic anhydride (100 μl, 1.06 mmol) under cooling with ice and continue stirring at the same temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate solution and then with saturated salt solution and then dried over sodium sulfate. The insoluble solid is removed by filtration, the solvent is evaporated under reduced pressure, obtaining mentioned in the title compound as a colourless solid (391 mg, yield: 99%).

1H-NMR (CDCl3): 7,71 (1H, d, J=8,5), 7,58 to 7.62 (2H, m), 7,27-7,33 (2H, m), 6,98-7,05 (2H, m), of 5.89 (1H, DD, J=4,6, 8,4), 4,37 (2H, s), 3,4-3,5 (2H, m), 2,84 to 3.0 (2H, m), 2,80 (1H, DD, J=8,4, 13,5), 2,52 (1H, DD, J=4,6, 13,5), 2,11 (3H, s), 1,9-2,2 (2H, m), a 1.7-1.8 (1H, m), 1,5-1,7 (2H, m), 1,2-1,4 (2H, m).

(b) Hydrochloride of (R,S)-5-bromo-2-[[1-[2-(4-forfinal)-2-acetoxyethyl]piperidine-4-yl]methyl]isoindoline-1-on the Sabbath.

Specified in the title compound obtained as a colorless solid (285 mg, yield: 69%), using the compound obtained in Example 21A (387 mg, 0,791 mmol), by methods similar to the methods of Example 1f.

Melting point: 193-200° C.

1H-NMR (DMSO-d6): 11,0 (1H, sh. C)of 7.90 (1H, s), of 7.69 (1H, d, J=8,1), a 7.62 (1H, d, J=8,1), 7,44-7,53 (2H, m), 7,22-7,31 (2H, m), 6,0-6,2 (1H, m), 4,49-to 4.52 (2H, m), of 3.2 to 3.7 (6H, m), 2.8 to 3.0 (2H, m), 2,12 (3H, s), 1,4-2,0 (5H, m).

Example 22: Hydrochloride 5-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-4,5-dihydro-6N-thieno{2,3-c}pyrrol-6-she (compound 776 Table 2)

a) Ethyl 3-methyl-2-thiophenecarboxylate

Specified in the title compound obtained as a pale yellow oil (1.20 g)using 3-methyl-2-thiencarbazone acid (1.5 g, 10,55 mmol), by methods similar to the methods of Example 3A. The product is used in subsequent reactions without purification.

b)Ethyl 3-methyl bromide-2-thiophenecarboxylate

Specified in the title compound obtained as a pale brown oil (1.88 g), using the compound obtained in Example 22A (1.20 g), by methods similar to the methods of Example 1b. The product is used in subsequent reactions without purification.

(C) Ethyl 3-[[1-tert-butoxycarbonyl)piperidine-4-yl]methylaminomethyl]-2-thiophenecarboxylate

Specified in the title compound obtained as a pale brown solid (2,02 g)using the connection obtained the Example 22b (1.88 g), by methods similar to the methods of Example 1C. The product is used in subsequent reactions without purification.

d) Ethyl 3-[[1-tert-butoxycarbonyl)piperidine-4-yl]methylaminomethyl]-2-thiencarbazone acid

The compound obtained in Example 22 ° C (1.0 g), dissolved in ethanol (15 ml). To the solution was added water (5 ml) and then add sodium hydroxide (400 mg, 10.0 mmol) with ice cooling and then the mixture is heated to room temperature and stirred. After 6 hours, the mixture was added concentrated hydrochloric acid while cooling with ice, to bring the pH to 7.0, and then extracted with dichloromethane. The organic layer is washed with water and dried over magnesium sulfate. The insoluble solid is removed by filtration and the filtrate evaporated under reduced pressure. The obtained solid is dissolved in dichloromethane (3 ml). To the solution was added diethyl ether (20 ml) and precipitated precipitated solid is collected by filtration, getting mentioned in the title compound (416 mg, 35%, stage 3).

1H-NMR (CDCl3): δ 11,4 (s, 2H), 7,32 (d, 1H, J=5,1 Hz)6,91 (d, 1H, J=4.5 Hz), is 4.21 (s, 2H), Android 4.04 (s, 2H),2.71 to 2,61 (m, 4H), 1,96 (sh. s, 1H), 1,79 (sh. d, 2H, J=12,6 Hz)of 1.41 (s, 9H), 1,16-of 1.03 (m, 2H).

(e) tert-Butyl 4-[(4,5-dihydro-6N-thieno[2,3-c]pyrrol-6-one)-2-ylmethyl]piperidine-1-carboxylate

The compound obtained in Example 22d (500 mg), dissolved in dichloromethane (14 ml) and to the races the thief add methanesulfonanilide (of 0.11 ml, of 1.41 mmol) under cooling with ice. The mixture was stirred at the same temperature for 1 hour and then warmed to room temperature and stirred for 17 hours. The reaction mixture was added water (5 ml) at the same temperature and extracted with a known amount of dichloromethane. The organic layer is washed with water and dried over magnesium sulfate. The insoluble solid is removed by filtration and the filtrate evaporated under reduced pressure. The resulting oil is purified column chromatography on silica gel (methanol-dichloromethane), getting mentioned in the title compound as a pale green solid (247 mg, yield: 52%).

1H-NMR (CDCl3): δ 7,63 (d, 1H, J=4.5 Hz),? 7.04 baby mortality (d, 1H, J=4,8 Hz)to 4.33 (s, 2H), 4,11 (sh. s, 2H), 3.45 points (sh. s, 2H), 2,69 (sh. DD, 2H, J=12,3, 12.3 Hz), 1.93 and-of 1.87 (m, 1H), 1,67 (sh. d, 2H, J=9,3 Hz), 1,45 (s, 9H), 1.30 and of 1.16 (m, 2H).

f) hydrochloride 5-(piperidine-4-ylmethyl)-4,5-dihydro-6N-thieno[2,3-c]pyrrole-6-she

Specified in the title compound obtained as a pale green solid (200 mg, yield: 80%)using the compound obtained in Example 22E (310 mg, 0.90 mmol), by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6): δ 8,90 (sh. s, 1H), 8,62 (sh. s, 1H), 7,98 (d, 1H, J=4,7 Hz), 7,24 (d, 1H, J=4,7 Hz), of 4.44 (s, 2H), 3,38 (d, 2H, J=7.4 Hz), 3,24 (sh. d, 2H, J=12,6 Hz), 2,80 (sh. DD, 2H, J=23,1, 12.1 Hz), 2,02 is 1.91 (m, 1H), 1,74 (sh. d, 2H, J=13,2 Hz), 1,43-of 1.29 (m, 2H).

g) 5-[[1-[2-(4-forfinal)2-oxoethyl]]piperidine-4-yl]methyl]-4,5-dihydro-6N-thieno[2,3-c]pyrrole-6-he

Specified in the title compound obtained as a pale brown solid (209 mg, yield: 79%)using the compound obtained in Example 22f (193 mg, 0.71 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,10-of 8.04 (m, 2H), a 7.62 (d, 1H,), 7,15-7,07 (m, 2H), 7,02 (m, 1H), 4,32 (s, 2H), and 3.72 (s, 2H), 3.45 points (d, 2H, 7,1 Hz), 2,96 (sh. d, 2H, J=11.5 Hz), 2,20-2,11 (m, 2H), 1,83 to 1.76 (m, 1H), 1,70 (sh. d, 2H, J=a 13.9 Hz), 1,51 was 1.43 (m, 2H).

h) hydrochloride, 5-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-4,5-dihydro-6N-thieno[2,3-c]pyrrole-6-she

Specified in the title compound obtained as a colorless solid (178 mg, yield: 78%), using the compound obtained in Example 22g (209 mg, 0,56 mmol), by methods similar to the methods of Example 1f.

Melting point: 167-171° C.

1H-NMR (DMSO-d6): δ 9,94 (sh. s, 1H), 8,19-of 8.06 (m, 2H), to 7.99 (d, 1H, J=4,8 Hz), 7,58 (DD, 2H, J=8,9, and 8.9 Hz), 7,26 (d, 1H, J=4,5Hz), 5,11-5,04 (m, 2H), 4,47 (s, 2H), 3,54 (sh. d, 2H, J=10,5 Hz), and 3.31 (sh. s, 2H),is 3.08-a 3.01 (m, 2H), 2,09-of 1.57 (m,5H).

Example 23: Dihydrochloride 6-[[1-[2-(4-Forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-she (Connection 796 Table 2)

a) Ethyl 2-bromomethylphenyl-3-carboxylate

Specified in the title compound obtained as a brown oil (1,02 g)using 2-bromomethylphenyl-3-carboxylic acid (2.0 g, 12,11 mmol), by methods similar to the methods of Example 1b. The product is used in subsequent the reaction without purification.

b) tert-Butyl 4-[(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one)-2-ylmethyl]piperidine-1-carboxylate

Specified in the title compound obtained as a brown oil (945 mg)using the compound obtained in Example 23a (1.01 g), by methods similar to the methods of Example 1C. The product is used in subsequent reactions without purification.

(C) dihydrochloride 6-(piperidine-4-ylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-she

Specified in the title compound obtained as a colorless solid (416 mg, yield: 33%), using the compound obtained in Example 23b (811 mg, 1.01 mmol), by methods similar to the methods of Example 1d.

1H-NMR (DMSO-d6): δ of 9.21 (s, 2H), 8,99 (s, 2H), 8,10 (DD, 1H, J=8,6, 1.2 Hz), 7,54 (DD, 1H, J=7,7, 5.0 Hz), of 4.57 (s, 2H), 3,47 (d, 2H, J=7.4 Hz), 3,24 (sh. d, 2H, J=12.3 Hz), 2,79 (sh. DD, 2H, J=23,5, 12.3 Hz), 2,09 of 1.99 (m, 1H), 1,75 (sh. d, 2H, J=12.9 Hz), 1,46-of 1.32 (m, 2H).

d) 2-[[1-[2-(4-Forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-he

Specified in the title compound obtained as a pale brown solid (377 mg, yield: 75%)using the compound obtained in Example 23C (416 mg, 1.37 mmol), by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): δ 8,72 (DD, 1H, J=4,7, and 1.4 Hz), 8,13-8,71 (m, 3H), 7,40 (DD, 1H, J=7,6, 5,1 Hz), 7,12 (DD, 2H, J=8,6, 8.6 Hz), 4,47 (s, 2H), of 3.73 (s, 2H), 3,55 (d, 2H, J=7,1 Hz), 2,97 (sh. d, 2H, J=11.5 Hz), of 2.15 (DDD, 2H, J=2,1, to 11.5, and 11.5 Hz), 1,86 and 1.80 (m, 1H), 1,70 (sh. d, 2H, J=13,0 G is), 1,56 of 1.46 (m, 2H).

e) the Dihydrochloride of 2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-she

Specified in the title compound obtained as a colorless solid (384 mg, yield: 85%), using the compound obtained in Example 23d (377 mg, of 1.03 mmol), by methods similar to the methods of Example 1f.

Melting point: 138-144° C.

1H-NMR (DMSO-d6): δ 10,1 (sh. s, 1H), 8,78 (DD, 1H, J=4,7, 1.1 Hz), 8,19 (m, 3H), EUR 7.57 was 7.45 (m, 3H), 5,13-of 5.05 (m, 2H), br4.61 (s, 2H), 3,62 (m, 3H), 3,32 (sh. s, 1H), 3.04 from (sh. DD, 2H, J=21,8, 10.1 Hz), 2,07 (sh. s, 1H), 1,89 is 1.60 (m, 4H).

Example 24: Hydrochloride 2-[[1-(3,3-dimethyl-2-oxobutyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 126 in Table 1)

a) 2-[[1-(3,3-Dimethyl-2-oxobutyl)piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 1d (500 mg, of 1.87 mmol), dissolved in DMF (DMF) (6 ml). To the solution add triethylamine (0,57 ml of 4.11 mmol) and 1-chlorination (0,24 ml of 1.87 mmol) and stirred at room temperature for 30 hours and then heated at 50° C for 7 hours. After the mixture has cooled, add water (10 ml) and extracted with ethyl acetate. The organic layer is washed three times with water and dried over magnesium sulfate. The insoluble solid is removed by filtration and the filtrate evaporated. The resulting oil is purified column chromatography on silica gel (methanol-dichloromethane), Paul is the tea mentioned in the title compound as a pale brown solid (369 mg, yield: 60%).

1H-NMR (CDCl3): δ to 7.84 (d, 1H, J=7,2 Hz), 7,56-7,42 (m, 3H), to 4.41 (s, 2H), 3,50 (d, 2H, J=7,3 Hz)to 3.36 (s, 2H), 2,88 (sh. d, 2H, J=11.3 Hz), was 2.05 (DDD, 2H, J=2,2, of 11.3, 11.3 Hz), 1,87 and 1.80 (m, 1H), 1.69 in (sh. d, 2H, J=12.9 Hz), 1,54 of 1.46 (m, 2H)and 1.15 (s,9H).

(b) hydrochloride of 2-[[1-(3,3-dimethyl-2-oxobutyl)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (323 mg, yield: 79%)using the compound obtained in Example 24A (369 mg, 1.12 mmol), by methods similar to the methods of Example 1f.

Melting point: 239-243° C.

1H-NMR (DMSO-d6): δ 9,73 (sh. s, 1H), 7,68 (d, 1H, J=7,5), to 7.61 (d, 2H), 7,53 was 7.45 (m, 1H), with 4.64-to 4.52 (m, 4H), of 3.60 3.21-in (m, 4H), 2.95 and (sh. d, 2H, J=10.5 Hz), 1,97 (sh. s, 1H), 1,79 (sh. d, 2H, J=13.5 Hz), 1,65-of 1.52 (m, 2H), 1,13 (s,9H).

Example 25: Hydrochloride 2-[[1-(2-methoxybenzyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 136 in Table 1)

a) 2-Methoxybenzylidene

2-Methoxybenzyloxy alcohol (1.01 g, 7,31 mmol) and triphosgene (757 mg, 2.55 mmol) was dissolved in tetrahydrofuran (5 ml). To the solution was added pyridine (1,18 ml, 14.6 mmol) under cooling with ice and then warmed to room temperature. After 20 minutes the insoluble solid is removed by filtration and the solvent is evaporated under reduced pressure. The resulting oil was diluted with ethyl acetate and then the insoluble solid is removed. The solvent is evaporated under reduced pressure, obtaining is shown in the title compound as a pale yellow oil (1,16 g, yield: 100%).

1H-NMR (CDCl3): 7,25-7,37 (2H, m), 6.87 in-6,97 (2H, m), of 4.66 (2H, s), 3,88 (3H, s).

b) 2-[[1-(2-Methoxybenzyl)piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 25A (339 mg, 2,17 mmol), the compound obtained in Example 1d (563 mg, 2,11 mmol) and triethylamine (700 μl, 5,02 mmol) are added to a dimethylformamide (6 ml) and the mixture was stirred at 60° C for 2 hours. The reaction mixture allow to cool to room temperature and then diluted with a mixed solvent of ethyl acetate-hexane. The mixture is washed with water, aqueous sodium bicarbonate solution and then with saturated salt solution and dried over sodium sulfate. The insoluble solid is removed by filtration and the solvent is evaporated under reduced pressure. The obtained solid is suspended and washed in a mixed solvent of diethyl ether-hexane and the solid is dried, obtaining mentioned in the title compound as a colourless solid (524 mg, yield: 71%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,2), 7,41-7,53 (3H, m), 7,35 (1H, DD, J=1,4, 7,7), 7,10-7,26 (1H, m), 6,83-to 6.95 (2H, m), and 4.40 (2H, s), of 3.80 (3H, s), 3,55 (2H, s), 3,50 (2H, d, J=7,2), 2,91-2,96 (2H, m), 1,97-to 2.06 (2H, m), of 1.5-1.9 (3H, m), 1,3-1,5 (2H, m).

c) the hydrochloride of 2-[[1-(2-Methoxybenzyl)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (470 mg, yield: 82%), COI is lsua connection, obtained in Example 25b (521 mg, 1,49 mmol), by methods similar to the methods of Example 1f.

Melting point: 195-203° C.

1H-NMR (DMSO-d6): 10,5 (1H, sh. C)7,58-7,71 (4H, m), 7,41-7,51 (2H, m), 7,11 (1H, d, J=8,4), 6,98? 7.04 baby mortality (1H, m), 4,48-to 4.52 (2H, m), 4,18 is 4.35 (2H, m), 3,82-a 3.87 (3H, m), 3,2-3,5 (4H, m), 2,7-2,9 (2H, m), 1,5-2,2 (5H, m).

Example 26: Hydrochloride 2-[[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 146 in Table 1)

a) 2-Methoxybenzenesulfonyl

2-Methoxyphenethyl alcohol (5.29 g, 34,74 mmol) and triethylamine (7.0 ml, 50 mmol) dissolved in tetrahydrofuran (45 ml). To the solution add methanesulfonate (3.0 ml, 39 mmol) under cooling with ice and continue stirring at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water, 10% aqueous citric acid solution, aqueous sodium bicarbonate solution and then with saturated salt solution and dried over magnesium sulfate. The insoluble solid is removed by filtration, the solvent is evaporated under reduced pressure. The resulting oil is purified column chromatography on silica gel (ethyl acetate-hexane)to give specified in the header connection (5,77 g, yield: 72%).

1H-NMR (CDCl3): 7,18-7,29 (2H, m), 6,85-6,93 (2H, m), 4,42 (2H, t, J=7,1), of 3.84 (3H, s), of 3.07 (2H, t, J=7,1), and 2.83 (3H, s).

b) 2-[[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

The connection is received in Example 26a (530 mg, 2,30 mmol), the compound obtained in Example 1d (563 mg, 2,11 mmol), sodium carbonate (553 mg, with 5.22 mmol) and sodium iodide (328 mg, 2,19 mmol) are added to N-organic (9 ml) and the mixture was stirred at 80° C for two hours. The reaction mixture allow to cool to room temperature and the mixture is then diluted with ethyl acetate. The mixture is washed with water, aqueous sodium bicarbonate solution and saturated salt solution and dried over sodium sulfate. The insoluble solid is removed by filtration and then the solvent is evaporated under reduced pressure. The resulting oil is purified column chromatography on silica gel (eluent: dichloromethane-methanol), getting mentioned in the title compound as a yellow oil (544 mg, yield: 71%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,42-rate of 7.54 (3H, m), 7,12-to 7.18 (2H, m), 6,82-of 6.90 (2H, m), 4,42 (2H, s), 3,81 (3H, s), 3,52 (2H, d, J=7,2), 3,01-of 3.06 (2H, m), 2,79-to 2.85 (2H, m), of 2.51-of 2.58 (2H, m), 1,99-of 2.08 (2H, m), 1,6-1,9 (3H, m), 1,3-1,5 (2H, m).

(C) the hydrochloride of 2-[[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a pale yellow solid (475 mg, yield: 81%), using the compound obtained in Example 26b (533 mg, of 1.46 mmol), by methods similar to the methods of Example 1f.

Melting point: 208-227°

1H-NMR (DMSO-d6): 10,3 (1H, sh. C)of 7.69 (1H, d, J=7,5), 7,60-7,63 (2H, m), of 7.48-7,53 (1H, m), 7.18 in-7,26 (H, m), 6,88-7,02 (2H, m), 4,51 (2H, s), 3,79-a 3.83 (3H, m), 3,1-3,6 (6H, m), of 2.7-3.0 (4H, m), 1.7 to 2.2 (3H, m), 1,5-1,7 (2H, m).

Example 27: the Hydrochloride of 2-(1-benzylpiperidine-4-ylmethyl)isoindoline-1-she (Compound 176 Table 1)

a) 2-(1-Benzylpiperidine-4-ylmethyl)isoindoline-1-he

Specified in the title compound is obtained by methods similar to the methods of Example 25b (yield: 80%).

1H-NMR (CDCl3): δ to 7.84 (d, J=7.5 Hz, 1H), 7,41-rate of 7.54 (m, 3H), 7,20-7,30 (m, 5H), 4,39 (s, 2H), 3,50 (d, J=6.6 Hz, 2H), 3,49 (s, 2H), 2,88 (sh. d, J=12 Hz, 2H), 1,96 (dt, J=11,7, 2.4 Hz, 2H), 1,79 (m, 1H), 1,66 (sh. d, J=12 Hz, 2H), 1,41 (DK, J=11,7, 3.6 Hz, 2H).

(b) Hydrochloride of 2-(1-benzylpiperidine-4-ylmethyl)isoindoline-1-it

Specified in the header connection receive (yield: 85%), using the compound obtained in Example 27A, by methods similar to the methods of Example 1f.

Melting point: 222-229° C.

1H-NMR (DMSO-d6): δ 13,50 (sh. s, 1H), EUR 7.57-of 7.60 (m, 4H), 7,46-7,51 (m, 4H), 4,50 (s, 2H), 4,23-to 4.41 (m, 2H), 3.40 in-the 3.65 (m, 2H), 2,79-to 3.34 (m, 4H), to 1.96 (m, 1H), 1,78 (m, 2H), 1.55V (m, 2H).

Example 28: Hydrochloride 2-[[1-(4-terbisil)piperidine-4-yl]methyl]isoindoline-1-she (Compound 186 Table 1)

a) 2-[[1-(4-Terbisil)piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound is obtained by methods similar to the methods of Example 25b (yield: 49%).

1H-NMR (CDCl3): δ to 7.84 (d, J=7.5 Hz, 1H), 7,42-7,53 (m, 3H), 7,26 (m, 2H), 6,98 (t, J=8.7 Hz, 2H), and 4.40 (s, 2H), 3,50 (d, J=7.5 Hz, 2H), 3.45 points (s, 2H), 2,86 (sh. d, J=12 Hz, 2H), was 1.94 (dt, J=11,7, 2,1 Hz, 2), of 1.80 (m, 1H), 1,66 (sh. d, J=12hz, 2H), 1,40 (DK, J=12,4 Hz, 2H).

(b) Hydrochloride of 2-[[1-(4-terbisil)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 85%), using the compound obtained in Example 28a, by methods similar to the methods of Example 1f.

Melting point: 241-249° C.

1H-NMR (DMSO-d6): δ 10.30 a.m. (sh. s, 1H), to 7.59-of 7.69 (m, 5H), to 7.50 (m, 1H), 7,31 (t, J=9 Hz, 2H), 4,49 (s, 2H), 4,25-to 4.41 (m, 2H), 3,41-to 3.64 (m, 2H), 2.77-to to 3.34 (m, 4H), to 1.96 (m, 1H), 1,78 (sh. d, J=12 Hz, 2H), 1,53 (sh. K, J=12 Hz, 2H).

Example 29: Hydrochloride 2-[[1-[2-(4-forfinal)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 196 Table 1)

a) 2-[[1-[2-(4-forfinal)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound is obtained by methods similar to the methods of Example 26b (yield: 27%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.8 Hz, 1H), 7,43-rate of 7.54 (m, 3H), 7,15 (m, 2H), of 6.96 (t, J=8,4 Hz, 2H), 4,42 (s, 2H), 3,52 (d, J=7.2 Hz, 2H), 2,99 (sh. d, J=12 Hz, 2H), 2,77 (m, 2H), by 2.55 (m, 2H), 2,02 (t, J=11 Hz, 2H)and 1.83 (m, 1H), 1,73 (sh. d, J=12 Hz, 2H), 1,40 (DK, J=12,4 Hz, 2H).

(b) Hydrochloride of 2-[[1-[2-(4-forfinal)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 48%), using the compound obtained in Example 29A, by methods similar to the methods of Example 1f.

Melting point: 230-237° C.

1H-NMR (DMSO-d6): δ 10,06 (sh. s, 1H), 7,69 (d, J=7.5 Hz, 1H), to 7.61 to 7.62 (m, 2H), 7,51 (m, 1H), 7,32 (m, 2H), 7,18 (t, J=8.7 Hz, 2H), to 4.52 (s, 2H), 354-3,60 (m, 2H), 3,42-of 3.46 (m, 2H), 2,86-to 3.34 (m, 6H), of 2.86 (m, 1H), 1,83 (sh. d, J=12 Hz, 2H), and 1.54 (sh. K, J=12 Hz, 2H).

Example 30: Hydrochloride 2-[[1-[3-phenyl-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 156 in Table 1)

a) 2-[[1-[3-phenyl-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound is obtained by methods similar to the methods of Example 26b (yield: 61%).

1H-NMR (CDCl3): δ of 7.96 (d, J=6,9 Hz, 2H), a 7.85 (d, J=7.2 Hz, 1H), 7,42-to 7.59 (m, 6H), to 4.41 (s, 2H), 3,51 (d, J=6,9 Hz, 2H), 3,19 (t, J=7.4 Hz, 2H), 2,96 (sh. t, J=12 Hz, 2H), 2,82 (t, J=7.4 Hz, 2H), 2,04 (dt, J=11,7, 1.8 Hz, 2H), is 1.81 (m, 1H), 1,71 (sh. d, J=12 Hz, 2H), 1,40 (DK, J=12, 4 Hz, 2H).

(b) Hydrochloride of 2-[[1-[3-phenyl-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 66%), using the compound obtained in Example 30A, by methods similar to the methods of Example 1f.

Melting point: 245-261° C.

1H-NMR (DMSO-d6): δ 10,38 (sh. s, 1H), 8,01 (d, J=7.5 Hz, 2H), 7,69 (m, 2H), 7,54 to 7.62 (m, 4H), 7,49 (m, 1H), to 4.52 (s, 2H), 2,88-3,70 (m, 10H), a 2.01 (m, 1H), 1,58 (sh. d, J=12 Hz, 2H)and 1.51 (sh. K, J=12 Hz, 2H).

Example 31: Hydrochloride 2-[[1-[4-(4-forfinal)-4-oxobutyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 166 in Table 1)

a) 2-[[1-[4-(4-forfinal)-4-oxobutyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound is obtained by methods similar to the methods of Example 26b.

1H-NMR (CDCl3): δ 8,00 (m, 2H), a 7.85 (d, J=7.5 Hz, 1H) 7,42-rate of 7.54 (m, 3H), 7,12 (t, J=8,4 Hz, 2H), and 4.40 (s, 2H), 3,48 (d, J=7.2 Hz, 2H), 2,96 (t, J=7.2 Hz, 2H), 2,90 (sh. d, J=12 Hz, 2H), 2,39 (t, J=7.2 Hz, 2H), 1,90-of 1.97 (m, 4H), of 1.78 (m, 1H), 1,66 (sh. d, J=12 Hz, 2H), 1,32 (DK, J=12, 4 Hz, 2H).

(b) Hydrochloride of 2-[[1-[4-(4-forfinal)-4-oxobutyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 20%), using the compound obtained in Example 31A, by methods similar to the methods of Example 1f.

Melting point: 195-199° C.

1H-NMR (DMSO-d6): δ 9,87 (sh. s, 1H), of 8.06 (m, 2H), 7,69 (d, J=7,4 Hz, 1H), 7,60-7,63 (m, 2H), 7,51 (m, 1H), 7,38 (t, J=8,8 Hz, 2H), 4,51 (s, 2H), 2,85-3,63 (m, 10H), 1,99-2,04 (m, 3H), 1,80 (sh. d, J=12 Hz, 2H), 1.55V (sh. K, J=12 Hz, 2H).

Example 32: Hydrochloride 2-[[1-[2-(4-torpedolike)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 206 Table 1)

a) 1-(2-Chlorethylene)-4-torbenson

4-Terfenol (of 8.92 mmol) and 1-chloro-2-bromatan region (13.4 mmol) dissolved in acetone (18 ml). In the resulting solution was added potassium carbonate (12.5 mmol) and refluxed for 10 hours. The mixture allow to cool to room temperature and then filtered. The filtrate is concentrated and the residue purified column chromatography on silica gel (hexane/ethyl acetate), obtaining mentioned in the title compound (yield: 31%).

1H-NMR (CDCl3): δ 7,02 (t, J=8.6 Hz, 1H), 6.87 in (m, 2H), 4,19 (t, J=5.8 Hz, 2H), 3,80 (t, J=5.8 Hz, 2H).

b) 2-[[1-[2-(4-torpedolike)ethyl]piperidine-4-yl]methyl]isoindoline-1-on the Sabbath.

Specified in the header connection receive (yield: 61%), using the compound obtained in Example 32A, by methods similar to the methods of Example 26b.

1H-NMR (CDCl3): δ a 7.85 (d, J=7.2 Hz, 1H), 7,42-rate of 7.54 (m, 3H), 6,93 (t, J=9 Hz, 2H), 6,83 (m, 2H), to 4.41 (s, 2H), of 4.05 (t, J=6.0 Hz, 2H), 3,51 (d, J=7.2 Hz, 2H), 3,00 W. d, J=12 Hz, 2H), 2,78 (t, J=6.0 Hz, 2H), 2,11 (dt, J=11,7, 2,1 Hz, 2H), is 1.81 (m, 1H), 1.69 in (m, 2H), 1,43 (DK, J=12,0, 3.6 Hz, 2H).

(C) the Hydrochloride of 2-[[1-[2-(4-torpedolike)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 56%), using the compound obtained in Example 32b, by methods similar to the methods of Example 1f.

Melting point: 198-204° C.

1H-NMR (DMSO-d6): δ 10,28 (sh. s, 1H), 7,68 (d, J=7.5 Hz, 1H), 7,60 to 7.62 (m, 2H), 7,50 (m, 1H), 7,16 (m, 2H), 7,02 (m, 2H), 4,51 (s, 2H), 4,36 (s, 2H), 2,96-3,61 (m, 8H), 1,99 (m, 1H), 1,80 (m, 2H), 1,59 (m, 2H).

Example 33: Hydrochloride 2-[[1-[3-(4-torpedolike)propyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 216 Table 1)

a) 1-(3-Chloropropoxy)-4-torbenson

Specified in the title compound is obtained by methods similar to the methods of Example 32A (yield: 94%).

1H-NMR (CDCl3): δ 6,97 (t, J=8,4 Hz, 2H), 6,84 (m, 2H), 4,07 (t, J=6.0 Hz, 2H), 3,74 (t, J=6.3 Hz, 2H), 2,22 (m, 2H).

b) 2-[[1-[3-(4-torpedolike)propyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the header connection receive (yield: 72%), using the compound obtained in Example 33a, SP the ways, similar to the methods of Example 26b.

1H-NMR (CDCl3): δ a 7.85 (d, J=6,9 Hz, 1H), 7,42-of 7.55 (m, 3H), of 6.96 (t, J=8,4 Hz, 2H), PC 6.82 (m, 2H), to 4.41 (s, 2H), 3.96 points (t, J=6.3 Hz, 2H), 3,51 (d, J=7.2 Hz, 2H), 2,94 (sh. d, J=12 Hz, 2H), 2.49 USD (t, J=7.4 Hz, 2H), 1,90 of 1.99 (m, 4H), of 1.81 (m, 1H), 1,70 (m, 2H), 1,41 (DK, J=12,3, 3,3 Hz, 2H).

(C) the Hydrochloride of 2-[[1-[3-(4-torpedolike)propyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 43%), using the compound obtained in Example 33b, by methods similar to the methods of Example 1f.

Melting point: 164° C.

1H-NMR (DMSO-d6): δ 10,14 (sh. s, 1H), 7,69 (d, J=7.5 Hz, 1H), to 7.61 to 7.62 (m, 2H), 7,51 (m, 1H), 7,13 (t, J=8.7 Hz, 2H), 6,95 (m, 2H), 4,51 (s, 2H), was 4.02 (t, J=6 Hz, 2H), 2,85-to 3.64 (m, 6H), of 2.16 (m, 2H), 1,99 (m, 1H), 1,80 (sh. d, J=12 Hz, 2H), and 1.56 (sh. K, J=12 Hz, 2H).

Example 34: Hydrochloride 2-[[1-[4-(4-torpedolike)butyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 226 Table 1)

a) 1-(4-Chlorobutyrate)-4-torbenson

Specified in the title compound is obtained by methods similar to the methods of Example 32A (yield: 97%).

1H-NMR (CDCl3): δ of 6.96 (t, J=8.7 Hz, 2H), PC 6.82 (m, 2H), 3.96 points (t, J=5.8 Hz, 2H), 3,61 (t, J=6.2 Hz, 2H), 1,89 of 1.99 (m, 4H).

b) 2-[[1-[4-(4-torpedolike)butyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the header connection receive (yield: 78%), using the compound obtained in Example 34a, by methods similar to the methods of Example 26b.

1H-NMR (CDCl3): δ a 7.85 (d, J=7.5 Hz, 1H), 7,42-7,53 (m, 3H), of 6.96 (t, J=8.5 Hz, 2H), for 6.81 (m, 2H), to 4.41 (s, 2H), 3,92 (t, J=6.3 Hz, 2H), 3,50 (d, J=7.2 Hz, 2H), 2,93 (sh. d, J=12 Hz, 2H), of 2.38 (t, J=7.5 Hz, 2H), 1.93 and (sh. t, J=12 Hz, 2H), 1,62-to 1.82 (m, 7H), 1,40 (DK, J=12.3 Hz, 2H).

(C) the Hydrochloride of 2-[[1-[4-(4-torpedolike)butyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 82%)using the compound obtained in Example 34b, by methods similar to the methods of Example 1f.

Melting point: 145-146° C.

1H-NMR (DMSO-d6): δ 10,08 (sh. s, 1H), 7,69 (d, J=7.5 Hz, 1H), 7,60 to 7.62 (m, 2H), 7,51 (m, 1H), 7,12 (t, J=9 Hz, 2H), 6,94 (m, 2H), 4,51 (s, 2H), 3.96 points (t, J=6 Hz, 2H), 2,81-3,62 (m, 8H), 1,99 (m, 1H), 1.70 to is 1.81 (m, 6H), of 1.55 (m, 2H).

Example 35: Hydrochloride 2-[[1-(1-benzofuran-2-ylmethyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 236 Table 1)

a) 1-Benzofuran-2-ylmethanol

Socialogical (467 mg, 12.3 mmol) is suspended in diethyl ether and the suspension is refluxed. To the suspension is added dropwise 1-benzofuran-2-carboxylic acid (2.00 g, 12.3 mmol)dissolved in tetrahydrofuran (10 ml)and then refluxed for 20 minutes. The reaction mixture was cooled to 0° and then it was added water (0.8 ml) and stirred at the same temperature for 30 minutes. The insoluble solid is removed by filtration using celite, and then the solvent is evaporated under reduced pressure, obtaining the specified reception in the e compound as a yellow oil (1,72 g, yield: 94%).

1H-NMR (CDCl3): 7,54-7,58 (1H, m), 7,45-7,49 (1H, m), 7,19-to 7.32 (2H, m), to 6.67 (1H, s), 4,78 (2H, d, J=4,5), was 1.94 (1H, sh. C).

b) 2-Chloromethyl-1-benzofuran

Specified in the header connection receive (1,17 g, yield: 100%)using the compound obtained in Example 35A (1,00 g of 6.75 mmol), by methods similar to the methods of Example 25A.

1H-NMR (CDCl3): 7,47-EUR 7.57 (2H, m), 7,20-7,20 (2H, m), 6,74 (1H, s), 4,71 (2H, s).

C) 2-[[1-(1-benzofuran-2-ylmethyl)piperidine-4-yl]methyl]isoindoline-1-he

Specified in the header connection receive (516 mg, yield: 49%), using the compound obtained in Example 35b (538 mg, 3,23 mmol)and the compound obtained in Example 1d (783 mg, to 2.94 mmol), by methods similar to the methods of Example 25b.

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,2), 7,41-of 7.55 (5H, m), 7,19-7,28 (2H, m), to 6.57 (1H, s), 4,39 (2H, s), 3,68 (2H, s), 3,50 (2H, d, J=6,9), 2,95-of 3.00 (2H, m), 2,03-2,12 (2H, m), 1,6-1,9 (3H, m), 1,4-1,6 (2H, m).

d) of the Hydrochloride of 2-[[1-(1-benzofuran-2-ylmethyl)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (252 mg, yield: 83%)using the compound obtained in Example 35C (277 mg, 0,769 mmol), by methods similar to the methods of Example 1f.

Melting point: 205-213° C.

1H-NMR (DMSO-d6): to 10.7 (1H, sh. C)7,58 to 7.75 (5H, m), 7,30-7,51 (3H, m), 7,21-of 7.25 (1H, m), 4,56-4,72 (2H, m), 4,47-4,51 (2H, m), of 3.2 to 3.7 (4H, m), 2.8 to 3.0 (2H, m), 1,6-2,2 (3H, m), 1,4-1,6 (2H, m).

Example 36: 2-[[1-[2-(indol-3-yl)ethyl]piperidin-4-yl]methyl]isoindoline-1-1/2 he(· )fumarate (Compound 241 Table 1)

a) 2-(Indol-3-yl)ethylmethanesulfonate

Specified in the title compound obtained as a brown oil (3,10 g, yield: 100%), using 3-idolatry (2,01 g, 12.5 mmol), by methods similar to the methods of Example 26a.

1H-NMR (CDCl3): 8,11 (1H, sh. C), 7,60 (1H, d, J=7,7), 7,38 (1H, d, J=8,0), 7,10-of 7.25 (3H, m), 4,48 (2H, t, J=7,1), 3,23 (2H, t, J=7,1), 2,85 (3H, s).

b) 2-[[1-[2-(Indol-3-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a pale yellow solid (465 mg, yield: 41%), using the compound obtained in Example 36A (980 mg, 3,40 mmol)and the compound obtained in Example 1d (818 mg, of 3.07 mmol) by methods similar to the methods of Example 26b.

1H-NMR (CDCl3): 8,08 (1H, sh. C)7,86 (1H, d, J=7,2), 7,34 to 7.62 (5H, m), 7.03 is-7,24 (3H, m), 4,42 (2H, s), 3,53 (2H, d, J=7,2), is 3.08-3,13 (2H, m), 2,97-3,03 (2H, m), 2,70 was 2.76 (2H, m), 2.06 to and 2.14 (2H, m), 1,7-2,0 (3H, m), 1,4-1,6 (2H,, m).

C) 2-[[1-[2-(Indol-3-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-1/2 he(· ) fumarate

The compound obtained in Example 36b (181 mg, 0,485 mmol)and fumaric acid (61,5 mg, 0,530 mmol) are added to ethanol (11 ml) and the resulting mixture is refluxed for 30 minutes. Precipitated precipitated solid is collected by filtration and dried, obtaining mentioned in the title compound as a colourless solid (108 mg, yield: 52%).

Melting point: 225-230° C.

p>  1H-NMR (DMSO-d6): to 10.8 (1H, s), to 7.68 (1H, d, J=7,5), 7,58-to 7.61 (2H, m), 7,42-7,53 (2H, m), 7,33 (1H, d, J=7,8), 7,16 (1H, s), 7.03 is-to 7.09 (1H, m), 6,93-6,99 (1H, m), 6,53 (1H, s, fumaric acid), 4,50 (2H, s), 3.43 points (2H, d, J=7,2), is 3.08-3,13 (2H, m), 2,86-2,90 (2H, m), 2,69 is 2.75 (2H, m), 2,14-of 2.23 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1,2-1,4 (2H, m).

Example 37: Hydrochloride 2-[[1-[(6-fluoro-1,2-benzisoxazol-3-yl)methyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 246 Table 1)

a) 2-[[1-[(6-fluoro-1,2-benzisoxazol-3-yl)methyl]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 20b (826 mg, 2,07 mmol) dissolved in N-organic (7 ml). To the solution was added t-piperonyl potassium (243 mg, 2,17 mmol) at room temperature and stirred for 3 hours. The reaction mixture was added water and the precipitated precipitated solid is collected by filtration. The solid is washed with water and dried, obtaining mentioned in the title compound as a pale yellow solid (573 mg, yield: 73%).

1H-NMR (CDCl3): of 7.90-7,94 (1H, m), to 7.84 (1H, d, J=7,8), 7,40-of 7.55 (3H, m), 7,21-7,27 (1H, m), 7.03 is-7,10 (1H, m), 4,39 (2H, s), 3,88 (2H, s), 3,52 (2H, d, J=7,2), 2,89-to 2.94 (2H, m), 2.05 is-of 2.15 (2H, m), 1,65-1,90 (3H, m), to 1.3-1.5 (2H, m).

(b) hydrochloride of 2-[[1-[(6-fluoro-1,2-benzisoxazol-3-yl)methyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (261 mg, yield: 79%)using the compound obtained in Example 37A (303 mg, 0,799 mmol), by methods similar to the methods of Example 1f.

Melting point: 175-181° C.

1H-NMR (DMSO-d6): 11,1 (1H, sh. (C)and 8.2 and 8.3 (1H, m), 7,86 (1H, d, J=7,5), to 7.67 (1H, d, J=7,2), 7,58-to 7.61 (2H, m), 7,40-to 7.50 (2H, m), 4,82-5,00 (2H, m), 4,48 (2H, s), 3,59-of 3.64 (2H, m), 3,2-3,5 (2H, m), 2,9-3,1 (2H, m), 1,4-2,2 (5H, m).

Example 38: Hydrochloride 2-[[1-[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 251 Table 1)

a) 1-(1,3-Benzodioxol-5-yl)-2-bromatan-1-he

1-(1,3-Benzodioxol-5-yl)Ethan-1-he (1,05 g, 6,40 mmol) was dissolved in a mixed solvent of dichloromethane (50 ml)-methanol (20 ml). To the solution add the hydrobromide of perbromide pyridinium (2.24 g, 7,00 mmol) at room temperature and then refluxed. After one hour the solvent is evaporated under reduced pressure and the residue was diluted with a mixed solvent of ethyl acetate-hexane. The mixture is washed with water, aqueous sodium bicarbonate solution and then with saturated salt solution and dried over sodium sulfate. The insoluble solid is removed by filtration and the solvent is evaporated under reduced pressure. The obtained solid is suspended and washed with hexane and then dried, obtaining mentioned in the title compound as a pale yellow solid (1,46 g, yield: 94%).

1H-NMR (CDCl3): to 7.61 (1H, DD, J=2,2, 8,2), 7,46 (1H, d, J=2,2), to 6.88 (1H, d, J=8,2), between 6.08 (2H, s), to 4.38 (2H, s).

b) 2-[[1-[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]piperidine-4-yl]methyl]every the of indolin-1-he

Using the compound obtained in Example 38A (491 mg, 2.02 mmol)and the compound obtained in Example 1d (507 mg, 1,90 mmol), get mentioned in the title compound as a pale yellow solid (703 mg, yield: 94%) by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,5), to 7.67 (1H, DD, J=1,8, 8,1), 7,42-7,56 (4H, m), at 6.84 (1H, d, J=8,1), 6,04 (2H, s)to 4.41 (2H, s), 3,70 (2H, s), 3,51 (2H, d, J=7,5), 2,95-of 3.00 (2H, m) 2,1-2,2 (2H, m), 1,6-2,0 (3H, m), 1,4-1,6 (2H, m).

(C) the Hydrochloride of 2-[[1-[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (549 mg, yield: 73%)using the compound obtained in Example 38b (690 mg, of 1.76 mmol), by methods similar to the methods of Example 1f.

Melting point: 162-166° C.

1H-NMR (DMSO-d6): 9,85 (1H, sh. C), 7,47-7,74 (6H, m), 7,13-7,19 (1H, m), is 6.19-6.22 per (2H, m), 4.95 points-to 5.03 (2H, m), 4,51-of 4.54 (2H, m), i.e., 3.3 to 3.6 (4H, m), 2,9-3,1 (2H, m), of 2.0-2.2 (1H, m), of 1.5-1.9 (4H, m).

Example 39: Hydrochloride 2-[[1-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 256 Table 1)

a) 2-Bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethane-1-he

Specified in the title compound obtained as a pale yellow solid (2,05 g, yield: 100%), using 1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethane-1-he (1.42 g, of 7.97 mmol) by methods similar to the methods of Example 38A.

1 H-NMR (CDCl3): 7,50-rate of 7.54 (2H, m), 6,93 (1H, m), 4,37 (2H, s), 4,32 is 4.35 (2H, m), 4,27-or 4.31 (2H, m).

b) 2-[[1-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 39A (571 mg, 2.22 mmol)and the compound obtained in Example 1d (576 mg, of 2.16 mmol), get mentioned in the title compound as a pale yellow solid (627 mg, yield: 71%) by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,5), 7,42-of 7.60 (5H, m), 6.89 in (1H, d, J=8,4), to 4.41 (2H, s), 4.26 deaths-4,34 (4H, m), of 3.69 (2H, s), 3,51 (2H, d, J=7,2), of 2.9-3.0 (2H, m), 2,08-2,17 (2H, m), 1,6-1,9 (3H, m), 1,4-1,6 (2H, m).

(C) the Hydrochloride of 2-[[1-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a pale yellow solid (263 mg, yield: 79%)using the compound obtained in Example 39b (306 mg, 0,753 mmol), by methods similar to the methods of Example 1f.

Melting point: 142-150° C.

1H-NMR (DMSO-d6)rating: 10.0 (1H, sh. C)of 7.69 (1H, d, J=7,5), of 7.48 to 7.62 (5H, m), 7,06 (1H, d, J=8,1), equal to 4.97-of 5.05 (2H, m), a 4.53 (2H, s), from 4.2 to 4.4 (4H, m), grows 3.4-3.7 (4H, m), 2,9-3,1 (2H, m), 1,5-2,2 (5H, m).

Example 40: Fumarate 2-[[1-[(1-benzofuran-3-yl)methyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 261 Table 1)

a) 3-Methyl-1-benzofuran-2-yl)carboxylic acid

Phenoxide sodium (15,4 g), obtained from phenol (10.8 g, 114 mmol) and sodium hydroxide (4,80 g, 114 mmol), EXT the keys to toluene (160 ml). To the mixture are added ethyl 2-chloroacetoacetate (18.6 g, 113 mmol)dissolved in toluene (20 ml), boiling under reflux, and the mixture is heated under stirring for 3 hours. The reaction mixture allow to cool to room temperature and then it was added water and extracted with toluene. The organic layer was washed with saturated salt solution and dried over magnesium sulfate. The insoluble solid is removed by filtration, the solvent is evaporated under reduced pressure, obtaining an orange oil (19.7 g). The product is slowly added to concentrated sulfuric acid (20 ml), cooled below 5° and continue stirring for 30 minutes at the same temperature. The reaction mixture was added to ice water and extracted with a mixed solvent of ethyl acetate-hexane. The extract was washed with aqueous sodium bicarbonate solution and then with saturated salt solution and dried over magnesium sulfate. The insoluble solid is removed by filtration and the solvent is evaporated under reduced pressure. The resulting oil is purified column chromatography on silica gel (ethyl acetate-hexane)to give an orange oil (7,12 g). The product is added to 10% aqueous solution (50 ml) of potassium hydroxide and the mixture refluxed for 1 hour. The reaction mixture allow to cool is about room temperature and in it add 35% sulfuric acid, to bring the pH to 1. Precipitated precipitated solid is collected by filtration and washed with water. The obtained solid is dried, obtaining mentioned in the title compound as a colourless solid (and 3.16 g, yield: 16%).

1H-NMR (CDCl3): to 7.68 (1H, d, J=7,7), 7,58 (1H, d, J=8,3), 7,47-7,53 (1H, m), 7,30-7,37 (1H, m), 2,65 (3H, s)

b) 3-Methyl-1-benzofuran

The compound obtained in Example 40A (1.07 g, 6,07 mmol), dissolved in quinoline (8 ml) and to the solution was added powdered copper (410 mg, of 6.45 mmol). The reaction mixture is heated at 200° C for 30 minutes and then give her a chance to cool to room temperature. The insoluble solid is removed by filtration using celite, and the filter cake washed with dichloromethane. The mother liquor is diluted with ethyl ether and washed with 10% hydrochloric acid, water, aqueous sodium bicarbonate solution and then with saturated salt solution and dried over magnesium sulfate. The insoluble solid is removed by filtration and then the solvent is evaporated under reduced pressure, obtaining mentioned in the title compound as a brown oil (819 mg, yield: 100%).

1H-NMR (CDCl3): 7,51-of 7.55 (1H, m), 7,43-7,47 (1H, m), 7,40 (1H, s), 7.23 percent-7,31 (2H, m), of 2.25 (3H, s).

C) 2-bromo-3-methyl bromide-1-benzofuran

The compound obtained in Example 40b (771 mg, 5.83 mmol), N-bromakin the MFA (2,07 g, 11.6 mmol) and a catalytic amount of benzoyl peroxide is added to carbon tetrachloride (20 ml) and the mixture is refluxed for 5 hours. The reaction mixture allow to cool to room temperature and then the insoluble solids are removed by filtration. The solvent is evaporated under reduced pressure, obtaining mentioned in the title compound as a yellow oil (1.54 g, yield: 91%).

1H-NMR (CDCl3): to 7.61-the 7.65 (1H, m), 7,44-of 7.48 (1H, m), 7,30-to 7.35 (2H, m), 4,56 (2H, s).

d) 2-[[1-[(2-bromo-1-benzofuran-3-yl)methyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 40C (1.50 g, 5.17 mmol)and the compound obtained in Example 1d (1.55 g, of 5.81 mmol), get mentioned in the title compound as a pale yellow solid (1,67 g, yield: 74%) by methods similar to the methods of Example 25b.

1H-NMR (CDCl3): 7,83 (1H, d, J=7,2), a 7.62-of 7.70 (1H, m), 7,38-7,53 (4H, m), 7,20-7,27 (2H, m), 4,37 (2H, s)and 3.59 (2H, s), 3,49 (2H, d, J=7,2), 2,90-2,95 (2H, m), 1,99-of 2.08 (2H, m), 1,6-1,9 (3H, m), 1,3-1,5 (2H, m).

e) 2-[[1-[(1-benzofuran-3-yl)methyl]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 40d (460 mg, 1.05 mmol), dissolved in a mixed solvent of tetrahydrofuran (5 ml)/ethanol (16 ml). To the solution was added a catalytic amount of Raney Nickel and the reaction mixture was stirred at room temperature in the course is E. 5 hours in an atmosphere of hydrogen. The reaction mixture was filtered using celite, and the filter cake washed with a mixed solvent of tetrahydrofuran-ethanol. The solvent is evaporated under reduced pressure, obtaining mentioned in the title compound as a yellow solid (290 mg, yield: 77%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,5), 7,68-of 7.70 (1H, m), 7,42-rate of 7.54 (5H, m), 7,20-7,31 (2H, m), 4,39 (2H, s), 3,63 (2H, s), 3,50 (2H, d, J=7,5), 2,94-to 2.99 (2H, m), 1,95-of 2.05 (2H, m), 1,6-1,9 (3H, m), 1,3-1,5 (2H, m).

f) Fumarate, 2-[[1-[(1-benzofuran-3-yl)methyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (413 mg, yield: 71%), using the compound obtained in Example 40E (440 mg, 1,22 mmol), by methods similar to the methods of Example 36C.

Melting point: 226-237° C.

1H-NMR (DMSO-d6): to $ 7.91 (1H, s), to 7.77 (1H, d, J=6,9), 7,66 (1H, d, J=7,5), 7,54-to 7.59 (3H, m), 7,45 is 7.50 (1H, m), 7.24 to 7,33 (2H, m), is 6.61 (2H, s, fumaric acid), to 4.46 (2H, s), 3,74 (2H, s), 3,40 (2H, d, J=7,5), 2,94-to 2.99 (2H, m,), 2.06 to to 2.15 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 41: Fumarate 2-[[1-[(2-bromo-1-benzofuran-3-yl)methyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 266 Table 1)

Specified in the title compound obtained as a pale yellow solid (305 mg, yield: 72%), using the compound obtained in Example 40d (336 mg, 0,765 mmol), by methods similar to the methods of Example 36C.

Melting point: 200-211° C.

Ȋ 1H-NMR (DMSO-d6): 7,73 for 7.78 (1H, m), 7,66 (1H, d, J=7,5), 7,55-of 7.60 (3H, m), 7,40-7,49 (1H, m), 7,26-7,34 (2H, m), 6,63 (2H, s, fumaric acid), to 4.46 (2H, s), 3,62 (2H, s), 3,39 (2H, d, J=7,5), 2,87 of 2.92 (2H, m), 2,00-2,09 (2H, m,), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 42: Hydrochloride 2-[[1-[2-(4-foronline)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 271 Table 1)

a) 2-Chloro-N-(4-forfinal)ndimethylacetamide

Chlorocatechol (of 0.60 ml, rate of 7.54 mmol) dissolved in toluene (6 ml) and to the solution was added 4-ftoranila (to 0.72 ml, 7,52 mmol) at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added water and extracted with ethyl acetate and the extract washed with saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure, obtaining mentioned in the title compound as a pale yellow solid (1.07 g, yield: 76%).

1H-NMR (CDCl3): 8,23 (1H, sh. s, NH), 7,47-of 7.55 (2H, m), 7,02-7,11 (2H, m), 4,20 (2H, s).

b) 2-[[1-[2-(4-foronline)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 42A (354 mg, 1,89 mmol), the compound obtained in Example 1d (501 mg, 1.88 mmol), and triethylamine (0,65 ml of 4.66 mmol), are added to a dimethylformamide (6 ml) and the mixture was stirred at 60° C for 3 hours. The reaction mixture allow to cool until on the second temperature and then added water. Precipitated precipitated solid is collected by filtration and dried under reduced pressure, obtaining mentioned in the title compound as a pale yellow solid (577 mg, yield: 81%).

1H-NMR (CDCl3): 9,14 (1H, sh. s, NH), 7,86 (1H, d, J=7,5), 7,43-EUR 7.57 (5H, m), 6,99-7,07 (2H, m), 4,42 (2H, s), 3,57 (2H, d, J=7,2), 3,10 (2H, s), 2,86-of 2.97 (2H, m), 2,19-of 2.30 (2H, m), 1.7 to 1.9 (3H, m), 1,3-1,5 (2H, m).

(C) the Hydrochloride of 2-[[1-[2-(4-foronline)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 70%)using the compound obtained in Example 42b, by methods similar to the methods of Example 1f.

Melting point: 201-219° ° C.

1H-NMR (DMSO-d6): 10,9 (1H, sh. s, NH), 9,9 (1H, sh. with, HCl), 7,58-7,71 (5H, m), 7,46-rate of 7.54 (1H, m), 7,21 (2H, t, J=8,7), to 4.52 (2H, s), 4.25 in (0,4H, C), 4,14 (1,6H, C), and 3.3 to 3.7 (4H, m), 2,9-3,1 (2H, m), 1,9-2,1 (1H, m), 1.7 to 1.9 (2H, m), 1,4-1,6 (2H,, m).

Example 43: Hydrochloride 2-[[1-[2-(diphenylamino)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 278 Table 1)

a) 2-Chloro-N,N-diphenylacetamide

Chlorocatechol (0,32 ml, 4.02 mmol) was dissolved in a mixed solvent of toluene (6 ml)/tetrahydrofuran (2 ml). To the resulting solution add diphenylamine (690 mg, 4,08 mmol) at room temperature and heated at 100° C for 80 minutes. The solvent is evaporated under reduced pressure and precipitated precipitated solid is suspended is washed with ethyl ether. The solid is collected by filtration and dried under reduced pressure, obtaining mentioned in the title compound as a colourless solid (746 mg, yield: 75%).

1H-NMR (CDCl3): 7,0-7,5 (10H, m), a 4.03 (2H, s).

b) 2-[[1-[2-(Diphenylamino)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a pale yellow solid (yield: 67%), using the compound obtained in Example 43A, by methods similar to the methods of Example 42b.

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,2), a 7.1 to 7.6 (13H, m), to 4.38 (2H, s), 3,48 (2H, d, J=7,2), 3,10 (2H, s), 2,82-2,90 (2H, m), 2,04-to 2.18 (2H, m), 1.5 and 1.8 (3H, m), 1,2-1,4 (2H, m).

(C) the Hydrochloride of 2-[[1-[2-(diphenylamino)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 84%), using the compound obtained in Example 43b, by methods similar to the methods of Example 1f.

Melting point: 197-209° C.

1H-NMR (DMSO-d6): 9,7 (1H, sh. with, HCl), to 7.68 (1H, d, J=7,4), 7,2-7,6 (13H, m), of 4.49 (2H, s), 4,10 (0,4H, C), was 4.02 (1,6H, s), i.e., 3.3 to 3.6 (4H, m), 2.8 to 3.0 (2H, m), 1.7 to 1.9 (1H, m), 1,6-1,7 (2H, m), 1,4-1,6 (2H, m).

Example 44: Hydrochloride 2-[[1-[2-(N-methylaniline)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 284 Table 1)

a) 2-[[1-[2-(N-methylaniline)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using N-methylaniline, get 2-chloro-N-methyl-N-FeNi is the ndimethylacetamide in the form of the crude product ways, similar to the methods of Example 43A. Using the resulting product, get mentioned in the title compound as a colourless oil (yield: 69%), by methods similar to the methods of Example 42b.

1H-NMR (CDCl3): 7,83 (1H, d, J=7,3), 7,16-rate of 7.54 (8H, m), to 4.38 (2H, s), of 3.46 (2H, d, J=7,2), 3,26 (3H, s), 2,92 (2H, s), of 2,75 2,85 (2H, m), 1,9-2,1 (2H, m), 1.5 and 1.8 (3H, m), 1,2-1,4 (2H, m).

(b) hydrochloride of 2-[[1-[2-(N-methylaniline)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 92%), using the compound obtained in Example 44a, by methods similar to the methods of Example 1f.

Melting point: 199-213° C.

1H-NMR (DMSO-d6): 9,6 (1H, sh. with, HCl), to 7.68 (1H, d, J=7,2), 7,56 to 7.62 (2H, m), 7,2-of 7.55 (6H, m), of 4.49 (2H, s), 3,9-4,0 (2H, m), 3,37 (3H, s), 3,1-3,7 (4H, m), 2.8 to 3.0 (2H, m), 1,6-1,9 (3H, m), 1,3-1,6 (2H, m).

Example 45: Hydrochloride 2-[[1-[3-(4-foronline)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 274 Table 1)

a) 3-Chloro-N-(4-forfinal)propanamide

Using 4-ftoranila and 3-chloropropionitrile get mentioned in the title compound (yield: 57%) by methods similar to the methods of Example 42A.

1H-NMR (CDCl3): 7,3-7,5 (3H, m), 6,98-7,05 (2H, m), 3,88 (2H, t, J=6,2), of 2.81 (2H, t, J=6,2).

b) 2-[[1-[3-(4-foronline)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-he

Specified in the title compound obtained as a pale yellow firmly what about the substance (yield: 86%), using the compound obtained in Example 45A, by methods similar to the methods of Example 26b.

1H-NMR (CDCl3): 11,04 (1H, s, NH), 7,87 (1H, d, J=7,2), 7,44-of 7.60 (5H, m), of 6.96-7.03 is (2H, m), 4,43 (2H, s)to 3.58 (2H, d, J=6,9), 3,06-of 3.12 (2H, m), 2,69 (2H, t, J=6,0), of 2.51 (2H, t, J=6,0), 2,03 with 2.14 (2H, m), 1.7 to of 2.0 (3H, m), 1,3-1,5 (2H, m).

(C) the Hydrochloride of 2-[[1-[3-(4-foronline)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 91%)using the compound obtained in Example 45b, by methods similar to the methods of Example 1f.

Melting point: 211-223° C.

1H-NMR (DMSO-d6): of 10.4 (1H, s, NH), 10,2 (1H, sh. with, HCl), to 7.59-7,71 (5H, m), 7,45-7,53 (1H, m), 7,12-7,20 (2H, m), 4,51 (2H, s), 3,1-3,6 (6H, m), of 2.8-3.0 (4H, m), 1,9-2,1 (1H, m), 1,6-1,8 (2H, m), 1,4-1,6 (2H, m).

Example 46: Hydrochloride 2-[[1-[3-(diphenylamino)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 281 Table 1)

a) 2-[[1-[3-(diphenylamino)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-he

Using diphenylamine, by methods similar to the methods

Example 43A, get 3-chloro-N,N-diphenylpropane in the form of a crude product. Using the resulting product, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 26b (yield: 89%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,4), of 7.0 and 7.6 (13H, m), to 4.38 (2H, s), 3,48 (2H, d, J=7,1), 2,74-2,84 (2H, m), by 2.73 (2H, t, J=7,5), of 2.45 (2H, t, J=7,5), 1,86 is 1.96 (2H, m), 1.5 and 1.8 (3H, m), 1,2-1,4 (2H, m).

(b) Hydrochloride of 2-[[1-[3-(diphenylamino)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 82%)using the compound obtained in Example 46a, by methods similar to the methods of Example 1f.

Melting point: 200-205° C.

1H-NMR (DMSO-d6): from 9.6 to 10.2 (1H, sh. HCl), to 7.68 (1H, d, J=7,5), 7,1-the 7.65 (13H, m), of 4.49 (2H, s), 3.0 to 3.6V (6H, m), 3,6-3,9 (4H, m), 1,8-2,0 (1H, m), 1,6-1,8 (2H, m), 1,3-1,6 (2H, m).

Example 47: Hydrochloride 2-[[1-[3-(N-methylaniline)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 287 Table 1)

a) 2-[[1-[3-(N-methylaniline)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-he

Using N-methylaniline, by methods similar to the methods of Example 43A, get 3-chloro-N-methyl-N-phenylpropanamide in the form of a crude product. Using the resulting product, by methods similar to the methods of Example 26b, get mentioned in the title compound as a colorless solid (yield: 57%).

1H-NMR (CDCl3): 7,83 (1H, d, J=7,2), 7,3-7,5 (6H, m), 7,18 (2H, DD, J=1,4, 7,2), 4,37 (2H, s), of 3.46 (2H, d, J=7,2), 3,26 (3H, s), 2,70-2,78 (2H, m)to 2.65 (2H, t, J=7,5), and 2.26 (2H, t, J=7,5), of 1.8-2.0 (2H, m), of 1.5-1.8 (3H, m), 1,2-1,4 (2H, m).

(b) Hydrochloride of 2-[[1-[3-(N-methylaniline)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid which CSOs substance (yield: 91%), using the compound obtained in Example 47A, by methods similar to the methods of Example 1f.

Melting point: 206-214° C.

1H-NMR (DMSO-d6): of 9.5 to 10.1 (1H, sh. HCl), to 7.67 (1H, d, J=7,5), 7,55 to 7.62 (2H, m), 7,1-7,5 (6H, m), 4,48 (2H, s), 3.0 to 3.6V (9H, m), 2,7-2,9 (2H, m), 2,5-2,6 (2H, m), 1,8-2,0 (1H, m), 1,6-1,8 (2H, m), 1,3-1,6 (2H, m).

Example 48: Hydrochloride 2-[[1-[2-(1,2,3,4-tetrahydroquinolin-1-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 320, Table 1)

a) 2-[[1-[2-(1,2,3,4-tetrahydroquinolin-1-yl)-2-oxoethyl]-piperidine-4-yl]methyl]isoindoline-1-he

Using 1,2,3,4-tetrahydroquinolin, by methods similar to the methods of Example 43A, get 2-chloro-1-(1,2,3,4-tetrahydroquinolin-1-yl)Ethan-1-it is in the form of a crude product.

Using the resulting product, by methods similar to the methods of Example 42b, get mentioned in the title compound as a pale yellow oil (yield: 82%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,2), 7,40-rate of 7.54 (4H, m), 7,06-7,17 (3H, m), to 4.38 (2H, s), 3,80 (2H, t, J=6,6), 3,48 (2H, d, J=7,2), with 3.27 (2H, s), 2,86-to 2.94 (2H, m), of 2.72 (2H, t, J=6,6), 2,04 with 2.14 (2H, m), 1,92-2,02 (2H, m), 1.5 and 1.8 (3H, m), 1,2-1,4 (2H, m).

(b) Hydrochloride of 2-[[1-[2-(1,2,3,4-tetrahydroquinolin-1-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 94%)using the compound obtained in Example 48A, by methods similar to the methods of Example 1f.

Melting point: 208-221° C.

1H-NMR (DMSO-d6): 9,6 (1H, sh. with, HCl), to 7.68 (1H, d, J=7,4), 7,55 to 7.62 (2H, m), 7,45-rate of 7.54 (1H, m), 7,0-7,4 (4H, sh), 4,51 (2H, s), 4,1-4,6 (2H, sh), of 3.2 to 3.8 (8H, m), 2.8 to 3.0 (2H, m), 2,6-2,8 (2H, m), 1.5 to 2.0 (7H, m).

Example 49: Hydrochloride 2-[[1-[3-(1,2,3,4-tetrahydroquinolin-1-yl)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 324 Table 1)

a) 2-[[1-[3-(1,2,3,4-tetrahydroquinolin-1-yl)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-he

By methods similar to the methods of Example 43A, using 1,2,3,4-tetrahydroquinolin receive 3-chloro-1-(1,2,3,4-tetrahydroquinolin-1-yl)propane-1-it is in the form of a crude product. Using the resulting product, get mentioned in the title compound as a colorless solid (yield: 79%) by methods similar to the methods of Example 26b.

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,2), 7,40-of 7.55 (3H, m), 7,07-of 7.25 (4H, m), to 4.38 (2H, s), of 3.78 (2H, t, J=6,6), 3,47 (2H, d, J=7,2), 2,6-2,9 (8H, m), of 1.8-2.0 (4H, m), 1.5 and 1.8 (3H, m), 1,2-1,4 (2H, m).

(b) Hydrochloride of 2-[[1-[3-(1,2,3,4-tetrahydroquinolin-1-yl)-3-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 97%)using the compound obtained in Example 49A, by methods similar to the methods of Example 1f.

Melting point: 227-232° C.

1H-NMR (DMSO-d6): 9,6 (1H, sh. with, HCl), of 7.4 to 7.7 (5H, m), 7,0 is 7.3 (3H, m), 4,50 (2H, s), 3,6-3,7 (2H, m), 3,2-3,6 (8H, m), to 3.0-3.2 (2H, m), 2.8 to 3.0 (2H, m), 2,6-2,8 (2H, m), 1,7-2,0 (5H, m), 1,3-1,6 (2H, m).

a) 2-[[1-[2-oxo-2-(piperidine-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using piperidine, by methods similar to the methods of Example 42A, get 2-chloro-1-(piperidine-1-yl)Ethan-1-it is in the form of a crude product. Using the resulting product, get mentioned in the title compound as a pale yellow oil (yield: 73%) by methods similar to the methods of Example 42b.

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,42-rate of 7.54 (3H, m), 4,39 (2H, s), 3,48-3,55 (6H, m), 3,13 (2H, s), 2,84-only 2.91 (2H, m), 1,97-of 2.08 (2H, m), 1,4-1,8 (9H, m), 1,2-1,4 (2H, m).

b) Fumarate, 2-[[1-[2-oxo-2-(piperidine-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 83%)using the compound obtained in Example 50A, by methods similar to the methods of Example 36C.

Melting point: 201-204° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,56-to 7.61 (2H, m), 7,45-7,52 (1H, m), 6,59 (2H, s, fumaric acid), 4,48 (2H, s), 3,3-3,5 (6H, m), 3,23 (2H, s), 2,83-of 3.00 (2H, m), 2,03 with 2.14 (2H, m), of 1.6-1.8 (1H, m), 1.3 to 1.6 (8H, m), 1,1-1,3 (2H, m).

Example 51: Fumarate 2-[[1-[2-(indolin-1-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 333 Table 1)

a) 2-[[1-[2-(indolin-1-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using indolin, by methods similar to the methods of Example 43A, get 2-chloro-1-(indolin-1-yl)Ethan-1-it is in the form of a crude product. Using the information is not already installed, by methods similar to the methods of Example 42b, get mentioned in the title compound as a pale yellow solid (yield: 84%).

1H-NMR (CDCl3): by 8.22 (1H, d, J=8,4), to 7.84 (1H, d, J=7,2), 7,42-7,56 (3H, m), 7,14-of 7.23 (2H, m), 7,14 (1H, t, J=7,7), and 4.40 (2H, s), 4,19 (2H, t, J=8,4), 3,51 (2H, d, J=7,2), 3,24 (2H, s)3,18 (2H, t, J=8,4), 2,94-a 3.01 (2H, m), 2,12-2,22 (2H, m), 1.7 to 1.9 (1H, m), of 1.5-1.7 (3H, m), 1,3-1,5 (2H, m).

b) Fumarate, 2-[[1-[2-(indolin-1-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

By methods similar to Example 36C, using the compound obtained in Example 51A, get mentioned in the title compound as a colorless solid (yield: 54%).

Melting point: 168-171° C.

1H-NMR (DMSO-d6): with 8.05 (1H, d, J=7,9), to 7.67 (1H, d, J=7,4), 7,55 to 7.62 (2H, m), 7,45-7,52 (1H, m), 7,24 (1H, d, J=7,3), 7,12-to 7.18 (1H, m), 6,97-7,03 (1H, m), is 6.61 (2H, s, fumaric acid), of 4.49 (2H, s)to 4.17 (2H, t, J=8,4), 3,42 (2H, d, J=7,2), to 3.35 (2H, s), of 3.13 (2H, t, J=8,4), 2,91 are 2.98 (2H, m), 2,15-of 2.26 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 52: Fumarate 2-[[1-[2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 229 Table 1)

Using 1,2,3,4-tetrahydroisoquinoline, by methods similar to the methods of Example 42A, get 2-chloro-1-(1,2,3,4-tetrahydroisoquinoline-2-yl)Ethan-1-it is in the form of a crude product. Using the resulting product, by methods similar to the methods of Example 42b will receive 2-[[1-[2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-ox the ethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of a crude product. Using the resulting product, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 36C (yield: 38%).

Melting point: 171-173° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-to 7.61 (2H, m), 7,45-7,52 (1H, m), 7,0-7,2 (4H, m), 6,60 (2H, s, fumaric acid), 4,73 (0,8H, s), 4,59 (1,2H, C), 4,48 (1,2H, C), 4,46 (0,8H, s), 3,74 (1,2H, t, J=5,7), 3,66 (0,8H, t, J=6,0), 3,32-of 3.43 (4H, m), of 2.6-3.0 (4H, m), of 2.0-2.2 (2H, m), of 1.6-1.8 (1H, m), 1,4-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 53: Fumarate 2-[[1-[2-(indolin-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 338 Table 1)

a) Ethyl 2-(Indolin-1-yl)acetate

Indolin (1.07 g, 8.98 mmol), ethylbromoacetate (1.20 ml, about 10.8 mmol), potassium carbonate (2.10 g, of 15.2 mmol) are added to a dimethylformamide (14 ml) and the mixture is heated at 80° C for 30 minutes. The reaction mixture is cooled to room temperature and diluted with ethyl acetate and then washed with water and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The resulting oil is purified column chromatography on silica gel (ethyl acetate-hexane), getting mentioned in the title compound as a yellow oil (1.35 g, yield: 73%).

1H-NMR (CDCl3): 7,01-7,11 (2H, m), of 6.68 (1H, t, J=7,4), 6,40 (1H, d, J=7,8), 4,20 (2H, K, J=7,2), 3,88 (2H, s), of 3.54 (2H, t, J=8,4), 3,03 (2H, t, J=8,4), of 1.27 (3H, t, J=7,2).

b) 2-(Indolin-1-yl)Ethan-1-ol

Liteally overid (300 mg, to $ 7.91 mmol) is mixed with tetrahydrofuran (9 ml) with the formation of the suspension and the resulting suspension is stirred under ice cooling. To the mixture slowly add the compound obtained in Example 53A (1,33 g, 6,48 mmol)which was dissolved in tetrahydrofuran (3 ml), and the mixture is then stirred at the same temperature for 15 minutes. The reaction mixture was added successively water (3 ml), 15% aqueous sodium hydroxide solution (0.3 ml), water (0.9 ml) and sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The resulting oil is purified column chromatography on silica gel (ethyl acetate-hexane), getting mentioned in the title compound as a colourless oil (873 mg, yield: 83%).

1H-NMR (CDCl3):? 7.04 baby mortality-7,13 (2H, m), of 6.71 (1H, t, J=7,4), to 6.57 (1H, d, J=7,8), 3,79-a-3.84 (2H, m), 3,39 (2H, t, J=8,4), 3,21 of 3.28 (2H, m)of 3.00 (2H, t, J=8,4), 2,08 (1H, sh. s, OH).

C) Fumarate, 2-[[1-[2-(indolin-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 53b, obtained by methods similar to the methods of Example 26a, 2-(indolin-1-yl)Ethan-1-ol methanesulfonate in the form of a crude product. Using the resulting product, by methods similar to the methods of Example 26b will receive 2-[[1-[2-(indolin-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of a crude product. Using the resulting product, receive is shown in the header of the connection means, similar to the methods of Example 36C (yield: 66%).

Melting point: 216-224° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-to 7.61 (2H, m), 7,45-7,52 (1H, m), 6,94-7,03 (2H, m), to 6.58 (2H, s, fumaric acid), 6,50-6,56 (2H, m), 4,48 (2H, s), 3,42 (2H, d, J=7,2), to 3.34 (2H, t, J=8,3), up 3.22 (2H, t, J=6,9), 3.04 from-3,11 (2H, m), of 2.86 (2H, t, J=8,3), 2,70 (2H, t, J=6,9), to 2.1-2.3 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1.1 to 1.4 (2H, m).

Example 54: Fumarate 2-[[1-[2-(1,2,3,4-tetrahydroquinolin-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 325 Table 1)

Using 1,2,3,4-tetrahydroquinolin, by methods similar to the methods of Example 53A, obtain ethyl 2-[1,2,3,4-tetrahydroquinolin-1-yl]acetate in the form of a crude product. Using the resulting product, obtained by methods similar to the methods of Example 53b, 2-[1,2,3,4-tetrahydroquinolin-1-yl]Ethan-1-ol in the form of a crude product. Using the latter, by methods similar to the methods of Example 26a will receive 2-[1,2,3,4-tetrahydroquinolin-1-yl]Ethan-1-ol methanesulfonate in the form of a crude product. Using the resulting product, by methods similar to the methods of Example 26b will receive 2-[[1-[2-(1,2,3,4-tetrahydroquinolin-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of a crude product. Using the resulting product, by methods similar to Example 36C, get mentioned in the title compound as a pale yellow solid (yield: 46%).

Melting point: 196-200° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-to 7.61 (2H, m), 7,45-7,52 (1H, m), 6.90 to-6,97 (1H, m), at 6.84 (1H, d, J=6,4), 6,59 (2H, s, fumaric acid), 6,56 (1H, d, J=8,3), 6,41-6,48 (1H, m), 4,48 (2H, s), 3,37-3,44 (4H, m), 3,26 (2H,, t, J=5.5), the 3,00-of 3.07 (2H, m), 2,56 of 2.68 (4H, m), to 2.1-2.3 (2H, m), 1.7 to 1.9 (3H, m), 1,5-1,7 (2H, m), 1.1 to 1.4 (2H, m).

Example 55: Hydrochloride 5-methoxy-2-[[1-[2-(4-forfinal)-2-(Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it (Z-isomer of Compound 99 in Table 1)

a) 5-Methoxy-2-[[1-[2-(4-forfinal)-2-(E,Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 3E (443 mg, 1.12 mmol), get the Z-isomer is specified in the title compound (239 mg, yield: 52%) and E-isomer (187 mg, yield: 41%) as colorless solids by methods similar to the methods of Example 18a.

(Z-isomer)

1H-NMR (CDCl3): 12-13 (1H, s, OH), of 7.75 (1H, d, J=8,4), 7,56-the 7.65 (2H, m), of 6.96-was 7.08 (3H, m), 6,92 (1H, d, J=2,1), 4,35 (2H, s), a 3.87 (3H, s), 3,74 (2H, s), 3,48 (2H, d, J=7,2), 3,00-of 3.07 (2H, m), 2,12-of 2.23 (2H, m), of 1.8-2.0 (1H, m), 1,6-1,8 (2H, m), 1,3-1,5 (2H, m).

(E-isomer)

1H-NMR (CDCl3): 7,74 (1H, d, J=8,4), 7,60-to 7.68 (2H, m), 7,05 for 7.12 (2H, m), 6,98 (1H, DD, J=2,1, 8,4), 6,91 (1H, d, J=2,1), 4,32 (2H, s), 3,86 (3H, s), 3,44 (2H, d, J=7,5), and 3.31 (2H, s), 2,88-2,95 (2H, m), 1,95-2,05 (2H, m), of 1.5-1.9 (3H, m), 1,2-1,4 (2H, m).

(b) Hydrochloride of 5-methoxy-2-[[1-[2-(4-forfinal)-2-(Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it

Using the Z-isomer obtained in Example 55A (232 mg, 0,564 mmol), get mentioned in the title compound as a colourless t is ejogo substances ways, similar to the methods of Example 1f (208 mg, yield: 82%).

Melting point: 173-178° C.

1H-NMR (DMSO-d6): was 12.61 (1H, s, OH), or 10.6 (1H, sh. with, HCl), 7,81-7,87 (2H, m), 7,56 (1H, d, J=8,4), 7,27-7,34 (2H, m), to 7.15 (1H, d, J=1,8), 7,02 (1H, DD, J=1,8, 8,4), 4,53 (0,4H, s), 4,42 (2H, s), 4,39 (1,6H, C)a 3.83 (3H, s), 2,9-3,6 (6H, m), 1,4 to 2.0 (5H, m).

Example 56: Hydrochloride 5-methoxy-2-[[1-[2-(4-forfinal)-2-(E)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it (E-isomer of Compound 99 in Table 1)

Using E-isomer obtained in Example 55A (180 mg, 0,438 mmol), by methods similar to the methods of Example 1f, get mentioned in the title compound as a colourless solid (140 mg, yield: 71%).

Melting point: 192-195 (in Russian)° C.

1H-NMR (DMSO-d6): up 11,86 (1H, s, OH)and 10.7 (1H, sh. with, HCl), 7.68 per-7,74 (2H, m), EUR 7.57 (1H, d, J=8,4), 7,29-7,37 (2H, m), to 7.15 (1H, d, J=1,8), 7,03 (1H, DD, J=1,8, 8,4), 4,43 (2H+0,4H, C), 4,30 (1,6H, C)a 3.83 (3H, s), 3,48-3,55 (2H, m), 3,37 (2H, d, J=6,9), 2,90-a 3.01 (2H, m), 1,8-2,0 (1H, m), 1,3-1,8 (4H, m).

Example 57: Fumarate 5-bromo-2-[[1-[2-(4-forfinal)-2-(Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it (Z-isomer of Compound 92 in Table 1)

a) 5-bromo-2-[[1-[2-(4-forfinal)-2-(E,Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 3E (481 mg, of 1.08 mmol), get the Z-isomer is specified in the title compound (217 mg, yield: 44%) and E-isomer (112 mg, yield: 23%) as colorless solids by methods similar to the methods of Example 18a.

(Z-isomer)

1H-NMR (CDCl3): 7,71 (1H, d, J=8,5), 7,56-the 7.65 (4H, m), 7,00-was 7.08 (2H, m), to 4.38 (2H, s), 3,74 (2H, s), 3,49 (2H, d, J=7,3), 3,00-of 3.07 (2H, m), 2,12-2,22 (2H, m), 1,8-2,0 (1H, m), 1,6-1,8 (2H, m), 1,3-1,5 (2H, m).

(E-isomer)

1H-NMR (CDCl3): of 7.70 (1H, d, J=8,4), 7,56-7,66 (4H, m),? 7.04 baby mortality for 7.12 (2H, m), 4,36 (2H, s), of 3.46 (2H, d, J=7,5), of 3.32 (2H, s), 2,90-2,96 (2H, m), 1,96-2,07 (2H, m), of 1.5-1.9 (3H, m), 1,2-1,4 (2H, m).

b) Fumarate 5-bromo-2-[[1-[2-(4-forfinal)-2-(Z)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it

Using the Z-isomer obtained in Example 57a (212 mg, 0,461 mmol), get mentioned in the title compound as colorless solid by methods similar to the methods of Example 36C (114 mg, yield: 43%).

Melting point: 171-174° C.

1H-NMR (DMSO-d6): 7,83 (1H, s), 7,75-of 7.82 (2H, m), 7,66 (1H, d, J=8,1), 7,58 (1H, d, J=8,1), 7,15-7,22 (2H, m), 6,62 (2H, s, fumaric acid), of 4.45 (2H, s), of 3.60 (2H, s)to 3.34 (2H, d, J=7,2), of 2,75 2,80 (2H, m), 1,96-of 2.05 (2H, m,), of 1.6-1.8 (1H, m), 1,4-1,6 (2H, m), 1,0-1,2 (2H, m).

Example 58: Fumarate 5-bromo-2-[[1-[2-(4-forfinal)-2-(E)-hydroxyimino]piperidine-4-yl]methyl]isoindoline-1-it (E-isomer of Compound 92 in Table 1)

Using the E-isomer of the compound obtained in Example 57a (109 mg, 0,237 mmol), get mentioned in the title compound as colorless solid by methods similar to the methods of Example 36C (36 mg, yield: 26%).

Melting point: 186-188° C.

1H-NMR (DMSO-d6): 10,98 (1H, sh. s, OH), 7,83 (1H, s), to 7.61-of 7.70 (3H, m), to 7.59 (1H, d, J=8,1), 715-7,25 (2H, m), 6,62 (2H, s, fumaric acid), of 4.45 (2H, s)to 3.35 (2H, d, J=7,2), 3,30 (2H, s), 2.77-to 2,85 (2H, m), 1,86-of 1.97 (2H, m), of 1.6-1.8 (1H, m), 1,4-1,6 (2H, m), 1,0-1,2 (2H, m).

Example 59: Fumarate 2-[[1-(2-phenylbenzyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 456 Table 1)

a) 2-[[1-(2-phenylbenzyl)piperidine-4-yl]methyl]isoindoline-1-he

2-Phenylbenzoate (462 mg, of 1.87 mmol) and the compound obtained in Example 1d, dissolved in dimethylformamide (6 ml).

To the solution was added potassium carbonate (517 mg, of 1.87 mmol) and heated at 80° under stirring. The reaction mixture was added water (10 ml) and precipitated in the sludge solids are collected by filtration, getting mentioned in the title compound as a colourless solid (633 mg, yield: 85%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7.5 Hz), 7,53-7,24 (12H, m), 4,36 (2H, s), 3,47 (2H, d, J=7,2 Hz), 3,37 (2H, s),2,78 (2H, sh. d, J=11.4 in Hz)and 1.83 (2H, sh. DD, J=11,6, the 11.6 Hz), 1,74 by 1.68 (1H, m), 1,63-of 1.57 (2H, m), 1,39-of 1.30 (2H, m).

b) Fumarate, 2-[[1-(2-phenylbenzyl)piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 59A (620 mg, 1.56 mmol), get mentioned in the title compound as colorless solid by methods similar to the methods of Example 36C (331 mg, yield: 41%).

Melting point: 188-193° C.

1H-NMR (DMSO-d6): to 7.67-7.23 percent (13H, m), 6,62 (2H, s), of 4.45 (2H, s), 3,42 (2H, s), 3,37 (2H, d, J=6.9 Hz), is 2.74 (2H, sh. d, J=11.4 in Hz)to 1.86 (2H, sh. DD, J=10,8, and 10.8 Hz), 1,69-of 1.65 (1H, m), of 1.52 (2H, sh. d, J=12,6 Hz), 1,17 (2, W. DD, J=22,4, 10.4 Hz).

Example 60: Hydrochloride 2-[[1-[2-(2-propoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 501 Table 1)

a) Ethyl 2-hydroxyphenylacetate

2-Hydroxyphenylazo acid (6,06 g, 39.8 mmol) was dissolved in ethanol (180 ml) and the solution was added concentrated sulfuric acid (2 ml) and refluxed for 90 minutes. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The mixture is washed with water and saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate concentrated under reduced pressure, obtaining mentioned in the title compound as an orange oil (to 7.67 g, yield: quantitative).

1H-NMR (CDCl3): 7,56 (1H, s, OH), 7,15-7,26 (1H, m), to 7.09 (1H, DD, J=1,5, 7,5), 4,20 (2H, K, J=7,2), to 3.67 (2H, s)of 1.29 (3H, t, J=7,2).

b) Ethyl 2-propoxyphenyl

The compound obtained in Example 60A (1.12 g, from 6.22 mmol), iodopropane (0,635 ml, is 6.54 mmol) and potassium carbonate (1.27 g, 9,19 mmol) are added to a dimethylformamide (10 ml) and the resulting mixture heated at 70° C for 2 hours. The reaction mixture was added water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, water and then saturated salt solution and dried over magnesium sulfate. Insoluble solids delete the Ute by filtration and the filtrate concentrated under reduced pressure, getting listed in the title compound as a yellow oil (1,15 g, yield: 83%).

1H-NMR (CDCl3): 7,15-7,26 (2H, m), 6,82-6,93 (2H, m), is 4.15 (2H, K, J=7,2), to 3.92 (2H, t, J=6,4), 3,62 (2H, s), 1,72-of 1.84 (2H, m), 1,25 (3H, t, J=7,2), of 1.03 (3H, t, J=7,4).

c) 2-[[1-[2-(2-Propoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 60b (1,00 g, 4,50 mmol), get 2-(2-propoxyphenyl)ethanol (834 mg) in the form of the crude product by methods similar to the methods of Example 53b. Using the resulting product, by methods similar to the methods of Example 26a, get 2-(2-propoxyphenyl)atenololatenolol (1.13 g) as a crude product. Using the resulting product, by methods similar to the methods of Example 26b, get mentioned in the title compound as a pale yellow solid (yield 68%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,41-of 7.55 (3H, m), 7,11-7,19 (2H, m), is 6.78-6.89 in (2H, m), 4,42 (2H, s), 3,91 (2H, t, J=6,3), 3,52 (2H, d, J=6,9), 3,00-is 3.08 (2H, m), 2,80-is 2.88 (2H, m), 2,53-2,61 (2H, m), 2,0-2,1 (2H, m), 1,6-1,9 (5H, m), 1,3-1,5 (2H, m), was 1.04 (3H, t, J=7,4).

d) of the Hydrochloride of 2-[[1-[2-(2-propoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 61%), using the compound obtained in Example 60, by methods similar to the methods of Example 1f.

Melting point: 169-180° C.

1H-NMR (DMSO-d6): of 10.3 to 10.7 (1H, sh. with,HCl), of 7.69 (1H, d, J=7,4), 7,60-7,63 (2H, m), 7,47-7,53 (1H, m), 7.18 in-7,26 (2H, m), 6.87 in-7,00 (2H, m)to 4.52 (2H, s), of 3.94 (2H, t, J=6,4), 2,8-3,7 (10H, m), 1,9-2,2 (1H, m), 1,6-1,9 (4H, m), 1,4-1,6 (2H, m), a 1.01 (3H, t, J=7,4).

Example 61: Fumarate 2-[[1-[2-(2-benzyloxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 506 Table 1)

a) 2-[[1-[2-(2-benzyloxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 60A, and benzylbromide, obtain ethyl 2-benzyloxyaniline in the form of the crude product by methods similar to the methods of Example 60b. Using the resulting product, by methods similar to the methods of Example 53b, get 2-(2-benzyloxyphenyl)ethanol in the form of a crude product. Using the resulting product, by methods similar to the methods of Example 26a, get 2-(2-benzyloxyphenyl)atenololatenolol in the form of a crude product. Using the resulting product, obtained by methods similar to the methods of Example 26b specified in the title compound as a yellow oil (yield 72%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,2), 7,28-OF 7.55 (8H, m), 7,11-7,19 (2H, m), 6,86-6,93 (2H, m), 5,07 (2H, s)to 4.41 (2H, s), 3,50 (2H, d, J=7,2), 2,95-to 3.02 (2H, m), 2,83 of 2.92 (2H, m), 2,55-2,63 (2H, m), 1,9-2,1 (2H, m), of 1.5-1.8 (3H, m), 1,3-1,5 (2H, m).

b) Fumarate, 2-[[1-[2-(2-benzyloxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 56%)using the connection, receive the TES in Example 61A, by methods similar to the methods of Example 36C.

Melting point: 184-188° C.

1H-NMR (DMSO-d6): to 7.68 (1H, d, J=7,5), 7,58 to 7.62 (2H, m), 7,2-7,5 (6H, m), 7,1-7,2 (2H, m),? 7.04 baby mortality (1H, d, J=8,4), 6.8 or 6.9 (1H, m), to 6.57 (2H, s, fumaric acid), 5,12 (2H, s), 4,48 (2H, s)to 3.41 (2H, d, J=7,1), 3,0-3,1 (2H,, m), 2,8-2,9 (2H, m), 2,6-2,7 (2H, m), to 2.1-2.3 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,6 (2H, m), 1,2-1,4 (2H, m).

Example 62: Fumarate 2-[[1-[2-[1,1’-biphenyl]-2-retil)piperidine-4-yl]methyl]isoindoline-1-she (Compound 511 Table 1)

a) 2-[1,1’-biphenyl]-2-ylacetonitrile

2-(methyl bromide)biphenyl (1.35 g, of 5.48 mmol), potassium cyanide (368 mg, the 5.65 mmol) and a catalytic amount of 18-crown-6-ether is added to acetonitrile (10 ml) and the mixture refluxed for 5 days. The reaction mixture was added water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate concentrated under reduced pressure. The resulting oil is purified column chromatography on silica gel (ethyl acetate-hexane), getting mentioned in the title compound as a colourless solid (1.07 g, yield: quantitative).

1H-NMR (CDCl3): 7,3-7,5 (6H, m), 7,2-7,3 (3H, m), 3,63 (2H, s).

b) 2-[1,1’-Biphenyl]-2-ilocana acid

The compound obtained in Example a (1.06 g, of 5.48 mmol), restore the t in ethylene glycol (30 ml). To the solution was added potassium hydroxide (5,98 g of 90.6 mmol) and heated at 190° C for 2 hours. The reaction mixture allow to cool to room temperature and then poured into 1N hydrochloric acid (200 ml). Precipitated precipitated solid is collected by filtration and washed with water and dried under reduced pressure, obtaining mentioned in the title compound as a colourless solid (of 1.05 g, yield: 91%).

1H-NMR (CDCl3): 7,25-7,42 (9H, m), 3,63 (2H, s).

C) 2-[[1-[2-[1,1’-biphenyl]-2-retil)piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 62b will receive 2-[1,1’-biphenyl]-2-retinol in the form of the crude product by methods similar to the methods of Example 53b. Using the resulting product, by methods similar to the methods of Example 26a will receive 2-[1,1’-biphenyl]-2-recanalisation in the form of a crude product. Using the resulting product, by methods similar to the methods of Example 26b, get mentioned in the title compound as a yellow oil (yield 70%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,4), 7,1-7,5 (12H, m), 4,37 (2H, s), of 3.45 (2H, d, J=7,0), 2,6-2,8 (4H, m), 2,36 is 2.46 (2H, m), of 1.5-1.9 (7H, m), 1,2-1,4 (2H, m).

d) Fumarate, 2-[[1-[2-[1,1’-biphenyl]-2-retil)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 68%), ispolzovanie, obtained in Example C, by methods similar to the methods of Example 36C.

Melting point: 198-206° C.

1H-NMR (DMSO-d6): 7,66 (1H, d, J=7,5), 7,56-7,66 (2H, m)and 7.1 and 7.5 (10H, m), to 6.57 (2H, s, fumaric acid), of 4.45 (2H, s), 3,37 (2H, d, J=7,3), 2,71-to 2.85 (4H, m), 2,50 at 2.59 (2H, m), 1,95 is 2.10 (2H, m), of 1.6-1.8 (1H, m), 1,4-1,6 (2H,, m), 1,1-1,3 (2H, m).

Example 63: Fumarate 2-[[1-[2-(2-penetrometer)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 516 Table 1)

a) 2-[[1-[2-(2-penetrometer)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 60A, and feitelberg, obtain ethyl 2-ventilationoutlet in the form of the crude product by methods similar to the methods of Example 60b. Using the resulting product, by methods similar to the methods of Example 53b, get 2-(2-penetrometer)ethanol in the form of a crude product. Using the resulting product, by methods similar to the methods of Example 26a, get 2-(2-penetrometer)atenololatenolol in the form of a crude product. Using the resulting product, obtained by methods similar to the methods of Example 26b specified in the title compound as a yellow oil (yield 70%).

1H-NMR (CDCl3): 7,86 (1H, d, J=7,1), 7,42-of 7.55 (3H, m), 7,11-7,33 (7H, m), is 6.78-6.89 in (2H, m), 4,42 (2H, s), 4,19 (2H, t, J=6,8), 3,52 (2H, d, J=7,0), 3,10 (2H, t, J=6,8), 2,94-a 3.01 (2H, m), 2,75-and 2.83 (2H, m), 2,46-of 2.54 (2H, m), of 1.8-2.0 (2H, m), 1.5 and 1.8 (3H, m), 1,3-1,5 (2H, m).

b) Fumarate, 2-[[1-[2-(2-fenet loxifene)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 56%), using the compound obtained in Example 63A, by methods similar to the methods of Example 36C.

Melting point: 178-180° C.

1H-NMR (DMSO-d6): to 7.68 (1H, d, J=7,5), EUR 7.57 to 7.62 (2H, m), between 7.4 to 7.5 (1H, m), 7,10-7,33 (7H, m), to 6.95 (1H, d, J=8,1), to 6.80-6.87 in (1H, m), to 6.57 (2H, s, fumaric acid), of 4.49 (2H, s), 4,20 (2H, t, J=6,3), 3,42 (2H, d, J=7,2), 3,05 (2H, t, J=6,3), 2,94-of 3.00 (2H, m), 2,65-of 2.72 (2H, m), 2,4-by 2.55 (2H, m), of 2.0-2.2 (2H, m), a 1.7-1.8 (1H, m), 1,5-1,6 (2H, m), 1,2-1,3 (2H, m).

Example 64: Fumarate 2-[[1-(2-fuelbased)piperidine-4-yl]methyl]isoindoline-1-she (Compound 461 Table 1)

a) 2-Bromofuran

Dimethylformamide (35 ml) is cooled to -20° and then he added dropwise bromine (13 ml, 253 mmol) for 25 minutes, obtaining a solution of bromine in dimethylformamide. Furan (25 ml, 345 mmol) was dissolved in dimethylformamide (35 ml) and then dropwise added a pre-prepared solution of bromine in dimethylforamide within 1 hour, maintaining the temperature at 25 to 30° C. the Reaction mixture is maintained at 30 to 35° C and stirred for 1 hour. The reaction mixture was poured into ice water (230 ml) and the mixture is then stirred for 2 minutes and extracted with diethyl ether. The extract is washed with water and then add to it diethylethanolamine (2 ml) and dried over sodium sulfate. Insoluble solids are removed f is trovanjem and distil the residue under atmospheric pressure, getting listed in the title compound as a colourless liquid fraction in the temperature range from 95 to 105° With (yield: 23%).

1H-NMR (CDCl3): 7,42 (1H, d, J=2.4 Hz), 6,37 (1H, d, J=2,GC), 6,30 (1H, d, J=4.0 Hz).

b) 2-Shrivenzale

2-Formylphenylboronic acid (300 mg, 2.0 mmol), 2-bromofuran obtained in Example 64A (588 mg, 4.0 mmol), and tetrakis-triphenylphosphine (15 mg) was dissolved in a mixed solvent of toluene (38 ml)-methanol (5 ml). To the solution was added 2M aqueous solution of sodium carbonate (20 ml) and heated at 80° With stirring for 6 hours. The reaction mixture was kept for cooling, and then the solvent is evaporated. The mixture is extracted with dichloromethane and the extract washed with a mixture of 2M aqueous sodium carbonate (10 ml) and aqueous ammonia (2 ml) and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure, obtaining mentioned in the title compound in the form of a crude yellow oil (126 mg). The crude product is used in subsequent reactions without purification.

C) 2-[[1-(2-fuelbased)piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 1d (267 mg, 1.0 ml), dissolved in methanol. To the solution was added the crude product obtained in Example 64b (126 mg), and cyanoborohydride sodium (157 mg, 2.5 mm is l), and the reaction mixture was added acetic acid (57 μl, 1.0 mmol)to bring the pH to about 6, and then heated at 40° C for 8 hours under stirring. The solvent is evaporated and then the residue is diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The crude product was then purified column chromatography on silica gel (methanol-dichloromethane), getting mentioned in the title compound as a yellow oil (165 mg, yield: 21%, stage 2).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7.5 Hz), 7,66 (1H, DD, J=7,4) and 1.7 Hz), 7,53-the 7.43 (5H, m), 7,31-of 7.25 (2H, m), of 6.75 (1H, d, J=3.0 Hz), 6.48 in (1H, DD, J=3.3, which is 1.8 Hz), 4,39 (2H, s), of 3.57 (2H, s), 3,50 (2H, d, J=7.5 Hz), 2.91 in (2H, sh. d, J=11.7 Hz), to 1.98 (2H, DDD, J=2,1, 11,6, the 11.6 Hz), 1,81 to 1.76 (1H, m), of 1.65 (2H, sh. d, J=12.9 Hz), 1,41 (2H, DDD, J=3,6, to 12.0, 12.0 Hz).

d) Fumarate, 2-[[1-(2-fuelbased)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (127 mg, yield: 59%), using the compound obtained in Example C (165 mg), by methods similar to the methods of Example 36C.

Melting point: 140-153° C.

1H-NMR (DMSO-d6): 7,79 (1H, d, J=1.5 Hz), the 7.65 (2H, d, J=7,9, 7.9 Hz), to 7.59-7,58 (2H, m), 7,49-7,46 (2H, m), of 7.36-to 7.32 (2H, m), 6,85 (1H, d, J=3.2 Hz), 6,63-6,62 (3H,m), 4,48 (2H, s)to 3.64 (2H, s), 3,40 (2H, d, J=7,3 Hz), 2,84 (2H, d, J=11.5 Hz), 2,03 (2H, sh. DD, J=10,9, up 10.9 Hz), 1,78-of 1.73 (1H, m), 1,58 (2H, sh. DD, J=11.0 cm Hz), 1,27-of 1.15 (2H, m).

Example 65: Fumarate 2-[[1-(2-benzoylphenyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 466 Table 1)

a) 2-Benzoylbenzoate

Specified in the title compound obtained as the crude yellow oil (1,74 g)using 2-methylbenzophenone (1.18 g, 6.0 mmol), by methods similar to the methods of Example 1b. The crude product is used in subsequent reactions without purification.

b) 2-[[1-(2-benzoylphenyl)piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 65A (1,74 g), dissolved in dimethylformamide (15 ml). To the solution was added the compound obtained in Example 1d (1.07 g, 4.0 mmol), and potassium carbonate (1.10 g, 8.0 mmol) and the mixture is stirred at room temperature for 16 hours. The reaction mixture was added water (30 ml) and extracted with ethyl acetate. The extract is washed with water and saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The crude product was then purified column chromatography on silica gel (methanol-dichloromethane), getting mentioned in the title compound as a brown semi-solid substances (1.07 g, yield: 63%).

1H-NMR (CDCl3): 7,78 to 7.75 (3H, m),7,51-7,26 (10H, m),4,28 (2H, s), 3,40 (2H, s), or 3.28 (2H, d, J=6.9 Hz), 2,46 (2H, d, J=11.4 in Hz)to 1.79 (2H, sh. DD, J=11,4, and 11.4 Hz), 1,59-of 1.56 (1H, m)of 1.34 (2H, sh. d, J=13,2 Hz), 0,86-of 0.82 (2H, m).

C) Fumarate, 2-[[1-(2-benzoylphenyl)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (971 mg, yield: 76%), using the compound obtained in Example 65b (1,00 g, 2.36 mmol), by methods similar to the methods of Example 36C.

Melting point: 166-169° C.

1H-NMR (DMSO-d6): to 7.67-7,29 (13H, m), 6,63 (2H, s), 4,36 (2H, s), of 3.54 (2H, s)3,18 (2H, d, J=6.9 Hz), 2,32 (2H, sh. d, J=11,1 Hz), 1.77 in (2H, sh. DD, J=a 10.5, 10.5 Hz), 1,50 is 1.48 (1H, m), 1,25 (2H, sh. d, J=11.7 Hz), of 0.67 (2H, sh. DD, J=20,1, an 11.7 Hz).

Example 66: Fumarate 2-[[1-[3-(2-penicillinase)propyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 691 Table 1)

a) 2-[3-(Tetrahydro-2H-Piran-2-yloxy)propoxy]benzaldehyde

Specified in the title compound obtained as a colorless oil (yield: quantitative)using 2-(3-bromopropane)tetrahydro-2H-Piran and salicylaldehyde, by methods similar to the methods of Example 60b.

1H-NMR (CDCl3): 10,52 (1H, s, OH), 7,83 (1H, DD, J=1,8, 7,8), 7,50-7,57 (1H, m), 6,98-7,05 (2H, m), 4,56-br4.61 (1H, m), 4,22 (2H, t, J=6,3), 3,91-4,00 (1H, m), 3.75 to of 3.85 (1H, m), 3,56-3,66 (1H, m), 3,38-3,50 (1H, m), 2.05 is-2,22 (2H, m), 1,4-1,9 (8H, m).

b) 3-(2-Penicillinase)propanol

Bromide benzyltriphenylphosphonium (2.25 g, 5,19 mmol) suspended in tetrahydrofuran (20 ml) and the suspension stirred at ohla the Denia ice. In the slurry, add t-piperonyl potassium (596 mg, 5,31 mol) and the mixture is stirred at the same temperature. The reaction mixture was added the compound obtained in Example 66A (1,09 g, 4,12 mmol)which was dissolved in tetrahydrofuran (4 ml), and then the resulting mixture is stirred for 1 hour. The reaction mixture was diluted with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract is washed with water, saturated aqueous sodium bicarbonate and then with saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure, obtaining 2-[3-[2-[(E,Z)-2-phenylethenyl]phenoxy]propoxy]tetrahydro-2H-Piran in the form of a crude product. The product is dissolved in methanol (50 ml) and the solution was added a catalytic amount of p-toluenesulfonic acid and then refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil purified column chromatography on silica gel (ethyl acetate-hexane)to give 3-[2-[(E,Z)-2-phenylethenyl]phenoxy]propanol. The product is dissolved in ethanol (12 ml) and the solution is added catalytic amount of 10% palladium on carbon and the mixture is stirred in hydrogen atmosphere, getting mentioned in the title compound as a colourless oil (464 mg, yield: 45%).

1H-NMR (CDCl3): 7,10-to 7.32 (7H, m), 6,85-6,92 (2H, m), of 4.12 (2H, t, J=5,9), 3,90 (2H, t, J=5,9), of 2.8-3.0 (4H, m), of 2.0-2.2 (2H, m).

C) 2-[[1-[3-(2-penicillinase)propyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 66b receive 3-(2-penicillinase)propenolatomethyl in the form of the crude product by methods similar to the methods of Example 26a. Using the resulting product, get mentioned in the title compound as a yellow oil (yield: 86%) by methods similar to the methods of Example 26b.

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,40-of 7.55 (3H, m), 7,07-7,29 (7H, m), 6,83-6,89 (2H, m)to 4.41 (2H, s)to 4.01 (2H, t, J=6,2), 3,51 (2H, d, J=7,2), 2,82-of 3.00 (6H, m), of 2.51 at 2.59 (2H, m), 1,9-2,1 (4H, m), 1,6-1,9 (3H, m), 1,3-1,5 (2H, m).

d) Fumarate, 2-[[1-[3-(2-penicillinase)propyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 60%), using the compound obtained in Example C, by methods similar to the methods of Example 36C.

Melting point: 166-169° C.

1H-NMR (DMSO-d6): to 7.68 (1H, d, J=7,3), EUR 7.57-to 7.61 (2H, m), between 7.4 to 7.5 (1H, m), 7,11-7,27 (7H, m), 6,93 (1H, d, J=8,0), 6.8 or 6.9 (1H, m), to 6.57 (2H, s, fumaric acid), 4,48 (2H, s), of 4.00 (2H, t, J=5,9), 3,42 (2H, d, J=7,3), 3,00-of 3.07 (2H, m), of 2.81 (4H, s), 2,6-2,7 (2H, m), to 2.1-2.3 (2H, m), 1,9-2,0 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1,2-1,4 (2H, m).

Example 67: Fumarate 2-[[1-[3-(2-benzoylperoxy)propyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 696 in Tab is itzá 1)

a) 3-(2-Benzoylperoxy)propanol

Using 2-hydroxydiphenylmethyl and 3-bromopropane get mentioned in the title compound as a colorless oil by methods similar to the methods of Example 60b (yield: 28%).

1H-NMR (CDCl3): 7,08-7,28 (7H, m), 6,86-6,94 (2H, m), 4,08 (2H, t, J=5,7), 3,98 (2H, s), 3,71 (2H, t, J=6,0), 1,93-2,03 (2H, m), 1,49 (1H, sh. s, OH).

b) 2-[[1-[3-(2-benzoylperoxy)propyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 67a, receive 3-(2-benzoylperoxy)propenolatomethyl in the form of the crude product by methods similar to the methods of Example 26a. Using the resulting product, by methods similar to the methods of Example 26b, get mentioned in the title compound as a pale yellow solid (yield 87%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,3), 7,41-of 7.55 (3H, m), 7,0 is 7.3 (7H, m), for 6.81-of 6.90 (2H, m), and 4.40 (2H, s), of 3.97 (2H, t, J=6,1), of 3.96 (2H, s), 3,50 (2H, d, J=7,1), 2,84-to 3.92 (2H, m), 2,36 is 2.44 (2H, m), of 1.8-2.0 (4H, m), of 1.5-1.8 (3H, m), 1,2-1,4 (2H, m).

c) Fumarate, 2-[[1-[3-[2-[2-(3-methoxyphenyl)ethyl]phenyloxy]propyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 80%)using the compound obtained in Example 67b, by methods similar to the methods of Example 36c.

Melting point: 185-191° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,2), 7,56-of 7.60 (2H, m), 7,46-7,52 (1H, m), 7,13-7,27 (7H, m), 6,9 (1H, d, J=7,8), 6,83-6,89 (1H, m), to 6.57 (2H, s, fumaric acid), 4,48 (2H, s), of 3.97 (2H, t, J=6,0), 3,88 (2H, s)to 3.41 (2H, d, J=7,2), 2,90-of 2.97 (2H, m), 2,48-2,52 (2H, m), a 2.0 to 2.15 (2H, m), 1,6-1,9 (3H, m), 1.5 to 1,6 (2H, m), 1,2-1,3 (2H, m).

Example 68: Fumarate 2-[[1-[3-[2-[2-(3-methoxyphenyl)ethyl]phenyloxy]propyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 701 Table 1)

a) Chloride 3-methoxybenzylideneamino

3-Methoxybenzylamine (1,05 g, 6,69 mmol), triphenylphosphine (1.75 g, to 6.67 mmol) dissolved in dimethylformamide (10 ml) and heated at 150°C for 40 minutes. The reaction mixture is cooled to room temperature, and precipitated precipitated solid is collected by filtration and washed with ethyl ether and then dried under reduced pressure, obtaining mentioned in the title compound as a colourless solid 1.70 g (yield: 61%).

1H-NMR (DMSO-d6): 7,87-of 7.95 (3H, m), of 7.64-7,79 (12H, m), 7,16 (1H, t, J=7,9), 6,86 (1H, d, J=8,3), is 6.61 (1H, d, J=7,4), of 6.49 (1H, s), 5,1-5,3 (2H, m), 3,50 (3H, s).

b) 3-[2-[2-(3-Methoxyphenyl)ethyl]phenyloxy]propanol

Using the compound obtained in Example 68A, and the compound obtained in Example 66A, get mentioned in the title compound as a colorless oil by methods similar to the methods of Example 66b (yield: 50%).

1H-NMR (CDCl3): 7,10-7,24 (3H, m), 6,70-6,93 (5H, m), of 4.12 (2H, t, J=5,9), 3,90 (2H, t, J=5,9), of 3.78 (3H, s), of 2.8-3.0 (4H, m), of 2.0-2.2 (2H, m), 1,72 (1H, sh. s, OH).

C) 2-[[1-[3-[2-[2-(3-Methoxyphenyl)ethyl]phenyloxy]-propyl]n is peridin-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 68b, receive 3-[2-[2-(3-methoxyphenyl)ethyl]phenyloxy]propenolatomethyl in the form of the crude product by methods similar to the methods of Example 26a. Using the resulting product, by methods similar to the methods of Example 26b, get mentioned in the title compound as a yellow oil (yield 84%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,42-of 7.55 (3H, m), 7,07-7,22 (3H, m), 6,70-6,89 (5H, m)to 4.41 (2H, s)to 4.01 (2H, t, J=6,1), of 3.77 (3H, s), 3,50 (2H, d, J=7,2), 2,80-3,00 (6H, m), of 2.51 at 2.59 (2H, m), 1,9-2,1 (4H, m), 1,6-1,9 (3H, m), 1,3-1,5 (2H, m).

d) Fumarate, 2-[[1-[3-[2-[2-(3-methoxyphenyl)ethyl]phenyloxy]propyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 73%)using the compound obtained in Example 68 pp., by methods similar to the methods of Example 36C.

Melting point: 181-184° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,4), 7,58-of 7.60 (2H, m), 7,47-7,51 (1H, m), 7,12-7,20 (3H, m), 6,93 (1H, d, J=8,0), 6,70-6,87 (4H, m), to 6.57 (2H, s, fumaric acid), 4,48 (2H, s), of 4.00 (2H, t, J=5,8), 3,70 (3H, s)to 3.41 (2H, d, J=7,2), 2,98 was 3.05 (2H, m), 2,7-2,9 (4H, m), 2,6-2,7 (2H, m), of 2.0-2.2 (2H, m), 1,9-2,0 (2H, m), a 1.7-1.8 (1H, m), 1,5-1,7 (2H, m), 1,2-1,4 (2H, m).

Example 69: Hydrochloride 2-[[1-[4-phenyl-2-oxobutyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 344 Table 1)

2M LDA/heptane, THF (THF)solution EtPh (3,07 ml, 6,14 mmol) are added to DME (3 ml), cooled at -78° and then to the mixture add recipients who have dropwise benzylacetone 0,700 g (4.72 in mmol/DME (5 ml). After stirring for 1 hour, to the mixture are added dropwise chlorotrimethylsilane (0,779 ml, 6,14 mmol) and then warmed to room temperature. The reaction mixture was diluted with hexane and washed twice with water, twice with saturated aqueous solution of NH4Cl and then with saturated salt solution and dried over Na2SO4.

The solvent is evaporated, the remaining oil is dissolved in THF (THF) (18 ml) and cooled to 0° and to this add NBS (0,924 g, 5,19 mmol). The reaction mixture is heated to room temperature and stirred for 1 hour, the reaction mixture was poured into an aqueous solution of Na4S2O3and extracted three times with ether. The combined organic layer is dried over Na2SO4.

After evaporation of the solvent, the oil obtained is dissolved in DMF (DMF) (10 ml) and the solution was added the compound obtained in Example 1d (1.26 g, 4,72 mmol), and triethylamine (1,64 ml of 11.8 mmol). After stirring at room temperature the reaction mixture was diluted with ethyl acetate and washed four times with water and then with saturated salt solution and dried over Na2SO4.

The desiccant is removed by filtration, the filtrate into a solution of ethanol (1.5 ml) and etelaat (3 ml). To the solution was added 4N HCl-AcOEt (1.08 ml, or 4.31 mmol). After stirring the mixture was added ethyl acetate (10 ml) and precipitated precipitated crystals by sobiratelyam and dried, getting listed in the title compound (yield: 39%).

Melting point: 183-187° C.

1H-NMR (DMSO-d6): δ to 9.93 (sh. s, 1H), 7,68 (d, J=7,4 Hz, 1H), to 7.61 (m, 2H), 7,49 (m, 1H), 7,16-7,31 (m, 5H), 4,51 (s, 2H), 4,33-4,50 (m, 2H), 2,84 is 3.57 (m, 10H)to 1.99 (m, 1H), 1,78 (sh. d, J=13 Hz, 2H), 1,58 (m, 2H).

Example 70: Hydrochloride 2-[[1-[3-phenyl-2-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 349 Table 1)

a) 2-[[1-[3-phenyl-2-hydroxypropyl]piperidine-4-yl]methyl]-isoindole-1-he

The compound obtained in Example 1d (994 mg, 3.73 mmol), and 2,3-epoxypropyl)benzene (0,500 g, 3.73 mmol) and triethylamine (0,78 ml, the ceiling of 5.60 mmol) dissolved in ethanol (8 ml) and the mixture is heated at 50° C. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed four times with water and then with saturated salt solution and dried over Na2SO4. After removal of the desiccant by filtration, the filtrate concentrated and the residue purified by chromatography on silica gel (acetone), getting mentioned in the title compound (yield: 44%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.2 Hz, 1H), 7,42-7,56 (m, 3H), 7,21-to 7.32 (m, 5H), 4,39 (s, 2H), 3,90 (m, 1H), 3,49 (d, J=9.6 Hz, 2H), 2,96 (sh. d, J=9 Hz, 1H), was 2.76-of 2.86 (m, 2H), 2,65 (m, 1H), 2,20-2,31 (m, 3H), of 1.87 (dt, J=12, 2 Hz, 1H), 1,79 (m, 1H), 1,67 (sh. d, J=13 Hz, 2H), 1,36 (DK, J=12, 4 Hz, 2H).

b) 2-[[1-[3-phenyl-2-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-he

(COCl)2(0.125 g, is 0.998 mmol)/CH2Cl2(3 ml) cooled to -78° and in the solution according to plan add DMSO (DMSO) (0,121 g, 1.55 mmol)and after stirring for 10 minutes, to the mixture was added dropwise the compound obtained in Example 70A (180 mg, 0,494 mmol) / CH2Cl2(1 ml). After stirring for 30 minutes to the reaction mixture dropwise added triethylamine (0,491 ml, to 3.52 mmol)and after stirring for 4 hours the reaction mixture is heated to room temperature. The reaction mixture was diluted with ethyl acetate (40 ml) and washed four times with water and then with saturated salt solution and dried over Na2SO4. After removal of the desiccant by filtration and concentration of the filtrate the residue is purified by chromatography on silica gel (acetone/hexane), getting mentioned in the title compound (yield: 50%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.5 Hz, 1H), 7,42-rate of 7.54 (m, 3H), 7,22-to 7.35 (m, 5H), and 4.40 (s, 2H, in), 3.75 (s, 2H), 3,51 (d, J=7.2 Hz, 2H), and 3.16 (s, 2H), 2,79 (sh. d, J=12 Hz, 2H), 2,03 (dt, J=11,4, 2,1 Hz, 2H), 1,78 (m, 1H), 1,67 (sh. d, J=10 Hz, 2H), 1,47 (DK, J=12, 4 Hz, 2H).

c) the Hydrochloride of 2-[[1-[3-phenyl-2-oxopropyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header connection receive (yield: 59%), using the compound obtained in Example 70b, by methods similar to the methods of Example 1f.

Melting point: 198-204° C.

1H-NMR (DMSO-d6): δ 9,84 (sh. s, 1H), 7,68 (d, J=7.5 Hz, 1H), to 7.61 (m, 2H), 7,50 (m, 1H), 7,22-7,37 (m, 5H), 4,40-of 4.54 (m, 4H), 3,88 (s, 2H), 2,94 of 3.56 (m, 6H), 1,99 (m, 1H), 1,78 (sh. d, J=14 Hz, 2H), and 1.56 (m, 2H).

Example 71: Guide klorid 2-[[1-[4-phenyl-3-oxobutyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 354 Table 1)

a) 1-Tosyloxy-3-hydroxy-4-phenylpropane

A solution of methyl(phenylacetyl)acetic acid (0,700g, to 3.64 mmol)obtained by the method described in the publication (Yonemitsu, O. et al, Org. Synth., 1984, 63, 198)in 24 ml of ethanol is cooled to 0° and to the solution was added NaBH4(1.10 g, of 29.1 mmol) and stirred at room temperature. The reaction mixture was added concentrated hydrochloric acid to acidification, and then diluted with saturated salt solution and extracted four times with dichloromethane. The combined organic layer is dried over Na2SO4.

After removal of the desiccant by filtration and concentration of the filtrate obtained oil was dissolved in dichloromethane (8 ml). To the solution was added pyridine (0,61 ml, rate of 7.54 mmol) and cooled to 0° C. To the solution was added with stirring taillored (0,694 g of 3.64 mmol) and stirred for 2 hours. Then the reaction mixture is diluted with ether and washed twice with water and dried over Na2SO4. After removal of the desiccant by filtration and concentration of the filtrate the residue is purified by chromatography on silica gel (ethyl acetate/hexane)to give specified in the title compound (yield: 32%).

1H-NMR (CDCl3): δ for 7.78 (d, J=8.1 Hz, 2H), 7,15-7,34 (m, 7H), 4.26 deaths (m, 1H), 4,17 (m, 1H), 3,94 (m, 1H), 2,78 (m, 1H), 2,64 (m, 1H), 2,44 (s, 3H), 1.93 and (m, 1H), 1,75 (m, 1H).

b) 2-[[1-[4-phenyl-3-oxobutyl]piperidine-4-yl]IU is Il]isoindoline-1-he

Using the compound obtained in Example 71A, by methods similar to the methods of Example 26b, receive the product, which is subjected, without purification processing by methods similar to the methods of Example 70b, getting mentioned in the title compound (yield: 27%).

1H-NMR (CDCl3): δ to 7.84 (d, J=7.2 Hz, 1H), 7,44-7,53 (m, 3H), 7.18 in-7,32 (m, 5H), 4,39 (s, 2H), 3,70 (s, 2H), 3,48 (d, J=7.2 Hz, 2H), 2,82 (sh. d, J=12 Hz, 2H), 2.05 is-to 2.65 (m, 4H), 1.91 a (dt, J=11,7, 2,1 Hz, 2H), of 1.75 (m, 1H), of 1.66 (m, 2H), 1,33 (DK, J=12, 3 Hz, 2H).

(C) the Hydrochloride of 2-[[1-[4-phenyl-3-oxobutyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header of the get connection using the connection obtained in Example 71b, by methods similar to the methods of Example 1f (yield: 61%).

Melting point: 163-166° C.

1H-NMR (DMSO-d6): δ 9,89 (sh. s, 1H), 7,68 (d, J=7.5 Hz, 1H), to 7.61 (m, 2H), 7,49 (m, 1H), 7,19-to 7.35 (m, 5H), 4,50 (s, 2H), 3,84 (s, 2H), 2,81-3,62 (m, 10H)of 1.97 (m, 1H), 1,78 (sh. d, J=13 Hz, 2H), 1,49 (m, 2H).

Example 72: Fumarate 2-[[1-[2-(2-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 376 Table 1)

a) 2-[[1-[2-(2-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

2’-Methoxyacetophenone (1,11 g, 7,39 mmol) and the hydrobromide of perbromide pyridinium (2,61 g, 8.16 mmol) was dissolved in a mixed solvent of dichloromethane (50 ml) - methanol (20 ml)and the mixture refluxed for 1 hour. The solvent is evaporated from the reaction mixture at eigendom pressure and the residue diluted with ethyl acetate. The mixture is washed with water and saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure, obtaining 2-bromo-1-(2-methoxyphenyl)Ethan-1-it is in the form of a crude product. By using the product, by methods similar to the methods of Example 1E, get mentioned in the title compound as a yellow oil (yield: 63%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,5), of 7.70 (1H, DD, J=2,0, 7,7), 7,42-7,55 (4H, m), 6,93-7,03 (2H, m)to 4.41 (2H, s)to 3.89 (3H, s), 3,80 (2H, s), 3,50 (2H, d, J=7,2), 2,92-of 3.00 (2H, m), 2,14-of 2.26 (2H, m), 1,6-1,9 (3H, m), 1,4-of 1.55 (2H, m).

b) Fumarate, 2-[[1-[2-(2-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 50%)using the compound obtained in Example 72A, by methods similar to the methods of Example 36C.

Melting point: 180-190° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,44-to 7.61 (5H, m), 7,17 (1H, d, J=8,2), 7,03 (1H, t, J=7,4), 6,60 (2H, s, fumaric acid), 4,48 (2H, s), 3,88 (3H, s), a-3.84 (2H, s), 3,40 (2H, d, J=7,3), 2,88-2,95 (2H, m), 2.21 are 2,31 (2H,, m)of 1.6-1.8 (1H, m), 1,4-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 73: Hydrochloride 2-[[1-[2-(4-tolyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 396 Table 1)

a) 2-[[1-[2-(4-Tolyl)-2-oxoethyl]piperidine-4-yl]methyl]-isoindole-1-he

Specified in the title compound obtained as a pale yellow solid ve is esta (yield: 83%), using 2-bromo-1-(4-were)ethane-1-he, by methods similar to the methods of Example 1E.

1H-NMR (CDCl3): to $ 7.91 (2H, d, J=8,2), to 7.84 (1H, d, J=7,5), 7,41-to 7.59 (3H, m), from 7.24 (2H, d, J=8,2), to 4.41 (2H, s), 3,76 (2H, s), 3,51 (2H, d, J=7,1), 2,95-3,03 (2H, m), is 2.41 (3H, s), 2,09-of 2.21 (2H, m), 1,6-1,9 (3H, m), 1,4-1,6 (2H, m).

(b) Hydrochloride of 2-[[1-[2-(4-tolyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 90%)using the compound obtained in Example 73a, by methods similar to the methods of Example 1f.

Melting point: 169-185° C.

1H-NMR (DMSO-d6): of 9.8 to 10.0 (1H, sh. with, HCl), 7,80 (0,5H, d, J=7,9), 7,89 (1,5H, d, J=7,9), of 7.69 (1H, d, J=7,4), EUR 7.57-7,63 (2H, m), 7,40-7,52 (3H, m), 5,09 (0,5H, s), 5,02 (1,5H, C), a 4.53 (2H, s), 3,51-to 3.58 (2H, m), 3,47 (2H, d, J=7,0), 2,9-3,1 (2H, m), is 2.41 (3H, s), 1,9-2,1 (1H, m), 1,4-1,9 (4H, m).

Example 74: Fumarate 2-[[1-[2-(3,4-differenl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 401, Table 1)

a) 2-[[1-[2-(3,4-differenl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 3’,4’-defloration get mentioned in the title compound as yellow solid (yield: 84%) by methods similar to the methods of Example 72A and Example 1E.

1H-NMR (CDCl3): 7,8-8,0 (3H, m), 7,40-EUR 7.57 (3H, m), 7,10-7,26 (1H, m), and 4.40 (2H, s)to 3.67 (2H, s), 3,51 (2H, d, J=7,2), 2,86-of 2.97 (2H, m), 2,08-of 2.20 (2H, m), 1,6-1,9 (3H, m), 1,3-1,5 (2H, m).

b) Fumarate, 2-[[1-[2-(3,4-differenl)-2-oxoethyl]piperidine-4-yl]methylisoquinoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 79%)using the compound obtained in Example a, by methods similar to the methods of Example 36C.

Melting point: 186-193° C.

1H-NMR (DMSO-d6): 8,00-of 8.09 (1H, m), a 7.85-of 7.95 (1H, m), 7,54-of 7.69 (4H, m), between 7.4 to 7.5 (1H, m), 6,62 (2H, s, fumaric acid), 4,48 (2H, s), 3,83 (2H, s), 3,40 (2H, d, J=7,2), 2,84-2,90 (2H, m), 2,08-to 2.18 (2H, m), of 1.6-1.8 (1H, m), 1,4-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 75: Hydrochloride 2-[[1-[2-(2-naphthyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 411 Table 1)

a) 2-[[1-[2-(2-naphthyl)-2-oxoethyl]piperidine-4-yl]methyl]-isoindole-1-he

Using 2-bromo-1-(2-naphthyl)Ethan-1-he, by methods similar to the methods of Example 1E, get mentioned in the title compound as a pale yellow solid (yield: 83%).

1H-NMR (CDCl3): to 8.57 (1H, s), 7,83-with 8.05 (4H, m), 7,41-7,66 (6H, m), 4,42 (2H, s), of 3.96 (2H, s), 3,53 (2H, d, J=7,2), 3.04 from-3,13 (2H, m), 2,20-2,31 (2H, m), 1,6-1,9 (3H, m), 1,4-1,6 (2H, m).

(b) Hydrochloride of 2-[[1-[2-(2-naphthyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a pale yellow solid (yield: 61%), using the compound obtained in Example 75A, by methods similar to the methods of Example 1f.

Melting point: 192-201° C.

1H-NMR (DMSO-d6): 9,8-10,2 (1H, sh. with, HCl), 8,81 (0,2H, C), 8,72 (0,8H, s), 7,97-8,19 (4H, m), 7,4-7,8 (6H, m), 5,26 (0,4H, C), 5,19 (1,6H, C)4,55 (2H, s), 3,57-of 3.64 (2H, m), 3,49 (2H, d, J=6,9), to 3.0-3.2 (2H, m), of 2.0-2.2 (1H, m), of 1.5-1.9 (4H, m).

Example 76: Fumarate 2-[[1-[2-(3-chlorophenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 406 Table 1)

a) 2-[[1-[2-(3-chlorophenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 3’-chloroacetophenone specified in the title compound is obtained by methods similar to the methods of Example 72A and Example 1E, in the form of an orange oil (yield: 79%).

1H-NMR (CDCl3): 7,98-8,00 (1H, m), of 7.90 (1H, d, J=8,1), a 7.85 (1H, d, J=7,5), and 7.3 and 7.6 (5H, m)to 4.41 (2H, s), 3,74 (2H, s), 3,52 (2H, d, J=7,4), 2,94-to 3.02 (2H, m), 2,08-of 2.20 (2H, m), 1,6-1,9 (3H, m), 1,3-1,5 (2H, m).

b) Fumarate, 2-[[1-[2-(3-chlorophenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 64%), using the compound obtained in Example 76A, by methods similar to the methods of Example 36C.

Melting point: 187-193° C.

1H-NMR (DMSO-d6): 8,00 (1H, d, J=1,5), of 7.97 (1H, d, J=8,4), to 7.64-7,74 (2H, m), 7,4-7,6 (4H, m), is 6.61 (2H, s, fumaric acid), 4,48 (2H, s), 3,88 (2H, s), 3,40 (2H, d, J=7,2), 2,86 of 2.92 (2H, m), 2,10-of 2.21 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 77: Fumarate 2-[[1-[2-(2-tolyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 386 Table 1)

a) 2-[[1-[2-(2-tolyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 2’-methylacetophenone specified in the header of the connection receiving means, analogion the mi way of Example 72A and Example 1E, as an orange oil (yield: 78%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,5), 7,33-7,66 (5H, m), 7,20-7,27 (2H, m)to 4.41 (2H, in), 3.75 (2H, s), 3,52 (2H, d, J=7,2), 2,99-of 3.07 (2H, m), 2,48 (3H, s), to 2.1-2.3 (2H, m), 1,8-2,0 (1H, m), 1,6-1,8 (2H, m), 1,4-1,6 (2H, m).

b) Fumarate, 2-[[1-[2-(2-tolyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 56%), using the compound obtained in Example 77A, by methods similar to the methods of Example 36C.

Melting point: 186-194° C.

1H-NMR (DMSO-d6): of 7.75 (1H, d, J=7,2), 7,66 (1H, d, J=7,5), 7,55-of 7.60 (2H, m), 7,39-7,51 (2H, m), 7,30 (2H, t, J=7,1), is 6.61 (2H, s, fumaric acid), 4,47 (2H, s), with 3.79 (2H, s), 3,39 (2H, d, J=7,2), 2,86-of 2.93 (2H, m), of 2.38 (3H with), 2,12-of 2.23 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 78: Fumarate 2-[[1-[2-(3-tolyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 391 Table 1)

a) 2-[[1-[2-(3-tolyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 3’-methylacetophenone specified in the title compound is obtained by methods similar to the methods of Example 72A and Example 1E, in the form of a yellow oil (yield: 58%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,5), to 7.77-of 7.82 (2H, m), 7,26-7,56 (5H, m)to 4.41 (2H, s), 3,82 (2H, s), 3,52 (2H, d, J=7,2), 2,99-of 3.06 (2H, m), is 2.40 (3H, s), 2,18-of 2.30 (2H, m), 1,8-2,0 (1H, m), 1,6-1,8 (2H, m), 1,4-1,6 (2H, m).

b) Fumarate, 2-[[1-[2-(3-tolyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header of the connection get in the ideal colorless solid (yield: 55%), using the compound obtained in Example 78A, by methods similar to the methods of Example 36C.

Melting point: 185-193° C.

1H-NMR (DMSO-d6): to 7.77-of 7.82 (2H, m), to 7.67 (1H, d, J=7,5), 7,55-of 7.60 (2H, m), 7,35-7,52 (3H, m), is 6.61 (2H, s, fumaric acid), 4,48 (2H, s), 3,88 (2H, s)to 3.41 (2H, d, J=7,3), of 2.8-3.0 (2H, m), is 2.37 (3H, s), of 2.0-2.2 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 79: Fumarate 2-[[1-[2-(3-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 381 Table 1)

a) 2-[[1-[2-(3-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 2-bromo-1-(3-methoxyphenyl)Ethan-1-he is listed in the title compound is obtained by methods similar to the methods of Example 1E, in the form of a yellow oil (yield: 90%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,2), 7,40-the 7.65 (5H, m), 7,35 (1H, t, J=8,0), 7,08-7,19 (1H, m)to 4.41 (2H, s), 3,85 (3H, s), 3,80 (2H, s), 3,52 (2H, d, J=7,2), 2,97-of 3.06 (2H, m), 2,15-to 2.29 (2H, m), 1,6-1,9 (3H, m)that is 1.4-1.6 (2H, m).

b) Fumarate, 2-[[1-[2-(3-methoxyphenyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 71%), using the compound obtained in Example 79A, by methods similar to the methods of Example 36C.

Melting point: 178-188° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-to 7.61 (3H, m), 7,40-7,52 (3H, m), 7,21 (1H, DD, J=2,3, 8,1), is 6.61 (2H, s, fumaric acid), 4,48 (2H, s), a 3.87 (2H, s), 3,81 (3H, s)to 3.41 (2H, d, J=7,2), of 2.8-3.0 (2H, m), of 2.0-2.2 (2H,, m)of 1.6-1.8 (1H, m), 5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 80: Fumarate 5-methoxy-2-[[1-(2-phenyl-2-oxoethyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 42 in Table 1)

a) 5-methoxy-2-[[1-(2-phenyl-2-oxoethyl)piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 9c, and pencilvania specified in the title compound is obtained by methods similar to the methods of Example 1E, in the form of a pale yellow oil (yield: 55%).

1H-NMR (CDCl3): 8,01 (2H, d, J=7,2), of 7.75 (1H, DD, J=2,6, 8,7), 7,53-7,61 (1H, m), 7,45 (2H, t, J=7,5), of 6.96-7,00 (1H, m), 6,92 (1H, s), 4,36 (2H, s), 3,88 (3H, s), 3,82 (2H, s), 3,48 (2H, d, J=7,2), 2,97 was 3.05 (2H, m), 2,15-of 2.27 (2H, m), 1,6-1,9 (3H, m), 1,4-1,6 (2H, m).

b) Fumarate 5-methoxy-2-[[1-(2-phenyl-2-oxoethyl)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (yield: 74%)using the compound obtained in Example 80A, by methods similar to the methods of Example 36C.

Melting point: 186-193° C.

1H-NMR (DMSO-d6): to 7.99 (2H, d, J=7,5), 7,66 (1H, t, J=7,5), 7,49 to 7.62 (3H, m), 7,13 (1H, d, J=1,5), 7,02 (1H, DD, J=2,1, 8,4), is 6.61 (2H, s, fumaric acid)to 4.41 (2H, s)to 3.89 (2H, s), 3,83 (3H, s)to 3.36 (2H, d, J=7,2), 2,88-2,95 (2H, m), 2,12-of 2.23 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 81: Hydrochloride 2-[[1-[2-(2-furyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 416 Table 1)

a) 2-Bromo-1-(2-furyl)ethane-1-he

Specified in the title compound obtained as a colorless poluting the substance (119 mg, yield: 14%), using 2-acetylfuran (500 mg, of 4.54 mmol), by methods similar to the methods of Example 72A.

1H-NMR (CDCl3): the 7.65 (1H, s), 7,35 (1H, d, J=3,9 Hz)to 4.33 (2H, s).

b) 2-[[1-[2-(2-furyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example a (119 mg, 0,63 mmol)and the compound obtained in Example 1d (160 mg, of 0.60 mmol)specified in the title compound obtained as crude product by methods similar to the methods of Example 1E (131 mg). The crude product is used in subsequent reactions without purification.

(C) the Hydrochloride of 2-[[1-[2-(2-furyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid using the compound obtained in Example 81b (131 mg), by methods similar to the methods of Example 1f (40 mg, yield: 18%, stage 2).

206-216° C (decomp).

1H-NMR (DMSO-d6): 9,98 (1H, sh. C), 8,17 (1H, s), 7,74-7,58 (4H, m), 7,53-7,47 (1H, m), 6,85 (1H, d, J=3.5 Hz), 4,87-4,78 (2H, m)to 4.52 (2H, s), 3,60-3,44 (4H, m), 3,05 are 2.98 (2H, m), a 2.01 (1H, sh. s)and 1.83 (2H, sh. d, J=a 13.9 Hz), 1,64 (2H, sh. DD, J=11,1, 11,1 Hz).

Example 82: Hydrochloride 2-[[1-[2-(2-thienyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 421 Table 1)

a) 2-Bromo-1-(2-thienyl)ethane-1-he 2-bromo-1-(5-bromo-2-thienyl)ethane-1-he

Using 2-acetylthiophene (500 mg, of 3.96 mmol), carry out a reaction similar to the reaction of Example 72A. The product cleans the column chromatography on silica gel, getting 2-bromo-1-(2-thienyl)ethane-1-it is in the form of a pale yellow oil (618 mg, yield: 76%) and 2-bromo-1-(5-bromo-2-thienyl)ethane-1-it is in the form of a pale yellow oil (171 mg, yield: 15%).

2-Bromo-1-(2-thienyl)ethane-1-he

1H-NMR (CDCl3): of 7.82 (1H, d, J=3.6 Hz), 7,73 (1H, d, J=4.0 Hz), 7,18 (1H, DD, J=5,2, 3.8 Hz), 4,37 (2H, s).

2-Bromo-1-(5-bromo-2-thienyl)ethane-1-he

1H-NMR (CDCl3): of 7.55 (1H, g, J=3.8 Hz), 7,14 (1H, d, J=3,8gts), 4,28 (2H, s).

b) 2-[[1-[2-(2-thienyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 2-bromo-1-(2-thienyl)ethane-1-he obtained in Example a (300 mg, of 1.46 mmol)and the compound obtained in Example 1d (389 mg, of 1.46 mmol), carry out a reaction similar to the reaction of Example 1e, getting mentioned in the title compound as a colourless solid (441 mg, yield: 85%).

1H-NMR (CDCl3): 7,98 (1H, DD, J=3,8, 1.1 Hz), the 7.85 (1H, d, J=7.5 Hz), 7,62-to 7.61 (1H, m), 7,56-the 7.43 (3H, m), 7,13-7,10 (1H, m)to 4.41 (2H, s)to 3.58 (2H, s), 3,53 (2H, d, J=7,3 Hz), 2,96 (2H, sh. d, J=11.5 Hz), 2,17 (2H, DDD, J=2,4, and 11.5, and 11.5 Hz), 1,84-of 1.78 (1H, m),1.70 to to 1.67 (2H, m)of 1.53 (2H, DDD, J=3,6, to 12.0, 12.0 Hz).

(C) the Hydrochloride of 2-[[1-[2-(2-thienyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 82b (435 mg, of 1.23 mmol), carry out a reaction similar to the reaction of Example 1f, getting mentioned in the title compound as a colourless solid (418 mg, yield: 87%).

Melting point: 182-186° C.

1H-NMR (DMSO-d6): 10,1 (1H, sh. C), 18 (1H, d, J=1,8 Hz), with 8.05 (1H, d, J=3.3 Hz), 7,69 (1H, d, J=7,2 Hz), 7,62-7,58 (2H, m), 7,53-7,47 (1H, m), of 7.36-7,34 (1H, m), 5,04-of 4.95 (2H, m), a 4.53 (2H, s), 3,55 (2H, sh. d, J=11.7 Hz), of 3.46 (2H, sh. d, J=6.9 Hz), 3,05 (2H, sh. C)2,03 (1H, sh. C)1,86-to 1.63 (4H, m).

Example 83: Hydrochloride 2-[[1-[2-(5-bromo-2-thienyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 426 Table 1)

a) 2-[[1-[2-(5-bromo-2-thienyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 2-bromo-1-(5-bromo-2-thienyl)ethane-1-he obtained in Example a (171 mg, 0,602 mmol), carry out a reaction similar to the reaction of Example 1E, receiving the crude product indicated in the title compounds as a pale brown solid (210 mg). The crude product is used in subsequent reactions without purification.

(b) Hydrochloride of 2-[[1-[2-(5-bromo-2-thienyl)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the crude product obtained in Example 83A (171 mg), carry out a reaction similar to the reaction of Example 1f, getting mentioned in the title compound as a pale brown solid (99 mg, yield: 38%, stage 2).

Melting point: 195-208° C (decomp.).

1H-NMR (DMSO-d6): 10,1 (1H, sh. C)8,03-7,89 (1H, m), 7,70-7,47 (5H, m), 5,01-of 4.90 (2H, m)to 4.52 (2H, s), to 3.58-3,44 (4H, m), 3.04 from-of 2.97 (2H, m), 2,03 is 1.60 (5H, m).

Example 84: Fumarate 2-[[1-(2-cyclohexyl-2-oxoethyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 446 Table 1)

a) 2-Chloro-1-(1-cyclohexyl)ethane-1-he

COI is lsua methylcyclohexanecarboxylic, specified in the header connection receive by way of getting haloketones described in international publication no WO/23756 (yield: 79%).

1H-NMR (CDCl3): of 4.16 (2H, s), 2,58-2,69 (1H, m), 1,6-1,9 (4H, m), 1,1-1,5 (6H, m).

b) 2-[[1-(2-cyclohexyl-2-oxoethyl)piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example a get mentioned in the title compound as a colorless oil by methods similar to the methods of Example 1E (yield: 51%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,2), 7,41-7,56 (3H, m), and 4.40 (2H, s), 3,50 (2H, d, J=7,2), 3,20 (2H, s), 2,81-is 2.88 (2H, m), 2,41-of 2.50 (1H, m), 1,98-of 2.09 (2H, m), 1,6-1,9 (7H, m), 1,1-1,5 (8H, m).

C) Fumarate, 2-[[1-(2-cyclohexyl-2-oxoethyl)piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 84b, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 36C (yield: 89%).

Melting point: 186-196° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-of 7.60 (2H, m), 7,45-7,52 (1H, m), is 6.61 (2H, s, fumaric acid), 4,48 (2H, s)to 3.41 (2H, d, J=7,4), 3,29 (2H, s), 2,75-of 2.81 (2H, m), 2,4-2,6 (1H, m), of 2.0-2.2 (2H, m), 1,53 to 1.76 (8H, m), 1,0-1,3 (7H, m).

Example 85: Fumarate 2-[[1-(2-cyclohexyl-2-hydroxyethyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 451 Table 1)

a) 2-[[1-(2-cyclohexyl-2-hydroxyethyl)piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 84b, produces the t specified in the title compound as colourless solids ways, similar to the methods of Example 16 (yield: 77%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,42-EUR 7.57 (3H, m), and 4.40 (2H, s), 3,48-of 3.53 (2H, m), 3,35 is-3.45 (1H, m), 3,0-3,1 (1H, m), 2,7-2,8 (1H, m), 2,2-2,4 (3H, m), 1.5 to 2.0 (9H, m), 0,9-1,5 (8H, m).

b) Fumarate, 2-[[1-(2-cyclohexyl-2-hydroxyethyl)piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 85a, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 36C (yield: 85%).

Melting point: 180-183° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,2), 7,55 to 7.62 (2H, m), 7,44-7,52 (1H, m), 6,53 (2H, s, fumaric acid), of 4.49 (2H, s), 3.45 points-of 3.60 (1H, m), 3,42 (2H, d, J=7,2), to 3.0-3.2 (2H, m), 2,5-2,7 (2H, m), 2,2-2,4 (2H, m), 0,90-2,0 (17H, m).

Example 86: Hydrochloride 2-[[1-[[5-(4-chlorophenyl)]furfuryl]-piperidine-4-yl]methyl]isoindoline-1-she (Compound 471 Table 1)

a) 2-[[1-[[5-(4-chlorophenyl)]furfuryl]piperidine-4-yl]methyl]isoindoline-1-he

Into a solution of the compound obtained in Example 1d (334 mg, 1,45 mmol)and 5-(4-chlorophenyl)furfural (300 mg, 1,45 mmol) in methanol (5 ml) is added acetic acid to bring the pH to 6. The mixture was added NaCNBH3(0.25 g, 3.58 mmol) and stirred at room temperature for 4 hours. Then the methanol is evaporated and the residue diluted with ethyl acetate. The mixture is washed twice with a saturated aqueous solution of NaHCO3and then with saturated salt solution and dried over Na2SO4. After UDA is placed desiccant by filtration, the filtrate concentrated and the residue purified by chromatography on silica gel (dichloromethane/methanol), getting listed in the title compound (yield: 55%).

1H-NMR (CDCl3): δ to 7.84 (d, J=7.2 Hz, 1H), EUR 7.57 (d, J=8.7 Hz, 2H), 7,43-7,53 (m, 3H), 7,32 (d, J=8.7 Hz, 2H), 6,56 (d, J=3.5 Hz, 1H), of 6.26 (d, J=3.5 Hz, 1H), 4,39 (s, 2H), 3,61 (s, 2H), 3,50 (d, J=6,9 Hz, 2H), 2,96 (sh. d, J=11,4 Hz, 2H), 2,07 (dt, J=11,4, 2,1 Hz, 2H), 1,78 (m, 1H), 1,70 (sh. d, J=12 Hz, 2H), 1,43 (DK, J=11,4, 3,3 Hz, 2H).

(b) Hydrochloride of 2-[[1-[[5-(4-chlorophenyl)]furfuryl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 86a, get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 82%).

Melting point: 218-226° C.

1H-NMR (DMSO-d6): δ 10,6 (sh. s, 1H), 7,78 (d, J=8,4 Hz, 2H), to 7.67 (d, J=7.5 Hz, 1H), 7,58 (m, 2H), 7,46-rate of 7.54 (m, 3H), was 7.08 (d, J=3 Hz, 1H), 6,83 (d, J=3 Hz, 1H), to 4.41 figure-4.49 (m, 4H), 2,88-of 3.43 (m, 6H), to 1.98 (m, 1H), 1,80 (sh. d, J=13 Hz, 2H), and 1.56 (sh. K, J=12 Hz, 2H).

Example 87: Fumarate 2-[[1-[[2-(1-phenyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 476, Table 1)

a) 2-Formyl-1-phenylpyrrole, 3-formyl-1-phenylpyrrole

561 mg (of 7.68 mmol) in DMF (DMF) cooled to 0° and added dropwise POCl3(1.18 g, to 7.68 mmol). The mixture is stirred at room temperature for 15 minutes, added dropwise a solution of 1-phenylpyrrole (1,00 g, 6,98 mmol)/DMF (DMF) (1.6 ml). After stirring at 50° C for 1.5 hours, the mixture is cooled to 0° and add saturated aqueous solution of Na2CO3to bring the pH to 8. The mixture is diluted with which the ethyl acetate and the organic layer separated. The layer is washed three times with water and dried over Na2SO4. The desiccant is removed by filtration and then the filtrate is concentrated. The residue was separated and purified by chromatography on silica gel (dichloromethane/hexane)to give specified in the header of the connection.

2-Formyl-1-phenylpyrrole (yield: 86%).

1H-NMR (CDCl3): δ to 9.57 (s, 1H), 7,43-7,47 (m, 5H), 7,17 (DD, J=3,9, 1.5 Hz, 1H), was 7.08 (t, J=1.8 Hz, 1H), 6,41 (DD, J=3,9, and 2.6 Hz, 1H).

3-Formyl-1-phenylpyrrole (yield: 14%)

1H-NMR (CDCl3): δ 9,86 (s, 1H), to 7.67 (t, J=1.8 Hz, 1H), 7,37-7,49 (m, 5H), to 7.09 (t, J=2.4 Hz, 1H), for 6.81 (DD, J=3,0, 1.5 Hz, 1H).

b) 2-[[1-[[2-(1-phenyl)pyrrolyl]methyl]piperidine-4-yl]methyl]-isoindole-1-he

Using the compound obtained in Example 87a, ie, 2-formyl-1-phenylpyrrole get mentioned in the title compound by methods similar to the methods of Example 86a (yield: 64%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.5 Hz, 1H), 7,31-7,56 (m, 8H), at 6.84 (t, J=2.4 Hz, 1H), from 6.22 (t, J=3.0 Hz, 1H), 6,17 (DD, J=3.3, which is 1.8 Hz, 1H), to 4.38 (s, 2H), 3,48 (d, J=7.2 Hz, 2H), and 3.31 (s, 2H), 2,86 (d, J=11,4 Hz, 2H), 1,86 (dt, J=11,4, 1.8 Hz, 2H), 1,74 (m, 1H), 1,61 (sh. d, J=12.9 Hz, 2H), 1,30 (DK, J=12, 3.6 Hz, 2H).

C) Fumarate, 2-[[1-[[2-(1-phenyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 87b, get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 75%).

Melting point: 281-284° C.

1H-NMR (DMSO-d6): δ 7,66 (who, J=7.5 Hz, 1H), 7,45 to 7.62 (m, 7H), was 7.36 (t, J=7 Hz, 1H), of 6.96 (t, J=2 Hz, 1H), 6,62 (s, 2H), 6,16 (sh. s, 2H), 4,46 (s, 2H), 3,37-3,39 (m, 4H), of 2.81 (d, J=11 Hz, 2H), 1.93 and (m, 2H), 1,71 (m, 1H), 1.55V (sh. d, J=12 Hz, 2H), 1,15 (sh. K, J=11 Hz, 2H).

Example 88: Fumarate 2-[[1-[[3-(1-phenyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 481 Table 1)

a) 2-[[1-[[3-(1-phenyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 87a, ie, 3-formyl-1-phenylpyrrole get mentioned in the title compound by methods similar to the methods of Example 86a (yield: 85%).

1H-NMR (CDCl3): δ to 7.84 (d, J=7.2 Hz, 1H), 7,35-rate of 7.54 (m, 7H), 7,21 (m, 1H), 7,01 (m, 2H), 6,27 (m, 1H), and 4.40 (s, 2H), 3,50-to 3.52 (m, 4H), to 3.02 (sh. d, J=11.7 Hz, 2H), 2,03 (dt, J=11,7, 2,1 Hz, 2H)and 1.83 (m, 1H), 1,71 (sh. d, J=12 Hz, 2H), 1,45 (DK, J=11,7, 3.6 Hz, 2H).

b) Fumarate, 2-[[1-[[3-(1-phenyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 88b, get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 81%).

Melting point: 222-227° C.

1H-NMR (DMSO-d6): δ to 7.67 (d, J=7,4 Hz, 1H), 7,42-7,58 (m, 7H), 7,35 (s, 2H), 7,24 (t, J=7.2 Hz, 1H), 6,55 (s, 2H), of 6.26 (s, 1H), 4,48 (s, 2H), 3,66 (s, 2H), 3,42 (d, J=7.2 Hz, 2H), is 3.08 (d, J=11.7 Hz, 2H), 2,28 (W. t, J=11 Hz, 2H), equal to 1.82 (m, 1H), 1,65 (sh. d, J=12 Hz, 2H), 1,33 (sh. K, J=11 Hz, 2H).

Example 89: Hydrochloride 2-[[1-[[2-(1-benzyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 486 Table 1)

a) 2-Formyl-1-benseler the ol

To a suspension of 60% NaH (252 mg, of 6.31 mmol) in DMF (DMF) (8 ml) under stirring is added dropwise (solution) pyrrol-2-carboxyaldehyde (0,500 g of 5.26 mmol)/DMF 4 ml in a nitrogen atmosphere at 0° C. After stirring for 10 minutes the mixture was added dropwise benzylbromide (0.75 ml, of 6.31 mmol). After stirring for 30 minutes the reaction mixture was diluted with ethyl acetate and washed four times with water and saturated salt solution and dried over Na2SO4. The desiccant is removed by filtration and then the filtrate is concentrated and the residue purified by chromatography on silica gel (dichloromethane/hexane), getting mentioned in the title compound (yield: 99%).

1H-NMR (CDCl3): δ of 9.56 (s, 1H), 7.23 percent-7,34 (m, 3H), 7,15 (d, J=7.2 Hz, 2H), 6,98 (m, 2H), 6,27 (m, 1H), to 5.57 (s, 2H).

b) 2-[[1-[[2-(1-benzyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 89a, get mentioned in the title compound by methods similar to the methods of Example 86a (yield: 52%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.2 Hz, 1H), 7,42-of 7.55 (m, 3H), 7,21-7,31 (m, 3H), 7,03 (d, J=7.2 Hz, 2H), 6,66 (m, 1H), between 6.08 (m, 1H), 6,00 (DD, J=3,0, 1.5 Hz, 1H), 5,22 (s, 2H), 4,37 (s, 2H), 3.46 in (d, J=7.5 Hz, 2H,), 3,26 (s, 2H), and 2.79 (d, J=11,Hz, 2H), equal to 1.82 (dt, J=11,7, 1.8 Hz, 2H), 1,72 (m, 1H), 1,58 (sh. d, J=12 Hz, 2H), 1,23 (DK, J=12,0, 3.6 Hz, 2H).

(C) the Hydrochloride of 2-[[1-[[2-(1-benzyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained is passed in Example 89b, get listed in the title compound by methods similar to the methods of Example 1f (yield: 84%).

Melting point: 171° C.

1H-NMR (DMSO-d6): δ 10,33 (sh. s, 1H), 7,68 (d, J=7.5 Hz, 1H), 7,60 (m, 2H), 7,49 (m, 1H), 7,26-7,35 (m, 3H), 7,02-was 7.08 (m, 2H), 6,95 (s, 1H), 6.42 per (m, 1H), 6,14 (m, 1H), 5,35-of 5.40 (m, 2H), 4,50 (s, 2H), 4,14-the 4.29 (m, 2H), 2,79-to 3.64 (m, 4H), of 1.94 (m, 1H), 1,76 (m, 2H), 1,59 (m, 2H).

Example 90: Hydrochloride 2-[[1-[[2-(1-butyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 491 Table 1)

a) 2-Formyl-1-butalbiral

Using n-butylated get mentioned in the title compound by methods similar to the methods of Example 89a (Yield: 92%).

1H-NMR (CDCl3): δ at 9.53 (s, 1H), 6,91-6,94 (m, 2H), 6,21 (DD, J=3,9, 2.4 Hz, 1H), or 4.31 (t, J=7.2 Hz, 2H), 1,74 (m, 2H), 1,29 (m, 2H), of 0.93 (t, J=7.2 Hz, 3H).

b) 2-[[1-[[2-(1-Butyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 90A, get mentioned in the title compound by methods similar to the methods of Example 86a (yield: 29%).

1H-NMR (CDCl3): δ to 7.84 (d, J=7.5 Hz, 1H), 7,42-of 7.55 (m, 3H), 6,62 (t, J=1.8 Hz, 1H), 6,02 (t, J=3.3 Hz, 1H), to 5.93 (DD, J=3.3, which is 1.8 Hz, 1H), 4,39 (s, 2H), 3,92 (t, J=7.5 Hz, 2H), 3,49 (d, J=7.5 Hz, 2H), 3,39 (s, 2H), 2,85 (sh. d, J=11.7 Hz, 2H), of 1.87 (dt, J=11,7, 2,1 Hz, 2H), 1,63 is 1.75 (m, 5H), 1,28-to 1.38 (m, 4H), were 0.94 (t, J=7.5 Hz, 3H).

(C) the Hydrochloride of 2-[[1-[[2-(1-butyl)pyrrolyl]methyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 90b, recip which are specified in the header of the connection means, similar to the methods of Example 1f (yield: 78%).

Melting point: 179° C.

1H-NMR (DMSO-d6): δ 10,04 (sh. s, 1H), 7,68 (d, J=7.5 Hz, 1H), to 7.59-to 7.61 (m, 2H), 7,49 (m, 1H), 6.90 to (s, 1H), 6.35mm (m, 1H), 6,07 (m, 1H), 4,50 (s, 2H), 4,23-4,37 (m, 2H), 3.96 points-Android 4.04 (m, 2H), 2,84-3,66 (m, 6H), of 1.95 (m, 1H), 1,78 (sh. d, J=12 Hz, 2H), 1,54-of 1.62 (m, 4H), to 1.21 (m, 2H), 0,87 (t, J=7.5 Hz, 3H).

Example 91: Hydrochloride 2-[[1-[(2-pyrrolyl)methyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 496 Table 1)

Specified in the title compound is obtained by methods similar to the methods of Example 86a and Example 1f (yield: 60%).

Melting point: 186° C.

1H-NMR (DMSO-d6): δ 11,09 (sh. s, 1H), 9,99 (sh. s, 1H), 7,65 (d, J=7.5 Hz, 1H), to 7.59 (m, 2H), of 7.48 (m, 1H), 6.89 in (s, 1H), 6,23 (m, 1H), between 6.08 (s, 1H), 4,49 (s, 2H), 4,18-to 4.33 (m, 2H), 2,73-of 3.60 (m, 6H), was 1.94 (m, 1H), 1,76 (sh. d, J=12 Hz, 2H), 1,48 (sh. K, J=12 Hz, 2H).

Example 92: the Dihydrochloride of 2-[[1-[2-(2-phenyl-1H-imidazol-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 591 Table 1)

a) t-Butyldimethylsilyl 2-(2-phenyl-1H-imidazol-1-yl)ethyl ester

2-Bromoethanol (3,44 g, 27,53 mmol), t-butyldimethylchlorosilane (to 4.23 g, 28,07 mmol) and imidazole (of 3.97 g, 58,31 mmol) dissolved in dimethylformamide (20 ml) and the solution stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and then with saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and then Phil is spending concentrated under reduced pressure, getting t-butyldimethylsilyl 2-bromatology ether (6,05 g) as a crude product. The crude product (1,83 g), 2-phenylimidazol (1,11 g of 7.70 mmol) and potassium carbonate (1.50 g, 10.9 mmol) is added to dimethylformamide (10 ml) and the mixture is heated at 80° C for 10 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with water and then with saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The resulting oil is purified column chromatography on silica gel (ethyl acetate-hexane), getting mentioned in the title compound as a pale yellow oil (1,16 g, yield: 50%).

1H-NMR (CDCl3): 7,62-to 7.68 (2H, m), 7,43-7,49 (3H, m), 7,18 (1H, d, J=1,2), 7,13 (1H, d, J=1,2), 4,14 (2H, t, J=5,4), a 3.87 (2H, t, J=5,4), FROM 0.84 (9H, s)-0,04 (6H, s).

b) 2-(2-Phenyl-1H-imidazol-1-yl)Ethan-1-ol

The compound obtained in Example 92A (1,11 g, to 3.67 mmol), dissolved in ethanol (8 ml) and the solution is stirred under ice cooling. To the solution add 18% aqueous solution (10 ml) of hydrochloric acid and stirred for 2 hours. The reaction mixture is washed with hexane and the aqueous layer was added sodium hydroxide to bring the pH above 11. The mixture is extracted with dichloromethane and dried over sodium sulfate. Insoluble solids are removed by filtration and fil the Rath concentrated under reduced pressure. The obtained solid is suspended and washed in ethyl ether, getting mentioned in the title compound as a colourless solid (636 mg, yield: 92%).

1H-NMR (CDCl3): 7,55-to 7.61 (2H, m), 7,38-7,42 (3H, m), 7,07 (1H, s), 7,05 (1H, s), 4,11 (2H, t, J=5,4), a 3.87 (2H, t, J=5,4), 2,85 (1H, sh. s, OH).

c) 2-[[1-[2-(2-phenyl-1H-imidazol-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 92b, get 2-(2-phenyl-1H-imidazol-1-yl)Ethan-1-ol methanesulfonate in the form of the crude product by methods similar to the methods of Example 26a. Using the resulting product, get mentioned in the title compound as a yellow oil by methods similar to the methods of Example 26b (yield: 50%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,2), 7,37 TO 7.62 (8H, m), 7,11 (1H, d, J=0,9), 7,10 (1H, d, J=0,9), to 4.38 (2H, s)4,08 (2H, t, J=6,8), 3,47 (2H, d, J=7,2), 2,75-2,82 (2H, m)of 2.64 (2H, t, J=6,8), 1,9-2,0 (2H, m,), of 1.5-1.9 (3H, m), 1,2-1,4 (2H, m).

d) the dihydrochloride of 2-[[1-[2-(2-phenyl-1H-imidazol-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid using the compound obtained in Example C, by methods similar to the methods of Example 1f (yield: 90%).

Melting point: 155-168° C.

1H-NMR (DMSO-d6): 13,0 (1H, sh. with, HCl), and 11.5 (1H, sh. with, HCl), 8,04-8,10 (1H, m), 7,81-7,89 (3H, m), EUR 7.57-7,76 (6H, m), 7,45-rate of 7.54 (1H, m), 4,60-4,69 (2H, m), of 4.49 (2H, s), of 3.0 to 3.7 (6H, m), 2,7-2,9 (2H, m), 1,4-1,8 (5H, m)

Example 93: Hydrochloride 2-[[1-[2-[2-(1-benzyl)pyrrolyl]-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 431 Table 1)

Using 2-acetylpyrrole, synthesize 1-benzyl-2-acetylpyrrole by methods similar to the methods of Example 89a, and the product is then processed by methods similar to the methods of Example 69, no cleaning, getting mentioned in the title compound (yield: 8%).

Melting point: 196-200° C.

1H-NMR (DMSO-d6): δ 9,71 (sh. s, 1H), 7,68 (d, J=7.8 Hz, 1H), to 7.61 (m, 2H), EUR 7.57 (m, 1H), 7,49 (m, 1H), 7.23 percent-7,33 (m, 4H), was 7.08 (m, 2H), 6.35mm (m, 1H), 5,59 (s, 2H), 4,69-4,78 (m, 2H), 4,51 (s, 2H), 2,89 of 3.56 (m, 6H), of 1.97 (m, 1H), to 1.79 (m, 2H), 1,58 (m, 2H).

Example 94: Hydrochloride 2-[[1-[2-[2-(1-butyl)pyrrolyl]-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 436 Table 1)

Using 2-acetylpyrrole, synthesize 1-butyl-2-acetylpyrrole by methods similar to the methods of Example 90A, and the product is then processed by methods similar to the methods of Example 69, no cleaning, getting mentioned in the title compound (yield: 67%).

Melting point: 200 to 207° C.

1H-NMR (DMSO-d6): δ 9,78 (sh. s, 1H), 7,69 (d, J=7.5 Hz, 1H), to 7.61 (m, 2H), 7,51 (m, 1H), 7,40 (m, 1H), 7,20 (m, 1H), and 6.25 (m, 1H), 4,70-4,78 (m, 2H), 4.53-in (s, 2H), 4,30 (t, J=7.2 Hz, 2H), 2,52-3,51 (m, 6H), was 1.94 (m, 1H), 1,82 (sh. d, J=12 Hz, 2H), 1,25 (m, 2H), from 0.88 (t,J=7.5 Hz, 3H).

Example 95: Hydrochloride 2-[[1-[2-[2-(1-phenyl)pyrrolyl]-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it (Connected to the e 441 Table 1)

a) 2-[[1-[2-[2-(1-phenyl)pyrrolyl]-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 1-phenyl-2-chloroacetonitrile obtained according to the method described in the literature (P.D.Croce, C.L.Rosa, A.Retieni, Synthesis, 1989, 783), get mentioned in the title compound by methods similar to the methods of Example 1E (yield: 52%).

1H-NMR (CDCl3): δ to 7.84 (d, J=7.2 Hz, 1H), 7,34-EUR 7.57 (m, 6H), 7,21-7,25 (m, 3H), to 6.95 (m, 1H), 6,29 (m, 1H), to 4.38 (s, 2H), 3,61 (s, 2H), 3,48 (d, J=7.2 Hz, 2H), 2,94 (sh. d, J=Hz, 2H), 2,12 (dt, J=11,4, 2.4 Hz, 2H), 1,80 (m, 1H), 1,65 (sh. d, J=12 Hz, 2H), 1,45 (DK, J=12, 3 Hz, 2H).

(b) Hydrochloride of 2-[[1-[2-[2-(1-phenyl)pyrrolyl]-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the header of the get connection using the connection obtained in Example 95A, by methods similar to the methods of Example 1f (yield: 89%).

Melting point: 193-197° C.

1H-NMR (DMSO-d6): δ 9,75 (sh. s, 1H), 7,65 (d, J=7.5 Hz, 1H), 7,33-to 7.50 (m, 8H), 6,46 (m, 1H), 4,76-a 4.86 (m, 2H), 4,51 (s, 2H), 2,98-3,61 (m, 6H), 1,99 (m, 1H), 1,78 (m, 2H), and 1.56 (m, 2H).

Example 96: Fumarate 2-[[1-[2-(2-triptoreline)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 521 Table 1)

Using 2-triftormetilfullerenov get mentioned in the title compound as colorless solid by methods similar to the methods of Examples 26a, 26b and 36C (yield: 29%).

Melting point: 204-220° C.

1H-NMR (DMSO-d6): to 7.68 (1H, d, J=7,8), EUR 7.57-7,66 (4H, m), 7,38-7,53(3H, m), 6,59 (2H, s), of 4.49 (2H, s), 3,42 (2H, d, J=7,2), 3,00 was 3.05 (2H, m), 2,90-to 2.99 (2H, m), 2,62-2,69 (2H, m), 2,14 was 2.25 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1,1-1,3 (2H, m).

Example 97: Fumarate 2-[[1-[2-(1-naphthyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 526 Table 1)

Using 1-naphthalenethiol get mentioned in the title compound as colorless solid by methods similar to the methods of Examples 26a, 26b and 36C (yield: 60%).

Melting point: 222-229° C.

1H-NMR (DMSO-d6): 8,08 (1H, d, J=7,9), to $ 7.91-of 7.95 (1H, m), 7,78-7,80 (1H, m), of 7.69 (1H, d, J=7,4), 7,41 to 7.62 (7H, m), 6,59 (2H, s, fumaric acid), 4,51 (2H, s), of 3.45 (2H, d, J=7,3), 3,26-to 3.34 (2H, m), 3,15 to be 3.29 (2H, m), 2,80-2,87 (2H, m), 2,27-2,39 (2H, m), 1.7 to 1.9 (1H, m), 1,6-1,7 (2H, m), 1,2-1,4 (2H, m).

Example 98: Fumarate 2-[[1-[2-(2-naphthyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 531 Table 1)

a) 2-[[1-[2-(2-naphthyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 2-naphthalenethiol get mentioned in the title compound as colorless solid by methods similar to the methods of Examples 26a and 26b (yield: 77%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,73-7,81 (3H, m), 7,63 (1H, s), 7,21-7,56 (6H, m), 4,42 (2H, s), 3,52 (2H, d, J=7,2), 2,93-of 3.07 (4H, m), 2,62-a 2.71 (2H, m), 1,99 is 2.10 (2H, m), 1,6-1,9 (3H, m), 1,3-1,5 (2H, m).

b) Fumarate, 2-[[1-[2-(2-naphthyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 98A, get mentioned in the title compound as a colourless solid substances is tion methods, similar to the methods of Example 36C (yield: 81%).

Melting point: 223-233° C.

1H-NMR (DMSO-d6): 7,83-7,87 (3H, m), 7,73 (1H, s), to 7.68 (1H, d, J=7,5), 7,56 to 7.62 (2H, m) 7,39-7,49 (4H, m), to 6.58 (2H, s), of 4.49 (2H, s), 3.43 points (2H, d, J=7,2), to 3.0-3.2 (2H, m), 2.8 to 3.0 (2H, m), 2,7-2,8 (2H, m), 2.1 to 2,3 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1,2-1,4 (2H, m).

Example 99: Fumarate 2-[[1-[2-(3-tolyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 536 Table 1)

Using 3-tolyloxy acid, receive 3-methylphenethylamine in the form of the crude product by methods similar to the methods of Example 53b. Using the resulting product, get mentioned in the title compound as colorless solid by methods similar to the methods of Examples 26a, 26b and 36C (yield: 55%).

Melting point: 214-220° C.

1H-NMR (DMSO-d6): to 7.68 (1H, d, J=7,5), 7,55-to 7.61 (2H, m), 7,44-7,52 (1H, m), 7,17 (1H, t, J=7,4), 6,98-7,05 (3H, m), to 6.57 (2H, s, fumaric acid), of 4.49 (2H, s), 3.43 points (2H, d, J=7,2), 3,07 is 3.15 (2H, m), 2,6-2,8 (4H, m), and 2.27 (3H with), to 2.1-2.3 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1,2-1,4 (2H, m).

Example 100: Fumarate 2-[[1-[2-(3-forfinal)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 541 Table 1)

Using 3-florfenicol acid, receive 3-fortuneteller in the form of the crude product by methods similar to the methods of Example 53b. Using the resulting product, get mentioned in the title compound as colourless solids ways, analogues of the different methods of Examples 26a, 26b and 36C (yield: 48%)

Melting point: 208-213° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,2), 7,55-to 7.61 (2H, m), 7,45-7,52 (1H, m), 7,27-to 7.35 (1H, m), 7,00 for 7.12 (3H, m), to 6.58 (2H, s, fumaric acid), of 4.49 (2H, s), 3,42 (2H, d, J=7,2), 3,03-3,10 (2H, m), 2,6-2,9 (4H, m), to 2.1-2.3 (2H,, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1,1-1,3 (2H, m).

Example 101: Fumarate 2-[[1-[2-(4-methoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 546 Table 1)

Using 4-methoxyphenethylamine get mentioned in the title compound as colorless solid by methods similar to the methods of Examples 26a, 26b and 36C (yield: 68%).

Melting point: 220-227° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,56-to 7.61 (2H, m), 7,45-7,51 (1H, m), 7,13 (2H, d, J=7,8), at 6.84 (2H, d, J=7,8), to 6.57 (2H, s, fumaric acid), of 4.49 (2H, s), 3,71 (3H, s), 3,42 (2H, d, J=7,2), 3,03-3,10 (2H, m), 2,6-2,8 (4H, m), 2,14-of 2.26 (2H, m), 1.7 to 1.9 (1H, m), 1,5-1,7 (2H, m), 1,2-1,4 (2H, m).

Example 102: Fumarate 2-[[1-[2-(3-methoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 551 Table 1)

Using 3-methoxyphenethylamine get mentioned in the title compound as colorless solid by methods similar to the methods of Examples 26a, 26b and 36C (yield: 43%).

Melting point: 200-206° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,56-to 7.61 (2H, m), 7,45-7,52 (1H, m), 7,19 (1H, t, J=8,0), 6.73 x-PC 6.82 (3H, m), to 6.57 (2H, s, fumaric acid), of 4.49 (2H, s), of 3.73 (3H, s), 3,42 (2H, d, J=7,2), 3,0-3,1 (2H, m), 2,6-2,8 (4H, m), to 2.1-2.3 (2H, m), 1.7 to 1.9 (1H, m), 1,6-1,7 (2H, m), 1,11,3 (2H, m).

Example 103: Hydrochloride 2-[[1-[2-(2-nitrophenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 556 Table 1)

a) 2-[[1-[2-(2-nitrophenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using 2-nitratenitrogen will receive 2-nitrophenylselenocyanate by methods similar to the methods of Example 26a. Using the resulting product, get mentioned in the title compound by methods similar to the methods of Example 26b (yield: 52%).

1H-NMR (CDCl3): δ of 7.97 (d, J=8,1 Hz, 1H), to 7.84 (d, J=7.5 Hz, 1H), 7,39-to 7.59 (m, 6H), of 4.44 (s, 2H), 3,57 (d, J=7.5 Hz, 2H), 3.33 and-of 3.42 (m, 4H), 3,03 (m, 2H), 2,10 (m, 1H), 1,63-to 1.98 (m, 4H).

(b) Hydrochloride of 2-[[1-[2-(2-nitrophenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 103A, get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 84%).

Melting point: 248-252° C.

1H-NMR (DMSO-d6): δ 11,60 (sh. s, 1H), 8,03 (d, J=7.7 Hz, 1H), 7.68 per to 7.75 (m, 2H), 7,50 to 7.62 (m, 5H), to 4.52 (s, 2H), 2,84-3,59 (m, 10H), 2,28 (m, 1H), 1,87 (m, 2H), 1,62 (m, 2H).

Example 104: Hydrochloride 2-[[1-[2-(2-AMINOPHENYL)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 561 Table 1)

a) 2-[[1-[2-(2-AMINOPHENYL)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

To 10% Pd-C (89 mg)/MeOH (12 ml) is added the compound obtained in Example 103A (0,500 g of 1.32 mmol), and HCO2NH4(208 mg, 3,30 mmol)/N2About (3 ml) and the mixture is boiled with reverse holo is rinicom and then remove Pd filtration and the filtrate concentrated. To the residue water is added and extracted three times with dichloromethane, and the combined organic layer is dried over Na2SO4. The desiccant is removed by filtration and then the filtrate is concentrated, getting mentioned in the title compound (yield: 93%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7,3 Hz, 1H), 7,42-7,53 (m, 3H), 6,97? 7.04 baby mortality (m, 2H), 6,65-6,70 (m, 2H), and 4.40 (s, 2H), 3,51 (d, J=7.2 Hz, 2H), 3,02 (sh. d, J=11,6 Hz, 2H), 2,70 (DD, J=7,1, 6.5 Hz, 2H), 2,56 (DD, J=7,1, 6.5 Hz, 2H), 2,00 (dt, J=11,6, 2.0 Hz, 2H), is 1.81 (m, 1H), 1,71 (sh. d, J=12 Hz, 2H), 1,40 (DK, J=12, 3 Hz, 2H).

(b) Hydrochloride of 2-[[1-[2-(2-AMINOPHENYL)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 93%).

Melting point: 239-243° C.

1H-NMR (DMSO-d6): δ of 7.69 (d, J=7.2 Hz, 1H), to 7.61 (m, 1H), 7,49 (m, 1H), 7,16-to 7.32 (m, 4H), to 4.52 (s, 2H), 2,87 of 3.75 (m, 10H)2,04 (m, 1H), of 1.84 (m, 2H), 1,59 (m, 2H).

Example 105: Hydrochloride 2-[[1-[2-(2-acetamidophenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 566 Table 1)

a) 2-[[1-[2-(2-Acetamidophenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example a (246 mg, 0,704 mmol), dissolved in pyridine (1 ml) and the solution was added acetic anhydride (144 mg, of 1.41 mmol) and heated at 60° C. After one hour the reaction mixture was diluted with saturated salt solution and extracted three times di is loretana and then the combined organic layer is dried over Na 2SO4. The desiccant is removed by filtration and the filtrate is concentrated and then the residue purified by chromatography on silica gel (dichloromethane/methanol), getting mentioned in the title compound (yield: 47%).

1H-NMR (CCDCl3): δ 10,01 (sh. s, 1H), to 7.93 (d, J=7.8 Hz, 1H), a 7.85 (d, J=7.2 Hz, 1H), 7,43-of 7.55 (m, 3H), 7,22 (m, 1H), 6,95-to 7.09 (m, 2H), to 4.41 (s, 2H), 3,54 (d, J=7.2 Hz, 2H), 3,06 (sh. d, J=12 Hz, 2H), 2,81 (m, 2H), 2,66 (m, 2H), of 2.23 (s, 3H), 2,18 (m, 2H), 1.91 a (m, 1H),1,78 (m, 2H), 1,50 (m, 2H).

(b) Hydrochloride of 2-[[1-[2-(2-acetamidophenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 105A, get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 77%).

Melting point: 134° C.

1H-NMR (DMSO-d6): δ 10,36 (sh. s, 1H), at 9.53 (sh. s, 1H), to 7.67 (d, J=7.8 Hz, 1H), to 7.59 (m, 2H), 7,15-7,35 (m, 4H), 4,50 (s, 2H), 2,81-to 3.58 (m, 10H), is 2.09 (s, 3H), 2,00 (m, 1H), 1,80 (m, 2H), and 1.56 (m, 2H).

Example 106: 2-[[1-[2-(2-methylaminophenol)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is a 1/4· ) fumarate (Compound 571 Table 1)

a) 2-[[1-[2-(2-methylaminophenol)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

To acetic anhydride (0,241 g, 2.36 mmol) is added dropwise formic acid (of 0.133 g, and 2.83 mmol) and heated at 50° C. After 2 hours the reaction mixture was diluted with THF (THF) (1 ml) and cooled to 0° and then added dropwise a solution of the compound obtained in Example a (411 mg, 1.18 mmol)in THF (3 ml After stirring for 30 minutes, the reaction mixture is added a saturated salt solution and extracted four times with dichloromethane and the combined organic layer is dried over Na2SO4.

The desiccant is removed by filtration and the filtrate is concentrated and the residue is dissolved in THF (1 ml). The solution is cooled to 0° and thereto are added dropwise BH3SMe2(90 μl, 0,952 mmol). The reaction mixture is heated to room temperature and stirred for 3 hours and then cooled to 0° and thereto are added dropwise methanol (0.5 ml). In the reaction mixture is then added 1N aqueous NaOH solution (3 ml) and mix for 30 minutes, and then add saturated salt solution and extracted four times with dichloromethane and the combined organic layer is dried over Na2SO4. The desiccant is removed by filtration and the filtrate is concentrated and the residue purified by chromatography on silica gel (dichloromethane/methanol), getting mentioned in the title compound (yield: 72%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.5 Hz, 1H), 7,45-of 7.55 (m, 3H), 7,18 (m, 1H), 6,97 (m, 1H), 6,60-of 6.65 (m, 2H), of 4.44 (s, 2H), 3,57 (d, J=6,9 Hz, 2H), 3,21 (sh. d, J=12 Hz, 2H), of 3.07 (m, 2H), 2,88 (s, 3H), 2,78 (m, 2H), 2,42 (sh. t, J=12 Hz, 2H), 2,16 (m, 2H), 2,02 (m, 1H), 1,64 (m, 2H).

b) 2-[[1-[2-(2-Methylaminophenol)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is a 1/4· ) fumarate

Using the compound obtained in Example a, get asanee in the header of the connection means, similar to the methods of Example 40f (yield: 77%).

Melting point: 155° C.

1H-NMR (DMSO-d6): δ of 7.69 (d, J=7.5 Hz, 1H), 7,60 (m, 2H), 7,49 (m, 1H), 7,07 (t, J=7.7 Hz, 1H), 6,95 (d, J=7.2 Hz, 1H), 6,62 (s, 0,5H), 6,50 return of 6.58 (m, 2H), 4,50 (s, 2H), 3,48 (d, J=6,1 Hz, 2H), 2,92-to 3.02 (m, 4H), 2,78 (m, 2 H), of 2.72 (s, 3H), 2.63 in (sh. t, J=Hz, 2H), 1,79-1,89 (m, 3H), of 1.52 (m, 2H).

Example 107: Hydrochloride 2-[[1-[2-(4-forfinally)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 706 Table 1)

a) 2-[[1-[2-(4-forfinally)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

4-Fermentation (0,50 ml, 4,69 mmol) and 2-bromoethanol (0,345 m, to 4.87 mmol) was dissolved in tetrahydrofuran (12 ml). To the solution was added 1N aqueous sodium hydroxide solution (4.8 ml, 4.8 mmol) and heated at 80° C for 80 minutes under stirring. The reaction mixture was diluted with a mixed solvent of ethyl acetate-hexane and washed with diluted aqueous sodium hydroxide solution, water and then saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate concentrated under reduced pressure, obtaining 2-(4-forfinally)ethanol in the form of a crude product. Using the resulting product, by methods similar to the methods of Example 26a, get 2-(4-forfinally)ethanol aconsultant in the form of a crude product. Using the resulting product, get mentioned in the title compound in the form of bestv the private solids ways, similar to the methods of Example 26b (yield: 64%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7,5), 7,40-of 7.55 (3H, m), 7,31-7,39 (2H, m), 6,98 (2H, t, J=8,9), 4,39 (2H, s), 3,49 (2H, d, J=7,2), 2,95-to 3.02 (2H, m), 2,85-to 2.94 (2H, m), 2,54-2,61 (2H, m), 1,94-2,04 (2H, m), 1,5-1,8 (3H, m), 1,2-1,4 (2H, m).

(b) Hydrochloride of 2-[[1-[2-(4-forfinally)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 107a, get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 86%).

Melting point: 185-192° C.

1H-NMR (DMSO-d6): 10,55 (1H, sh. with, HCl), to 7.68 (1H, d, J=7,5), to 7.59 to 7.62 (2H, m), 7,46-7,52 (3H, m), 7.18 in-to 7.25 (2H, m), 4,50 (2H, s), 3,1-3,7 (8H, m), 2,7-2,9 (2H, m), 1,7-2,0 (3H, m), 1,4-1,6 (2H, m).

Example 108: Hydrochloride 2-[[1-[3-(4-forfinally)propyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 711 Table 1)

a) 3-(4-Forfinally)propanol

4-Fermentation (788 mg, 6,15 mmol) and 3-bromopropane (0,535 ml, 6,16 mmol) dissolved in tetrahydrofuran (20 ml). To the solution was added 1N aqueous sodium hydroxide solution (6.2 ml, 6.2 mmol) and heated at 80° C for 3 hours under stirring. The reaction mixture was diluted with a mixed solvent of ethyl acetate-hexane and washed with diluted aqueous sodium hydroxide solution, water and then saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate concentrated under reduced pressure. The floor of the obtained oil is purified column chromatography on silica gel (ethyl acetate-hexane), getting listed in the title compound as a colourless oil (592 mg, yield: 52%).

1H-NMR (CDCl3): 7,33-7,39 (2H, m), 6,97-7,03 (2H, m), of 3.77 (2H, t, J=6,0), to 2.99 (2H, t, J=7,3), 1,80 is 1.91 (2H, m), 1,49 (1H, sh. s, OH).

b) 2-[[1-[3-(4-forfinally)propyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 108A, receive 3-(4-forfinally)propenolatomethyl in the form of the crude product by methods similar to the methods of Example 26a. Using the resulting product, get mentioned in the title compound as a pale yellow solid by methods similar to the methods of Example 26b (yield: 86%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,41-of 7.55 (3H, m), 7,30-7,37 (2H, m), 6,98 (2H, t, J=8,6), and 4.40 (2H, s), 3,40 (2H, d, J=7,3), 2,83 of 2.92 (4H, m), is 2.41 (2H, t, J=7,5), 1,86 is 1.96 (2H, m), 1,5-1,8 (5H, m), 1,2-1,4 (2H, m).

(C) the Hydrochloride of 2-[[1-[3-(4-forfinally)propyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 108b, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 1f (yield: 52%).

Melting point: 162-164° C.

1H-NMR (DMSO-d6): of 9.8 to 10.6 (1H, sh. with, HCl), to 7.68 (1H, d, J=7,5), 7,60 to 7.62 (2H, m), 7,42-7,52 (3H, m), 7,17-7,24 (2H, m), 4,50 (2H, s), 2,9-3,7 (8H, m), 2,6-2,8 (2H, m), of 1.8-2.0 (3H, m), 1,6-1,8 (2H, m), 1,4-1,6 (2H, m).

Example 109: Fumarate 2-[[1-[2-(phenylthio)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 726 in the Tables is 1)

Using thiophenol will receive 2-[[1-[2-(phenylthio)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of the crude product by methods similar to the methods of Example 107a. Using the resulting product, by methods similar to Example 36C, get mentioned in the title compound as a colorless solid (yield 62%).

Melting point: 188-192° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-of 7.60 (2H, m), 7,45-7,52 (1H, m), 7,27-to 7.35 (4H, m), 7,14-7,20 (1H, m), 6,60 (2H, s, fumaric acid), 4,47 (2H, s), 3,40 (2H, d, J=7,2), 3,06-3,18 (2H, m), 2,88-2,95 (2H, m), 2,5-2,6 (2H,, m), 1,9-2,1 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 110: Fumarate 2-[[1-[2-(2-methoxybenzylthio)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 731 Table 1)

Using 2-methoxybenzoyl will receive 2-[[1-[2-(2-methoxybenzylthio)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of the crude product by methods similar to the methods of Example 107a. Using the resulting product, by methods similar to Example 36C, get mentioned in the title compound as a colorless solid (yield 53%).

Melting point: 166-169° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-of 7.60 (2H, m), 7,45-7,52 (1H, m), 7,14-of 7.25 (2H, m), 6.90 to-6,99 (2H, m), 6,60 (2H, s, fumaric acid), 4,48 (2H, s), of 3.80 (3H, s)to 3.41 (2H, d, J=7,3), 2,99-of 3.06 (2H, m), 2.91 in are 2.98 (2H, m,), 2,55-of 2.64 (2H, m), 2,01-2,11 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 111: Fumarate 2[[1-[2-(3-methoxybenzylthio)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 736 Table 1)

Using 3-methoxybenzoyl will receive 2-[[1-[2-(3-methoxybenzylthio)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of the crude product by methods similar to the methods of Example 107a. Using the resulting product, by methods similar to Example 36C, get mentioned in the title compound as a colorless solid (yield 40%).

Melting point: 156-159° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,4), 7,56-to 7.61 (2H, m), 7,45-7,52 (1H, m), 7,21 (1H, t, J=7,9), 6,84-6,91 (2H, m), of 6.71-6,77 (1H, m), is 6.61 (2H, s, fumaric acid), 4,48 (2H, s), 3,74 (3H, s), 3,40 (2H, d, J=7,3), of 3.07-3.15 in (2H,, m), 2,90-of 2.97 (2H, m), 2,56-2,63 (2H, m), 2,02-of 2.09 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 112: Fumarate 2-[[1-[2-(2-forfinally)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 716 Table 1)

Using 2-fermentation will receive 2-[[1-[2-(2-forfinally)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of the crude product by methods similar to the methods of Example 107a. Using the resulting product, by methods similar to Example 36C, get mentioned in the title compound as a colorless solid (yield 46%).

Melting point: 187-189° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,2), 7,55-of 7.60 (2H, m), 7,41-7,52 (2H, m), 7,14-7,28 (3H, m), is 6.61 (2H, s, fumaric acid), 4,47 (2H, s), 3,39 (2H, d, J=7,2), 3,05-3,13 (2H, m), 2,86 of 2.92 (2H, m), of 2.54 2.63 in (2H, m), 1,9-2,1 (2H,, m)of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 13: Fumarate 2-[[1-[2-(3-forfinally)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 721 Table 1)

Using 3-fermentation will receive 2-[[1-[2-(3-forfinally)ethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of the crude product by methods similar to the methods of Example 107a. Using the resulting product, by methods similar to Example 36C, get mentioned in the title compound as a colorless solid (yield 48%).

Melting point: 194-198° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,4), 7,55-to 7.61 (2H, m), 7,45 was 7.45-7,52 (1H, m), 7,28 and 7.36 (1H, m), 7,11-7,22 (2H, m), 6,94-7,02 (1H, m), 6,60 (2H, s, fumaric acid), 4,48 (2H, s), 3,40 (2H, d, J=7,2), 3,12-3,19 (2H, m), 2,90-2,96 (2H, m), 2,56-of 2.64 (2H, m), 1,97-of 2.08 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 114: Fumarate 2-[[1-(2-phenoxyethyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 611 Table 1)

a) 1-(4-Methylbenzoyl)sulfonyloxy-2-phenoxyethane

2-Phenoxyethanol (500 mg, 3.62 mmol) dissolved in dichloromethane (7 ml) and the solution was added p-toluensulfonate (690 mg, 3.62 mmol) and triethylamine (0.51 ml, 3.62 mmol) and stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane and washed with water and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure, obtaining mentioned in the title compound (1.08 g, yield: quantitative).

1H-NMR (CDCl3): 7,83 (2H, d, J=1,8 Hz), 7,34 (2H, d, J=8,4 Hz), 7,28-of 7.23 (2H, m),6,98-6,93 (1H, m), is 6.78 (2H, d, J=7.8 Hz), 4,37 (2H, t, J=4,8 Hz), 4,14 (2H, t, J=5.0 Hz), 2,44 (3H, s).

b) 2-[[1-(2-phenoxyethyl)piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example a (547 mg, of 1.87 mmol) dissolved in dimethylformamide (3 ml) and the solution was added the compound obtained in Example 1d (500 mg, of 1.87 mmol), and potassium carbonate (517 mg, 3,74 mmol) and then heated at 60° C for 7 hours under stirring. The reaction mixture was kept for cooling and then add water (10 ml) and extracted with ethyl acetate. The extract is washed with water and saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The obtained solid is suspended and washed in a mixture of diethyl ether-hexane and collected by filtration, getting mentioned in the title compound in the form of the crude product (171 mg). The product is used in subsequent reactions without purification.

C) Fumarate, 2-[[1-(2-phenoxyethyl)piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid (170 mg, yield: 19%, stage 2)by using the compound obtained in Example 114b (170 mg), by methods similar to the methods of Example 36c.

Melting point: 178-181° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7.5 Hz), to 7.59 (2H, d, J=4, 2 Hz), 7,51-7,47 (1H, m), 6,95-of 6.90 (3H, m, 6,59 (2H, s), 4,48 (2H, s), 4,11 (2H, sh. t, J=5.7 Hz), 3,42 (2H, sh. d, J=10,2 Hz), 2,85 (2H, sh. t, J=5.4 Hz), of 2.23 (2H, sh. DD, J=to 11.3, 11.3 Hz), 1,80 is 1.75 (1H, m)to 1.61 (2H, sh. d, J=12.9 Hz), 1.28 (in 2H, sh. DD, J=23,0, 10,2 Hz).

Example 115: Fumarate 2-[[1-[2-(4-chlorophenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 626 Table 1)

a) 1-Bromo-2-(4-chlorophenoxy)ethane

4-Chlorophenol (500 mg, with 3.89 mmol), 2-bromoethanol (of 0.28 ml, with 3.89 mmol), triphenylphosphine (1,02 g, to 3.89 mmol) was dissolved in tetrahydrofuran (8 ml). In the solution added dropwise diisopropylethylamine (from 0.84 ml, with 3.89 mmol) and stirred at room temperature for 3 hours. The solvent of the reaction mixture is evaporated and then the solid substance precipitated using diethyl ether-hexane and removed by filtration. The filtrate is evaporated under reduced pressure, obtaining mentioned in the title compound in the form of the crude product (1.18 g). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(4-chlorophenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example a (500 mg), dissolved in dimethylformamide (2 ml). To the solution was added the compound obtained in Example 1d (440 mg, of 1.65 mmol), potassium carbonate (456 mg, 3,30 mmol) and sodium iodide (247 mg, of 1.65 mmol) and the mixture is heated at 60° C for 17 hours with stirring. The reaction mixture was kept to cool and then diluted with ethyl acetate. See the camping washed with water and saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The crude product was then purified column chromatography on silica gel (methanol-dichloromethane), getting mentioned in the title compound as a pale brown solid (273 mg, 18%, stage 2).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,4 Hz), 7,56-7,42 (3H, m), 7.23 percent-7,19 (2H, m), 6,84-to 6.80 (2H, m), and 4.40 (2H, s), of 4.05 (2H, t, J=5.8 Hz), 3,51 (2H, d, J=7,3 Hz), 2,98 (2H, sh. d, J=11.8 Hz), 2,77 (2H, t, J=5,9 Hz), 2,10 (2H, DDD, J=2,3, 11,6, the 11.6 Hz), 1,84 by 1.68 (3H, m), 1,45-of 1.40 (2H, m)

c) Fumarate, 2-[[1-[2-(4-chlorophenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Specified in the title compound obtained as a colorless solid using the compound obtained in Example 115b (270 mg, 0.70 mmol), by methods similar to the methods of Example 36C (272 mg, yield: 78%).

Melting point: 189-192° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,4 Hz), to 7.59 (2H, d, J=1.4 Hz), 7,58-7,46 (1H, m), 7,31 (1H, DD, J=7,5, and 2.1 Hz), 6,97 (2H, DD, J=6,7, and 2.1 Hz), 6,59 (2H, s), 4,48 (2H, s), 4,10 (2H, t, J=5.7 Hz), to 3.41 (2H, d, J=7,3 Hz), of 3.00 (2H, sh. d, J=11.7 Hz), 2,80 (2H, t, J=5.8 Hz), 2,17 (2H, DD, J=of 10.7 and 10.7 Hz), to 1.79 (1H, m), 1,60 (2H, sh. d, J=12,4 Hz), 1,33-to 1.21 (2H, m).

Example 116: Fumarate 2-[[1-[2-(2-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 631 Table 1)

a) 1-Bromo-2-(2-methoxyphenoxy)ethane

Using 2-methoxyphenol (186 mg, 1.5 mmol), receive specified in the header of the connection in view of the crude product ways, similar to the methods of Example a (551 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(2-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 116A (551 mg), get mentioned in the title compound as a brown oil by methods similar to the methods of Example 115b (119 mg, yield: 21%, stage 2).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7.5 Hz), 7,56-7,42 (3H, m), 6,92-6,87 (4H, m)to 4.41 (2H, s), 4,14 (2H, t, J=6.2 Hz), 3,85 (3H, s), 3,51 (2H, d, J=7,2 Hz), to 3.02 (2H, sh. d, J=11.7 Hz), and 2.83 (2H, t, J=6.2 Hz), 2,15-2,07 (2H, m), 1,87 was 1.69 (3H, m)and 1.51 to 1.37 (2H, m).

C) Fumarate, 2-[[1-[2-(2-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 116b (119 mg, 0.32 mmol), get mentioned in the title compound as colorless solid by methods similar to the methods of Example 36C (108 mg, yield: 69%).

Melting point: 188-191° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7.5 Hz), to 7.59-to 7.50 (3H, m), 7,00-6,84 (4H, m), 6,59 (2H, s), 4,48 (2H, s), 4.09 to (2H, t, J=5.7 Hz), 3,74 (3H, s)to 3.41 (2H, d, J=7,2 Hz), 3,05 (2H, sh. d, J=11,1 Hz), and 2.83 (2H, sh. C)2,22 (2H, sh. DD, J=11.0 in, and 11.0 Hz), 1,78-to 1.77 (1H, m)of 1.62 (2H, sh. d, J=12.0 Hz), 1.28 (in 2H, sh. DD, J=21,8, and 11.4 Hz).

Example 117: Fumarate 2-[[1-[2-(2-pertenece)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 616 Table 1)

a) 1-Bromo-2-(2-pertenece)ethane

Using 2-terfenol (168 mg, 1.5 mmol), get pointed to by the e in the title compound as crude product, carrying out a reaction similar to the reaction of Example a (418 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(2-pertenece)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 117a (418 mg), get mentioned in the title compound as a brown oil, carrying out reactions similar to reactions of Example 115b (240 mg, yield: 43%, stage 2).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,2 Hz), 7,53-7,42 (3H, m), 7,07-of 6.96 (4H, m)to 4.41 (2H, s)to 4.16 (2H, t, J=6.0 Hz), 3,51 (2H, d, J=7,2 Hz), 3,01 (2H, sh. d, J=11.7 Hz), 2,82 (2H, t, J=6.0 Hz), 2,13 (2H, DDD, J=23,3, 11,6, the 11.6 Hz), 1,84 by 1.68 (3H, m), 1,49-of 1.40 (2H, m).

C) Fumarate, 2-[[1-[2-(2-pertenece)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 117b (240 mg), get mentioned in the title compound as a colourless solid, carrying out a reaction similar to the reaction of Example 36C (108 mg, yield: 78%).

Melting point: 168-171° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7.5 Hz), 7,58 (2H, sh. C)7,50-7,47 (1H, m), 7,22-7,11 (3H, m), 6,94-6,92 (1H, m), 6,60 (2H, s), 4,48 (2H, s)to 4.17 (2H, t, J=5.6 Hz), 3,40 (2H, d, J=7,2 Hz)of 3.00 (2H, sh. d, J=11,1 Hz), of 2.81 (2H, sh. DD, J=5,6, and 5.6 Hz), 2,17 (2H, sh. DD, J=of 10.7 and 10.7 Hz), 1,76-of 1.73 (1H, m)of 1.62 (2H, sh. d, J=12.0 Hz), 1,25 (2H, sh. DD, J=22,4, a 10.6 Hz).

Example 118: Fumarate 2-[[1-[2-(3-pertenece)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 621 Table 1)

a) 1-Bromo-2-(3-pertenece)ethane

ISOE is isua 3-terfenol (500 mg, to 4.46 mmol), get mentioned in the title compound in the form of the crude product by reaction similar to the reaction of Example a (1.26 g). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(3-pertenece)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 118a (1.26 g), get mentioned in the title compound as a brown oil, carrying out reactions similar to reactions of Example 115b (823 mg, yield: 50%, stage 2).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,2 Hz), 7,53-7,42 (3H, m), 7,21-7,16 (1H, m), 6,69-6,59 (3H, m)to 4.41 (2H, s)4,07 (2H, t, J=5,9 Hz), 3,51 (2H, d, J=7,2 Hz), 2,99 (2H, sh. d, J=12.0 Hz), 2,78 (2H, t, J=6.0 Hz), 2,11 (2H, DDD, J=2,5, 11,6, the 11.6 Hz), 1,82 by 1.68 (3H, m), 1,49-of 1.40 (2H, m).

C) Fumarate, 2-[[1-[2-(3-pertenece)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 118b (823 mg), get mentioned in the title compound as a colourless solid, carrying out a reaction similar to the reaction of Example 36C (720 mg, yield: 67%).

Melting point: 193-194° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,4 Hz), 7,60-7,58 (2H, m), 7,51-of 7.48 (1H, m), 7,34-7,31 (1H, m), 6,84 to 6.75 (3H, m), 6,59 (2H, s), 4,48 (2H, s), of 4.12 (2H, t, J=5.7 Hz), to 3.41 (2H, d, J=7,3 Hz), to 3.02 (2H, sh. d, J=11.7 Hz), of 2.81 (2H, sh. DD, J=5,7, 5,7 Hz), 2,19 (2H, sh. DD, J=a 10.5, 10.5 Hz), 1,79-of 1.74 (1H, m)to 1.61 (2H, sh. d, J=12.0 Hz), 1.32 to-1,20 (2H, m).

Example 119: Fumarate 2-[[1-[2-(4-methylphenoxy)ethyl]piperidine-4-yl]methyl]the of isoindoline-1-she (Connection 656 Table 1)

a) 1-Bromo-2-(4-methylphenoxy)ethane

Using 4-METHYLPHENOL (162 mg, 1.5 mmol), get mentioned in the title compound in the form of the crude product by reaction similar to the reaction of Example a (458 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(4-methylphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example a (458 mg), get mentioned in the title compound as a brown oil, carrying out reactions similar to reactions of Example 115b (210 mg, yield: 38%, stage 2).

1H-NMR (CDCl3): to 7.84 (1H, d, J=6.9 Hz), 7,55-7,42 (3H, m), 7,06 (2H, d, J=8,4 Hz), for 6.81-6,77 (2H, m), and 4.40 (2H, s)4,06 (2H, t, J=6.0 Hz), 3,50 (2H, d, J=7,2 Hz)of 3.00 (2H, sh. d, J=11.7 Hz), 2,77 (2H, t, J=6.0 Hz), and 2.27 (3H, s), 2,10 (2H, DDD, J=2,3, 11,6, the 11.6 Hz), 1,84 is 1.70 (3H, m), 1,49-of 1.40 (2H, m).

C) Fumarate, 2-[[1-[2-(4-methylphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 119b (210 mg), get mentioned in the title compound as a colourless solid, carrying out a reaction similar to the reaction of Example 36C (220 mg, yield: 79%).

Melting point: 183-185° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,6 Hz), 7,62-7,58 (2H, m), 7,52 was 7.45 (1H, m), 7,07 (2H, d, J=8,3 Hz), PC 6.82 (2H, d, J=8,4 Hz), 6,59 (2H, s), 4,48 (2H, s), of 4.05 (2H, t, J=5.7 Hz), to 3.41 (2H, d, J=7,2 Hz)of 3.00 (2H, sh. d, J=11,6 Hz), 2,78 (2H, t, J=5.7 Hz), 2,22-2,09 (5H, m), 1,79-of 1.73 (1H, m)to 1.61 (2H, sh. d, J=13.3 Hz), 1.26 in (2H, sh. DD, J=21,4, 11.4 G is).

Example 120: Fumarate 2-[[1-[2-(3-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 636 Table 1)

a) 1-Bromo-2-(3-methoxyphenoxy)ethane

Using 4-methoxyphenol (186 mg, 1.5 mmol), get mentioned in the title compound in the form of the crude product by reaction similar to the reaction of Example a (953 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(3-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 120A (953 mg), get mentioned in the title compound as a brown oil, carrying out reactions similar to reactions of Example 115b (192 mg, yield: 34%, stage 2).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,2 Hz), 7,55-7,42 (3H, m), 7,16 (1H, DD, J=8,0, 8.0 Hz), 6,51-6,46 (3H, m)to 4.41 (2H, s)4,08 (2H, t, J=6.0 Hz), of 3.78 (3H, s), 3,51 (2H, d, J=7,2 Hz)of 3.00 (2H, sh. d, J=11.7 Hz), and 2.79 (2H, t, J=6.0 Hz), 2,16-of 2.08 (2H, m), 1,83 by 1.68 (3H, m), 1,50-of 1.41 (2H, m).

C) Fumarate, 2-[[1-[2-(3-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 120b (190 mg), get mentioned in the title compound as a colourless solid, carrying out a reaction similar to the reaction of Example 36C (200 mg, yield: 81%).

Melting point: 173-174° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7.5 Hz), 7,62-7,58 (2H, m), 7,52 was 7.45 (1H, m), 7,17 (1H, DD, J=8,3, 8.0 Hz), 6,59 (2H, s), 6,53-of 6.49 (3H, m), 4,48 (2H, is), 4.09 to (2H, t, J=5.4 Hz), and 3.72 (3H, s)to 3.41 (2H, d, J=7,2 Hz), 3,03 (2H, sh. d, J=11.2 Hz), 2,82 (2H, sh. C)of 2.21 (2H, sh. DD, J=11,4, and 11.4 Hz), 1,78-to 1.77 (1H, m)of 1.62 (2H, sh. d, J=12,5 Hz), 1.28 (in 2H, sh. DD, J=22,0, and 11.0 Hz).

Example 121: Fumarate 2-[[1-[2-(3-methylphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 651 Table 1)

a) 1-Bromo-2-(3-methylphenoxy)ethane

Using 3-METHYLPHENOL (162 mg, 1.5 mmol), get mentioned in the title compound in the form of the crude product by reaction similar to the reaction of Example a (410 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(3-methylphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example a (410 mg), get mentioned in the title compound as a brown oil, carrying out reactions similar to reactions of Example 115b (213 mg, yield: 39%, stage 2).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7.5 Hz), 7,55-7,42 (3H, m), 7,14 (1H, DD, J=7,7, 7,7 Hz), 6,76-6,69 (3H, m), and 4.40 (2H, s)4,08 (2H, t, J=5,9 Hz), 3,51 (2H, d, J=6,9 Hz)of 3.00 (2H, sh. d, J=11.7 Hz), and 2.79 (2H, t, J=5,9 Hz), 2,31 (3H, s), 2,12 (2H, sh. DD, J=a 10.5, 10.5 Hz), 1,82 was 1.69 (3H, m), 1,49-of 1.26 (2H, m).

C) Fumarate, 2-[[1-[2-(3-methylphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 121b (210 mg), get mentioned in the title compound as a colourless solid, carrying out a reaction similar to the reaction of Example 36C (252 mg, yield: 91%).

The point is as melting point: 202-203° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,4 Hz), to 7.59-7,58 (2H, m), 7,50 was 7.45 (1H, m), to 7.15 (1H, DD, J=7,8, and 7.8 Hz), 6.75 in-of 6.71 (3H, m), 6,59 (2H, s), 4,48 (2H, s), 4.09 to (2H, t, J=5.5 Hz), to 3.41 (2H, d, J=7,3 Hz), 3.04 from (2H, sh. d, J=11.3 Hz), and 2.83 (2H, t, J=5.0 Hz), 2.26 and-2,19 (5H, m), 1,78 (1H, sh. C)of 1.62 (2H, sh. d, J=a 12.7 Hz), 1.28 (in 2H, sh. DD, J=21,9, to 10.7 Hz).

Example 122: Fumarate 2-[[1-[2-(4-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 641 Table 1)

a) 1-Bromo-2-(4-methoxyphenoxy)ethane

Using 4-methoxyphenol (186 mg, 1.5 mmol), get mentioned in the title compound in the form of the crude product by reaction similar to the reaction of Example a (347 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(4-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example a (347 mg), get mentioned in the title compound as a brown oil, carrying out reactions similar to reactions of Example 115b (274 mg, yield: 48%, stage 2).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,2 Hz), 7,56-7,42 (3H, m), 6,82-of 6.78 (4H, m)to 4.41 (2H, s), of 4.05 (2H, t, J=5,9 Hz), 3,76 (3H, s), 3,51 (2H, d, J=7,2 Hz)of 3.00 (2H, sh. d, J=12.0 Hz), 2,77 (2H, t, J=6.0 Hz), 2,11 (2H, DDD, J=2,3, 11,6, the 11.6 Hz), 1,82 by 1.68 (3H, m)and 1.51-of 1.41 (2H, m).

C) Fumarate, 2-[[1-[2-(4-methoxyphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 122b (270 mg), get mentioned in the title compound as colourless what about solids, carrying out a reaction similar to the reaction of Example 36C (232 mg, yield: 82%).

Melting point: 165-168° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,3 Hz), to 7.59-7,58 (2H, m), 7,52 was 7.45 (1H, m), 6,89-PC 6.82 (4H, m), 6,59 (2H, s), 4,48 (2H, s), Android 4.04 (2H, t, J=5.7 Hz), to 3.41 (2H, d, J=7,3 Hz), 3,03 (2H, sh. d, J=11,6 Hz), 2,80 (2H, t, J=5.7 Hz), of 2.21 (2H, sh. DD, J=of 10.7 and 10.7 Hz), 1,80-to 1.79 (1H, m)to 1.61 (2H, sh. d, J=11,6 Hz), 1,33-of 1.18 (2H, m).

Example 123: Fumarate 2-[[1-[2-(2-methylphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 646 Table 1)

a) 1-Bromo-2-(2-methylphenoxy)ethane

Using 2-METHYLPHENOL (162 mg, 1.5 mmol), get mentioned in the title compound in the form of the crude product by reaction similar to the reaction of Example a (334 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(2-methylphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 123A (334 mg), get mentioned in the title compound as a brown oil, carrying out a reaction similar to the reaction of Example 115b (485 mg). The crude product is used in subsequent reactions without purification.

C) Fumarate, 2-[[1-[2-(2-methylphenoxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 123b (485 mg), get mentioned in the title compound as a colourless solid substances through reaction, similar reassembler 36C (89 mg, yield: 14%, stage 3).

Melting point: 214-218° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,2 Hz), to 7.59-7,58 (2H, m), 7,52 was 7.45 (1H, m), 7,16-7,11 (2H, m), 6,92 (1H, d, J=8.1 Hz), PC 6.82 (1H, DD, J=7,5, 7.5 Hz)), 6,59 (2H, s), 4,48 (2H, s), 4,10 (2H, t, J=5.6 Hz), to 3.41 (2H, d, J=7,2 Hz), 3,03 (2H, sh. d, J=12.0 Hz), 2,85 (2H, sh. C)of 2.23 (2H, sh. DD, J=11.0 in, and 11.0 Hz), to 2.13 (s, 3H), 1.77 in (1H, sh. C)to 1.61 (2H, sh. d, J=12.3 Hz), 1.32 to 1,24 (2H, m).

Example 124: Fumarate 2-[[1-[2-(4-triptoreline)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 661 Table 1)

a) 1-Bromo-2-(4-triptoreline)ethane

Using 4-triptoreline (243 mg, 1.5 mmol), get mentioned in the title compound in the form of the crude product by reaction similar to the reaction of Example a (519 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(4-triptoreline)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 124A beaches (519 mg), get mentioned in the title compound, carrying out reactions similar to reactions of Example 115b (150 mg, yield: 19%, stage 2).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,2 Hz), 7,56-7,42 (5H, m), to 6.95 (2H, d, J=8.7 Hz), to 4.41 (2H, s), of 4.13 (2H, t, J=5,9 Hz), 3,51 (2H, d, J=6,9 Hz)of 3.00 (2H, sh. d, J=11.4 in Hz)of 2.81 (2H, t, J=5,9 Hz), 2,17-of 2.09 (2H, m), 1.85 to and 1.63 (3H, m), 1,50-to 1.38 (2H, m).

C) Fumarate, 2-[[1-[2-(4-triptoreline)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 124b (150 mg), produces the t specified in the title compound as a colourless solid, carrying out a reaction similar to the reaction of Example 36C (171 mg, yield: 89%).

Melting point: 198-199° C.

1H-NMR (DMSO-d6): 7.68 per-7,56 (5H, m), 7,52 was 7.45 (1H, m), 7,12 (2H, d, J=8.6 Hz), 6,60 (2H, s), 4,48 (2H, s), 4,18 (2H, t, J=5.7 Hz), to 3.41 (2H, d, J=7,2 Hz), 2,98 (2H, sh. d, J=11,6 Hz), and 2.79 (2H, t, J=5.7 Hz), 2,13 (2H, sh. DD, J=11,7, 11.7 Hz), 1,79-1,72 (1H, m), 1,60 (2H, sh. d, J=12.3 Hz), 1,38-of 1.18 (2H, m).

Example 125: Fumarate 2-[[1-[2-(4-triftormetilfosfinov)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 666 Table 1)

a) 1-Bromo-2-(4-triftormetilfosfinov)ethane

Using 4-cryptomaterial (267 mg, 1.5 mmol), get mentioned in the title compound in the form of the crude product by reaction similar to the reaction of Example a (598 mg). The crude product is used in subsequent reactions without purification.

b) 2-[[1-[2-(4-triptoreline)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 125 (598 mg)will be specified in the title compound in the form of the crude product by reaction similar to the reaction of Example 115b (589 mg). The crude product is used in subsequent reactions without purification.

C) Fumarate, 2-[[1-[2-(4-triptoreline)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 125b (589 mg), get mentioned in the title compound as a colourless solid, ASU is estley reaction, similar reactions of Example 36C (304 mg, yield: 55%, stage 3).

Melting point: 181-183° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,3 Hz), to 7.59-7,58 (2H, m), 7,50 was 7.45 (1H, m), 7,28 (2H, d, J=8,9 Hz), 7,06-7,00 (2H, m), 6,60 (2H, s), 4,48 (2H, s), 4,11 (2H, t, J=5.7 Hz), to 3.41 (2H, d, J=7,2 Hz), 2,98 (2H, sh. d, J=11.7 Hz), 2,78 (2H, t, J=5.7 Hz), 2,18-of 2.09 (2H, m), 1,80-1,72 (1H, m)to 1.60 (2H, m), 1.30 and 1,19 (2H, m).

Example 126: Fumarate 2-[[1-[2-(1,3-benzodioxol-5-yloxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 671 Table 1)

Using 3,4-methylenedioxyphenol get mentioned in the title compound as colorless solid by methods similar to the methods of Example a and Example 36C (yield: 52%).

Melting point: 220-232° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-of 7.60 (2H, m), 7,45-7,52 (1H, m), 6,79 (1H, d, J=8,4), 6,62 (1H, d, J=2,4), 6,59 (2H, s, fumaric acid), 6,36 (1H, DD, J=2,4, 8,4), 5,94 (2H, s), 4,48 (2H, s), 3,98-Android 4.04 (2H, m), 3,41 (2H, d, J=7,2), 2,94-a 3.01 (2H, m), 2.71 to 2,77 (2H, m), 2,08-2,19 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1,1-1,3 (2H, m).

Example 127: Fumarate 2-[[1-[2-(2,3-dihydro-1H-inden-5-yloxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 676 Table 1)

Using a 5-indanol get mentioned in the title compound as colorless solid by methods similar to the methods of Example a and Example 36C (yield: 22%).

Melting point: 181-185° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,2), 7,55-of 7.60 (2H, m), 7,45-7,52 (1H, m), was 7.08 (1H, d, J=8,4), to 6.80 (1H, d, J=2,1), to 6.67 (1H, d is, J=2,1, 8,4), 6,59 (2H, s, fumaric acid), of 4.49 (2H, s), as 4.02-4,08 (2H, m)to 3.41 (2H, d, J=7,2), 2,96-3,03 (2H, m), 2,72-2,84 (6H, m), 2,12-2,22 (2H, m), 1.93 and-2,04 (2H, m), of 1.6-1.8 (1H, m), 1,5-1,6 (2H, m), 1.1 to 1,3 (2H, m).

Example 128: Fumarate 2-[[1-[2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 681 Table 1)

Using 5,6,7,8-tetrahydro-2-naphthol, get mentioned in the title compound as colorless solid by methods similar to the methods of Example a and Example 36C (yield: 19%).

Melting point: 186 to 190° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,2), 7,55-of 7.60 (2H, m), 7,45-7,52 (1H, m), 6,92 (1H, d, J=8,1), 6,60 is 6.67 (2H, m), 6,59 (2H, s, fumaric acid), 4,48 (2H, s), 3,99-4,06 (2H, m)to 3.41 (2H, d, J=7,2), 2,95-to 3.02 (2H, m), 2,72-2,79 (2H, m), 2,60-2,69 (4H, m), 2,10-of 2.20 (2H, m), 1.55V and 1.80 (7H, m), 1,1-1,3 (2H, m).

Example 129: Fumarate 2-[[1-[2-(5,6,7,8-tetrahydronaphthalen-1 yloxy)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 686 Table 1)

Using 5,6,7,8-tetrahydro-1-naphthol, get mentioned in the title compound as colorless solid by methods similar to the methods of Example a and Example 36C (yield: 13%).

Melting point: 196-203° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,55-of 7.60 (2H, m), 7,45-7,52 (1H, m), 6,97-7,05 (1H, m), 6,70 (1H, d, J=8,1), only 6.64 (1H, d, J=7,5), 6,59 (2H, s, fumaric acid), 4,48 (2H, s), a 4.03-4.09 to (2H, m)to 3.41 (2H, d, J=7,2), 2,98 was 3.05 (2H, m), 2,80-to 2.85 (2H, m), 2,62-2,70 (2H, m), 2,50 is 2.55 (2H, m), to 2.1-2.3 (2H, m), 1.5 and 1.8 (7H, m), 1,1-1,3 (2H, m).

Example 130: Hydrochlor the d 2-[[1-[2-[Methyl(4-forfinal)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 295 Table 1)

a) tert-Butyl N-(4-forfinal)carbamate

To a solution of 4-foronline (2.00 g, 18.0 mmol) in dichloromethane (15 ml) add (Side)2About ((Boc)2O) (3,93 g, 18.0 mmol) and a catalytic amount of triethylamine and the mixture is then stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate and washed with water, twice 0,5N aqueous solution of HCl, a saturated solution of NaHCO3and then with saturated salt solution and dried over Na2SO4.

The desiccant is removed by filtration and the filtrate concentrated. The obtained solid is suspended and washed in hexane, getting mentioned in the title compound (yield: 80%).

1H-NMR (CDCl3): δ 7,31 (m, 2H), 6,98 (m, 2H), 6.42 per (W. s, 1H)and 1.51 (s, 9H).

b) 2-[Methyl(4-forfinal)amino]ethylmethanesulfonate

To a stirred suspension of 60% NaH (273 mg, 6,82 mmol)/1.5 ml is added dropwise a solution of the compound obtained in Example 130A, in NMP ((1.20 g, of 5.68 mmol)/3 ml NMP) under nitrogen atmosphere at 0° C. After stirring for 10 minutes, the reaction mixture was added dropwise Bromeliaceae (0,995 g, 5,96 mmol) and then warmed to room temperature. After stirring for 1 hour the reaction mixture was diluted with ethyl acetate and washed four times with water and then with saturated salt solution and dried over Na2SO4.

The desiccant is removed by filtration the filtrate is concentrated and to a solution of the obtained compound in THF ((0,600 g, 2.02 mmol)/8 ml THF) is added dropwise LiAlH4in THF ((230 mg, the 6.06 mmol)in 5 ml THF and refluxed for 4 hours. The reaction mixture was diluted with ether (10 ml) and add water (0.25 ml), 15% aqueous NaOH solution (0.25 ml) and water (0.75 ml) and then filtered. The filtrate is concentrated and the resulting oil purified by chromatography on silica gel (ethyl acetate/hexane).

The compound obtained (0,401 g, is 2.37 mmol) dissolved in dichloromethane (2 ml) and the solution is added triethylamine (and 0.46 ml of 3.32 mmol) and cooled to 0° C. To the mixture is added dropwise methanesulfonanilide (0,220 ml, 2,84 mmol) and stirred for 1.5 hours. The reaction mixture is diluted with ether and washed three times with water and then with saturated salt solution and dried over Na2SO4. The desiccant is removed by filtration and the filtrate is concentrated and receiving specified in the header of the connection.

1H-NMR (CDCl3): δ to 6.95 (m, 2H), of 6.68 (m, 2H), 4,36 (t, J=5.8 Hz, 2H), to 3.64 (t, J=5.8 Hz, 2H), 2,69 (s, 3H), equal to 2.94 (s, 3H).

(C) the Hydrochloride of 2-[[1-[2-[Methyl(4-forfinal)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 130b, obtained by methods similar to the methods of Example 26b, the product, which is then to get listed in the title compound, processed by methods similar to the methods P is the iMER 1f, without purification (yield: 60%).

Melting point: 223-231° C.

1H-NMR (DMSO-d6): δ 10,59 (sh. s, 1H), 7,69 (d, J=7.5 Hz, 1H), to 7.61 (m, 2H), 7,50 (m, 1H), 7,03 (t, J=9 Hz, 2H), 6,83 (m, 2H), 4,51 (s, 2H), to 3.73 (m, 2H), 2,87-of 3.54 (m, 11H), 1,99 (m, 1H), 1,80 (m, 2H), 1,59 (m, 2H).

Example 131: Fumarate 2-[[1-[2-[Benzyl(4-forfinal)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 301 Table 1)

a) Benzyl(4-forfinal)Amin

A solution of 4-foronline (1.50 g, 13.5 mmol) and triethylamine (and 2.26 ml, 16.2 mmol) in dichloromethane (7 ml) cooled to 0° and the solution is added dropwise benzylbromide (1,61 ml, 13.5 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate and washed three times with water and then with saturated salt solution and dried over Na2SO4. The desiccant is removed by filtration and the filtrate is concentrated and the residue purified by chromatography on silica gel (ethyl acetate/hexane)to give specified in the title compound (yield: 46%).

1H-NMR (CDCl3): δ 7,26 and 7.36 (m, 5H), to 6.88 (m, 2H), 6,56 (m, 2H), 4,29 (s, 2H).

b) 2-[Benzyl(4-forfinal)amino]ethylmethanesulfonate

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 130b (yield: 93%).

1H-NMR (CDCl3): δ 7,19-7,34 (m, 5H), 6,91 (m, 2H), 6,69 (m, 2H), 4,55 (s, 2H), 4,34 (m, 2H), 3,74 (m, 2H), 2.91 in (s, 3H).

C) 2-[[1-[2-[Benzyl(forfinal)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 131b, get mentioned in the title compound by methods similar to the methods of Example 26b (yield: 79%).

1H-NMR (CDCl3): δ 7,86 (d, J=7.2 Hz, 1H), 7,41-7,58 (m, 3H), 7,19-to 7.32 (m, 5H), 6.87 in (m, 2H), 6,60 (m, 2H), 4,50 (s, 2H), 4,39 (s, 2H), 3,48-of 3.53 (m, 4H), 2,90 (m, 2H), by 2.55 (m, 2H), 2,00 (dt, J=11,7, 2,1 Hz, 2H), of 1.78 (m, 1H), 1,67 (m, 2H), 1,38 (m, 2H).

d) Fumarate, 2-[[1-[2-[Benzyl(4-forfinal)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example s get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 33%).

Melting point: 174-185° C.

1H-NMR (DMSO-d6): δ to 7.67 (d, J=7.5 Hz, 1H), to 7.59 (m, 2H), of 7.48 (m, 1H), 7,25 (m, 2H), 7,20-7,21 (m, 3H), 6,94 (t, J=8,8 Hz, 2H), only 6.64 (m, 2H), 5,59 (s, 2H), 4.53-in (s, 2H), 4,47 (s, 2H), 3,55 (t, J=7,0 Hz, 2H), 3,40 (d, J=7,3 Hz, 2H), 2,98 (d, J=11,4 Hz, 2H) 2,62 (t, J=7,0 Hz, 2H), and 2.14 (t, J=11.2 Hz, 2H), 1.77 in (m, 1H), 1,59 (sh. d, J=12 Hz, 2H), 1.27mm (m, 2H).

Example 132: Hydrochloride 2-[[1-[2-[(4-forfinal)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 275 Table 1)

a) 2-[[1-[2-[(4-forfinal)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example s get mentioned in the title compound by methods similar to the methods of Example a (yield: 96%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7,1 Hz, 1H), 7,42-7,53 (m, 3H), to 6.88 (m, 2H), 6,55 (m, 2H), and 4.40 (s, 2H), 3,52 (d, J=7.2 Hz, 2H), to 3.09 (t, J=6.0 Hz, 2H), 2,89 (sh. d, J=11.5g is, 2H), 2,59 (t, J=6.0 Hz, 2H), 1,98 (dt, J=11,5, 2,2 Hz, 2H), 1,79 (m, 1H), 1,68 (sh. d, J=12 Hz, 2H), 1.39 in (m, 2H).

(b) Hydrochloride of 2-[[1-[2-[(4-forfinal)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 132A, get mentioned in the title compound by methods similar to the methods of Example 1f.

Melting point: 221-230° C.

1H-NMR (DMSO-d6): δ of 7.69 (d, J=7,4 Hz, 1H), to 7.61 (m, 2H), 7,50 (m, 1H), 6,99 (m, 2H), 6,72 (m, 2H), 4,51 (s, 2H), 2,80-of 3.97 (m, 10H)to 1.99 (m, 1H), 1,80 (m, 2H), 1,62 (m, 2H).

Example 133: Fumarate 2-[[1-[2-[(4-methoxyphenyl)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 307 Table 1)

a) 2-[[1-(2-Hydroxyethyl)piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 1d (1.50 g, 5,62 mmol)and 2-bromoethanol (0,703 g, 5,62 mmol) dissolved in acetonitrile (10 ml) and the solution was added NaI (0,842 g, 5,62 mmol) and potassium carbonate (2,34 g of 16.9 mmol) and heated at 80° C. After 3 hours the solvent is evaporated and to the residue is added saturated aqueous solution of NaHCO3and extracted four times with dichloromethane. The extract is dried over Na2SO4and the desiccant is removed by filtration and the filtrate concentrated. The obtained solid is suspended and washed in ether, getting mentioned in the title compound (yield: 76%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.5 Hz, 1H), 7,44-7,56 (m, 3H), to 4.41 (s, 2H)and 3.59 (t, J=5.4 Hz, 2H), 3,51 (d, J=7.5 Hz, 2H), 2.91 in (sh. d, J12 Hz, 2H), of 2.51 (t, J=5.4 Hz, 2H), 2.06 to (dt, J=11,7, 2.4 Hz, 2H)and 1.83 (m, 1H), 1,70 (sh. d, J=12 Hz, 2H), 1.39 in (m, 2H).

(b) Hydrochloride of 2-[[1-(2-methanesulfonylaminoethyl)piperidine-4-yl]methyl]isoindoline-1-it

A solution of the compound obtained in Example a (1,00 g, 4.20 mmol), and triethylamine (0,88 ml of 6.31 mmol) in dichloromethane (5 ml) cooled to 0° and thereto are added dropwise methanesulfonanilide (0,488 ml of 6.31 mmol). The mixture is heated to room temperature and stirred for 1 hour, then the reaction mixture was diluted with ethyl acetate and washed with saturated solution of NaHCO3twice with water and then with saturated salt solution and dried over Na2SO4. The desiccant is removed by filtration and the filtrate is treated 1,30 ml 4N HCl-AcOEt. Precipitated precipitated crystals are collected by filtration, getting mentioned in the title compound (49%).

1H-NMR (DMSO-d6): δ 10,61 (sh. s, 1H), 7,69 (d, J=7.5 Hz, 1H), to 7.61 (m, 2H), 7,49 (m, 1H), 4,51 (s, 2H), Android 4.04 (t, J=6.9 Hz, 2H), 2,88-3,62 (m, 11H), 1,99 (m, 1H), 1,80 (m, 2H), 1,59 (m, 2H).

C) 2-[[1-[2-[(4-Methoxyphenyl)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-he

To a solution of the compound obtained in Example 133b (200 mg, 0,514 mmol), and para-methoxyaniline (63 mg, 0.51 mmol) in acetonitrile (2 ml) is added sodium iodide (77 mg, 0.51 mmol) and potassium carbonate (178 mg, 1,29 mmol) and heated at 70° C. After 2 hours the solvent is evaporated and then the residue is added a saturated solution of Sol and 1N aqueous solution of NaOH and the mixture extracted three times with dichloromethane and dried over Na 2SO4. The desiccant is removed by filtration and the filtrate is concentrated and the residue purified by chromatography on silica gel (dichloromethane/methanol), getting mentioned in the title compound (yield: 47%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.2 Hz, 1H), 7,42-7,53 (m, 3H), 6,79 (d, J=9.0 Hz, 2H), 6,60 (d, J=9.0 Hz, 2H), and 4.40 (s, 2H, in), 3.75 (s, 3H), 3,51 (d, J=7.2 Hz, 2H), 3,10 (t, J=6.0 Hz, 2H), 2,90 (sh. d, J=11.7 Hz, 2H), 2,59 (t, J=6.0 Hz, 2H), 1,98 (dt, J=11,7, 2,1 Hz, 2H), is 1.81 (m, 1H), 1,68 (sh. d, J=12 Hz, 2H), 1,40 (m, 2H).

d) Fumarate, 2-[[1-[2-[(4-methoxyphenyl)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example s get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 84%).

Melting point: 202° C.

1H-NMR (DMSO-d6): δ to 7.67 (d, J=7.5 Hz, 1H), to 7.59 (m, 2H), 7,49 (m, 1H), of 6.71 (d, J=9 Hz, 2H), return of 6.58 (s, 2H), is 6.54 (d, J=9 Hz, 2H), 4,48 (s, 2H), 3,63 (s, 3H), 3,42 (d, J=7.2 Hz, 2H), 3,12 (t, J=6.6 Hz, 2H), 3,03 (d, J=12 Hz, 2H), 2,66 (t, J=6.6 Hz, 2H), of 2.21 (t, J=12 Hz, 2H), is 1.81 (m, 1H), 1,63 (sh. d, J=12 Hz, 2H), 1,31 (m, 2H).

Example 134: Fumarate 2-[[1-[2-[(3-methoxyphenyl)amino]-ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 313 Table 1)

a) 2-[[1-[2-[(3-methoxyphenyl)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using meta-methoxyaniline get mentioned in the title compound by methods similar to the methods of Example C (yield: 31%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.5 Hz, 1H), 7,42-7,53 (m, 3H), was 7.08 (t, J=8,1 G is, 1H), 6,26 (m, 2H), 6,18 (m, 1H), and 4.40 (s, 2H), of 3.78 (s, 3H), 3,52 (d, J=7.2 Hz, 2H), 3,14 (t, J=6.0 Hz, 2H), 2.91 in (sh. d, J=11.7 Hz, 2H), 2,60 (t, J=6.0 Hz, 2H), 1,99 (sh. t, J=12 Hz, 2H), equal to 1.82 (m, 1H), 1,68 (m, 2H), 1,40 (m, 2H).

b) Fumarate, 2-[[1-[2-[(3-methoxyphenyl)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 134a get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 88%).

Melting point: 178-182° C.

1H-NMR (DMSO-d6): δ to 7.67 (d, J=7.5 Hz, 1H), 7,60 (m, 2H), 7,50 (m, 1H), of 6.96 (t, J=8,4 Hz, 1H), return of 6.58 (s, 2H), 6,11-to 6.19 (m, 3H), 4,48 (s, 2H), 3,66 (s, 3H), 3,42 (d, J=7.2 Hz, 2H), and 3.16 (t, J=6.6 Hz, 2H), 3,02 (W. d, J=11.7 Hz, 2H), 2,65 (t, J=6.6 Hz, 2H), 2,20 (sh. t, J=12 Hz, 2H), equal to 1.82 (m, 1H), 1,63 (sh. d, J=12 Hz, 2H), 1,31 (m, 2H).

Example 135: Fumarate 2-[[1-[2-[(2-methoxyphenyl)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 319 Table 1)

a) 2-[[1-[2-[(2-methoxyphenyl)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using ortho-methoxyaniline get mentioned in the title compound by methods similar to the methods of Example C (yield: 36%).

1H-NMR (CDCl3): δ a 7.85 (d, J=7.5 Hz, 1H), 7,45-7,53 (m, 3H), 6,86 (m, 1H), 6,77 (m, 1H), 6,58 is 6.67 (m, 2H), and 4.40 (s, 2H), 3,86 (s, 3H), 3,52 (d, J=7.5 Hz, 2H), 3,19 (t, J=6.0 Hz, 2H), 2,93 (sh. d, J=11,4 Hz, 2H), 2,64 (t, J=6.0 Hz, 2H), 1,99 (m, 2H), 1,80 (m, 1H), 1,68 (m, 2H), 1,41 (m, 2H).

b) Fumarate, 2-[[1-[2-[(2-methoxyphenyl)amino]ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example a receive the decree of the TES in the header of the connection means, similar to the methods of Example 40f (yield: 89%).

Melting point: 183 to 191° C.

1H-NMR (DMSO-d6): δ to 7.67 (d, J=7.5 Hz, 1H), to 7.59 (m, 2H), of 7.48 (m, 1H), 6.75 in-for 6.81 (m, 2H), return of 6.58 (s, 2H), 6,56 (m, 2H), 4,49 (s, 2H), of 3.77 (s, 3H), 3.43 points (d, J=7,3 Hz, 2H), 3,18 (t, J=6.3 Hz, 2H), 3,00 W. d, J=11 Hz, 2H), 2,69 (t, J=6.3 Hz, 2H), 2,17 (m, 2H), is 1.81 (m, 1H), and 1.63 (m, 2H), 1.28 (in m, 2H).

Example 136: Hydrochloride 2-[[1-[2-(4-forfinal)allyl]piperidine-4-yl]methyl]isoindoline-1-she (compound 358 Table 1)

Bromide methyltriphenylphosphonium (801 mg, 2,24 mmol) suspended in tetrahydrofuran (4 ml) and to suspendee add t-piperonyl potassium (257 mg, to 2.29 mmol) at room temperature. To the mixture add a solution of the compound obtained in Example 1E (819 mg, 2,24 mmol)dissolved in tetrahydrofuran (4 ml), and the mixture is then stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and then saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate concentrated under reduced pressure, obtaining 2-[[1-[2-(4-forfinal)allyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of a crude product.

Using the resulting product, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 1f (yield: 34%).

Point is melting: 173-181° C.

1H-NMR (DMSO-d6): 9,6-10,0 (1H, sh. with, HCl), to 7.59-of 7.70 (5H, m), 7,45-7,51 (1H, m), 7,22-7,30 (2H, m), 5,79 (1H, s)5,72 (1H, s), 4,48 (2H, s), 4,37-4,40 (0,4H, m), 4,20-to 4.23 (1,6H, m), 3,1-3,6 (4H, m), 2,7-2,9 (2H, m), 1,4-2,2 (5H, m).

Example 137: Hydrochloride 2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-3,4-dihydroisoquinoline-1(2H)-she (Connection 761 Table 1)

a) tert-Butyl 4-(4-methylbenzenesulfonamide)piperidine-1-carboxylate

Tert-butyl 4-hydroxyethylpiperazine-1-carboxylate [obtained according to the display Japanese patent application (not the examined) No. 11-217377; 12,12 g, 56,30 mmol] is dissolved in dichloromethane (26 ml) and to the solution was added p-toluensulfonate (of 10.73 g, 56,30 mmol) and triethylamine (8,63 ml of 61.9 mmol) at room temperature, and then the reaction mixture was stirred at the same temperature for 5 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water and saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The residue is recrystallized from hexane (100 ml), getting mentioned in the title compound as a colourless solid (14,13 g, yield: 85%).

1H-NMR (CDCl3): for 7.78 (2H, d, J=8.1 Hz), 7,35 (2H, d, J=8,4 Hz), 4.09 to (2H, sh. C)of 3.85 (2H, d, J=6.9 Hz), 2,65 (2H, sh. DD, J=12,5, 12,5 Hz), the 2.46 (3H, s), 1,87-to 1.79 (1H, m), 1,65-of 1.62 (2H, m)of 1.44 (9H, s), 1,17-of 1.03 (2H, m).

b) tert-Bout the l-4-[3,4-dihydroisoquinoline-2(1H)-ylmethyl]piperidine-1-carboxylate

The compound obtained in Example a (1.0 g, 2,71 mmol), potassium carbonate (375 mg, a 2.71 mmol) and 3,4-dihydroisoquinoline (399 mg, a 2.71 mmol) dissolved in dimethylformamide (9 ml) and the mixture is heated at 80° C for 13 hours with stirring. The reaction mixture was kept to cool and then diluted with ethyl acetate and washed with water and then dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The crude product was then purified column chromatography on silica gel (methanol-dichloromethane), getting mentioned in the title compound as a colourless oil (948 mg, yield: quantitative).

1H-NMR (CDCl3): 7,20-7,07 (3H, m), 7,02-7,00 (1H, m), 4,11 (2H, sh. C)of 3.60 (2H, s), 2.91 in-2,87 (2H, m), was 2.76 of 2.68 (4H, m), 2,35 (2H, d, J=6.6 Hz), 1,80 by 1.68 (3H, m)of 1.46 (9H, s), 1.18 to 1,09 (2H, m).

c) tert-Butyl 4-[[1-oxo-3,4-dihydroisoquinoline-2(1H)-yl]methyl]piperidinecarboxylate

The compound obtained in Example 137b (488 mg, 1.48 mmol) dissolved in dichloromethane (15 ml) and the solution was added potassium permanganate (702 mg, of 4.44 mmol) and chloride of triethylenediamine (337 mg, 1.48 mmol), and refluxed for 5.5 hours. The reaction mixture was kept for cooling and then there is added a saturated aqueous Hydrosulphite solution of sodium (15 ml) and stirred for 20 minutes. The reaction mixture extrag the shape dichloromethane and washed with water and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure and the residue purified column chromatography on silica gel (methanol-dichloromethane), getting mentioned in the title compound as a colourless oil (281 mg, yield: 55%).

1H-NMR (CDCl3): 8,07 (1H, DD, J=7,5, 1.2 Hz), 7,45-to 7.32 (2H, m), 7,19-7,17 (1H, m), 4,10 (2H, sh. C)of 3.57 (2H, DD, J=6,6, and 6.6 Hz)of 3.00 (2H, DD, J=6,6, and 6.6 Hz), to 3.02 (2H, sh. C)2,69 (2H, sh. DD, J=12,1, 12.1 Hz), 1,96-1,90 (1H, m), 1,72-of 1.62 (2H, m)of 1.46 (9H, s), 1,31-of 1.18 (2H, m).

d) of the Hydrochloride of 2-(piperidine-4-ylmethyl)-3,4-dihydroisoquinoline-1-(2H)-it

Using the crude product obtained in Example C (281 mg), get mentioned in the title compound as colorless solid by methods similar to the methods of Example 1d (232 mg, yield: quantitative).

e) 2-[[1-[2-(4-Forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-3,4-dihydroisoquinoline-1-(2H)-he

Using the compound obtained in Example 137d (230 mg, 0.82 mmol), get mentioned in the title compound as a brown oil by methods similar to the methods of Example 1E (110 mg, yield: 35%).

1H-NMR (CDCl3): 8,10-with 8.05 (3H, m), 7,43-7,33 (2H, m), 7,19-to 7.09 (3H, m), of 3.73 (2H, s), of 3.57 (2H, DD, J=6,8, 6,8 Hz), of 3.45 (2H, d,J=7,2 Hz), 3,01-2,95 (4H, m), of 2.15 (2H, DDD, J=1,1, and 11.5, and 11.5 Hz), 1,83-of 1.44 (5H, m).

f) of the Hydrochloride of 2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-3,4-dihydroisoquinoline-1(2H)-it

Using the connection, the floor is built in Example a (110 mg, 0.29 mmol), get mentioned in the title compound as a pale brown solid by methods similar to the methods of Example 1f (80 mg, yield: 66%).

Melting point: 151-156° C.

1H-NMR (DMSO-d6): 10,02 (1H, sh. C), 8,19-of 8.06 (2H, m), 7,87 (1H, d, J=7.8 Hz), 7,51 was 7.45 (3H, m), 7,38-7,29 (2H, m), 5,11-5,04 (2H, m), 3,60-of 3.53 (4H, m), 3,44-3,37 (2H, m), 3,07 are 2.98 (4H, m), 1,99-1,07 (5H, m).

Example 138: Fumarate 2-[[1-[(E)-2-(4-forfinal)-2-methoxymethyl]piperidine-4-yl]methyl]isoindoline-1-it (E-isomer Compound 741 Table 1)

a) 2-[[1-[(E)-2-(4-forfinal)-2-methoxymethyl]piperidine-4-yl]methyl]isoindoline-1-he 2-[[1-[(Z)-2-(4-forfinal)-2-methoxymethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 1E, and hydrochloride methoxylamine get mentioned in the title compound by methods similar to the methods of Example 18a.

2-[[1-[(E)-2-(4-forfinal)-2-methoxymethyl]piperidine-4-yl]methyl]isoindoline-1-he (yield: 30%)

1H-NMR (CDCl3): δ to 7.84 (d, J=7.5 Hz, 1H), 7,78 (m, 2H), 7,41-7,52 (m, 3H), 7,01 (t, J=9 Hz, 2H), 4,37 (s, 2H), of 3.94 (s, 3H), of 3.57 (s, 2H), 3.46 in (d, J=7,4 Hz, 2H), 2,82 (sh. d, J=11,6 Hz, 2H), 2,04 (t, J=10 Hz, 2H), 1,74 (m, 1H), 1,59 (m, 2H), 1,30 (m, 2H).

2-[[1-[(Z)-2-(4-forfinal)-2-methoxymethyl]piperidine-4-yl]methyl]isoindoline-1-he (yield: 6%)

1H-NMR (CDCl3): δ to 7.84 (d, J=7.5 Hz, 1H), to 7.59 (m, 2H), 7,42-7,53 (m, 3H), 7,05 (t, J=8,9 Hz, 2H), to 4.38 (s, 2H), 3,86 (s, 3H), 3,48 (d, J=7,3 Hz, 2H), 3,30 (s, 2H), 2.91 in (sh. d, J=11,6 Hz, 2H), 2,01 (sh. t, J=11 is C, 2H), 1,76 (m, 1H), 1,62 (m, 2H), 1,33 (m, 2H).

b) Fumarate, 2-[[1-[(E)-2-(4-forfinal)-2-methoxymethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 66%).

Melting point: 176° C.

1H-NMR (DMSO-d6): δ 7,79 (m, 2H), 7,65 (d, J=7.5 Hz, 1H), 7,58 (m, 2H), 7,49 (m, 1H), 7,21 (m, 2H), 6,63 (s, 2H), of 4.45 (s, 2H), 3,88 (s, 3H)and 3.59 (s, 2H), 3,35 (d, J=7,3 Hz, 2H), was 2.76 (sh. d, J=11.5 Hz, 2H), 1,99 (sh. t, J=10 Hz, 2H), 1.69 in (m, 1H), 1,51 (sh. d, J=11,4 Hz, 2H), 1,08 (m, 2H).

Example 139: Fumarate 2-[[1-[(Z)-2-(4-forfinal)-2-methoxymethyl]piperidine-4-yl]methyl]isoindoline-1-it (Z-isomer Compound 741 Table 1)

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 91%).

Melting point: 164° C.

1H-NMR (DMSO-d6): δ the 7.65 (d, J=7.5 Hz, 1H), 7,55 to 7.62 (m, 4H), 7,47 (m, 1H), 7.23 percent (t, J=8,9 Hz, 2H), is 6.61 (s, 2H), 4,49 (s, 2H, in), 3.75 (s, 3H), 3,35 (d, J=7,4 Hz, 2H), 3,30 (s, 2H), 2,80 (sh. d, J=11.5 Hz, 2H), 1.93 and (sh. t, J=11 Hz, 2H), by 1.68 (m, 1H), 1,52 (sh. d, J=11.8 Hz, 2H), 1,07 (m, 2H).

Example 140: 2-[[1-[(E)-2-(4-forfinal)-2-methoxycarbonylethyl]piperidine-4-yl]methyl]isoindoline-1-it is a 1/4· ) fumarate (E-isomer Compound 746 Table 1)

a) 2-[[1-[(E)-2-(4-forfinal)-2-methoxycarbonylethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in the Use of the e 1E, and methylhydroperoxide get mentioned in the title compound by methods similar to the methods of Example 18a (yield: 46%).

1H-NMR (CDCl3): δ 11,95 (s, 1H), a 7.85 (d, J=6,9 Hz, 1H), 7,68 (m, 2H), 7,43-of 7.55 (m, 3H), 7,03 (t, J=9 Hz, 2H), to 4.41 (s, 2H), 3,85 (s, 3H), of 3.64 (s, 2H), 3,54 (d, J=7.2 Hz, 2H), 2.95 and (sh. d, J=11 Hz, 2H), 2,08 (sh. t, J=11 Hz, 2H), 1,87 (m, 1H), 1,76 (sh. d, J=12 Hz, 2H), 1,44 (m, 2H).

2-[[1-[(Z)-2-(4-forfinal)-2-methoxycarbonylethyl]piperidine-4-yl]methyl]isoindoline-1-he (yield: 15%)

1H-NMR (CDCl3): δ to 7.84 (d, J=7.2 Hz, 1H), 7,45-7,53 (m, 3H), 7,28 (m, 2H), 7,18 (t, J=9 Hz, 2H), to 4.38 (s, 2H), 3,78 (sh. s, 3H), 3,47 (d, J=7.5 Hz, 2H), 3,36 (s, 2H), 2,85 (sh. d, J=11 Hz, 2H), 2.06 to (sh. t, J=10 Hz, 2H), 1,72 (m, 1H), 1,61 (m, 2H), 1.28 (in m, 2H).

b) 2-[[1-[(E)-2-(4-forfinal)-2-methoxycarbonylethyl]piperidine-4-yl]methyl]isoindoline-1-he ģ fumarate

Using the compound obtained in Example 140A, get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 76%).

Melting point: 154° C.

1H-NMR (DMSO-d6): δ 12,08 (sh. s, 1H), to 7.75 (m, 2H), to 7.67 (d, J=7.5 Hz, 1H), to 7.59 (m, 2H), 7,50 (m, 1H), 7,22 (t, J=9 Hz, 2H), 6,63 (s, 0,5H), 4,48 (s, 2H), of 3.73 (s, 2H), 3,71 (s, 3H), 3,42 (d, J=7.2 Hz, 2H), 2,82 (sh. d, J=12 Hz, 2H), 2,08 (sh. t, J=11 Hz, 2H), 1.77 in (m, 1H), 1,64 (sh. d, J=12 Hz, 2H), 1,18 (m, 2H).

Example 141: Fumarate 2-[[1-[(Z)-2-(4-forfinal)-2-methoxycarbonylethyl]piperidine-4-yl]methyl]isoindoline-1-it (Z-isomer Compound 746 Table 1)

Using the compound obtained in Primera, get listed in the title compound by methods similar to the methods of Example 40 (yield: 73%).

Melting point: 153° C.

1H-NMR (DMSO-d6): δ 9,39 (s, 1H), 7,65 (d, J=7.5 Hz, 1H), 7,58 (m, 2H), of 7.48 (m, 1H), 7,38 (m, 2H), 7,27 (t, J=9 Hz, 2H), 6,62 (s, 2H), of 4.45 (s, 2H), 3,60 (s, 3H), 3,35 (d, J=7.5 Hz, 2H), 3,32 (s, 2H), 2,80 (W. d, J=11 Hz, 2H), up to 1.98 (m, 2H), 1.70 to (m, 1H), of 1.52 (m, 2H), 1,07 (m, 2H).

Example 142: Fumarate 2-[[1-[(E)-2-(4-forfinal)-2-acetylhydrazone]piperidine-4-yl]methyl]isoindoline-1-it (E-isomer Compound 751 Table 1)

a) 2-[[1-[(E)-2-(4-forfinal)-2-acetylhydrazone]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 1E, and acetic acid hydrazide, get mentioned in the title compound by methods similar to the methods of Example 18a (yield: 64%).

1H-NMR (CDCl3): δ 11,98 (s, 1H), to 7.84 (d, J=7.2 Hz, 1H), to 7.67 (m, 2H), 7.24 to rate of 7.54 (m, 3H), 7,06 (t, J=8.7 Hz, 2H), to 4.41 (s, 2H), 3,63 (s, 2H), 3,51 (d, J=7.5 Hz, 2H), 2.91 in (sh. d, J=11,4 Hz, 2H), 2,32 (s, 3H), 2,09 (sh. t, J=10 Hz, 2H)and 1.83 (m, 1H), 1,76 (sh. d, J=12 Hz, 2H), 1,47 (m, 2H).

b) Fumarate, 2-[[1-[(E)-2-(4-forfinal)-2-acetylhydrazone]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 142a, get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 75%).

Melting point: 168-170° C.

1H-NMR (DMSO-d6): δ 12,06 (s, 1H), 7,80 (m, 2H), to 7.67 (d, J=7.5 Hz, 1H), to 7.59 (m, 2H), of 7.48 (m, 1H), 7.23 percent (t, J=9 Hz, 2H), 4,48 (s, H), of 3.75 (s, 2H), 3,42 (d, J=7.2 Hz, 2H), 2,83 (sh. d, J=11 Hz, 2H), measuring 2.20 (s, 3H), 2,08 (sh. t, J=11 Hz, 2H), 1,76 (m, 1H), 1,64 (sh. d, J=12 Hz, 2H), 1,19 (m, 2H).

Example 143: Fumarate 2-[[1-[(Z)-2-(4-forfinal)-2-acetylhydrazone]piperidine-4-yl]methyl]isoindoline-1-it (Z-isomer Compound 751 Table 1)

a) N’-[2-Chloro-1-(4-forfinal)ethylidene]acetohydrazide

2-Chloro-4’-peracetate (1,00 g, 5,79 mmol) and acetic acid hydrazide (0,472 g, 6,37 mmol) dissolved in ethanol (10 ml) and the mixture is stirred at room temperature for 8 hours. The reaction mixture was concentrated and then the remaining solid is suspended and washed in hexane. The obtained solid is purified column chromatography on silica gel (dichloromethane/ethyl acetate), obtaining mentioned in the title compound (yield: 94%).

1H-NMR (CDCl3): δ 9,19 (sh. s, 1H), to 7.75 (m, 2H), 7,12 (m, 2H), of 4.44 (s, 2H), 2,41 (s, 3H).

b) 2-[[1-[(Z)-2-(4-forfinal)-2-acetylhydrazone]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 143a, get mentioned in the title compound by methods similar to the methods of Example 1f, and then spend the purification using chromatography on silica gel (dichloromethane/methanol) (yield: 53%).

1H-NMR (CDCl3): δ 8,29 (s, 1H), a 7.85 (d, J=7.2 Hz, 1H), 7,42-rate of 7.54 (m, 3H), 7,24 (m, 2H), 7,16 (t, J=8.7 Hz, 2H), 4,39 (s, 2H), 3,49 (d, J=7.2 Hz, 2H), 3,30 (s, 2H), 2,90 (sh. d, J=11.7 Hz, 2H), 2,30 (s, 3H), of 2.06 (m, 2H), 1,78 (m, 1H), 1,65 (m, 2H), 1,34 (who, 2H).

C) Fumarate, 2-[[1-[(Z)-2-(4-forfinal)-2-acetylhydrazone]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 143b, get mentioned in the title compound by methods similar to the methods of Example 40f (yield: 63%).

Melting point: 157° C.

1H-NMR (DMSO-d6): δ 9,34-9,92 (m, 1H), 7,66 (d, J=7.2 Hz, 1H), 7,58 (m, 2H), 7,40-EUR 7.57 (m, 3H), 7,31 (t, J=9.0 Hz, 2H), 6,62 (s, 2H), of 4.45 (s, 2H), 3,35 is 3.40 (m, 4H), and 2.83 (m, 2H), 1,82-of 2.15 (m, 5H), 1,71 (m, 1H), of 1.53 (m, 2H), 1,08 (m, 2H).

Example 144: Fumarate (E,Z)-2-[[1-[2-(4-forfinal)-2-(benzyloxy)aminoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Connection 756 Table 1)

The compound obtained in Example 1E (581 mg, of 1.59 mmol)and hydrochloride benzyloxyaniline (568 mg, of 3.56 mmol) was dissolved in a mixed solvent of pyridine (12 ml)-ethanol (12 ml) and the mixture is stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with saturated salt solution and dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate concentrated under reduced pressure, obtaining the (E,Z)-2-[[1-[2-(4-forfinal)-2-(benzyloxy)aminoethyl]piperidine-4-yl]methyl]isoindoline-1-it is in the form of a crude product. Using the resulting product, get mentioned in the title compound as a colourless solid matter what means, similar to the methods of Example 36C (255 mg, yield: 27%).

Melting point: 151-155° C.

1H-NMR (DMSO-d6): 7,18-7,78 (13H, m), 6,63 (2H, s, fumaric acid), 5,17 (0,8H, C)5,07 (1,2H, C), of 4.45 (2H, s), 3,63 (0,8H, s), 3,2-3,4 (3,2H, m), 2.70 height is 2.80 (2H, m), 1,86-2,03 (2H, m), of 1.6-1.8 (1H, m), 1,4-1,5 (2H, m,), 0,9-1,1 (2H, m).

Example 145: Hydrochloride 2-[[1[(E)-3-phenylpro-2-penyl]piperidine-4-yl]methyl]isoindoline-1-it (E-isomer Compound 364 Table 1)

a) 2-[[1[(E)-3-phenylpro-2-penyl]piperidine-4-yl]methyl]isoindoline-1-he

The compound obtained in Example 1 (500 mg, of 1.87 mmol)and 3-bromo-1-phenyl-1-propene (369 mg, of 1.87 mmol) dissolved in dimethylformamide (6 ml) and to the solution was added potassium carbonate (516 mg, 3,74 mmol) and stirred at room temperature for 20 hours. To the reaction mixture are added water (20 ml) and precipitated precipitated solid is collected by filtration, getting mentioned in the title compound as a colourless solid (402 mg, yield: 62%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,0 Hz), 7,83-7,22 (8H, m), 6,50 (1H, d, J=16.0 Hz), 6,28 (1H, dt, J=15,8, 6,7 Hz)to 4.41 (2H, s), 3,51 (2H, d, J=7,1 Hz), 3,14 (2H, d, J=6,7 Hz), 2,98 (2H, sh. d, J=11.0 in Hz)of 1.97 (2H, DD, J=11,4 Hz), 1,86 was 1.69 (3H, m)of 1.42 (2H, DDD, J=24.5 cm, 12,5, 2,9 Hz).

(b) Hydrochloride of 2-[[1[(E)-3-phenylpro-2-penyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example a get mentioned in the title compound as colourless solids ways, than the ranks to the methods of Example 1f (197 mg, yield: 45%).

Melting point: 212-215° C.

1H-NMR (DMSO-d6): 10,8 (1H, m), 7,68 (1H, d, J=4,8 Hz), to 7.61 (2H, d, J=3,9 Hz), 7,53-7,46 (3H, m), 7,41-7,30 (3H, m), for 6.81 (1H, d, J=15,9 Hz), to 6.43 (1H, dt, J=15,9, a 7.6 Hz), 4,51 (2H, s), a-3.84 (2H, s), 3,44 (2H, d, J=6,9 Hz), at 3.35 (2H, s), 2,90-2,87 (2H, m), 1,99 (1H, sh. C)is 1.81 (2H, sh. d, J=13.5 Hz), of 1.57 (2H, sh. DD, J=15,2, and 11.6 Hz).

Example 146: Hydrochloride 2-[[1[(Z)-3-phenylpro-2-penyl]-piperidine-4-yl]methyl]isoindoline-1-it (Z-isomer (Compound 364 Table 1)

a) (Z)-3-Phenylpro-2-pen-1-ol

3-Phenylpro-2-pen-1-ol (500 mg, of 3.78 mmol) was dissolved in ethanol (3 ml) and then suspended in the solution Lindlar catalyst (25 mg). The mixture is stirred for 6 hours in a stream of hydrogen. The reaction mixture is filtered and the filtrate is concentrated and then the residue is purified column chromatography on silica gel (dichloromethane), getting mentioned in the title compound as a yellow oil (500 mg, quantitative).

1H-NMR (CDCl3): 7,41-7,19 (5H, m), to 6.58 (1H, d, J=11.7 Hz), 5,88 (1H, dt, J=11,7, 6.2 Hz), of 4.44 (2H, DD, J=6,3, 1.5 Hz).

b) (Z)-3-Chloro-1-phenylprop-1-pins

The compound obtained in Example 146a (300 mg, 2,24 mmol) dissolved in dichloromethane (7 ml) and to the solution was added p-toluensulfonate (427 mg, 2,24 mmol) and triethylamine (0.31 in ml, of 2.24 mmol) under cooling with ice. The mixture is then warmed to room temperature and stirred for 16 hours. The reaction mixture was added water (10 ml) and extracted with dichloromethane. Extra is t washed with water and saturated salt solution and then dried over sodium sulfate. Insoluble solids are removed by filtration and the filtrate evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel (hexane), getting mentioned in the title compound as a colourless oil (113 mg, yield: 33%).

1H-NMR (CDCl3): 7,41-7,26 (5H, m), of 6.66 (1H, d, J=11,4 Hz), 5,90 (1H, dt, J=11,4, 8,2 Hz), 4,27 (2H, d, J=6,9 Hz).

C) 2-[[1[(Z)-3-Phenylpro-2-penyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 146b (110 mg, 0,721 mmol)and the compound obtained in Example 1d (183 mg, 0,685 mmol), get mentioned in the title compound as colorless solid by methods similar to the methods of Example a (236 mg, yield: quantitative).

1H-NMR (CDCl3): to 7.84 (1H, d, J=7.5 Hz), 7,54-7,21 (8H, m), 6,55 (1H, d, J=11,9 Hz), 5,79 (1H, dt, J=11,2, 6,1 Hz), and 4.40 (2H, s), 3,50 (2H, d, J=7,0 Hz), 3,26 (2H, DD, J=6,1, 1.2 Hz), 2,96 (2H, sh. d, J=8,3 Hz) 1,98-to 1.87 (2H, m), 1,79-to 1.67 (3H, m), 1,48-of 1.40 (2H, m).

d) of the Hydrochloride of 2-[[1[(Z)-3-phenylpro-2-penyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 146s (230 mg, 0,664 mmol), get mentioned in the title compound as colorless solid by methods similar to the methods of Example 1f (148 mg, yield: 58%).

Melting point: 206-215° C (decomp.)

1H-NMR (DMSO-d6); 10,96 (1H, sh. C)to 7.68 (1H, d, J=7,2 Hz), 7,60 (2H, d, J=3,9 Hz), 6,83 (1H, d, J=12.0 Hz), 6,00 (1H, dt, J=11,7, ,2 Hz), of 4.49 (2H, s), 4,11-3,99 (2H, m), 3,62-to 3.41 (2H, m), 2,85 (2H, sh. DD, J=21,8, 10.1 Hz), 1,99 is 1.91 (1H, m), of 1.78 (2H, sh. d, J=12.3 Hz), of 1.62 (2H, sh. d, J=23,7, 12.3 Hz).

Example 147: Hydrochloride 2-[[1-(3-phenylpro-2-penyl)piperidine-4-yl]methyl]isoindoline-1-she (Compound 370 Table 1)

a) 3-Chloro-1-phenylprop-1-pin

Using 3-phenylpro-2-pin-1-ol (300 mg, of 2.27 mmol), get mentioned in the title compound as a colourless oil, carrying out a reaction similar to the reaction of Example 146b (99 mg, yield: 29%).

1H-NMR (CDCl3): 7,47-7,44 (2H, m), 7,45-to 7.32 (3H, m), to 4.38 (2H, s).

b) 2-[[1-(3-phenylpro-2-penyl)piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example a (99 mg, 0,657 mmol)and the compound obtained in Example 1d (158 mg, 0,591 mmol), get mentioned in the title compound as colorless solid by methods similar to the methods of Example a (163 mg, yield: 80%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7.5 Hz), 7,56-7,41 (5H, m), 7,31-7,26 (3H, m), 4,42 (2H, s), 3,53-3,51 (4H, m), 2,98 (2H, sh. d, J=12,6 Hz), and 2.27 (2H, DDD, J=2,2, 11,6, the 11.6 Hz), 1.85 to at 1.73 (3H, m), 1,53 was 1.43 (2H, m).

(C) the Hydrochloride of 2-[[1-(3-phenylpro-2-penyl)piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 147b (160 mg, 0,465 mmol), get mentioned in the title compound as colorless solid by methods similar to the methods of Example 1f (138 mg, yield: 78%).

Melting point: 205-211° C.

1H-NMR (DMSO-d sub> 6): 11,16 (1H, sh. C), 7,70-the 7.43 (9H, m)to 4.52 (2H, s), or 4.31 (2H, s), 3,57-to 3.36 (4H, m), to 3.02 (2H, sh. C)2,03-to 1.59 (5H, m).

Example 148: Hydrochloride 2-[[1-[2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 576 Table 1)

a) Methanesulfonate 2-(hydroxyethyl)isoindoline-1-it

Using the compound obtained in Example 1b and 2-aminoethanol will receive 2-(hydroxyethyl)isoindoline-1-it is in the form of the crude product by methods similar to the methods of Example 1C. Using the resulting product, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 26a (yield: 30%).

b) 2-[[1-[2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 148b, get mentioned in the title compound as a pale yellow oil by methods similar to the methods of Example 26b (yield: 72%).

1H-NMR (CDCl3): to 7.84 (2H, d, J=7,2), 7,41-7,56 (6H, m), 4,51 (2H, s), 4,39 (2H, s), and 3.72 (2H, t, J=6,3), 3,50 (2H, d, J=7,2), 2,92-of 3.00 (2H, m), 2,62 (2H, t, J=6,3), 1,95 e 2.06 (2H, m), of 1.5-1.9 (3H, m), 1,2-1,4 (2H, m).

(C) the Hydrochloride of 2-[[1-[2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 148b, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 1f (yield: 51%).

That is ka melting point: 212-218° C.

1H-NMR (DMSO-d6): 9,6-10,0 (1H, sh. HCl), 7,56-7,73 (6H, m), 7,45-rate of 7.54 (2H, m), 4,55 (2H, s), 4,50 (2H, s), 3,93 (2H, t, J=6,0), to 3.58-3,68 (2H, m), 3,3-3,5 (4H, m), 2,84 are 2.98 (2H, m), 1,9-2,1 (1H, m), 1.7 to 1.9 (2H, m), 1.3 to 1.7 (2H, m).

Example 149: Hydrochloride 2-[[1-[3-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)propyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 581 Table 1)

a) Methanesulfonate 3-(hydroxypropyl)isoindoline-1-it

Using the compound obtained in Example 1b, and 3-aminopropanol receive 3-(hydroxypropyl)isoindoline-1-it is in the form of the crude product by methods similar to the methods of Example 1C. Using the resulting product, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 26a (yield: 38%).

b) 2-[[1-[3-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)propyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 149b, get mentioned in the title compound as a yellow solid by methods similar to the methods of Example 26b (yield: 54%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=6,0), 7,83 (1H, d, J=6,3), 7,41-7,56 (6H, m), 4,39 (4H, s), the 3.65 (2H, t, J=7,1), 3,48 (2H, d, J=7,2), 2,87-of 3.95 (2H, m), 2,39 (2H, t, J=7,4), of 1.5-1.9 (7H, m), 1,2-1,4 (2H, m).

(C) the Hydrochloride of 2-[[1-[2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 149b, get specified header connection in vie the e colorless solids ways, similar to the methods of Example 1f (yield: 58%).

Melting point: 236-246° C.

1H-NMR (DMSO-d6): of 9.8 to 10.0 (1H, sh. HCl), to 7.68 (2H, d, J=7,3), 7,56-the 7.65 (4H, m), 7,45-7,53 (2H, m)to 4.52 (2H, s), 4,50 (2H, s), of 3.60 (2H, t, J=6,6), of 3.0-3.5 (4H, m), of 2.9-3.0 (2H, m), 2,6-2,8 (2H, m), 1,8-2,2 (3H, m), 1,6-1,8 (2H, m,), 1,3-1,6 (2H, m).

Example 150: Hydrochloride 2-[[1-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)butyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 586 Table 1)

a) Methanesulfonate of 4-(Hydroxybutyl)isoindoline-1-it

Using the compound obtained in Example 1b and 4-aminobutanol, receive a 4-(hydroxybutyl)isoindoline-1-it is in the form of the crude product by methods similar to the methods of Example 1C. Using the resulting product, get mentioned in the title compound as a colorless oil by methods similar to the methods of Example 26a (yield: 43%).

b) 2-[[1-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)butyl]-piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 150A, get mentioned in the title compound as a yellow solid by methods similar to the methods of Example 26b (yield: 87%).

1H-NMR (CDCl3): to 7.84 (1H, d, J=6,6), 7,83 (1H, d, J=6,9), 7,42-7,56 (6H, m), 4,39 (2H, s), 4,37 (2H, s), 3,63 (2H, t, J=7,1), 3,49 (2H, d, J=7,2), 2,84 of 2.92 (2H, m), of 2.34 (2H, t, J=7,5), 1,4-1,9 (9H, m), 1,2-1,4 (2H, m).

(C) the Hydrochloride of 2-[[1-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)butyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the connection is s, obtained in Example 150b, get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 87%).

Melting point: 207-216° C.

1H-NMR (DMSO-d6): a 10.1-10,4 (1H, sh. HCl), to 7.68 (2H, d, J=7,5), 7,56-the 7.65 (4H, m), 7,46-7,53 (2H, m), 4,50 (4H, s), 3,50-3,62 (2H, m), 3.0 to 3.5 (4H, m), of 2.9-3.0 (2H, m), 2,6-2,8 (2H, m), 1,4-2,2 (9H, m).

Example 151: Fumarate 2-[[1-[3-[2-oxo-3,4-dihydroquinoline-1(2H)-yl]propyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 601 Table 1)

a) 1-(3-Hydroxypropyl)-3,4-dihydroquinoline-2(1H)-he

3,4-Dihydro-2(1H)-chinoline (1.20 g, 8,15 mmol) dissolved in dimethylformamide (10 ml) and to the solution was added 60% sodium hydride (376 mg, 9,40 mmol) at room temperature and stirred at the same temperature for 30 minutes. The mixture was added 2-(3-bromopropane)tetrahydro-2H-Piran (1,94 g to 8.70 mmol) and heated at 70° C for 1 hour. The reaction mixture is cooled to room temperature and diluted with water and then extracted with a mixed solvent of ethyl acetate-hexane. The extract is washed with saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate concentrated under reduced pressure. The oil obtained is dissolved in methanol (90 ml) and the solution was added a catalytic amount of p-toluenesulfonic acid and stirred at room temperature for 19 hours. Dissolve the ü from the reaction mixture is evaporated under reduced pressure and the residue diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and then with saturated salt solution and dried over magnesium sulfate. Insoluble solids are removed by filtration and the filtrate concentrated under reduced pressure. The resulting oil is purified column chromatography on silica gel (ethyl acetate-hexane), getting mentioned in the title compound as a colourless oil (1.47 g, yield: 88%).

1H-NMR (CDCl3): 7,15-7,29 (2H, m), 7,00-7,11 (2H, m), of 4.12 (2H, t, J=6,2), of 3.56 (2H, t, J=5,6), to 3.38 (1H, sh. s, OH), 2,89-2,96 (2H, m), 2,67-to 2.74 (2H, m), 1,83-of 1.94 (2H, m).

b) 2-[[1-[3-[2-oxo-3,4-dihydroquinoline-1(2H)-yl]propyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example a get methanesulfonate 1-(3-hydroxypropyl)-3,4-dihydroquinoline-2(1H)-it is in the form of the crude product by methods similar to the methods of Example 26a. Using the resulting product, get mentioned in the title compound as a yellow oil by methods similar to the methods of Example 26b (yield: 59%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,4), 7,41-rate of 7.54 (3H, m), 7,20-7,26 (1H, m), to 7.15 (1H, d, J=7,2), was 7.08 (1H, d, J=8.0 a), of 6.99 (1H, t, J=7,6), and 4.40 (2H, s), of 3.96 (2H, t, J=7,5), 3,51 (2H, d, J=7,2), 2,84-2,96 (4H, m), 2,59-to 2.67 (2H, m), 2,34 is 2.43 (2H, m), 1,6-2,1 (7H, m), 1,3-1,5 (2H, m).

C) Fumarate, 2-[[1-[3-[2-oxo-3,4-dihydroquinoline-1(2H)-yl]propyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 151b, get specified the OE in the title compound as colourless solids ways, similar to the methods of Example 36C (yield: 55%).

Melting point: 185-193° C.

1H-NMR (DMSO-d6): to 7.67 (1H, d, J=7,5), 7,56-to 7.61 (2H, m), 7,45-7,52 (1H, m), 7,14-7,27 (3H, m), of 6.99 (1H, t, J=7,2), 6,56 (2H, s, fumaric acid), 4,48 (2H, s)to 3.89 (2H, t, J=7,2), to 3.41 (2H, d, J=7,2), 2,94-to 3.02 (2H, m), 2,84 (2H, t, J=7,6), 2,4-2,6 (4H, m), of 2.0-2.2 (2H, m), of 1.5-1.9 (5H, m), 1,1-1,3 (2H, m).

Example 152: Fumarate 2-[[1-[3-[2-oxoindole-1(2H)-yl]propyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 606 Table 1)

a) 1-(3-Hydroxypropyl)quinoline-2(1H)-he

Using 2-hydroxyquinolin get mentioned in the title compound as colorless solid by methods similar to the methods of Example a (yield: 41%).

1H-NMR (CDCl3): 7,76 (1H, d, J=9,5), EUR 7.57-to 7.64 (2H, m), 7,46 (1H, d, J=8,9), 7,25-to 7.32 (1H, m), of 6.75 (1H, d, J=9,5), 4,51 (2H, t, J=6,0), and 3.6 to 4.4 (1H, sh. OH), 3,51 (2H, t, J=5.5), the 1,97-2,07 (2H, m).

b) 2-[[1-[3-[2-oxoindole-1(2H)-yl]propyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 152a, get methanesulfonate 1-(3-hydroxypropyl)quinoline-2(1H)-it is in the form of the crude product by methods similar to the methods of Example 26a. Using the resulting product, get mentioned in the title compound as a yellow oil by methods similar to the methods of Example 26b (yield: 88%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,2), 7,66 (1H, d, J=9,5), 7,42-7,58 (6H, m), 7,15-7,27 (2H, m), of 6.68 (1H, d, J=9,5), and 4.40 (2H, s), 4,34 (2H, t, J=7,4), 3,52 (2H, d, J=7,2), 2,90 are 2.98 (2H, m), 2,46 (2H, t, J=69), of 2.0-2.2 (2H, m), 1,6-2,0 (7H, m), 1,3-1,5 (2H, m).

C) Fumarate, 2-[[1-[3-[2-oxoindole-1(2H)-yl]propyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 152b, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 36C (yield: 82%).

Melting point: 208-215° C.

1H-NMR (DMSO-d6): of 7.90 (1H, d, J=9,5), EUR 7.57-7,74 (6H, m), 7,45-7,52 (1H, m), 7,22-of 7.3 (1H, m), 6,60 (1H, d, J=9.5)is, to 6.57 (2H, s, fumaric acid), 4,48 (2H, s), 4,25 (2H, t, J=7,2), 3,42 (2H, d, J=7,1), 2,95-3,03 (2H, m), 2.57 m (2H, t, J=6,9), 2.06 to to 2.18 (2H, m), 1.7 to 1.9 (3H, m), 1,5-1,6 (2H, m), 1,2-1,4 (2H, m).

Example 153: Hydrochloride 2-[[1-[2-[2-oxo-3-phenylimidazoline-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 596 Table 1)

a) 1-(2-Hydroxyethyl)-3-phenylimidazoline-2-he

Using 1-phenylimidazoline-2-it is obtained by the method described in literature (J. Org. Chem., 1951, 16, 1829), and t-butyldimethylsilyl-2-bromatology ether, obtained by the method of Example 92A, receive 1-[2-(t-butyldimethylsilyloxy)ethyl]-3-phenylimidazoline-2-it is in the form of the crude product by methods similar to the methods of Example a. Using the resulting product, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 92b (yield: 75%).

1H-NMR (CDCl3): 7,53 (2H, d, J=8,0), 7,34 (2H, t, J=8,4), 7,05 (1H, t, J=7,4), 3,82-to 3.89 (4H, m)and 3.59 (2H, t, J=7,3), of 3.45 (2H, t, =5,1), a 3.01 (1H, sh. s, OH).

b) 2-[[1-[2-[2-oxo-3-phenylimidazoline-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example a get methanesulfonate 1-(2-hydroxyethyl)-3-phenylimidazoline-2-it is in the form of the crude product by methods similar to the methods of Example 26a. Using the resulting product, get mentioned in the title compound as a colorless oil by methods similar to the methods of Example 26b (yield: 65%).

1H-NMR (CDCl3): a 7.85 (1H, d, J=7,5), 7,41-EUR 7.57 (5H, m), 7,32 (2H, t, J=7,5), 7,02 (1H, t, J=7,5), and 4.40 (2H, s), of 3.77-a-3.84 (2H, m), 3,53-of 3.60 (2H, m), 3,50 (2H, d, J=7,2), 3,42 (2H, t, J=6,3), 2,93-to 3.02 (2H, m), to 2.55 (2H, t, J=6,6), 1,95-2,07 (2H, m), 1.5 and 1.8 (3H, m), 1,2-1,4 (2H, m).

(C) the Hydrochloride of 2-[[1-[2-[2-oxo-3-phenylimidazoline-1-yl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 153b, get mentioned in the title compound as colorless solid by methods similar to the methods of Example 1f (yield: 93%).

Melting point: 207-219° C.

1H-NMR (DMSO-d6): 9,6-10,0 (1H, sh. HCl), to 7.68 (1H, d, J=7,5), 7,45 to 7.62 (5H, m), 7,33 (2H, t, J=7,8), 7,01 (1H, t, J=7,4), 4,51 (2H, s), 3,80-3,88 (2H, m), 3,50-3,62 (6H, m), 3.43 points (2H, d, J=7,5), with 3.27 (2H, t, J=5,9), 2,80 to 3.0 (2H, m), 1,9-2,1 (1H, m), 1,6-1,8 (2H, m), 1,4-1,6 (2H, m).

Example 154: Hydrochloride 5-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (Compound 9 in Table 1)

a) ethyl ester of 4-fluoro-2-methylbenzoic acid

<> To magnesium (0,644 g of 26.5 mmol) is added THF (4 ml) and a small amount of iodine. After stirring to the mixture is added dropwise a solution of 1-bromo-4-fluoro-2-methylbenzene (5,00 g of 26.5 mmol) in THF (50 ml). The mixture is stirred at room temperature for 30 minutes and then cooled at -78° and add dropwise a solution of ethylchloride (of 3.80 ml, 39.8 mmol) in THF (40 ml). The mixture is slowly warmed to room temperature and continue stirring at room temperature for 2 hours. The reaction mixture is diluted with ether and washed with water, saturated aqueous sodium bicarbonate and then with saturated salt solution and dried over sodium sulfate. The desiccant is removed by filtration and the filtrate is concentrated and the resulting oily substance is purified column chromatography on silica gel (hexane/ether)to give specified in the header connection (3,65 g, yield: 76%).

1H-NMR (CDCl3): δ of 1.39 (t, J=7.0 Hz, 3H), 2,61 (s, 3H), 4,35 (K, J=7,0 Hz, 2H), 6.89 in-to 6.95 (m, 2H), 7,95 (m, 1H).

b) Tert-butyl 4-(5-fluoro-1-occaisonaly-2-ylmethyl)piperidine-1-carboxylate

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Examples 1b and 1C (yield: 57%).

1H-NMR (CDCl3): δ 1,25 (m, 2H), 1,45 (s, 9H), of 1.64 (m, 2H), 1.93 and (m, 1H), 2,69 (m, 2H), 3,47 (m, 2H), 4,11 (m, 2H), 4,39 (s, 2H), 7,12-7,20 (m, 2H), 7,82 (DD, J=5,0, 8,3 Hz, 1H).

(C) the hydrochloride of 5-fluoro-2-(piperidine-4-ylmethyl)isoindoline-1-it

Using the compound obtained in Example 154b, get mentioned in the title compound by methods similar to the methods of Example 1d (yield: 91%).

1H-NMR (DMSO-d6): δ of 1.36 (m, 2H), 1,73 (m, 2H), 2,00 (m, 1H), 2,80 (m, 2H), 3,24 (m, 2H), 3,42 (d, J=7.5 Hz, 2H), 4,49 (s, 2H), 7,32 (m, 1H), 7,49 (d, J=8.6 Hz, 1H), 7,71 (DD, J=5,1, and 8.4 Hz, 1H), 8,49 (sh. s, 1H), 8,78 (sh. s, 1H).

d) 5-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example 154c, get mentioned in the title compound by methods similar to the methods of Example 1E (yield: 85%).

1H-NMR (CDCl3): δ to 1.47 (m, 2H), by 1.68 (m, 2H), is 1.81 (m, 1H), 2,15 (m, 2H), 2,96 (m, 2H), 3,49 (d, J=7.2 Hz, 2H), and 3.72 (s, 2H), to 4.38 (s, 2H), 7,08-to 7.18 (m, 4H), 7,81 (DD, J=5,0, 8,3 Hz, 1H), 8,07 (m, 2H).

e) of the Hydrochloride of 5-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]-piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 154d, get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 90%).

Melting point: 209-216° C.

1H-NMR (DMSO-d6): δ 1,58 is 1.86 (m, 4H), 2,03 (m, 1H), 3.04 from (m, 2H), 3.45 points (d, J=8,8 Hz, 2H), 3,54 (m, 2H), 4.53-in (s, 2H), 5,04-5,10 (m, 2H), 7,33 (m, 1H), 7,45-7,53 (m, 3H), 7,73 (DD, J=5,2, 8,3 Hz, 1H), 8,06-8,15 (m, 2H), 9,96 (sh. s, 1H).

Example 155: Hydrochloride 6-metiloksi-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it (Compounds is their 18 in Table 1)

a) methyl ester of 3-hydroxy-2-methylbenzoic acid

Using 3-hydroxy-2-methylbenzoic acid, get mentioned in the title compound by methods similar to the methods of Example 3A (yield: 97%).

1H-NMR (CDCl3): δ the 2.46 (s, 3H), with 3.89 (s, 3H), 6,94 (d, J=8,3 Hz, 1H), 7,11 (t, J=8,3 Hz, 1H), 7,42 (d, J=8,3 Hz, 1H).

b) methyl ester of 3-(tert-butyldimethylsilyloxy)-2-methylbenzoic acid

The compound obtained in Example a (4,99 g, 30.0 mmol), dissolved in DMF (DMF) (26 ml) and then the solution was added tert-butyldimethylchlorosilane (5,43 g, 36,0 mmol) and imidazole (5,11 g, 75,0 mmol) and stirred at room temperature. The reaction mixture was added saturated aqueous sodium bicarbonate solution and extracted four times with hexane and then the combined organic layer is dried over sodium sulfate. The desiccant is removed by filtration and the filtrate is concentrated and the obtained oily substance is purified column chromatography on silica gel (hexane/ethyl acetate), obtaining specified in the header connection (8,24 g, yield: 93%).

1H-NMR (CDCl3): δ of 0.21 (s, 6H), of 1.02 (s, 9H), is 2.41 (s, 3H), 3,88 (s, 3H), 6,93 (d, J=8,4 Hz, 1H), to 7.09 (t, J=8,4 Hz, 1H), 7,42 (d, J=8,4 Hz, 1H, c).

C) Tert-butyl 4-[6-(tert-butyldimethylsilyloxy)-1-occaisonaly-2-ylmethyl]piperidine-1-carboxylate

Using the compound obtained in Example 155b, receive specified in the header is Obedinenie ways, similar to the methods of Example 1b and 1C (yield: 71%).

1H-NMR (CDCl3): δ of 0.25 (s, 6H), of 1.02 (s, 9H), 1.26 in (m, 2H), 1,45 (s, 9H), of 1.66 (m, 2H), 1,95 (m, 1H), 2,70 (m, 2H), 3,49 (m, 2H), 4,10 (m, 2H), 4,30 (s, 2H), 6,93 (d, J=7.7 Hz, 1H), 7,33 (t, J=7.7 Hz, 1H), was 7.45 (d, J=7.7 Hz, 1H).

(d) Tert-butyl 4-(6-hydroxy-1-occaisonaly-2-ylmethyl]piperidine-1-carboxylate

The compound obtained in Example C (9,20 g, 20.0 mmol), and acetic acid (9,44 ml) dissolved in THF (100 ml) and the resulting solution was cooled to 0° and added thereto dropwise 1M solution of tetrabutylammonium fluoride in THF (of 20.0 ml, 20.0 mmol). After 30 minutes the reaction mixture was diluted with ethyl acetate and washed three times 0,5N aqueous solution of hydrochloric acid and then with saturated salt solution and dried over sodium sulfate. The desiccant is removed by filtration and the filtrate is concentrated and the obtained oily substance is crystallized from a mixture of dichloromethane/ether/hexane, getting mentioned in the title compound (5,70 g, yield: 82%).

1H-NMR (CDCl3): δ of 1.23 (m, 2H), of 1.46 (s, 9H), of 1.65 (m, 2H), 1,95 (m, 1H), 2,69 (m, 2H), 3,50 (m, 2H), 4,12 (m, 2H), to 4.41 (s, 2H), 7,03 (d, J=7.5 Hz, 1H), 7,29 (t, J=7.5 Hz, 1H), 7,39 (d, J=7.5 Hz, 1H).

e) of the hydrochloride of 6-metiloksi-2-(piperidine-4-ylmethyl]isoindoline-1-it

To a solution of the compound obtained in Example 155d (0,600 g of 1.74 mmol)in acetonitrile (6 ml) add itmean (0,216 ml, 3.46 mmol) and potassium carbonate (478 mg, 3.46 mmol) and heated at 60° C. After 2.5 hours the mixture is cooled to room temperature and diluted with ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution and saturated salt solution and then dried over sodium sulfate. The desiccant is removed by filtration and the filtrate is concentrated and the crude substance was processed by methods similar to the methods of Example 1d without treatment, getting mentioned in the title compound (yield: 94%).

1H-NMR (DMSO-d6): δ of 1.36 (m, 2H), 1,71 (m, 2H), 2,04 (m, 1H), and 2.79 (m, 2H), 3,24 (m, 2H), 3,42 (d, J=7,4 Hz, 2H), with 3.89 (s, 3H), to 4.41 (s, 2H), 7,21 (d, J=8,1 Hz, 1H), 7,26 (d, J=7,4 Hz, 1H), 7,47 (DD, J=7,4, 8,1 Hz, 1H), 8,55 (sh. s, 1H), 8,84 (sh. s, 1H).

f) of the Hydrochloride of 6-metiloksi-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-he

Using the compound obtained in Example I get mentioned in the title compound by methods similar to the methods of Examples 1E and 1f (yield: 67%).

Melting point: 213-229° C.

1H-NMR (DMSO-d6): d1,57-1,84 (m, 4H), of 2.05 (m, 1H), to 3.02 (m, 2H), 3.45 points (d, J=6,9 Hz, 2H), 3,53 (m, 2H), with 3.89 (s, 3H), of 4.45 (s, 2H), 5,03-5,09 (m, 2H), 7,22 (d, J=8,1 Hz, 1H), 7,27 (d, J=7,4 Hz, 1H), 7,45 is 7.50 (m, 3H), 8,05-of 8.15 (m, 2H), 9,95 (sh. s, 1H).

Example: 156: Hydrochloride 6-ethyloxy-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

a) hydrochloride of 6-acyloxy-2-(piperidine-4-ylmethyl)isoindoline-1-it

Using the compound obtained in Example 155d, get indicated the data in the header of the connection means, similar to the methods of Example e (yield: 97%).

1H-NMR (DMSO-d6): δ of 1.36 (m, 2H), of 1.37 (t, J=6.9 Hz, 3H), 1,71 (m, 2H), 2.05 is (m, 1H), and 2.79 (m, 2H), 3,23 (m, 2H), 3,42 (d, J=7,1 Hz, 2H), 4.16 the (K, J=6,9 Hz, 2H), to 4.41 (s, 2H), 7,19 (d, J=8,1 Hz, 1H), 7,25 (d, J=7,4 Hz, 1H), 7,45 (DD, J=7,4, 8,1 Hz, 1H), total of 8.74 (sh. s, 1H), 9,02 (sh. s, 1H).

(b) Hydrochloride of 6-acyloxy-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Examples 1E and 1f (yield: 43%).

Melting point: 200-209° C.

1H-NMR (DMSO-d6): δ to 1.37 (t, J=6.9 Hz, 3H), 1,57-of 1.84 (m, 4H), of 2.08 (m, 1H), 3,01 (m, 2H), 3.45 points (d, J=6,8 Hz, 2H), 3,53 (m, 2H), 4,17 (K, J=6,9 Hz, 2H), of 4.44 (s, 2H), 5,03-5,09 (m, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,26 (d, J=7,4 Hz, 1H), 7,42-to 7.50 (m, 3H), 8,06-8,16 (m, 2H), to 9.93 (sh. s, 1H).

Example 157: Hydrochloride 6-isopropoxy-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

a) Hydrochloride of isopropoxy-2-(piperidine-4-ylmethyl)isoindoline-1-it

Using the compound obtained in Example 155d, get mentioned in the title compound by methods similar to the methods of Example e (yield: 99%).

1H-NMR (DMSO-d6): δ of 1.30 (d, J=5.5 Hz, 6H), of 1.34 (m, 2H), 1,71 (m, 2H), 2,04 (m, 1H), and 2.79 (m, 2H), 3,23 (m, 2H), 3,41 (d, J=6.6 Hz, 2H), 4,37 (s, 2H), 4,74 (m, 1H), 7,21-of 7.23 (m, 2H), 7,43 (m, 1H), 8,60 (sh. s, 1H), 8,88 (sh. s, 1H).

b) Fumarate, 6-isopropoxy-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindol the Jn-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Examples 1E and 36C (yield: 53%).

Melting point: 132° C.

1H-NMR (DMSO-d6): δ to 1.21 (m, 2H), 1,30 (d, J=6.0 Hz, 6H), of 1.55 (m, 2H), 1,76 (m, 1H), 2,13 (m, 2H), 2,87 (m, 2H), 3,38 (d, J=7.2 Hz, 2H), 3,81 (s, 2H), 4,35 (s, 2H), 4,74 (m, 1H), is 6.61 (s, 2H), 7,19-of 7.23 (m, 2H,), 7,35 (t, J=8.7 Hz, 2H), 7,42 (t, J=7.8 Hz, 1H), 8,09 (DD, J= 5,7, to 8.7 Hz, 2H).

Example 158: Fumarate 5-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-4,5-dihydro-6N-furo[2,3-c]pyrrole-6-she (Connection 817 Table 2)

a) Methyl 3-bromomethylphenyl-2-carboxylate

Using methyl 3-methylpyridoxine (2.00 g, 14,27 mmol), get mentioned in the title compound in the form of the crude product as a yellow oil by reaction similar to the reaction of Example 1C (3.51 g). The crude product is used in subsequent reactions without purification.

b) Methyl 3-[[1-(tert-butoxycarbonyl)piperidine-4-yl]methylaminomethyl]-2-furancarboxylic

Using the compound obtained in Example 58A (3.51 g), get mentioned in the title compound as a yellow oil by reaction similar to the reaction of Example 1C (1.80 g, yield: 36%, stage 2).

1H-NMR (CDCl3): of 7.48 (1H, d, J=1.5 Hz), 6,55 (1H, d, J=1,8 Hz), 4.09 to (2H, sh. d, J=11.7 Hz), 3,94-3,91 (5H, m), 2,69 (2H, sh. t, J=12,5 Hz), of 2.51 (2H, d, J=6.6 Hz), 1,73 is 1.58 (3H, m)of 1.45 (9H, s), 1,18 was 1.06 (2H, m).

C) 3-[[1-(tert-Butoxycarbonyl who yl)piperidine-4-yl]methylaminomethyl]-2-francebuy acid

Using the compound obtained in Example 158b (180 g), get mentioned in the title compound as a yellow semi-solid substances, carrying out a reaction similar to the reaction of Example 22d (1.35 g, yield: 78%).

1H-NMR (CDCl3): 10,36 (2H, sh. C)of 7.48 (1H, d, J=1.5 Hz), to 6.58 (1H, d, J=1.2 Hz), to 4.23 (2H, sh. s), 4.09 to (2H, sh. d, J=7,4 Hz), 2,97-2,70 (4H, m), 2,08 (1H, sh. C)of 1.85 (2H, sh. d, J=12.0 Hz), of 1.42 (9H, s), 1,25-1,11 (2H, m).

(d) tert-Butyl 4-[(4,5-dihydro-6N-furo[2,3-C]pyrrol-6-one)-2-ylmethyl]piperidine-1-carboxylate

The compound obtained in Example s (658 mg, 1.94 mmol), 2,2’-piperidinedione (513 mg, of 2.33 mmol) and triphenylphosphine (611 mg, of 2.33 mmol) dissolved in acetonitrile (6 ml) and the mixture refluxed for 4 hours. The reaction mixture was kept for cooling and the solvent is evaporated. To the residue water is added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and then saturated salt solution and dried over anhydrous sodium sulfate. Insoluble solids are removed by filtration and the solvent is evaporated under reduced pressure. The crude product chromatographic on silica gel (ethyl acetate/hexane=1/1), getting mentioned in the title compound as a yellow oil (694 mg, mixture of reagent).

e) Hydrochloride 5-(piperidine-4-ylmethyl)-4,5-dihydro-6N-furo[2,3-c]pyrrol-6-he is

Using the compound obtained in Example 158d (658 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 1d (161 mg, yield: 12%, 3 phase).

1H-NMR (DMSO-d6): of 8.92 (1H, sh. C), 8,65 (1H, sh. C)to 7.99 (1H, s), 6,77 (1H, s), 4,30 (2H, s)to 3.33 (1H, d, J=7,4 Hz),3,24 (1H, sh. d, J=a 12.7 Hz), and 2.79 (2H, sh. DD, J=23,2, 12.0 Hz), 1,99 is 1.91 (1H, m), 1,72 (2H, d, J=13,2 Hz), 1,42-of 1.29 (2H, m).

f) 5-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl)-4,5-dihydro-6N-furo[2,3-c]pyrrole-6-he

Using the compound obtained in Example a (80 mg, 0,312 mmol), get mentioned in the title compound as a colourless solid, carrying out a reaction similar to the reaction of Example 1 (90 mg, yield: 81%).

1H-NMR (CDCl3): 8,10-with 8.05 (2H, m), to 7.61 (1H, d, J=1.7 Hz), 7,12 (2H, t, J=8.7 Hz), 6,50 (1H, d, J=1.6 Hz), 4,18 (2H, s), and 3.72 (2H, s)to 3.41 (2H, d, J=7,2 Hz), 2,96 (2H, sh. d, J=11,4 Hz), 2,18 is 2.10 (2H, m), 1,78-of 1.62 (3H, m), 1,50-of 1.41 (2H, m).

g) Fumarate, 4-fluoro-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]isoindoline-1-it

Using the compound obtained in Example 158f (90 mg, 0,253 mmol), get mentioned in the title compound as a colourless solid, carrying out a reaction similar to the reaction of Example 36C (109 mg, yield: 91%).

Melting point: 230-232° C.

1H-NMR (DMSO-d6): 8,11-8,07 (2H, m), of 7.97 (1H, d, J=1.7 Hz), 7,38-to 7.32 (2H, m), of 6.75 (1H, d, J=1.6 Hz), is 6.61 (2H, s), 4,27 (2H, s), a-3.84 (2H, s), 3,29 (2H, d, J=7,2 Hz) is 2.88 (2H, W. d, J=11.4 in Hz), and 2.14 (2H, t, J=10,8 Hz), 1.70 to to 1.67 (1H, m), and 1.56 (2H, d, J=12.3 Hz) 1,26-of 1.16 (2H, m).

Example: 159: Fumarate 5-methoxy-2-[1-[2-(4-forfinal)ethyl]-piperidine-4-ylmethyl]isoindoline-1-she (Compound 204 in Table 1)

Using the compound obtained in Example 8C, get mentioned in the title compound by methods similar to the methods of Examples 26b and 36C.

Melting point: 178-180° C.

1H-NMR (DMSO-d6): δ of 1.26 (m, 2H), and 1.63 (m, 2H), 1,79 (m, 1H, in), 2.25 (m, 2H), 2,72 (m, 2H), 2,78 (m, 2H), is 3.08 (m, 2H), 3,38 (d, J=7,1 Hz, 2H), 3,83 (s, 3H), 4,42 (s, 2H), to 6.57 (s, 2H), 7,00-7,14 (m, 4H), 7,27 (m, 2H), EUR 7.57 (d, J=8,4 Hz, 1H).

Example 160: Fumarate 5-bromo-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]isoindoline-1-she (Compound 198 in Table 1)

Using the compound obtained in Example 3d, get mentioned in the title compound by methods similar to the methods of Examples 26b and 36C.

Melting point: 203-219° C.

1H-NMR (DMSO-d6): δ of 1.26 (m, 2H), 1,62 (m, 2H), 1,79 (m, 1H), measuring 2.20 (m, 2H), 2,69 (m, 2H), 2,77 (m, 2H), 3,05 (m, 2H), 3,40 (d, J=7,0 Hz, 2H), 4,49 (s, 2H), return of 6.58 (s, 2H), 7,10 (t, J=8.6 Hz, 2H), 7.24 to 7,29 (m, 2H,), to 7.59 (m, 2H), 7,86 (s, 1H).

Example 161: Fumarate 5-chloro-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]isoindoline-1-she (Compound 203 in Table 1)

a) 5-Chloro-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]-isoindole-1-he

Using the compound obtained in Example 9c (250 mg, 0.83 mmol)and the compound obtained in Example 26a (181 mg, 0.83 mmol), receive specified in is the head of the compound as a crude product as a pale brown solid, carrying out a reaction similar to the reaction of Example 26b (245 mg). The crude product is used in subsequent reactions without purification.

b) Fumarate 5-chloro-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]isoindoline-1-it

Using the compound obtained in Example a (240 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (299 mg, yield: 72%, stage 2).

Melting point: 220-229° C.

1H-NMR (DMSO-d6): of 7.69 (2H, t, J=7,7 Hz), 7,54 (1H, DD, J=7,9,1,4 Hz), 7,27 (2H, DD, J=8,4, 5.7 Hz), 7,10 (2H, t, J=8,9 Hz), to 6.57 (2H, s), of 4.49 (2H, s)to 3.41 (2H, d, J=7,2 Hz), 3,10 (2H, sh. d, J=11,6 Hz), 2,82-2,70 (4H, m), and 2.26 (2H, sh. t, J=11,0 Hz)and 1.83-1.77 in (1H, m)of 1.64 (2H, sh. d, J=11.7 Hz), 1.32 to 1,24 (2H, m).

Example 162: Fumarate 5-cyano-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]isoindoline-1-she (Compound 205 in Table 1)

a) 5-cyano-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]isoindoline-1-he

Using the compound obtained in Example 10C (300 mg, of 1.03 mmol)and the compound obtained in Example 26a (225 mg, of 1.03 mmol), get mentioned in the title compound as a crude product as a pale brown solid, carrying out a reaction similar to the reaction of Example 26b (224 mg). The crude product is used in subsequent reactions without purification.

b) Fumarate 5-cyano-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]isoindoline-one

Using the compound obtained in Example a (224 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (258 mg, yield: 50%, stage 2).

Melting point: 201-208° C.

1H-NMR (DMSO-d6): 8,13 (1H, s), of 7.96 (1H, d, J=7.9 Hz), the 7.85 (1H, d, J=7,7 Hz), 7,27 (2H, DD, J=8,4,5,7 Hz), to 6.57 (2H, s), of 4.57 (2H, s), of 3.45 (2H, d, J=7,3 Hz), is 3.08 (2H, sh. d, J=11.5 Hz), 2,82 of 2.68 (4H, m), of 2.23 (2H, sh. t, J=11,1 Hz)of 1.29 (2H, sh. DD, J=21,7,11,4 Hz),

Example 163: Fumarate 5-fluoro-2-[[1-[2-(4-forfinal)ethyl]-piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example s get mentioned in the title compound by methods similar to the methods of Examples 26b and 36C (yield: 72%).

Melting point: 197-204° C.

1H-NMR (DMSO-d6): δ of 1.26 (m, 2H), 1,62 (m, 2H), 1,76 (m, 1H), 2,16 (m, 2H), 2,66 (m, 2H), 2,78 (m, 2H), 3,03 (m, 2H), 3,40 (d, J=7.2 Hz, 2H), 4,48 (s, 2H), return of 6.58 (s, 2H), 7,10 (t, J=9.0 Hz, 2H), 7.24 to 7,35 (m, 3H), 7,46 (DD, J=2,0, a 8.9 Hz, 1H), 7,71 (DD, J=5,1, and 8.4 Hz, 1H).

Example 164: Fumarate 4-fluoro-2-[1-[2-(4-forfinal)ethyl]-piperidine-4-ylmethyl]isoindoline-1-she (Compound 202 in Table 1)

a) 4-fluoro-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]-isoindole-1-he

Using the compound obtained in Example 6d (500 mg, of 1.76 mmol)and the compound obtained in Example 26a (384 mg, of 1.76 mmol), get mentioned in the title compound in the form of the crude product as a colourless oil, done is vlaa reaction, similar reaction of Example 26b (478 mg). The crude product is used in subsequent reactions without purification.

b) Fumarate, 4-fluoro-2-[1-[2-(4-forfinal)ethyl]piperidine-4-ylmethyl]isoindoline-1-it

Using the compound obtained in Example a (478 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (560 mg, yield: 89%, stage 2).

Melting point: 230-232° C.

1H-NMR (DMSO-d6): EUR 7.57-7,53 (2H, m), 7,47-7,42 (1H, m), 7,26 (2H, DD, J=8,6, 5,7 Hz), 7,12-7,06 (2H, m), to 6.58 (2H, s), 4,58 (2H, s), 3,42 (2H, d, J=7,3 Hz), to 3.02 (2H, sh. d, J=sh. d, J=11,9 Hz), 2,79-to 2.74 (2H, m), 2,66-2,61 (2H, m), and 2.14 (2H, sh. t, J=11,6 Hz), is 1.81 (1H, sh. C), and 1.63 (2H, sh. d, J=13.1 Hz), 1,27-1,20 (2H, m).

Example 165: Hydrochloride of 2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl}-5-methoxyindol-1-she (Compound 154 Table 1)

a) 2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl}-5-methoxyindol-1-he

The compound obtained in Example 9c (297 mg, 1 mmol)and 1-methoxy-2-(2-methansulfonate)ethylbenzene (230 mg, 1 mmol) is subjected to interaction in N,N-dimethylformamide in the presence of sodium carbonate (233 mg), sodium iodide (165 mg) at 80° C for 8 hours. The reaction mixture was added water and extracted with ethyl acetate and the extract washed with water and the solvent is evaporated under reduced pressure. The resulting oil is purified column chromatography on what silicagel (methylene chloride-methanol), getting listed at the beginning of the connection.

1H-NMR (CDCl3): δ of 7.75 (d, J=8,4 Hz, 1H), 7,15 (m, 2H), 6,99-for 6.81 (m, 3H), 4,35 (s, 2H), 3,86 (s, 3H), of 3.80 (s, 3H), 3,47 (d, J=7,1 Hz, 2H), 3,03 (sh. d, J=11.5 Hz, 2H), 2,85-and 2.79 (m, 2H), 2,58-2,52 (m, 2H), 2,04 (t, J=10.0 Hz), of 1.80 (m, 1H), 1,74 by 1.68 (m, 2H), 1,50-of 1.39 (m, 2H).

(b) Hydrochloride of 2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl}-5-methoxyindol-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 46%).

Melting point: 204-207° C.

1H-NMR (DMSO-d6): δ 10,12 (sh. s, 1H), 7,58 (d, J=8,4 Hz), 7,28-7,17 (m, 3H), 7,05-6,89 (m, 3H), of 4.45 (s, 2H), of 3.84 (s, 3H), of 3.80 (s, 3H), 3,57-of 3.53 (m, 2H), 3,41 (d, J=7,2 Hz), 3,20-of 3.12 (m, 2H), 3,02-is 2.88 (m, 4H), to 1.98 (m, 1H), 1,83-of 1.78 (m, 2H), 1.56 to a rate of 1.51 (m, 2H).

Example 166: 5-Chloro-2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]isoindoline-1-3/2 he(· ) fumarate (Compound 153, Table 1)

a) 5-chlor-2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]isoindoline-1-he

Using the compound obtained in Example 8E (250 mg, 0.83 mmol)and the compound obtained in Example 26a (191 mg, 0.83 mmol), get mentioned in the title compound in the form of the crude product as a pale brown solid, carrying out a reaction similar to the reaction of Example 26b (270 mg). The crude product is used in subsequent reactions without purification.

b) 5-Chloro-2-[1-[2-(2-methoxyphenyl)ethyl]piperidin-ylmethyl]isoindoline-1-1,5 he(· ) fumarate

Using the compound obtained in Example 166a (270 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (269 mg, yield: 60%, stage 2).

Melting point: 165-185° C.

1H-NMR (DMSO-d6): of 7.69 (2H, t, J=7.5 Hz), 7,54 (1H, DD, J=8,1, 1.5 Hz), 7.23 percent-7,14 (2H, m), of 6.96 (1H, d, J=7.8 Hz), 6.87 in (1H, d, J=7.5 Hz), 6,57 (3H, s), 4,50 (2H, s), of 3.78 (2H, s), 3,42 (2H, d, J=7,2 Hz), 3,20 (2H, sh. d, J=12.0 Hz), of 2.81 (2H, sh. C)2,43 (2H, sh. t, J=11,1 Hz) to 1.86 (1H, sh. C)was 1.69 (2H, sh. d, J=11.4 in Hz)of 1.36 (2H, sh. DD, J=22,5, and 10.8 Hz),

Example 167: Hydrochloride of 2-[1-[2-(2-methoxyphenyl)ethyl]-piperidine-4-ylmethyl]-5-promisingly-1-she (Compound 148 in Table 1)

a) 2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]-5-promisingly-1-he

Using the compound obtained in Example 3d, get mentioned in the title compound by methods similar to the methods of Example a (yield: 43%).

1H-NMR (CDCl3): δ of 7.70 (d, J=8,4 Hz), to 7.59 (m, 2H), 7,17-7,11 (m, 2H), 6.89 in-for 6.81 (m, 2H), to 4.38 (s, 2H), 3,80 (s, 3H), 3,49 (d, J=7,1 Hz, 2H), 3,02 (sh. d, J=11.7 Hz, 2H), 2,85-and 2.79 (m, 2H), 2,58-2,52 (m, 2H), 2,04 (t, J=11,6 Hz), equal to 1.82 (m, 1H), 1,73 by 1.68 (m, 2H), 1,47-of 1.41 (m, 2H)

(b) Hydrochloride of 2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]-5-promisingly-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 81%).

Melting point: 240-245° C.

P the emer 168: Fumarate 5-cyano-2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]isoindoline-1-she (Compound 155 in Table 1)

a) 5-cyano-2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]isoindoline-1-he

Using the compound of Example 10C (300 mg, of 1.03 mmol) and the compound obtained in Example 26a (237 mg, of 1.03 mmol), get mentioned in the title compound in the form of the crude product as a pale brown solid, carrying out a reaction similar to the reaction of Example 26b (174 mg). The crude product is used in subsequent reactions without purification.

b) Fumarate 5-cyano-2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]isoindoline-1-it

Using the compound obtained in Example a (174 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (202 mg, yield: 39%, stage 2).

Melting point: 201-208° C.

1H-NMR (DMSO-d6): to 8.14 (1H, s), of 7.96 (1H, d, J=8.1 Hz), the 7.85 (1H, d, J=7.5 Hz), 7,22-7,14 (2H, m), to 6.95 (1H, d, J=8.1 Hz), 6,86 (1H, t, J=7.5 Hz), to 6.57 (2H, s), of 4.57 (2H, s), of 3.77 (3H, s), of 3.45 (2H, d, J=7,2 Hz), 3,09 (2H, sh. d, J=10,8 Hz), 2,80-of 2.75 (2H, m)to 2.66 (2H, sh. d, J=8.7 Hz), 2,24 (2H, sh. t, J=11,0 Hz), equal to 1.82 (1H, sh. C)of 1.65 (2H, sh. d, J=12 Hz), 1,29 (2H, sh. DD, J=21,8, and 11.6 Hz),

Example 169: Fumarate 5-fluoro-2-[[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example s get mentioned in the title compound by methods similar to the methods of Examples 26b and 36C (yield: 69%).

Melting point: 210-216° C.

1H-NMR (DMSO-d6): δ of 1.30 (m, 2H), 1,65 (m, 2H), 1,76 (m, 1H), and 2.27 (m, 2H), 2,68 (m, 2H), 2,77 (m, 2H), 3,10 (m, 2H), 3,41 (d, J=7.2 Hz, 2H), of 3.77 (s, 3H), of 4.49 (s, 2H), 6,56 (s, 2H), 6.87 in (t, J=7,4 Hz, 1H), to 6.95 (d, J=8,1 Hz, 1H), 7,14-7,22 (m, 2H), 7,32 (m, 1H), 7,47 (DD, J=2.1 a, 8,7 Hz, 1H), 7,71 (DD, J=5,3, 8,3 Hz, 1H),

Example 170: Fumarate 5-cyano-2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]isoindoline-1-she (Compound 562 Table 1)

a) 5-cyano-2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]isoindoline-1-he

Using the compound obtained in Example 10C (300 mg, 1.05 mmol)and the compound obtained in Example 26a (242 mg, 1.05 mmol), get mentioned in the title compound in the form of the crude product as a pale brown solid, carrying out a reaction similar to the reaction of Example 26b (308 mg). The crude product is used in subsequent reactions without purification.

b) Fumarate 5-cyano-2-[1-[2-(2-methoxyphenyl)ethyl]piperidine-4-ylmethyl]isoindoline-1-it

Using the compound obtained in Example a (308 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (346 mg, yield: 86%, stage 2).

Melting point: 242-247° C.

1H-NMR (DMSO-d6): EUR 7.57-rate of 7.54 (2H, m), 7,47-7,42 (1H, m), 7,22-7,14 (1H, m), to 6.95 (1H, d, J=7,6 Hz), 6.89 in-6,87 (1H, m), 6,56 (2H, s), 4,58 (2H, s), of 3.78 (3H, s), 3.43 points (2H, d, J=7,3 Hz), 3,13 (2H, sh. d, J=11.8 Hz), 2,82 of 2.68 (4H, m), 2,32 (2H, sh. t, J=11,0 Hz)to 1.86 (1H, sh. C)to 1.67 (2H, the. d, J=11,1 Hz), 1,38-of 1.27 (2H, m).

Example 171: Hydrochloride of (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-4-horizontalis-1-she (Compound 83 in Table 1)

a) (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-4-horizontalis-1-he

Using the compound obtained in Example 6, get mentioned in the title compound by methods similar to the methods of Example 16 (yield: 85%).

1H-NMR (CDCl3): δ 7,66 (d, J=7.8 Hz, 1H), 7,46 (m, 1H), 7,35-7,30 (m, 2H), 7,22 (t, J=8,1 Hz, 1H),? 7.04 baby mortality-of 6.99 (m, 2H), 4,71-of 4.66 (m, 1H), 4,46 (s, 2H), 3,53 (d, J=7.2 Hz, 2H), 3.15 in (sh. d, J=11.7 Hz, 1H), 2,82 (sh. d, J=10,2 Hz, 1H), of 2.51-2,31 (m, 3H), 2,04 (m, 1H), of 1.85 (m, 1H), 1,80-of 1.65 (m, 2H), 1,49-1,22 (m, 2H)

(b) Hydrochloride of (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-4-horizontalis-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 78%).

Melting point: 221-224° C.

1H-NMR (DMSO-d6): δ 9,63 (sh. s, 1H), 7,56-7,42 (m, 5H), 7,20 (t, J=8.7 Hz, 2H), 6,24 (sh. s, 1H), 5,11 (sh. s, 1H), 4,59 (s, 2H), 3,55-2,90 (m, 8H), 2,00 (m, 1H), 1,86-of 1.56 (m, 4H).

Example 172: Hydrochloride of (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-horizontalis-1-she (Compound 84 in Table 1)

a) (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-horizontalis-1-he

Using the compound obtained in Example 8, receive specified in the header is connected to the e ways, similar to the methods of Example 16 (yield: 82%).

1H-NMR (CDCl3): δ for 7.78 (d, J=8.7 Hz, 1H), 7,44 (m, 2H), 7,35-7,30 (m, 2H), 7,02 (m, 2H), 4,69 (m, 1H), of 4.44 (s, 2H), 4.09 to (sh. s, 1H), 3,51 (d, J=7.2 Hz, 2H), 3.15 in (sh. d, J=11,4 Hz, 1H), 2,81 (sh. d, J=11,1 Hz, 1H), 2,49-of 2.30 (m, 3H), 2,02 (m, 1H), 1,80 (m, 1H), 1,80-1,20 (m, 4H)

(b) Hydrochloride of (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-horizontalis-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 90%).

Melting point: 254-256° C.

1H-NMR (DMSO-d6): δ 9,59 (sh. s, 1H), 7,74-to 7.67 (m, 2H), 7,56-the 7.43 (m, 3H), 7,25-7,20 (m, 2H), 6,27 (sh. s, 1H), 5,13 (sh. s, 1H), to 4.52 (s, 2H), 3,64-2,95 (m, 8H), 1,99-of 1.57 (m, 5H).

Example 173: Hydrochloride of (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-horizontalis-1-it

a) (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-horizontalis-1-he

Using the compound obtained in Example 154, get mentioned in the title compound by methods similar to the methods of Example 16 (yield: 61%).

1H-NMR (CDCl3): δ 7,83 (m, 1H), 7,35-7,25 (m, 2H), 7,17 for 7.12 (m, 2H), 7,05-of 6.99 (m, 2H), 4,67 (m, 1H), of 4.44 (s, 2H), 4,08 (sh. s, 1H), 3,51 (d, J=7.2 Hz, 2H), 3.15 in (sh. d, J=11,1 Hz, 1H), 2,82 (sh. s, J=11,1 Hz, 1H), 2,49-of 2.28 (m, 3H), 2,02 (m, 1H), 1,80 (m, 1H), 1.77 in-1,25 (m, 4H).

(b) Hydrochloride of (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-horizontalis-1-it

Using the connection, receive the TES in the Example a, get listed in the title compound by methods similar to the methods of Example 1f (yield: 70%).

Melting point: 243-245° C.

1H-NMR (DMSO-d6): δ 9,66 (sh. s, 1H), 7,71 (m, 1H), 7,43 (m, 3H), 7,34-7,17 (m, 3H), 6,24 (d, J=3,9 Hz, 1H), 5,11 (sh. s, 1H), 4,49 (s, 2H), 3,66-only 2.91 (m, 8H), 1,97-of 1.52 (m, 5H).

Example 174: Hydrochloride of (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-cyanoethyl-1-she (Compound 87 in Table 1)

a) (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-cyanoethyl-1-he

Using the compound obtained in Example 10, get mentioned in the title compound by methods similar to the methods of Example 16 (yield: 37%).

1H-NMR (CDCl3): δ to 7.95 (d, J=7.8 Hz, 1H), 7,76 (m, 2H), 7,32 (m, 2H), 7,01 (m, 2H), 4,69 (m, 1H), 4,47 (s, 2H), 3,55 (d, J=7.2 Hz, 2H), 3,14 (sh. d, J=10.5 Hz, 1H), 2,81 (sh. d, J=10.5 Hz, 1H), 2,79-to 2.29 (m, 3H), 2,03 (m, 1H), 1,95-of 1.35 (m, 5H).

(b) Hydrochloride of (R,S)-2-[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-5-cyanoethyl-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 74%).

Melting point: 255-262° C.

1H-NMR (DMSO-d6): δ 9,66 (sh. s, 1H), 8,16 (s, 1H), of 7.96 (d, J=7.5 Hz, 1H), 7,86 (d, J=7.8 Hz, 1H), 7,45 (m, 2H), 7,22 (m, 2H), 6,27 (sh. s, 1H), 5,13 (sh. s, 1H), 4,59 (s, 2H), 3,60 of 2.92 (m, 8H), 1,98-and 1.54 (m, 5H).

Example 175: Fumarate (R,S)-5-[1-[2-(forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-,5-dihydro-6N-thieno[2,3-c]pyrrole-6-she (Compound 780 Table 2)

a) (R,S)-5-[1-[2-(forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-4,5-dihydro-6N-thieno[2,3-c]pyrrole-6-he

Using the compound obtained in Example 22, get mentioned in the title compound by methods similar to the methods of Example 16 (yield: 87%).

1H-NMR (CDCl3): δ 7,63 (d, J=4,8 Hz, 1H), 7,32 (m, 3H), 7,01 (m, 3H), of 4.67 (m, 1H), 4,34 (s, 2H), 4,11 (sh. s, 1H), 3,47 (d, J=6,9 Hz, 2H), 3.15 in (sh. d, J=11,1 Hz, 1H), 2,82 (sh. d, J=10,8 Hz, 1H), 2,50-of 2.30 (m, 3H), 2,03 (m, 1H), 1,81-1,71 (m, 3H), 1,47 to 1.37 (m, 1H).

b) Fumarate (R,S)-5-[1-[2-(forfinal)-2-hydroxyethyl]piperidine-4-ylmethyl]-4,5-dihydro-6N-thieno[2,3-c]pyrrole-6-she

The compound obtained in Example a (70 mg), dissolved in ethanol (1 ml) and ethyl acetate (3 ml) and to the solution was added fumaric acid (26 mg). Phase precipitate crystals, which appeared after complete dissolution, collected by filtration, getting mentioned in the title compound (yield: 87%).

Melting point: 174-176° C.

1H-NMR (DMSO-d6): δ to 7.95 (d, J=5,1 Hz, 1H), 7,41-7,35 (m, 2H), 7.23 percent-7,11 (m, 3H), to 6.57 (s, 2H), 4,76 (sh. s, 1H), 4,42 (s, 2H), 3.33 and-of 2.15 (m, 8H), 1,72-of 1.57 (m, 3H), 1,25-of 1.15 (m, 2H).

Example 176: Hydrochloride of 2-[1-[2-(4-torpedolike)ethyl]-piperidine-4-ylmethyl]-5-methoxyindol-1-she (Compound 214 Table 1)

a) 2-[1-[2-(4-torpedolike)ethyl]piperidine-4-ylmethyl]-5-methoxyindol-1-he

Using the compound obtained in Example 9c, and 1-fluoro-4-(2-bromoethoxy)benzene, receive specified in the header of the connect is, the ways, similar to the methods of Example a (yield: 78%).

1H-NMR (CDCl3): δ of 7.75 (d, J=8,4 Hz), 7,00-6,91 (m, 4H), 6,85-to 6.80 (m, 2H), 4,34 (s, 2H), Android 4.04 (t, J=6.0 Hz, 2H), a 3.87 (s, 3H), 3,47 (d, J=7.2 Hz, 2H), 2,98 (sh. d, J=11.7 Hz, 2H), was 2.76 (t, J=6.0 Hz, 2H), 2,09 (t, J=9,3 Hz, 2H), 1.77 in (m, 1H), 1,72 (m, 2H), 1,48-of 1.39 (m, 2H).

(b) Hydrochloride of 2-[1-[2-(4-torpedolike)ethyl]piperidine-4-ylmethyl]-5-methoxyindol-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 47%).

Melting point: 216-219° C.

1H-NMR (DMSO-d6): δ 10,44 (sh. s, 1H), 7,58 (d, J=8,4 Hz), 7,19-7,13 (m, 3H), 7,06-of 6.99 (m, 3H), of 4.44 (s, 2H), 4,37 (t, J=4.5 Hz, 2H), of 3.84 (s, 3H), 3,59 is-3.45 (m, 2H), 3,45-3,30 (m, 4H), 3,05-to 2.94 (m, 2H), of 1.97 (m, 1H), 1,81 to 1.76 (m, 2H,), 1,64-of 1.52 (m, 2H).

Example 177: Hydrochloride of 2-[1-[2-(4-torpedolike)ethyl]piperidine-4-ylmethyl]-5-promisingly-1-she (Compound 208, Table 1)

a) 2-[1-[2-(4-torpedolike)ethyl]piperidine-4-ylmethyl]-5-promisingly-1-he

Using the compound obtained in Example 3d, and 1-fluoro-4-(2-bromoethoxy)benzene, get mentioned in the title compound by methods similar to the methods of Example a (yield: 66%).

1H-NMR (CDCl3): δ 7,71 (d, J=8,4 Hz, 1H), 7,62-to 7.59 (m, 2H), 6,99-6,93 (m, 2H), 6,85-to 6.80 (m, 2H), to 4.38 (s, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 3,48 (d, J=4.9 Hz), 2,99 (sh. d, J=11.7 Hz), 2,77 (t, J=6.0 Hz), 2,10 (t, J=11.7 Hz), of 1.80 (m, 1H), 1,78 is 1.70 (m, 2H), 1,48-of 1.39 (m, 2H).

(b) Hydrochloride of 2-[1-[2-(4-torpedolike)ethyl]piperidine-4-metil]-5-promisingly-1-it

Using the compound obtained in Example a get mentioned in the title compound by methods similar to the methods of Example 1f (yield: 86%).

Melting point: 222-225° C.

Example 178: Fumarate 5-chloro-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-she (compound 213 Table 1)

a) 5-chloro-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-he

Using the compound obtained in Example 8E (250 mg, 0.83 mmol)and the compound obtained in Example 32A (182 mg, 0.83 mmol), get mentioned in the title compound in the form of the crude product as a pale brown solid by methods similar to the methods of Example 26b (321 mg). The crude product is used in subsequent reactions without purification.

b) Fumarate 5-chloro-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-it

Using the compound obtained in Example a (321 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (320 mg, yield: 74%, stage 2).

Melting point: 172-176° C.

1H-NMR (DMSO-d6): to 7.68 (2H, t, J=7,6 Hz), 7,55 (1H, d, J=2.7 Hz), 7,11 (2H, t, J=8,8 Hz), 6,93-6,79 (2H, m), 6,59 (2H, s), of 4.49 (2H, s)4,08 (2H, t, J=5.6 Hz), 3,40 (2H, d, J=7,2 Hz), 3,01 (2H, sh. d, J=11.5 Hz), 2,80 (2H, t, J=5.6 Hz), 2.21 are to 2.14 (2H, m), 1,76-1,72 (1H, m), 1,60 (2H, sh. d, J=12.1 Hz), 1.26 in (2H, sh. DD, J=21,4, 11.3 Hz).

Example 179: Fomar the t 5-cyano-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-she (Compound 215 Table 1)

a) 5-cyano-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-he

Using the compound obtained in Example 8E (300 mg, of 1.03 mmol)and the compound obtained in Example 10C (226 mg, of 1.03 mmol), get mentioned in the title compound as a crude product as a pale brown solid, carrying out a reaction similar to the reaction of Example 26b (314 mg). The crude product is used in subsequent reactions without purification.

b) Fumarate 5-cyano-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-it

Using the compound obtained in Example a (314 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (331 mg, yield: 63%, stage 2).

Melting point: 194-198° C.

1H-NMR (DMSO-d6): 8,13 (1H, s), 7,95 (1H, d, J=7.9 Hz), to 7.84 (1H, d, J=7,7 Hz), 7,14-7,07 (2H, t, J=5.6 Hz), 6,99 (2H, m), 6,59 (2H, s), of 4.57 (2H, s), 4,11 (2H, t, J=5.6 Hz), 3,44 (2H, d, J=7,2 Hz), 3,06 (2H, sh. d, J=11,6 Hz), 2,87 (2H, t, J=5.5 Hz), and 2.27 (2H, sh. t, J=11,0 Hz)and 1.83-1.77 in (1H, m), and 1.63 (2H, sh. d, J=11.7 Hz), 1,36 is 1.23 (2H, m).

Example 180: Fumarate 5-fluoro-2-[[1-[2-(4-torpedolike)ethyl]piperidine-4-yl]methyl]isoindoline-1-it

Using the compound obtained in Example 154c, get mentioned in the title compound by methods similar to the methods of Examples 26b and 36C (yield: 88%).

Melting point: 174-176° C.

1H-NMR (DMSO-d 6): 1,25 (m, 2H), 1,60 (m, 2H), 1,76 (m, 1H), 2,17 (m, 2H), and 2.79 (t, J=5.6 Hz, 2H), 3,50 (m, 2H), 3,39 (d, J=7.2 Hz, 2H), 4,07 (t, J=5.6 Hz, 2H), 4,47 (s, 2H), 6,60 (s, 2H), 6,95 (m, 2H), 7,10 (t, J=8,9 Hz, 2H), 7,31 (m, 1H), 7,46 (DD, J=1,9, and 8.7 Hz, 1H), of 7.70 (DD, J=5,2, 8,3 Hz, 1H).

Example 181: Fumarate 4-fluoro-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-she (Compound 212 Table 1)

a) 4-fluoro-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-he

Using the compound obtained in Example 6d (300 mg, 1.05 mmol)and the compound obtained in Example 32A (230 mg, 1.05 mmol), get mentioned in the title compound as a crude product as a pale brown solid, carrying out a reaction similar to the reaction of Example 26b (356 mg). The crude product is used in subsequent reactions without purification.

b) Fumarate, 4-fluoro-2-[1-[2-(4-pertenece)ethyl]piperidine-4-ylmethyl]isoindoline-1-it

Using the compound obtained in Example a (356 mg), get mentioned in the title compound as a colourless solid, carrying out reactions similar to reactions of Example 36C (412 mg, yield: 89%, stage 2).

Melting point: 196-198° C.

1H-NMR (DMSO-d6): 7,56-7,53 (2H, m), 7,46 (1H, m), 7,13-7,07 (2H, m), 6,97-6,92 (2H, m), 6,60 (2H, s), of 4.57 (2H, s)4,07 (2H, t, J=5.7 Hz), to 3.41 (2H, d, J=7,4 Hz), 2,99 (2H, sh. d, J=11.7 Hz), 2,78 (2H, t, J=5.7 Hz), of 2.16 (2H, sh. t, J=10,9 Hz), 1,80 is 1.75 (1H, m)to 1.61 (2H, sh. d, J=11,6 Hz), 1,32 is 1.23 (2H, m).

Example 182: Dihydrate hydrochloride 2-[[-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it

Hydrochloride of 2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-she (the compound of Example 1; to 39.4 mmol) is placed in water (30 ml) and acetone (210 ml) and the resulting mixture is heated at 60° for dissolution. To the mixture is added dropwise ethyl acetate (100 ml) and stand for cooling to room temperature. Precipitated precipitated crystals are collected by filtration, and the obtained crystals are washed with ethyl acetate and dried under reduced pressure, obtaining mentioned in the title compound (yield: 79%).

Analytical analysis (Calculated), 60,20; N, To 6.43; N, 6,38; Cl, 8,08 (Found) C, 60,02; N, 6,24; N, 5,97; Cl, 7,74.

Analysis of water content (Karl Fischer method) (Calculated) Of 8.2%; (Found) of 8.3%.

Example tests: test for inhibition of the binding site of Sigma binding.

Test of inhibition of binding of the selective Sigma-2 receptor was performed using [3H]-di-o-tolylguanidine (DTG (DTG)), final concentration: 1Nm, 37 CI/mmol (New England Nuclear, Dupont de Nemours) as the radioactive ligand. The crude membrane fraction P2 was obtained from the liver of male rats (rat lines Sprague-Dawley) by the method described in the literature (X. He, et al., J. Med. Chem. 36, pp.566-571, 1993). In the presence of 500 nm of pentazocine and test compounds at various concentrations (haloperidol, 10-10up to 10-6M) or test ligand at various concentrations (from 10-1010 -5M) together with the radioactive ligand was incubated with the P2 fraction (0.4 ml) in 50 mm Tris-HCl (pH 7.4, final volume: 0.5 ml) at 25° C for 2 hours. The reaction mixture was quickly filtered on a Brandel harvester using filter paper Whatman GF/B, which previously was immersed in 0.5% polyethylenimine 1 hour to stop the reaction. Filter paper was washed four times with buffer for incubation, chilled with ice. The results of nonspecific binding was assessed using a 1 μm haloperidol, scintillation analysis and analysis of the curves was carried out as described above. The Kd value for [3H]-DTG (DTG) was 6.9 nm. The results are presented in Tables 3 and 4 below.



Table 3
Test connectionSigma 2 Ki(nm)
Example 113
Example 22,8
Example 37
Example 47,6
Example 68,7
Example 716
Example 83,1
Example 9a 4.9
Example 136,6
Example 1724
Example 22 22
Example 2413
Example 2610
Example 3022
Example 3122
Example 322,8
Example 3650
Example 5014
Example 843,4
Example 1377,8
Example 15416
Example 15925
Example 16010
Table 4
Test connectionSting inhibition with respect to σ 2 (%, 10 nm)
Example 4859
Example 5052
Example 5174
Example 5357
Example 7255
Example 7684
Example 7780
Example 7886
Example 8458
Example 8559
Example 9483
Example 9569
Example 9666
Example 9759
68
Example 11068
Example 11151
Example 11260
Example 11364
Example 11451
Example 11752
Example 11850
Example 15857
Example 16762
Example 17052
Example 17755
Example 17850
Example 18170

Examples of formulations

The pharmaceutical compositions of the present invention can be obtained using the methods and pharmaceutical additives traditionally used in this area. Examples of typical formulations are presented below. However, the pharmaceutical compositions of the present invention is not limited to these examples.

1) Tablet

The compound of Example 2 From 0.1 to 50 mg

Calcium phosphate 20 mg

Lactose 30 mg Talc 10 mg

Magnesium stearate 5 mg

Potato starch, 200 mg

2) Suspension

Add water to the compound of Example 2 (from 1 to 5 mg), sodium carboxymethyl cellulose (50 mg), sodium benzoate (1 mg) and sorbitol (500 mg) to obtain the aqueous suspension for oral administration in which the total volume of 1 ml.

3) Injection

The compound of Example 2 are mixed in the amount of 1.5 wt.% as the active ingredient with a mixture of propylene glycol (10%, by volume) and distilled water for injection by mixing and the resulting solution was sterilized by filtering through a membrane filter to obtain a composition for injection.

4) Ointment

The compound of Example 2 From 1 to 1000 mg

Stearyl alcohol 3 g

Lanolin 5 g

White petrolatum 15 g

Water To 100 g

Industrial applicability

Compounds of the present invention have high affinity for the Sigma binding site. In addition, the compounds of the present invention have excellent pharmacokinetic characteristics, such as high degree of absorption by oral administration and low metabolic rate, and, in addition, they are highly safe and have high efficiency in pharmacological research using animal models. Thus, the compounds of the present invention are useful as Sigma ligands for therapeutic and/or prophylactic treatment of various types of diseases and symptoms involving Sigma ligands.

1. Derivatives of cyclic amide represented by the formula (I)or its salt, or hydrate, or MES:

where X represents C -C6alkyl, C1-C6alkyl substituted by phenyl; C2-C6alkenyl, substituted phenyl or halogenfree; C2-C6quinil substituted by phenyl; phenyl which may be substituted With1-C6by alkyl; one or more halogen; nitro; phenyl; C1-C6alkoxy; halogen-C1-C6by alkyl; halogen-C1-C6alkoxy; phenyl-C1-C6by alkyl; C1-C6alkoxyphenyl-C1-C6by alkyl; amino, optionally substituted C1-C6the alkyl, acetyl; C1-C6alkoxygroup, substituted phenyl; phenylcarbinol; TuranAlem; 1 - or 2-naphthyl; monocyclic3-C8cycloalkyl; an amino group substituted by one or more substituents selected from phenyl; halogenfree; C1-C6the alkoxyphenyl; C1-C6of alkyl; halogen-C1-C6of alkyl; phenyl-C1-C6of alkyl; 5 - or 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatom, such as nitrogen, oxygen, sulfur, optionally substituted by halogenfree, halogen, benzyl,1-C6the alkyl, phenyl; 8-10-membered bicyclic heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, optionally substituted with halogen; 8-10-membered polycyclic cycloalkyl the th group;

Q represents a group-CH2-, -CO-, -O-, -S-, -CH(OR7)- or-C(=NR8)-, where R7represents a hydrogen atom, a C1-C6alkanoyloxy group, and R8represents a hydroxyl group, With1-C6alkoxygroup, allmenalp,1-C6alkoxycarbonylmethyl, phenyl-C1-C6-alkoxygroup;

n represents an integer from 0 to 5;

R1and R2each independently represents a hydrogen atom;

In represents any of the following groups:

where R3, R4, R5and R6each independently represents a Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro, C1-C6alkoxygroup and cyanopropyl;

m is 1 or 2;

ring

represents 5 - or 6-membered aromatic heterocyclic ring containing one or two heteroatoms selected from oxygen, sulfur, nitrogen.

2. The compound or its salt, or hydrate, or MES according to claim 1, where R1and R2independently represent a hydrogen atom.

3. The compound or its salt, or hydrate, or MES according to claim 1, where X represents C1-C6alkyl group, a substituted dryer is scrap With 1-C6alkyl group, substituted phenyl With2-C6alkenylphenol group, phenyl group, a monocyclic3-C8cycloalkyl group, 5 - or 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatom, such as nitrogen, oxygen, sulfur, an 8-10 membered bicyclic heteroaryl group containing 1 or 2 heteroatom, such as nitrogen, sulfur and oxygen, or amino group, substituted C1-C6alkyl group or phenyl group; Q represents a group-CH2-, -CO-, -O-, -S-, -CH(OR7)- or-C(=NR8)-, where R7represents a hydrogen atom, a C1-C6alkanoyloxy group, and R8represents a hydroxyl group, With1-C6alkoxygroup or alluminare; n represents an integer from 0 to 4; each of R1and R2represents a hydrogen atom; R3, R4, R5and R6each independently represents a Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro, C1-C6CNS group and cyanopropyl; m is 1 or 2; and ring

represents a heterocyclic ring selected from the group consisting of a furan ring, a thiophene ring and a pyridine ring.

4. The compound or its salt, or hydrate, or solve the t according to claim 3, where X represents a substituted or unsubstituted phenyl group, where the Deputy represents one or more substituents selected from the group consisting of a halogen atom, a C1-C6alkyl groups, halogen-C1-C6alkyl group, a C1-C6alkoxy, halogen - C1-C6alkoxygroup, 5 - or 6-membered monocyclic heterocyclic group, or an 8-10 membered bicyclic heteroaryl group containing one or two heteroatoms.

5. The compound or its salt, or hydrate, or MES according to claim 3, where In the formula

where three of R3, R4, R5and R6are hydrogen atoms, and one remaining is the Deputy selected from the group consisting of hydrogen atom, halogen atom, nitro, C1-C6alkoxygroup and ceanography.

6. The compound or its salt, or hydrate, or MES according to claim 1, where X represents a substituted or unsubstituted phenyl group, where the specified Deputy represents one or more substituents selected from the group consisting of a halogen atom, and C1-C6alkoxygroup, Q is-CH2-, -CO-, -O - or-CH(OH)-, n is an integer from 1 to 3, each of R1and R2represents a hydrogen atom, three of R3, R4, R 5and R6represent hydrogen atoms, and the remaining represents a hydrogen atom, halogen atom or C1-C6alkoxygroup, m is 1 or 2,

and the ring

represents a thiophene ring or furan ring.

7. The compound or its salt, or hydrate, or MES according to claim 6, where X is p-florfenicol group, n is 1, three of R3, R4, R5and R6represent hydrogen atoms, and the remaining represents a hydrogen atom, a halogen atom or a methoxy group, m is 1.

8. The compound or its salt, or hydrate, or MES according to claim 7, where Q is-CH2-.

9. The compound or its salt, or hydrate, or MES according to claim 7, where Q is-CO-.

10. The compound or its salt, or hydrate, or MES according to claim 7, where Q is-O-.

11. The compound or its salt, or hydrate, or MES according to claim 7, where Q is-CH(OH)-.

12. The compound according to claim 1, which represents a 2-((1-(2-(4-forfinal)-2-oxoethyl)piperidine-4-yl)methyl)isoindoline-1-it, or its salt, or hydrate, or MES.

13. The compound according to claim 1, which represents 4-fluoro-2-((1-(2-(4-forfinal)-2-oxoethyl)piperidine-4-yl)methyl)isoindoline-1-it, or its salt, or hydrate, or MES.

14. The compound according to claim 1, which represents 5-chloro-2-((1-(2-(4-forfinal)-2-oxoethyl)piperidine-4-yl)methyl)isoindole the-1-it, or its salt, or hydrate, or MES.

15. The compound according to claim 1, which represents 5-((1-(2-(4-forfinal)-2-oxoethyl)piperidine-4-yl)methyl)-4,5-dihydro-6N-thieno[2,3-C]pyrrol-6-he, or its salt, or hydrate, or MES.

16. The compound according to claim 1, which represents 5-fluoro-2-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]isoindoline-1-it, or its salt, or hydrate, or MES.

17. The compound according to claim 1, which represents 5-[[1-[2-(4-forfinal)-2-oxoethyl]piperidine-4-yl]methyl]-4,5-dihydro-6N-furo[2,3-C]pyrrol-6-he, or its salt, or hydrate, or MES.

18. Drug, possess inhibitory binding to the Sigma receptor activity, which comprises a substance selected from the group comprising compounds according to any one of claims 1 to 17, and their salt, and hydrate, and MES as an active ingredient.

19. Drug for p, which is used in the case of diseases that can be treated therapeutically and/or prophylactically through regulatory actions on nerve Sigma ligand.

20. Drug in claim 19, where disease that can be treated therapeutically and/or prophylactically through regulatory actions on nerve Sigma-ligand, is a disease of the Central nervous system selected from the group including anxiety, depression, or emotional disorder, schizophrenia, substance abuse, intoxi what the situation or drug addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, including Alzheimer's disease, Parkinson's disease, brain tumor, and a disorder associated with attention deficit; disease of the gastrointestinal tract selected from the group including irritable bowel syndrome, irritable bowel syndrome, spastic condition of the colon, colitis mucosa, enterocolitis, diverticulitis, dysentery, or disease of the cardiovascular system, selected from the group including hypertension, arrhythmia and angina.

21. The compound according to any one of claims 1 to 17, and salt and hydrate, and its MES, inhibiting binding to the Sigma receptor.



 

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EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, pharmacy.

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The invention relates to compounds of the formula I

in which

R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

X is R4, R5or R6, monosubstituted R7,

R4is unbranched or branched alkylene with 1-10 atoms, in which one or two CH2groups can be substituted by a group-CH=CH-,

R5is cycloalkyl or cycloalkylation containing 5-12 With atoms

R6is phenyl or vinylmation,

R7is COOH, cooa, CONH2, CONHA, CON(A)2or CN,

And is alkyl having from 1 to 6 atoms

Hal represents F, Cl, Br or I,

where at least one of the radicals R1or R2HE is a,

and their pharmaceutically acceptable salts

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12 cl, 5 tbl, 52 ex

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