Allosteric modulators of metabolic glutamate receptors

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

 

The technical field to which the invention relates

The present invention relates to new compounds of formula I, represents the modulators of metabotropic receptors-subtype 5 (“mGluR5”)that are applicable for the treatment of disorders of the Central nervous system, such as, for example, chronic progressive decline in cognitive abilities, both positive and negative symptoms in schizophrenia, and other disorders mediated by mGluR5 receptors.

The level of technology

Glutamate, the primary amino acid neurotransmitter in the Central nervous system (CNS) of mammals, holds the exciting synaptic nanoperiodic through activation of receptor-channels, ionotropic glutamate receptor (abbreviated iGluR, namely NMDA, AMPA and kainate) and metabotropic glutamate receptors (mGluR). iGluR responsible for the fast exciting transfer (S. Nakanishi et al., (1998) Brain Res Brain Res Rev., 26:230-235), whereas mGluR receptors play in a more modulatory role, which contributes to the fine regulation of synaptic efficacy. Glutamate performs numerous physiological functions, such as long-term potentiation long-term potentiation - LTP), a process that is believed to underlie cognitive abilities and memory, as well as cardio-vessel the flock stabilization, sensory perception and the development of synaptic plasticity. In addition, glutamate plays an important role in the pathophysiology of various neurological and psychiatric diseases, especially when the imbalance glutamatergic neuropterida.

mGluR receptors are seven-transmembrane G-protein-coupled receptors. Eight representatives of this family are divided into three groups (groups I, II and III) in accordance with the homology sequences and pharmacological properties (Schoepp D.D. et al. (1999) Neuropharmacology, 38:1431-1476). The mGluR activation leads to a great variety of intracellular reactions and activation of various metabolic cascades. Among the representatives of mGluR receptors are of considerable interest receptors subtype mGluR5 as receptors counteract insufficient or excessive neuropterida in neuropsychiatric diseases. mGluR5 belong to group I, and its activation initiates cellular responses through mechanisms mediated G-protein. mGluR5 linked to phospholipase C and stimulates phosphoinositide hydrolysis and intracellular mobilization of calcium.

It was shown that mGluR5 protein localized in postsynaptic elements adjacent to the postsynaptic density (Lujan R et al. (1996) Eur. J. Neurosci. 8:1488-500; Lujan, R. et al. (1997) J. Chem. Neuroanat., 13:219-41), and are rarely found in presin pricheski elements (Romano C. et al. (1995) J. Comp. Neurol. 355:455-69). Thus, mGluR5 receptors can modify the postsynaptic response to a neurotransmitter or regulate the release of neurotransmitter.

In the CNS mGluR5 receptors are distributed mainly in the cortex, hippocampus, areas of the brain Caudate-putamen and Nucleus accumbens. Since it has been shown that these brain areas are involved in the processes of excitation, motives and in a large number of aspects of cognitive function, it is assumed that mGluR5 modulators are of interest as therapeutic agents.

As targets for the development of selective receptor modulators mGLuR subtype has been proposed a number of possible clinical indications. These indications include epilepsy, neuropathic and inflammatory pain, various mental disorders (such as anxiety and schizophrenia), disorders of motor function (e.g., Parkinson's disease), neuroprotection (protection from stroke, head injury, migraine and addiction/drug dependency (see Brauner-Osborne, H. et al. (2000) J. Med. Chem. 43:2609-45; F. Bordi and Ugolini, A. (1999) Prog. Neurobiol. 59:55-79; W. Spooren et al. (2003) Behav. Pharmacol: 14:257-77).

The hypothesis that the alleged cause of schizophrenia is hypofunction glutamatergic system, which is the reflection of the hypofunction of NMDA receptors, in the last few years recip is no increasing support (see Goff D.C. and J.T. Coyle (2001) Am. J. Psychiatry, 158:1367-1377; Carlsson et al. (2001) Annu. Rev. Pharmacol. Toxicol., 41:237-260). Data implicating dysfunction glutamatergic neurotransmission confirmed by the detection of the fact that the antagonists of glutamate receptors of the NMDA subtype can reproduce the full range of symptoms, and physiological symptoms of schizophrenia, such as hypofrontality syndrome, deterioration inhibiting pulse fluctuations in blood pressure and increase the release of subcortical dopamine. In addition, clinical studies have shown that the frequency of alleles associated with mGluR5 schizophrenia among some groups of patients (Devon R.S. et al. (2001), Mol. Psychiatry. 6:311-4), and increased mGluR5 transmission was detected in cortical pyramidal cell layers of the brain of the patient with schizophrenia (Ohnuma T. et al. (1998), Brain Res. Mol. Brain Res. 56:207-17).

The involvement of mGluR5 in neurological and psychiatric disorders is confirmed by the fact that activation of mGluR receptors group I induces a potentiation of the function of NMDA receptors in different brain areas, mainly through activation of mGluR5 receptors (Mannaioni G. et al. (2001), Neurosci. 21:5925-34; Awad H. et al. (2000), J. Neurosci, 20:7871-7879; Pisani A. et al. (2001) Neuroscience 106:579-87; P. Benquet et al. (2002), J. Neurosci. 22:9679-86).

In addition, in the last decade have been precisely defined the role of glutamate in memory processes (Martin S.J. et al. (2000) Annu. Rev. Neurosci. 23:649-711; Baudry M. and Lynch G. (200), Neurobiol. Learn Mem., 76:284-297). The use of mGluR5 zero-mutant mice clearly confirmed the role of mGluR5 in learning and memorization. These mice show a selective loss of the ability in the two tasks of spatial learning and memory, and reduced CA1 LTP (Lu et al. (1997), J. Neurosci., 17:5196-5205; B. Schulz et al. (2001), Neuropharmacology, 41:1-7; Z. Jia et al. (2001) Physiol. Behav., 73:793-802; Rodrigues et al. (2002), J. Neurosci., 22:5219-5229).

Identifying what mGIuR5 is responsible for the potentiation of currents conducted by the NMDA receptor, increases the probability of use of agonists of this receptor as a means of enhancing cognitive function, as well as a new neuroleptic funds, which are exposed through the selective enhancement of the function of the NMDA receptor.

Activation of NMDARS could give effect to NMDAR hypofunction cellular neural circuits that occur in schizophrenia. Recent data in vivo studies clearly confirm that activation of mGluR5 could provide a new and effective approach to the treatment of lower cognitive abilities, as well as both positive and negative symptoms in schizophrenia (Kinney G.G. et al. (2002) 43:292).

Thus, MGluR5 receptor as a potential target for drugs to treat psychiatric and neurological disorders, including diseases to be treated, such as is ustroystva, characterized by anxiety, disorders of attention, eating disorders, mood disorders, psychotic disorders, cognitive abilities, personality disorders, and disorders associated with drug dependency.

Most of the currently known modulators of mGluR5 function was designed as structural analogues of glutamate, hiquality or phenylglycine (Schoepp D.D. et al. (1999) Neuropharmacology, 38:1431-1476), and a significant challenge is the development of in vivo active and selective mGluR5 modulators acting on the glutamate-binding site. New through the development of selective modulators is to identify molecules that act through allosteric mechanisms, modulating receptor binding him to the site, other than hard orthostereoscopic binding site.

Positive allosteric modulators of the receptor mGluR emerged recently as a new pharmacological entities that provide such an attractive alternative. Molecules of this type have been developed for mGluRl, mGluR2, mGluR4 and mGluR5 (F. Knoflach et al. (2001), Proc. Natl. Acad. Sci. USA. 98:13402-13407; O'brien J.A. et al. (2003), Mol. Pharmacol. 64:731-40; K. Johnson et al. (2002), Neuropharmacology 43:291; M.P. Johnson et al. (2003), J. Med. Chem. 46:3189-92; Marino, M.J. et al. (2003), Proc. Natl. Acad. Sci. USA. 100(23):13668-73; see review Mutel V. (2002), Expert Opin. Ther. Patents 12:1-8). DFB and related the s molecules were described as positive allosteric modulator, but with low potential in vitro ((O'brien J.A. et al. (2003), Mol. Pharmacol. 64:731-40). Patented recently developed benzamidine modulators of mGluR5 receptors (WO 2004/087048). Was also described a new class of positive allosteric modulators; these molecules are derivatives of aminopyrazole (C. W. Lindsley et al. (2004), J. Med. Chem. Epub 10/23/2004 jm049400d).

None of the specifically described compounds structurally not related to the compounds of the present invention.

The present invention relates to a method of treatment or prevention in a mammal, including humans, condition, treatment or prevention of which is mediated or can be facilitated by the neuromodulatory effect of mGluR5 modulators.

The invention

In accordance with the present invention provided new connections, replaced the bridge And or unsaturated five - or six-membered aryl or heteroaryl cycle containing atoms independently selected from carbon atoms, nitrogen, sulfur and oxygen. In addition, the invention relates to pharmaceutically acceptable forms of these compounds.

The invention is applicable also to the treatment of disorders of the Central nervous system exposed to neuromodulatory effect of mGluR5 positive allosteric modulators, such as a disorder of cognitive ability, as well as for treatment as a positive, t is K and negative symptoms in schizophrenia.

Drawings

Figure 1 shows the increase in the mobilization of CA2+induced by 1 μm of glutamate in cultured rat astrocytes in the presence of 3 μm of the compounds of examples 12, 55 and 56 of the present invention.

Figure 2 shows the debilitating effect of typical compounds of the present invention to increase locomotor activity induced by PCP (f=13,39, df=(2,45), n=16/group)at a dose of 100 mg/kg I.P.

Figure 3 shows the debilitating effect of typical compounds of the present invention to increase locomotor activity induced by amphetamine (f=13,04, df=(4,82), n=8-33 mice per group)at doses of 50 and 100 mg/kg I.P.

Detailed description of the invention

According to the present invention provided new compounds of General formula I

or a pharmaceutically acceptable salt, hydrate or solvate of such compounds,

where

W represents a 5 to 7-membered cycloalkyl or geteroseksualnoe ring;

R1and R2independently represent hydrogen, C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, arylalkyl, heteroallyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, C1-C6-alkoxy, or R1and R2together may form a C3-C7-cycloalkyl ring, a carbonyl bond C=O or double the second carbon-carbon bond;

P and Q, each independently, selected from cycloalkyl, aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, -heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9,

-NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9,

-C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic geteroseksualnoe, aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C -C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil,

halogen-C1-C6-alkyl, heteroseksualci, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-,

-C(=S)-, -O-, -N=, -N(R3)- or-S-;

A is an azo-N=N-, ethyl, ethynyl, ethinyl, -NR8C(=O)-, NR8S(=O)2-,

-C(=O)NR8-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR8-, -C(=O)-O-, -O-C(=O)-, -C(=NR8)NR9-C(=NOR8)NR9-, -NR8C(=NOR9)-, =N-O-, -O-N=CH -, or aryl or heteroaryl group of the formula

R3, R4, R5and R6illegal is isimo take the values defined above;

D, E, F, G and H independently represent a carbon atom, oxygen, nitrogen or sulfur, or a double bond;

B represents a single bond, -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-, -C(=O)-C2-C6-quinil-, -C(=O)-O-, -C(=O)NR8-C0-C2-alkyl-,

-C(=NR8)NR9-S(=O)-C0-C2-alkyl-, -S(=O)2-C0-C2-alkyl-, -S(=O)2NR8-C0-C2-alkyl-,

C(=NR8)-C0-C2-alkyl-, -C(=NOR8)-C0-C2-alkyl -, or-C(=NOR8)NR9-C0-C2-alkyl-; where R8and R9independently take the values defined above;

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

In the above definition the term "C1-C6-alkyl" includes a group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl or the like,

The term "C2-C6alkenyl" includes groups such as ethynyl, 1-propenyl, allyl, Isopropenyl, 1-butenyl, 3-butenyl, 4-pentenyl etc.

The term "C2-C6-quinil" includes such groups as ethinyl, PROPYNYL, butynyl, pentenyl etc.

The term "halogen" includes the fluorine atoms, bromine, chlorine and iodine.

The term "cycloalkyl" refers to optionally substituted by carbocycle, not containing heteroatoms, and includes mono-, bi - or tricyclic saturated carbocycle, and condensed cyclic system. Such condensed cyclic system may include a ring which is partially or fully unsaturated, such as a benzene ring to form a condensed cyclic systems, such as benzododecinium carbocycle. Cycloalkyl include condensed cyclic system, as pyrocondensation cyclic system. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, fluorenyl, 1,2,3,4-tetrahydronaphthalen etc.

The term "heteroseksualci" refers to optionally substituted by carbocycle containing at least one heteroatom independently selected from the atoms O, N and S. It includes mono-, bi - or tricyclic saturated carbocycle, and condensed cyclic system. Such condensed cyclic system may include a loop that is partially or fully unsaturated, such as a benzene ring to form a condensed cyclic systems, such as benzododecinium carbocycle. Examples heterocyclyl the sludge include piperidine, piperazine, morpholine, tetrahydrothiophene, indolin, isoquinoline, etc.

The term "aryl" refers to C6-C10aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.

The term "arylalkyl" refers to C6-C10-aryl-C1-C3is an alkyl group, such as benzyl group, 1-phenylethylene group, 2-phenylethylene group, 1-phenylpropionate group, 2-phenylpropionate group, 3-phenylpropionate group, 1-naphthylmethyl group, 2-naphthylmethyl group or the like

The term "heteroaryl" refers to a 5-10 membered heterocyclic group containing from 1 to 4 heteroatoms selected from oxygen atoms, nitrogen or sulfur, to form a loop, such as furyl (furan ring), benzofuranyl (benzofuran), thienyl (thiophene), benzothiophene (benzothiophen), pyrrolyl (pyralinae ring), imidazolyl (imidazole ring), pyrazolyl (pyrazol ring), thiazolyl (thiazole ring), isothiazole (isothiazol ring), triazolyl (triazole ring), tetrazolyl (tetrazole ring), pyridyl (peregrinae ring), pyrazinyl (pyrazinone ring), pyrimidinyl (pyrimidinamine ring), pyridazinyl (pyridinoline ring), indolyl (indole ring), isoindolyl (isoindoline ring), benzimidazolyl (benzimidazole ring), polylina group (polyline ring), chinolin (quinoline ring), phthalazine (f is alisamilano ring), naphthyridine (naphthyridine ring), honokalani (hinoksolinov ring), cannoli (cinnoline ring), pteridinyl (pteridine ring), oxazolyl (oxazoline ring), isoxazolyl (isoxazoline ring), benzoxazolyl (benzoxazole ring), benzothiazolyl (benzothiazoline ring), furutani (furazane ring), etc.

The term "heteroaromatic" refers to heteroaryl-C1-C3is an alkyl group, examples of heteroaryl include groups represented in the above definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazolidinyl, 2-imidazolidinyl, 2-triazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 1-chenailler or similar

The term "MES" refers to a complex of variable stoichiometry formed the dissolved substance (for example, a compound of formula (I) and a solvent. The solvent is a pharmaceutically acceptable solvent, preferably water, which does not adversely affect the biological activity of the solute.

The term "optional" means that the described(s) next event(I) can(can) to have or not to have a place and includes both the event(I)that(s) occur(s)and event(s) (s) occur(s).

The term "substituted" refers to substitution specified the Deputy is m or substituents, moreover, except where otherwise indicated, a valid multiple levels of substitution.

Preferred compounds of the present invention are the compounds of formula I-A, below

or a pharmaceutically acceptable salt, hydrate or solvate of such compounds,

where

R1and R2independently represent hydrogen, C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, arylalkyl, heteroallyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, C1-C6-alkoxy, or R1and R2together may form a C3-C7-cycloalkyl ring, a carbonyl bond C=O or double carbon-carbon bond;

P and Q each independently represents cycloalkyl, aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, -heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2 9, NR8SO2R9,

-NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9,

-C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic geteroseksualnoe, aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol),

-N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil,

halogen-C1-C6-alkyl, heteroseksualci, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0/sub> -C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-,

-C(=S)-, -O-, -N=, -N(R3)- or-S-;

A is an azo-N=N-, ethyl, ethynyl, ethinyl, -NR8C(=O)-, NR8S(=O)2-,

-C(=O)NR8-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR8-, -C(=O)-O-, -O-C(=O)-, -C(=NR8)NR9-C(=NOR8)NR9-, -NR8C(=NOR9)-, =N-O-, -O-N=CH -, or aryl or heteroaryl group of the formula

R3, R4, R5and R6independently take the values defined above;

D, E, F, G and H independently represent a carbon atom, oxygen, nitrogen or sulfur, or a double bond;

B represents a single bond, -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-, -C(=O)-C2-C6-quinil-, -C(=O)-O-, -C(=O)NR8-C0-C2-alkyl-,

-C(=NR8)NR9-S(=O)-C0-C2-alkyl-, -S(=O)2-C0-C2-alkyl-, -S(=O)2NR8-C0-C2-alkyl-,

C(=NR8)-C0-C2-alkyl-, -C(=NOR8)-C0-C2-alkyl -, or-C(=NOR8)NR9-C0-C2-Ala is l-; where R8and R9independently take the values defined above;

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

More preferred compounds of the present invention are the compounds of formula I-B

or a pharmaceutically acceptable salt, hydrate or solvate of such compounds;

where

R1and R2independently represent hydrogen, C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, arylalkyl, heteroallyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, C1-C6-alkoxy, or R1and R2together may form a C3-C7-cycloalkyl ring, a carbonyl bond C=O or double carbon-carbon bond;

P and Q each independently represents cycloalkyl, aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, -heteroaryl, heteroaryl is l, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic geteroseksualnoe, aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroseksualci, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which the s is optionally substituted by 1-5 substituents, independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H in P and Q independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

D, E and G independently in A take the values defined above for A;

B represents a single bond, -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-, -C(=O)-C2-C6-quinil-, -C(=O)-O-, -C(=O)NR8-C0-C2-alkyl-, -C(=NR8)NR9-S(=O)-C0-C2-alkyl-, -S(=O)2-C0-C2-alkyl-, -S(=O)2NR8-C0-C2-alkyl-, C(=NR8)-C0-C2-alkyl-, -C(=NOR8)-C0-C2-alkyl -, or-C(=NOR8)NR9-C0-C2-alkyl-; where R8and R9independently take the values defined above;

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Particularly preferred compounds of the present invention are the compounds of formula I-C

or farmaci is almost acceptable salt, the hydrate or solvate of such compounds,

where

R1and R2independently represent hydrogen, C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, arylalkyl, heteroallyl, hydroxy, hydroxyalkyl, C1-C6-alkoxy, or R1and R2together may form a carbonyl bond C=O or double carbon-carbon bond;

P and Q each independently represents cycloalkyl, aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, -heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms form bizi the symbolic geteroseksualnoe, aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroseksualci, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

B represents a single bond, -C(=O)-C -C2-alkyl-, -C(=O)-C2-C6alkenyl-, -C(=O)-C2-C6-quinil-, -C(=O)-O-, -C(=O)NR8-C0-C2-alkyl-, -C(=NR8)NR9-S(=O)-C0-C2-alkyl-, -S(=O)2-C0-C2-alkyl-, -S(=O)2NR8-C0-C2-alkyl-, C(=NR8)-C0-C2-alkyl-, -C(=NOR8)-C0-C2-alkyl -, or-C(=NOR8)NR9-C0-C2-alkyl-; where R8and R9independently take the values defined above;

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Other preferred compounds of the present invention are the compounds of formula I-D

or a pharmaceutically acceptable salt, hydrate or solvate of such compounds,

where

P and Q each independently represents cycloalkyl, aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, -heteroaryl, heteroaromatic, arylalkyl, the reel, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic geteroseksualnoe, aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroseksualci, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is neo Astelin substituted by 1-5 substituents, independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

In accordance with another aspect of the compound of the present invention is a compound of formula (I-E) or its pharmaceutically acceptable salt

where

P and Q each independently represents cycloalkyl, aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, -heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9, N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic geteroseksualnoe, aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroseksualci, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents, independently of wybrand the mi from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

In accordance with an additional aspect, the compound of the present invention is a compound of the formula (I-F) or its pharmaceutically acceptable salt

where

P and Q each independently represents cycloalkyl, aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, -heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9/sub> , -NR8COR9, NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic geteroseksualnoe, aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroseksualci, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-Csub> 6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Another aspect of the present invention are the compounds of formula I-G

where

R1and R2independently represent hydrogen, C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, arylalkyl, heteroallyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, C1-C6-alkoxy, or R1and R2together may form a C3-C7-cycloalkyl ring, a carbonyl bond C=O or double carbon-carbon bond;

P and Q each independently represents an aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6 -cycloalkyl, C3-C7-cycloalkyl, C1-C6alkenyl, C1-C6-quinil, halogen-C1-C6-alkyl, -heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C 2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

A is an azo-N=N-, ethyl, ethynyl, ethinyl, -NR8C(=O)-, NR8S(=O)2-, -C(=O)NR8-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR8-, -C(=O)-O-, -O-C(=O)-, -C(=NR8)NR9-C(=NOR8)NR9-, -NR8C(=NOR9)-, =N-O-, -O-N=CH -, or aryl or heteroaryl group of the formula

R3, R4, R5and R6independently take the values defined above;

D, E, F, G and H independently take the values defined above in A;

B represents a single bond, -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-, -C(=O)-C2-C6-quinil-, -C(=O)-O-, -C(=O)NR8-C0-C2-alkyl-, -C(=NR8)NR9-S(=O)-C0-C2-alkyl-, -S(=O)2 -C0-C2-alkyl-, -S(=O)2NR8-C0-C2-alkyl-, C(=NR8)-C0-C2-alkyl-, -C(=NOR8)-C0-C2-alkyl -, or-C(=NOR8)NR9-C0-C2-alkyl-; where R8and R9regardless, take the values defined above;

J represents-C(R11, R12), -O-, -N(R11)- or-S-;

R11, R12independently represent hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

One variant of implementation of the present invention includes compounds of formula I-H

where

R1and R 2independently represent hydrogen, C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, arylalkyl, heteroallyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, C1-C6-alkoxy, or R1and R2together may form a C3-C7-cycloalkyl ring, a carbonyl bond C=O or double carbon-carbon bond;

P and Q each independently represents an aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic aryl rigamarole ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H in P and Q independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

D, E and G independently in A take the values defined above for A;

B represents Odie is ary communication, -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-, -C(=O)-C2-C6-quinil-, -C(=O)-O-, -C(=O)NR8-C0-C2-alkyl-, -C(=NR8)NR9-S(=O)-C0-C2-alkyl-, -S(=O)2-C0-C2-alkyl-, -S(=O)2NR8-C0-C2-alkyl-, C(=NR8)-C0-C2-alkyl-, -C(=NOR8)-C0-C2-alkyl -, or-C(=NOR8)NR9-C0-C2-alkyl-; where R8and R9regardless, take the values defined above;

J represents-C(R11, R12), -O-, -N(R11)- or-S-;

R11, R12independently represent hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only is asamati, but the individual enantiomers of the compounds.

Another variant of implementation of the present invention includes compounds of formula I-I

where

R1and R2independently represent hydrogen, C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, arylalkyl, heteroallyl, hydroxy, hydroxyalkyl, C1-C6-alkoxy, or R1and R2together may form a carbonyl bond C=O or double carbon-carbon bond;

P and Q each independently represents an aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, -NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9 substituents; where optionally two Deputy together with in between the atoms to form a bicyclic aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3 4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

B represents a single bond, -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-, -C(=O)-C2-C6-quinil-, -C(=O)-O-, -C(=O)NR8-C0-C2-alkyl-, -C(=NR8)NR9-S(=O)-C0-C2-alkyl-, -S(=O)2-C0-C2-alkyl-, -S(=O)2NR8-C0-C2-alkyl-, C(=NR8)-C0-C2-alkyl-, -C(=NOR8)-C0-C2-alkyl -, or-C(=NOR8)NR9-C0-C2-alkyl-; where R8and R9independently take the values defined above;

J represents-C(R11, R12), -O-, -N(R11)- or-S-;

R11, R12independently represent hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

any N may be an N-oxide.

<> The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Variant implementation of the present invention includes compounds of formula I-J

where

P and Q each independently represents an aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NR10CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected the data from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

J represents-C(R11, R12), -O-, -N(R11)- or-S-;

R11, R12independently represent hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl,C 2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Another variant implementation of the present invention includes compounds of formula I-K

where

P and Q each independently represent an aryl or heteroaryl group of the formula

where

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NRsub> 8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NRl0CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1- 6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

J represents-C(R11, R12), -O-, -N(R11)- or-S-;

R11, R12independently represent hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Another option is the implementation of this image is the shadow includes compounds of formula I-L

where

P and Q each independently represents an aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NRl0CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C -C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

J represents-C(R11, R12), -O-, -N(R11)- or-S-;

R11, R12independently represent hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 mandated what teli, independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Another variant implementation of the present invention includes compounds of formula I-M

where

P and Q each independently represents an aryl or heteroaryl group of the formula

R3, R4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NRl0CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8 R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents; where optionally two Deputy together with in between the atoms to form a bicyclic aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10each independently represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cyclol the sludge), or-N(C 0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

J represents-C(R11, R12), -O-, -N(R11)- or-S-;

R11, R12independently represent hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Another variant implementation of the present invention includes compounds of formula I-N

where

P and Q each independently represents an aryl or heteroaryl group of the formula

R3, R 4, R5, R6and R7independently represent hydrogen, halogen, -CN, nitro, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl, aryl, -OR8, -NR8R9, -C(=NR10)NR8R9N(=NR10)NR8R9, -NR8COR9, NR8CO2R9, NR8SO2R9, -NRl0CONR8R9, -SR8, -S(=O)R8, -S(=O)2R8, -S(=O)2NR8R9, -C(=O)R8, -C(=O)2R8, -C(=O)NR8R9, -C(=NR8R9or C(=NOR8R9substituents, where the optional two Deputy together with in between the atoms to form a bicyclic aryl or heteroaryl ring; where each ring is optionally additionally substituted by 1-5 groups independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -O(C1-C3-alkylaryl), -O(C1-C3-alkylglycerol), -N(C0-C6-alkyl)(C0-C3-alkylaryl) or-N(C0-C6-alkyl)(C0-C3-alkylglycerol);

R8, R9, R10, each independently, submitted is a hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0-C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

D, E, F, G and H independently represent-C(R3)=, -C(R3)=C(R4)-, -C(=O)-, -C(=S)-, -O-, -N=, -N(R3)- or-S-;

J represents-C(R11, R12), -O-, -N(R11)- or-S-;

R11, R12independently represent hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C7-cycloalkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C6-alkyl, heteroaryl, heteroaromatic, arylalkyl or aryl, each of which is optionally substituted by 1-5 substituents independently selected from halogen, -CN, C1-C6-alkyl, -O(C0-C6-alkyl), -O(C3-C7-cycloalkenyl), -O(aryl), -O(heteroaryl), -N(C0-C6-alkyl)(C0 -C6-alkyl), -N(C0-C6-alkyl)(C3-C7-cycloalkyl) or-N(C0-C6-alkyl)(aryl);

any N may be an N-oxide.

The present invention includes all possible stereoisomers and not only the racemates and individual enantiomers of the compounds.

Specific preferred compounds are:

(4-forfinal)-[3-(4-perforating)piperidine-1-yl]metano;

(4-forfinal)-{3-[5-(4-forfinal)-4H-[1,2,4]triazole-3-yl]piperidine-1-yl}meanon;

(S)-(4-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(S)-(thiophene-2-yl)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-methyl-2-pyrazin-2-iltiazem-5-yl)methanon;

(2,4-differenl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(3,4,5-tryptophanyl)methanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-pyridin-2-althofen-2-yl)methanon;

cyclopentyl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(3,4-differenl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

benzothiazol-6-yl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(3,5-dimethylisoxazol-4-yl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(4-forfinal)-{(S)-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(4-forfinal)-[(S)-3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

(4-forfinal)-[(S)-3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

{(S)-3-[3-(2,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-forfinal)methanon;

(4-forfinal)-[(S)-3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

(4-forfinal)-{(S)-3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(4-forfinal)-[(S)-3-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

(4-forfinal)-{3-[5-(4-forfinal)-[1,3,4]oxadiazol-2-yl]piperidine-1-yl}meanon;

(2-forfinal)-{(S)-3-[2-(3,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(4-forfinal)-{2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]morpholine-4-yl}meanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}thiophene-3-ylmethanone;

(4-forfinal)-[3-(5-phenyltetrazol-2-yl)piperidine-1-yl]metano;

(4-forfinal)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

(3,4-differenl)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

{3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}phenylmethanone;

{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}phenylmethanone;

(4-forfinal)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

(3-forfinal)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-the l]metano;

(4-forfinal)-{3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(3-forfinal)-{3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(4-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(3-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(R)-(4-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(4-forfinal)-{3-[5-(4-forfinal)-[1,2,4]oxadiazol-3-yl]piperidine-1-yl}meanon;

(4-forfinal)-{3-[5-(4-forfinal)-4-methyl-4H-[1,2,4]triazole-3-yl]piperidine-1-yl)methanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-phenylthiazol-4-yl)methanon;

{{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-methyl-6-triptorelin-3-yl)methanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-[1,2,3]thiadiazole-4-ylmethanone;

benzothiazol-2-yl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-methylisoxazol-3-yl)methanon;

(1,5-dimethyl-1H-pyrazole-3-yl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-triptoreline)methanon;

4-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carbonyl}benzonitrile;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}isoxazol-5-ylmethanol;

(3-chloro-4-fluoro who enyl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-phenyl-2H-pyrazole-3-yl)methanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl)methanon;

(4-fluoro-3-were)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(3-methylthiophene-2-yl)methanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(1-methyl-1H-pyrrol-2-yl)methanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}thiazole-2-ylmethanone;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-methylthiazole-5-yl)methanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(6-morpholine-4-espiridion-3-yl)methanon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(1H-indol-5-yl)methanon;

2-(4-forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}Etalon;

3-(4-forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}propane-1-it;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}isoquinoline-3-ylmethanone;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}cinoxacin-6-ylmethanol;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}benzimidazole-6-ylmethanol;

(4-forfinal)-[(S)-3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

{(S)-3-[3-(2,6-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-performation;

(4-forfinal)-{(S)-3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(4-forfinal)-[(S)-3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;

(4-forfinal)-{3-[5-(4-forfinal)-[1,2,4]oxadiazol-3-yl]piperidine-1-yl}meanon;

(4-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-4-methylpiperazin-1-yl}meanon;

(4-forfinal)amide (S)-1-(4-perbenzoic)piperidine-3-carboxylic acid;

(4-forfinal)methylamide (S)-1-(4-perbenzoic)piperidine-3-carboxylic acid;

(E)-3-(4-forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}propenone;

1-(4-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl}piperidine-1-carbonyl}piperidine-1-yl)Etalon;

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-imidazol-1-ylphenyl)methanon;

(4-forfinal)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;

(3,4-differenl)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}mechanon.

Other illustrative examples of compounds of formula I are the following compounds:

(4-forfinal)(3-(5-(4-forfinal)isoxazol-3-yl)piperidine-1-yl)methanon;

(4-forfinal)(3-(5-(4-forfinal)-1H-imidazol-2-yl)piperidine-1-yl)methanon;

(4-forfinal)(3-(4-(4-forfinal)-1H-imidazol-1-yl)piperidine-1-yl)methanon;

(4-forfinal)(3-(4-(4-forfinal)-1H-pyrazole-1-yl)piperidine-1-yl)methanon;

N-(1-(4-perbenzoic)piperidine-3-yl)-4-perbenzoic;

(2-torfin the l)-{3-[2-(4-forfinal)oxazol-5-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[5-(4-forfinal)oxazol-2-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[5-(4-forfinal)thiazol-2-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[2-(4-forfinal)thiazol-5-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[5-(4-forfinal)-[1,3,4]thiadiazole-2-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[5-(4-forfinal)-[1,2,4]oxadiazol-3-yl]piperidine-1-yl}meanon;

(2-forfinal)(3-(5-(4-forfinal)isoxazol-3-yl)piperidine-1-yl)methanon;

(2-forfinal)(3-(5-(4-forfinal)-1H-imidazol-2-yl)piperidine-1-yl)methanon;

(2-forfinal)(3-(4-(4-forfinal)-1H-imidazol-1-yl)piperidine-1-yl)methanon;

(2-forfinal)(3-(4-(4-forfinal)-1H-pyrazole-1-yl)piperidine-1-yl)methanon;

N-(1-(4-perbenzoic)piperidine-3-yl)-2-perbenzoic;

(2-forfinal)-{3-[2-(3,4-forfinal)oxazol-5-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[5-(3,4-forfinal)oxazol-2-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[5-(3,4-forfinal)thiazol-2-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[2-(3,4-forfinal)thiazol-5-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[5-(3,4-forfinal)-[1,3,4]thiadiazole-2-yl]piperidine-1-yl}meanon;

(2-forfinal)-{3-[5-(3,4-forfinal)-[1,2,4]oxadiazol-3-yl]piperidine-1-yl}meanon;

(2-forfinal)(3-(5-(3,4-forfinal)isoxazol-3-yl)piperidine-1-yl)methanon;

(2-forfinal)(3-(5-(3,4-forfinal)-1H-imidazol-2-yl)piperidine-1-yl)methanon;

(2-forfinal)(3-(4-(3,4-forfinal)-1H-imidazol-1-yl)piperidine-1-yl)methanon;

(2-forfinal)(3-(4-(3,4-forfinal)-1H-pyrazole-1-yl)piperidine-1-yl)methanon;

N-(1-(3,4-perbenzoic)piperidine-3-yl)-2-perbenzoic.

The present invention relates to pharmaceutically acceptable acid additive salts of compounds of formula (I) or pharmaceutically acceptable carriers or excipients.

The present invention relates to a method of treatment or prevention in a mammal, including humans, condition, treatment or prevention of which is mediated or can be facilitated by the neuromodulatory effect of allosteric modulators of mGluR5 and especially positive allosteric modulators.

The present invention relates to a method of treatment or prevention of disorders of the peripheral and Central nervous system selected from the group including tolerance or dependence, anxiety, depression, psychiatric illness, such as psychosis, inflammatory or neuropathic pain, memory impairment, Alzheimer's disease, ischemia, drug abuse and drug dependence (addiction).

The present invention relates to pharmaceutical compositions comprising from about 0.01 to 1000 mg of active ingredient in a unit dose. Compositions can be administered in any suitable way, for example, orally in capsules, etc., part eraline in the form of solutions for injection, topically in the form of ointments (onguents) or lotions, eye in the form of eye lotion, rectally in the form of candles.

The pharmaceutical preparations according to the present invention can be obtained by standard methods of the art; the form used in the pharmaceutical composition will depend upon the desired route of administration. The total daily dose usually ranges from about 0.05 to 2000 mg.

Methods synthesis

Compounds of General formula I can be obtained by methods known in the field of organic synthesis, which are briefly described below by using diagrams. It is quite clear that all of the schemes described below, for sensitive or reactive groups, when necessary, apply protective groups in accordance with the General principles of chemistry. The introduction of protective groups is carried out in accordance with standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1991),Protective Groups in Organic Synthesis, John Wiley et Sons). Such groups are removed at an appropriate stage of the synthesis of compounds using methods known to the skilled specialist in a given field of technology. The choice of method, as well as the reaction conditions and procedure for execution of works should be compatible with the formation of compounds of formula I.

The compound of the formula I can be represented as a mixture of enantiomers, colorature be separated pure R - or S-enantiomers. If, for example, a desirable specific enantiomer of the compounds of formula I, it can be obtained by asymmetric synthesis, or by derivation with a chiral auxiliary substance, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to obtain the desired pure enantiomers. Alternatively, when the molecule contains a basic functional group such as amino group or an acid functional group such as carboxyl group, a separation may conveniently be carried out by fractional crystallization of the compounds of formula I with an optically active acid from various solvents, salts or other methods described in the literature, for example, chiral column chromatography. The selection of the final product, intermediate product or source material may be any suitable means known in the art, which are described in the publication E.L. Eliel, S.H. Wilen and L.N. Mander (1984),Stereochemistry of Organic Compounds, Wiley-Interscience.

A large number of heterocyclic compounds of the formula I, where a represents a heteroaromatic group can be obtained using methods of synthesis are well known in the art (A.R. A.R. Katrizky and C.W. Rees (1984)Comprehensive Heterocyclic Chemistry, Pergamon Press).

The reaction product can be isolated and purified with IP is the use of standard techniques, such as extraction, chromatography, crystallization, distillation, etc.

The compound of formula I-A in the case when a is a triazole group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in schemes 1-3,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

In accordance with scheme 1 predecessor nicotinebuy acid (for example, utilipath) is subjected to interaction with the aryl - or heteroaryl-derived, for example, 4-tormentilla, using a method known qualified specialists in this field of technology. In scheme 1 takes the values defined above, X represents halogen, PG1represents a protective group such as benzyl, tert-butyl, ethyl, allyl and the like, the Reaction can be accelerated by a base, such as triethylamine, Diisopropylamine, pyridine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane). The reaction is usually carried out under the condition of slow heating of the reaction mixture from 0°C to room temperature over a period of the time interval from 4 to 12 hours. The protective group PG1deleted by normal means.

In turn substituted derivative of the acid (represented in scheme 1) can be converted into hydrazide-derived using the approach illustrated in scheme 2. PG2figure 2 is aminosidine group, such as tert-butyloxycarbonyl, benzyloxycarbonyl, etoxycarbonyl, benzyl and the like, the Reaction can be accelerated with the help of an agent, the reaction combinations known in the field of organic synthesis such as EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), DCC (N,N'-dicyclohexylcarbodiimide), in a suitable solvent (such as tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane). Usually in the reaction mixture will be present in the second catalyst such as HOBT (hydroxybenzotriazole). The reaction is usually carried out at room temperature over a period of time in the range of from about 4 to 12 hours. The protective group PG2deleted by normal means.

Scheme 3 illustrates the final stage of the synthesis.

Hydrazide-derived undergoes interaction with nitrilotri (for example, 4-phthorbenzotephum) in basic conditions such as sodium methylate or sodium ethylate and the like, in a suitable solvent (n is an example, methyl alcohol, ethyl alcohol). The reaction is usually carried out under the condition of slow heating of the reaction mixture from room temperature to 65°C for a period of time in the range of from about 24 hours to 48 hours (see, for example, Alcalde, Ermitas; Gisbert, Maria; Perez-Garcina. Lluisa; Tetrahedron; 51; 48; 1955; 13365-13378).

In accordance with another embodiment of the present invention the compounds of formula I-A, where a is aand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in schemes 4-6,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl; -S(=O)2-C0-C2-alkyl-.

In accordance with the present invention acetylene derivatives can be obtained by methods known in the art, for example, as described above. Free nitrogen piperidino cycle is protected by a protective group of amino group PG2.

Suitable aldehyde derivative, for example, tert-butyl ester 3-formylpiperidine-1-carboxylic acid, converted to the corresponding unsaturated gem-dibromide is derived by means of a Wittig reaction in accordance the with way, described in the patent WO 02/088114. The Wittig reaction can be accelerated by using a mixture of methylene predecessors (for example, tetrabromide carbon) and phosphine, such as triphenylphosphine, in a suitable solvent (e.g. dichloromethane, tetrahydrofuran, diethylether). If necessary, the reaction mixture will be present in the catalyst, such as zinc powder. The reaction is usually carried out, maintaining room temperature over a period of time in the range of from about 12 hours to 24 hours. Unsaturated gem-dibromide compound then undergoes interaction with ORGANOMETALLIC compounds, such as n-utility, tert-utility etc. that can undergo exchange reactions of metal with subsequent dehydrohalogenation. The reaction can be accelerated in a suitable solvent (e.g. tetrahydrofuran, ether and the like) at a temperature of about -78°C for 1 hour.

Scheme 5 illustrates the receiving disubstituted acetylene derivatives of the interaction alkalinous derived (the receipt of which is described in scheme 4), for example tert-butyl ester 3-ethenylpyridine-1-carboxylic acid, substituted with R, such as 1-fluoro-4-yogansonom. Thus, in scheme 5 X is a halide, such as Cl, Br, I, or trifloromethyl and paratoluenesulfonyl. Such a common way of synthesis was the description of the n in the publication of J. Med. Chem.2000, 43, 4288-4312.

For this reaction-With-linking catalyzed by palladium, the necessary catalyst, such as PdCl2(PPh3)2Pd(PPh3)4Pd(OAc)2or Pd on carbon, in a suitable solvent, such as DMF, acetonitrile or benzene. Usually in the reaction mixture will be present in the second catalyst such as copper iodide (I), and base (e.g. triethylamine, Diisopropylamine, potassium acetate, and so on). The reaction mix is usually done while ensuring slow heating from about 0°C. to room temperature or when heated to a temperature in the range from 30°to 150°C. After that the reaction mixture is maintained at a suitable temperature over a period of time in the range of from about 1 hour to 24 hours, and usually good for about 12 hours. The protective group PG2deleted by normal means.

Scheme 6 illustrates the last stage of the method, similar to the way presented in figure 1.

The compounds of formula I-A, where A is a

and W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in the diagrams 7-10,

where

P and Q, each independently, PR is dstanley an aryl or heteroaryl, above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

Source amidoxime can be obtained by methods known in the field of organic synthesis, as shown in the following synthesis scheme 7.

Nitrile derivative (for example, 4-perbenzoate) is subjected to interaction with hydroxylamine at neutral or basic conditions, such as triethylamine, diisopropylethylamine, sodium carbonate, sodium hydroxide and the like, in a suitable solvent (for example, methyl alcohol, ethyl alcohol). The reaction is usually carried out under the condition of slow heating from ambient temperature to a temperature in the range from 70°C to 80°C. inclusive for time period in the range of from about 1 hour to 48 hours (see, for example, Lucca, George V. De; Kim, Ui, T.; Liang, Jing; Cordova, Beverly; Klabe, Ronald M.; et al.; J. Med. Chem.; EN; 41; 13; 1998; 2411-2423; Lila, Christine; Gloanec, Philippe; Cadet, Laurence; Herve, Yolande; Fournier, Jean; et al.; Synth. Commun.; EN; 28; 23; 1998; 4419-4430; see also: Sendzik, Martin; Hui, Hon C.; Tetrahedron Lett.; EN; 44; 2003; 8697-8700 and the references listed in this publication for the reaction in neutral conditions).

Substituted amidoxime-derivative (described in scheme 7) subject to transformation in acylaminoacyl-derived using approach, as the th in scheme 8. PG2figure 8 represents a protective group as described above. The reaction mix can be accelerated with the help of an agent, the reaction combinations known in the field of organic synthesis such as EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), DCC (N,N'-dicyclohexylcarbodiimide), in the presence of a suitable base, such as triethylamine, diisopropylethylamine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane). Usually in the reaction mixture may be present in the second catalyst, such as NOT (hydroxybenzotriazole), NEAT (1-hydroxy-7-asobancaria). The reaction is usually conducted at a temperature in the range from ambient temperature up to 60°C, inclusive for time period in the range of from about 2 hours to 12 hours to obtain an intermediate arylamidase. The cyclization reaction can be carried out by heating the reaction mixture to a temperature in the range of from about 80°to about 150°C for a period of time in the range of from about 2 hours to 18 hours (see, for example, Suzuki, Takeshi; Iwaoka, Kiyoshi; Imanishi, Naoki; Nagakura, Yukinori; Miyata, Keiji; et al.; Chem. Pharm. Bull.; EN; 47; 1; 1999; 120-122). The product obtained in the reaction can be isolated and purified using standard techniques such as extraction, chromatography, crystallization, distillation, etc.

The conclusion of the positive phase can be performed in a manner described in scheme 9, or by the method described in scheme 10.

As shown in scheme 9, the protective group PG2removed using standard methods. The combination shown in figure 9, similar to the combination shown in figure 1.

As shown in scheme 10, the protective group PG2deleted by standard means. The reaction mix can be accelerated with the help of agents of combination reaction, known in the field of organic synthesis such as EDCI (1-(2-dimethylaminopropyl)-3-ethylcarbodiimide), DCC (N,N'-dicyclohexylcarbodiimide), or agents of combination reaction, deposited on a polymer carrier, such as carbodiimide deposited on a polymer carrier (PS-DCC, for example, Argonaut Technologies), in the presence of a suitable base, such as triethylamine, diisopropylethylamine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane). Usually in the reaction mixture may be present in the second catalyst, such as NOT (1-hydroxybenzotriazole), NEAT (1-hydroxy-7-asobancaria) and the like, the Reaction is usually carried out at ambient temperature over a period of time in the range of from about 2 hours to 12 hours.

The compounds of formula I, where a is a

and W a 2-substituted morpholinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in the diagrams 11-12,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

In accordance with scheme 11 substituted amidoxime-derivative (described in scheme 7) subject to transformation in acylaminoacyl-derived interaction with morpholine-derived by a method similar to those shown in scheme 8. Similarly, acylaminoacyl-derivative can undergo cyclization to [1,2,4]oxadiazol-derived in accordance with the method presented in figure 8.

Figure 12 group PG2deleted by standard means. The combination presented in figure 12, similar to the reactions presented in scheme 9 and scheme 10.

The compounds of formula I, where a is a

and W represents a 2-substituted pieperazinove cycle, can be obtained in accordance with the sequence of the synthesis presented in the diagrams 13-15,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2and the Kil-; -S(=O)2-C0-C2-alkyl-.

Figure 13 piperazine-2-carboxylic acid selectively protected on the nitrogen atom in position 4. PG2represents a protective group of amino group, such as tert-butyloxycarbonyl etc. This reaction can be carried out using such compounds as 2-(BOC-oxyimino)-2-phenylacetonitrile, di-tributilphosphat and the like, in a suitable organic solvent (e.g. dioxane, tetrahydrofuran) in a mixture with water. Usually the pH of the reaction mixture is brought to a value in the interval from 8 to 12 by addition of a suitable base, such as sodium hydroxide, potassium hydroxide, triethylamine and the like, the Reaction usually proceeds at room temperature over a period of time in the range of from about 1 hour to 4 hours (see, for example: Bigge, Christopher F.; Hays, Sheryl J.; Novak, Perry M.; Drummond, James T. et al.; Tetrahedron Letters; 30, 39; 1989; 5193-5196 and WO 2004/022061). N4-protected piperazine-derivative can podvergatsya becoming a piperazine-derivative substituted in position 1, using standard conditions of reductive amination. R11can represent, for example, With1-C6-alkyl, C3-C6-cycloalkyl,3-C7-cycloalkenyl, arylalkyl, heteroallyl. The reaction may be carried out by the interaction of N4-secure the oho pyrazin is derived from an aldehyde or a ketone (for example, formaldehyde) in the presence of a suitable reductant, such as triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride and the like, in a suitable solvent, such as acetonitrile, tetrahydrofuran, methanol, ethanol, 1,2-dichloroethane, etc. are Usually used for the reaction may be necessary to add acid to reduce the pH of the reaction mixture to less than about 7, and this acid is an acetic acid, hydrochloric acid, and the like, the Reaction usually proceeds at room temperature over a period of time in the range of from about 2 hours to 4 hours.

In figure 14 substituted amidoxime-derived (obtained as shown in scheme 7) subject to transformation to acylaminoacyl-derived interaction with a piperazine-derivative (described in scheme 13) by the method similar to that described in scheme 8. Acylaminoacyl-derivative can undergo cyclization to [1,2,4]oxadiazol-derived in accordance with the method described in scheme 8.

In scheme 15 PG2the group is removed using standard methods. The combination presented in figure 15, similarly to the reactions represented in the diagrams 9-10.

The compounds of formula I-A, where a represents a group of the formulaand W Ave is dstanley a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in figure 16,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

Oxadiazolyl cycle described above shall be given in accordance with the sequence of synthesis are well known in the art (A.R. Katrizky and C.W. Rees(1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in the diagrams 17-19,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

Alkylation of triazole derivatives (obtained, as shown in schemes 1-3) an alkylating agent, such as methyliodide etc. in basic conditions (for example, NaH, MeONa, etc.) results in N-alkylthiol-derived (see, for example, Tarrago, Georges; Marzin, Claude; Najiumi, Ouafa; Pellegrin, Valdo; J. Org. Chem.; 55; 2; 1990; 420-425). Alternatively, obtained for the I these derivatives can be used by another sequence of reactions, as shown in the diagrams 18-19.

Secondary amide (e.g. N-methyl-4-perbenzoic) converted into imidocloprid using the approach presented in figure 18. R3can represent, for example, With1-C6-alkyl, C3-C6-cycloalkyl,3-C7-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl. Usually the secondary amide is subjected to interaction with gloriouse agent such as thionyl chloride, pentachloride phosphorus, phosphorus oxychloride and the like, in a suitable solvent (e.g. dichloromethane, chloroform, tetrahydrofuran) or using glorieuses agent in a large excess as a solvent. The reaction is usually carried out while ensuring slow heating from ambient temperature to a temperature in the range from 40°C to 110°C inclusive for time period in the range of from about 1 hour to 4 hours.

Figure 19 hydrazide derivative (described in scheme 2) subject to interaction with imidocloprid (described in scheme 18) in accordance with the method described in scheme 19. The reaction can be accelerated using a suitable base, such as triethylamine, diisopropylethylamine, calcium carbonate, in a suitable solvent (e.g. toluene, di is the Ksan, tetrahydrofuran). The reaction is usually carried out under the condition of slow heating of the reaction mixture from ambient temperature to a temperature in the range from 60°C to 110°C, inclusive, during the time period in the range of from about 1 hour to 8 hours (see, for example; Clemence, Francois; Joliveau-Maushart, Claudine; Meier, Jean; Cerede, Jean et al.; Eur. J. Med. Chem.; 20; 2; 1985; 257-266, and references cited in these publications).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in the diagrams 20-21.

Oxadiazolyl cycle described above shall be given in accordance with the methods of synthesis are well known in the art (A.R. Katrizky and C.W. Rees (1984)Comprehensive Heterocyclic Chemistry, Pergamon Press).

Alternatively, you may use another method of synthesis is shown in figure 21.

Derived hydrazide (obtained as described in scheme 2) subject to interaction with the acid in a suitable combination of conditions. The combination can be accelerated by agents of combination reaction, known in the field of organic synthesis such as EDCI (1-(3-dimethylaminopropyl)-3-e is incarnational), DCC (N,N'-dicyclohexylcarbodiimide), or binding agent deposited on a polymer carrier, such as carbodiimide deposited on a polymer carrier (PS-DCC, ex Argonaur Technologies), in the presence of a suitable base, such as triethylamine, diisopropylethylamine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane). Usually in the reaction mixture may contain a second catalyst, such as NOT (1-hydroxybenzotriazole), NEAT (1-hydroxy-7-asobancaria) and the like, the Reaction usually proceeds at ambient temperature over a period of time in the range of from about 2 hours to 12 hours.

Stage cyclization can be carried out in the presence of a dehydrating agent such as phosphorus oxychloride, thionyl chloride and the like, in a suitable solvent (e.g. acetonitrile, pyridine), or using a dehydrating agent, taken in excess as a solvent. Usually, the reaction proceeds at a temperature in the range from 70°C to 110°C for a period of time in the interval from 2 hours to 4 hours. An alternative and more preferably, the phase cyclization can be carried out in the presence of 4-toluensulfonate and WEMR deposited on a solid carrier, in a suitable solvent, such as THF, dioxane and the like, using conventional or microwave on the Reva in accordance with the methodology described in the literature (see: Brain, Christopher T., Brunton, Shirley A.; Synlett, 3, 2001, 382-384).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in the diagrams 28-29,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

Oxazolines cycle described above shall be given in accordance with the methods of synthesis are well known in the art (A.R. Katrizky and C.W. Rees (1984)Comprehensive Heterocyclic Chemistry, Pergamon Press).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in figure 23,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

The original α-Bratton-derivatives shown above are in accordance with the synthesis methods, well known for the mi in this field of technology.

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in figure 24,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

In accordance with another embodiment of the present invention substituted acetylene derivative (described in scheme 4) may be subjected to transformation in oxazol-derived interactions aminochlorides aryloxy in accordance with the methods of synthesis are well known in the art (see, for example, Diana, Guy D.; Volkots, Deborah L., Nitz, Theodore J.; Bailey, Thomas R.; Long, Melody A.; et al.; J. Med. Chem. 37; 15; 1994; 2421-2436).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in figure 25,

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

In accordance with the present invention substituted acetylene derivative may be subjected to transformation in oxazol-derived interactions aminochlorides aryloxy in accordance with methods well known in the art (see, e.g., Diana, Guy D.; Volkots, Deborah L., Nitz, Theodore J.; Bailey, Thomas R.; Long, Melody A.; et al.; J. Med. Chem.; 37; 15; 1994; 2421-2436).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in the diagrams 26,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

According to the present invention, substituted amiden-derivative may be subjected to transformation in the imidazole-derived interaction with α-bromoketones in accordance with the methods of synthesis are well known in the art (A.R. Katrizky and C.W. Rees (1984)Comprehensive Heterocyclic Chemistry, Pergamon Press).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with posledovatelno the s synthesis, presented in figure 27,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

The original N-arylamido-derivative gain in accordance with the methods of synthesis are well known in the art (A.R. Katrizky and C.W. Rees (1984)Comprehensive Heterocyclic Chemistry, Pergamon Press).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in the diagrams 28-29,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

Source aristocrats-derivative gain in accordance with the methods of synthesis are well known in the art (A.R. Katrizky and C.W. Rees (1984)Comprehensive Heterocyclic Chemistry, Pergamon Press).

Alternatively, these derivative can be synthesized in accordance with the sequence of the synthesis presented in figure 29.

Aristocrats obtained in accordance the methods of synthesis, well known in the art, may be subjected to alkylation of 3-hydroxypiperidine derived under the reaction conditions combination Mitsunobu, as described in the literature (see, for example: Synthetic Commun.; 26; 14; 1996; 2687-2694).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the methods of synthesis presented in figure 30,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

Source arylpyrazole-derivative gain in accordance with the methods of synthesis are well known in the art (A.R. Katrizky and C.W. Rees (1984)Comprehensive Heterocyclic Chemistry, Pergamon Press).

The compounds of formula I-A, where a represents a group of the formula

and W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in figure 31,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in figure 32,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

Scheme 32 illustrates obtaining disubstituted ethylene-derived interaction protected vinylpyridine substituted with R, such as 1-fluoro-4-yogansonom. Thus, in scheme 5 X is a halide, such as Cl, Br, I, or trifloromethyl and p-toluensulfonyl. Such a common way of synthesis described in the publication Arthzhur D: Brosius and al.;JACS. 1999, 121, 700-709.

For this reaction-With-linking catalyzed by palladium, the necessary catalyst, such as PdCl2(PPH3)2Pd(PPH3)4Pd(OAc)2or Pd on carbon, in a suitable solvent, such as DMF, acetonitrile or benzene. Usually in the reaction mixture contains a second catalyst such as copper iodide (I), and base (e.g. triethylamine, Diisopropylamine, potassium acetate). The reaction mix is usually performed under slow heating condition on t is mperature about 0°C. to ambient temperature or heating to a temperature in the range from 30°to 150°C. Then the reaction mixture is maintained at a suitable temperature over a period of time in the range of about 1 to 24 hours, and usually it is enough for about 12 hours. The protective group PG2deleted by normal means.

Original protected vinylpyridin-derived receive in accordance with the methods of synthesis are well known in the art (see, for example, Arthzhur D: Brosius and al.;JACS. 1999, 121, 700-709).

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in figure 33,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

In scheme 33 PG2represents a protective group of amino group, such as tert-butoxycarbonyl, benzyloxycarbonyl, etoxycarbonyl, benzyl and the like, takes on the values defined above, X represents halogen. The amide formation can be accelerated by using agents binding assays known in the field of organic synthesis such as EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), DCC (N,N'-dicyclohexylcarbodiimide), K is included solvent (for example, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane). Usually in the reaction mixture may contain a second catalyst, such as NOT (hydroxybenzotriazole) and the like, the Reaction usually takes place either at room temperature or at a temperature in the range from 40°C to 80°C, inclusive, during the time period in the range of from about 4 hours to 48 hours. The protective group PG2deleted by standard means. The final stage is presented in figure 33, can be accelerated by using a base such as triethylamine, Diisopropylamine, pyridine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane). The reaction is usually carried out under the condition of slow heating of the reaction mixture at temperatures from 0°C to ambient temperature over a period of time in the range of from about 2 hours to 12 hours.

The compounds of formula I-A, where a represents a group of the formulaand W represents a 3-substituted piperidinyl cycle, can be obtained in accordance with the sequence of the synthesis presented in figure 34,

where

P and Q each independently represents an aryl or heteroaryl above

Represents a-C(=O)-C0-C2-alkyl-; -S(=O)2-C0-C2-alkyl-.

The compounds of formula I, which by nature are basic can form a wide range of different pharmaceutically acceptable salts with various inorganic and organic acids. Such salts are readily obtained by treatment of the basic compounds are essentially equivalent amount of the chosen mineral or organic acid in a suitable organic solvent, such as methanol, ethanol or isopropanol (see P. Heinrich Stahl, Camille G: Wermuth,Handbook of pharmaceutical Salts, Properties, Selection and Use, Wiley, 2002).

The following examples are not to limit the scope of the present invention, are intended only to illustrate the present invention. The physical properties of the compounds presented in the examples are consistent with the structure of these compounds.

EXAMPLES

Except where otherwise noted, all source materials were obtained from commercial suppliers and were used without further purification.

In the examples and the description can be used the following abbreviations:

g (grams)Tr (retention time)
mg (milligrams)MeOH (methanol)
ml (milliliters)MeOH (methanol)
ál (Microlitre)Hz (Hertz)
M (mol)IHMS (liquid chromatography-mass spectrum)
MHz (megahertz)HPLC (high performance liquid chromatography)
mmol (mmol)NMR (nuclear magnetic resonance)
min (minutes)1H (proton)
AcOEt (ethyl acetate)Na2SO4(sodium sulfate)
K2CO3(potassium carbonate)MgSO4(magnesium sulfate)
PdCl2(PPh3)2(dichloride bis(triphenylphosphine)palladium(II))
CDCl3(deuterated chloroform)HOBT (1-hydroxybenzotriazole)
EDCI·HCl (hydrochloride 1-3(dimethylaminopropyl)-3-ethylcarbodiimide)R.T. (room temperature)
EtOH (ethyl alcohol)NaOH (sodium hydroxide)
% (percentage)hours (hours)
DHM (dichloromethane)HCl (hydrochloric acid)
DIEA (diisopropylethylamine)n-BuLi (n-utility)
TPL (melting point)THF (tetrahydrofuran)

All references to an aqueous solution of NaCl belong to the saturated aqueous solution of NaCl. Except where otherwise indicated, all temperatures are expressed in °C (degrees Celsius). All reactions are carried out in an atmosphere which is inert at room temperature, except where otherwise noted.

lH-NMR spectra were recorded on a spectrometer Bruker 500 MHz or Bruker 300 MHz. Chemical shifts are expressed in ppm (ppm, δ). The binding constants are presented in Hertz (Hz). Characteristics of the splitting described by multipletness and designated as s (singlet), d (doublet), t (triplet), square (Quartet), Quint. (quintet), m (multiplet).

IHMS recorded in the following conditions:

Method A: Waters 1525u Micromass ZQ. Column stainless steel of 2.1×50 mm, filled with 2.5 ám XTerra RP C-18; flow rate 0.25 ml/min; mobile phase: A phase = water/acetonitrile 95/5 + 0.1% TFUK, B phase = water/acetonitrile 5/95 + 0.1% TFUCK. 0-1,5 min (A: 98%, B: 2%), 1,5-8,0 min (A: 0%, B: 100%), 8,0-11,0 min (A: 0%, B: 100%), 11,0-11,1 min (A: 98%, B: 2%); a diode detector UV detection: 200-400 nm; volume of injection: 5 ál.

Method B): Waters Alliance 2795 HT Micromass ZQ. Column of 4.6×75 mm stainless steel, filled with 3.5 µm Symmetry RP C-18; flow rate 1.0 ml/min; mobile phase: A phase = water/acetonitrile 95/5 + 0.05 TFUK, B phase = water/acetonitrile 5/95 + 0.05 TFUCK. 0-1,0 min (A: 95%, B: 5%), from 1.0 to 11.0 min (A: 0%, B: 100%), 11,0-12,0 min (A: 0%, B: 100%), 12,0-12,1 min (A: 95%, B: 5%); a diode detector UV detection: 200-400 nm; volume of injection: 5 ál.

Method C: Waters Micromass ZQ 2996. Column of 3.0×50 mm stainless steel, filled with 5 ám XTerra RP C-18; flow rate 1 ml/min; mobile phase: phase A=0.1% of formic acid in water, B phase=0,07% formic acid in acetonitrile. 0-0,5 min (A: 95%, B: 5%), 0,5-6,0 min (A: 0%, B: 100%), 6,0-6,5 min (A: 95%, B: 5%), a 6.5-7 min (A: 95%, B: 5%); a diode detector UV detection: 200-400 nm; volume of injection: 3 µl.

All mass spectra were recorded by the method of electrocapillary ionization in the form of a positively charged ion (ESI method).

Most of the reactions were monitored using thin-layer chromatography on silicagel plates of 0.25 mm, Macherey-Nagel (60F-2254) with visualization under UV light. Flash chromatography was performed on silica gel (220-440 mesh, Fluka). The melting temperature was measured on the apparatus Buchi B-540.

Example 1

(4-Forfinal)-{3-[5-(4-forfinal)-4H-[1,2,4]triazole-3-yl]piperidine-1-yl}metano

1(A). Ethyl ester of 1-(4-perbenzoic)piperidine-3-carboxylic acid

To a mixture of Eternitate (2 is, 12,72 mmol) in THF (25 ml, 0,5M) is added DIEA (4,79 ml, 27,99 mmol). The reaction mixture was cooled to 0°C and to the mixture is added slowly 4-perbenzoate (2.5 g - 15,76 mmol). The reaction mixture is allowed to warm to room temperature and the mixture is stirred for 24 hours. The solution is concentrated and consistently add DHM and 1 N. HCl. The aqueous phase is separated and the organic phase is extracted twice 1 N. HCl and twice with water, dried over Na2SO4filter and concentrate the receiving of 1.15 g (33%) of ethyl ester 1-(4-perbenzoic)piperidine-3-carboxylic acid as a colourless oil, which is used further without additional purification.

1(B). 1-(4-Perbenzoic)piperidine-3-carboxylic acid

Ethyl ester of 1-(4-perbenzoic)piperidine-3-carboxylic acid (1,15 g, was 4.42 mmol) is added to a mixture of EtOH/NaOH 3 N. :1/1 (8 ml) and the resulting heterogeneous solution was stirred at room temperature for 1 hour. To this mixture fuming HCl to achieve pH=1. The solution is poured into DHM. The organic layer is separated and the aqueous phase is twice extracted with DHM. The combined organic phase washed twice with water. The solution is dried over Na2SO4filter and concentrate, receiving 1.13 g (100%) 1-(4-perbenzoic)piperidine-3-carboxylic acid in the form of an orange oil, which is used further without additional purification.

1(C). tert-Butyl ether N'-[1-(4-f is orbinson)piperidine-3-carbonyl]hydrazinecarboxamide acid

To a solution of 1-(4-Perbenzoic)piperidine-3-carboxylic acid (1.13 g, 4,50 mmol) in DHM (6.5 ml) is added excess tert-butyl ether hydrazinecarboxamide acid (0,59 g, 4,50 mmol), HOBT (0,69 g, 4,50 g) and EDCI·HCl (1.29 g, 6,758 mmol). The mixture is stirred at room temperature for 72 hours. The solvent is removed under reduced pressure and the residue diluted with DHM. The organic layer is washed twice with water, twice 1 N. HCl and twice again with water. The organic layer is dried over Na2SO4, filtered and evaporated, getting 1.19 g (73%) tert-butyl ether N'-[1-(4-perbenzoic)piperidine-3-carbonyl]hydrazinecarboxamide acid as colorless semi-solid substance.

1(D). Hydrazide 1-(4-perbenzoic)piperidine-3-carboxylic acid

tert-Butyl ether N'-[1-(4-perbenzoic)piperidine-3-carbonyl]hydrazinecarboxamide acid are dissolved in 8 ml of 4 N. HCl solution in dioxane). The resulting reaction mixture was stirred at room temperature for 1 hour and concentrated, gaining 0.88 g (100%) hydrazide hydrochloride 1-(4-perbenzoic)piperidine-3-carboxylic acid as white solid.

1(E). (4-Forfinal)-{3-[5-(4-forfinal)-4H-[1,2,4]triazole-3-yl]piperidine-1-yl}mechanon.

A solution of 4-perbenzoate (0,48 g, 4.02 mmol) in methanol (3 ml) is treated with metallic sodium (77 mg, 0.35 mmol) and stirred at ambient environments is within 1 hour. After that, the mixture was added to a solution of hydrazide 1-(4-perbenzoic)piperidine-3-carboxylic acid (0,89 g, 3.35 mmol) in methanol (2 ml) and the resulting solution was refluxed for 72 hours. The mixture is concentrated, dissolved in water and neutralized 1 N. HCl. The aqueous phase is extracted with DHM and the organic layer dried over Na2SO4filter and concentrate. Cleanup with SPE reversed phase (water/ACN 45/55) results 87 mg (7%) (4-forfinal)-{3-[5-(4-forfinal)-4H-[1,2,4]triazole-3-yl]piperidine-1-yl}methanone in the form of a white solid.

Rf=0,16 (DHM/MeOH:98/2); IHMS (Tr): 3,66 min (method C); MS (ES+) m/z: 369,2; TPL=95°C;

1H-NMR (CDCl3), δ (ppm): 8,50 (s, NH), with 8.05 (m, 2H), 7,52 (m, 2H), 7,15-7,03 (m, 4H), 3,65-3,30 (m, 4H), of 2.45 (m, H), 1.85 to of 1.52 (m, 4H).

Example 2

(4-Forfinal)-[3-(4-perforating)piperidine-1-yl]metano

2(A). tert-Butyl ether 3-(2,2-dibromovinyl)piperidine-1-carboxylic acid

To the mixture CBr4(1.63 g, to 4.92 mmol) and PPh3(1.29 g, to 4.92 mmol) in DHM (25 ml) at room temperature was added 1 g (4,69 mmol) tert-butyl ether 3-formylpiperidine-1-carboxylic acid (commercially available). The reaction mixture was stirred at room temperature for 24 hours and the solvent is removed. The crude product was purified flash chromatography (cyclohexane/AcOEt 90/10)to give 0.15 g (9%) tert-butyl ether 3-2,2-dibromovinyl)piperidine-1-carboxylic acid as a colourless oil.

2(B). tert-Butyl ether 3-ethenylpyridine-1-carboxylic acid

To a solution of tert-butyl methyl ether 3-(2,2-dibromovinyl)piperidine-1-carboxylic acid (0.15 g, 0.42 mmol) in THF (1 ml) at -78°C add 0.5 ml of 2.5 M n-BuLi in hexane (1,23 mmol). The mixture was incubated for 1 hour at -78°C, then quenched with 1 ml water and the aqueous phase is extracted with AcOEt. The combined organic phase is dried over K2CO3, filtered and evaporated, receiving 80 mg (93%) of tert-butyl methyl ether 3-ethenylpyridine-1-carboxylic acid as white solid.

2(C). tert-Butyl ether 3-(4-perforating)piperidine-1-carboxylic acid

To a suspension of CuI (4 mg, 0.02 mmol) in Et3N (1 ml) is added tert-butyl ether 3-ethenylpyridine-1-carboxylic acid (80 mg, 0.38 mmol) followed by the addition PdCl2(PPh3)2(13 mg, 0.02 mmol) and 1-iodine-4-fervently (85 mg, 0.38 mmol). The mixture is stirred for 1 hour at room temperature, then heated to 60°C and kept at this temperature for 12 hours. Et3N removed by evaporation. The product was then purified flash chromatography (DHM 100%)to give 0.1 g (89%) of tert-butyl methyl ether 3-(4-perforating)piperidine-1-carboxylic acid in the form of a yellow oil.

2(D). 3-(4-Perforating)piperidine

tert-Butyl ether N'-3-(4-perforating)piperidine-1-carboxylic acid (80,1 mg, 0.34 mmol) dissolved in 0.2 ml N. HCl solution in dioxane). The resulting reaction mixture was stirred at room temperature for 1 hour and concentrated, gaining 0.14 g (100%) of the hydrochloride of 3-(4-perforating)piperidine in the form of a solid brown color.

2(E). (4-Forfinal)-[3-(4-perforating)piperidine-1-yl]metano

To a mixture of the hydrochloride of 3-(4-perforating)piperidine (0.14 g, of 0.58 mmol) in THF (2.3 ml, 0,5M) is added DIEA (0.5 ml, of 2.92 mmol). The reaction mixture was cooled to 0°C and to the mixture is added slowly 4-perbenzoate (0,139 Mr. 0.87 mmol). The reaction mixture is allowed to warm to room temperature and the mixture is stirred for 24 hours. The solution is concentrated and consistently add DHM and 1 N. HCl. The aqueous phase is separated and the organic phase is extracted twice 1 N. HCl and twice with water, dried over Na2SO4filter and concentrate. The crude product was purified flash chromatography (DHM/MeOH:98/2)to give 0,86 mg (45%) (4-forfinal)-[3-(4-perforating)piperidine-1-yl]methanone in the form of a brown oil. Rf=0,39 (DHM/MeOH:98/2); IHMS (Tr): 4,14 min (method C); MS (ES+) m/z: 326,2;

1H-NMR (CDCl3), δ (ppm): 8,10 (d, 2H), 7,60 (d, 2H), 7,15 (d, 2H), 6,94 (d, 2H), 3,47-3,30 (m, 4H), of 2.54 (m, H), 1,63 of 1.50 (m, 4H).

Example 3

{3-[3-(4-Methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}phenylmethanone

3(A). N-Hydroxy-4-methoxybenzamide

To a mixture of 4-methoxy what benzonitrile (1.07 g, 8 mmol) and DIEA (4,11 ml, 24 mmol) in EtOH (12.5 ml) is added 1.7 g of hydroxylamine hydrochloride (24 mmol), the reaction mixture is heated to 70°C and kept at this temperature for 48 hours. Half of the volume of the solvent is removed under reduced pressure. The mixture is then poured into DHM (100 ml) and water (30 ml). To the mixture is added 2.5 ml of 1 N. NaOH to achieve pH=9-10. The organic phase is separated and the aqueous phase extracted with DHM. The organic layers are combined, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure, obtaining 1.3 g (98%) of N-hydroxy-4-methoxybenzylidene in the form of a colorless oil, which was used further without additional purification.

3(B). tert-Butyl ester 3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

A mixture of N-hydroxy-4-methoxybenzamide (0.20 g, 1.50 mmol), 1-Boc-piperidine-3-carboxylic acid (0.34 g, 1.50 mmol), HOBT (0,23 g, 1.50 mmol) and EDCI·HCl (0,43 g, 2.25 mmol) in dioxane (2.5 ml) was stirred at room temperature for 7 hours. After that, the mixture is heated to 80°C and kept at this temperature during the night using the carousel of Radley (the carousel Radley's). The mixture is concentrated. The organic layer is washed with water, 1 N. NaOH and again with water. The organic layer is dried over Na2SO4, filtered and evaporated. The crude product was purified flash chromatography (DHM/MeOH:99/1), receiving 0,39 mg (72%) of tert-butyl is the first ester 3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid as white solid.

3(C). 3-[3-(4-Methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine

tert-Butyl ester 3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid (0.39 g, a 1.08 mmol) dissolved in 2 ml of 4 N. HCl solution in dioxane). The reaction mixture was stirred at room temperature for 1 hour and concentrated, obtaining 0,320 g (100%) of the hydrochloride of 3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine in the form of a solid brown color.

3(D). {3-[3-(4-Methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}phenylmethanone

To a mixture of the hydrochloride of 3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine (0,320 g at 1.08 mmol) and THF (2.3 ml, 0,5M) is added pyridine (0.3 ml, of 3.78 mmol). The reaction mixture was cooled to 0°C and to the mixture is added slowly 4-perbenzoate (0.172 g, 0.87 mmol). The reaction mixture is allowed to warm to room temperature and the mixture is stirred for 24 hours. The solution is concentrated and the solution successively added DHM and 1 N. HCl. The aqueous phase is separated and the organic phase is extracted twice 1 N. HCl and twice with water, dried over Na2SO4filter and concentrate. The crude product was purified flash chromatography (DHM/MeOH:99/1)to give 0.26 mg (66%) of {3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}phenylmethanone in the form of a white powder.

Rf=0,40 (DHM/MeOH:99/2); IHMS (Tr): 4,35 min (method C); TPL=121°C; MS (ES+) m/z: 364,5;

1H-NMR (CDCl3), δ (m is.): of 7.95 (d, 2H), 7,51 (m, H), 7,44-7,37 (m, 4H), 6,83 (d, 2H, in), 3.75 (s, 3H), 3,63-to 3.34 (m, 4H), 2,48 (m, H), 1,90 of 1.50 (m, 4H).

Example 4

(4-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

4(A). tert-Butyl ester 3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 3, using 4-fluoro-N-hydroxybenzamide (commercially available) and 1-Boc-piperidine-3-carboxylic acid (yield: 60%).

4(B). 3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine

Connection receive in accordance with the procedure described in example 3(C) (yield: 100%).

4(C). (4-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 3(D)using 4-perbenzoate as selected acylchlorides. Output: 22%; TPL=118,5-to 121.5°C (white powder); Rf=0,30 (DHM/MeOH:98/2); IHMS (Tr): 4,87 min (method C); MS (ES+) m/z: 370,1;

1H-NMR (CDCl3), δ (ppm): 8,10 (d, 2H), 7,51 (m, 2H), 7,15-7,03 (m, 4H), 3,63-to 3.34 (m, 4H), 2,48 (m, H), 1,90 of 1.50 (m, 4H).

Elemental analysis. Calculated for C20H17F2N3O2: C 65,03; H, WITH 4.64; N, 11,38; F, 10,29. Found: C, 64,89; H, 4.75 V; N, Of 11.26; F, 10,36.

Example 5

{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}phenylmethanone

Connection get in line the AI methodology, described in example 3(D)using 4-perbenzoate as acylchlorides hydrochloride and 3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in example 4(B)). Yield: 30% (white powder); TPL=82-83°C; Rf=0,25 (DHM/MeOH:98/2);

IHMS (Tr): 4,70 min (method C); MS (ES+) m/z: 352,3.

1H-NMR (CDCl3), δ (ppm): 8,10 (d, 2H), 7,51 (m, 3H), 7,15-7,03 (m, 4H), 3,63-to 3.34 (m, 4H), 2,48 (m, H), 1,90 of 1.50 (m, 4H).

Example 6

(3-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 3(D)using 3-perbenzoate as selected acylchlorides hydrochloride and 3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 4(B).

Yield: 42%; TPL=139-140°C (powder beige color); Rf=0,32 (DHM/MeOH:98/2); IHMS (Tr): 4,87 min (method C); MS (ES+) m/z: 370,1;

1H-NMR (CDCl3), δ (ppm): with 8.05 (d, 2H), 7,40-to 7.50 (m, 3H), 7,22-7,00 (m, 3H), 3,65-of 3.32 (m, 4H), 2,53 (m, H), 1,86-of 1.45 (m, 4H).

Example 7

(4-Forfinal)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

7(A). tert-Butyl ether 3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 3(B), using N-hydroxybenzamide (commercially available) and 1-Boc-piperidine-3-carbon is th acid (yield: 58%).

7(B). 3-(3-Phenyl-[1,2,4]oxadiazol-5-yl)piperidine

Connection receive in accordance with the procedure described in example 3(C) (yield: 94%).

7(C). (4-Forfinal)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 3(D)using 4-perbenzoate as selected acylchlorides. Yield: 35%; TPL=78-79°C (white powder); Rf=0,24 (DHM/MeOH:98/2); IHMS (Tr): 4,75 min (method C); MS (ES+) m/z: 352,3.

1H-NMR (CDCl3), δ (ppm): 8,10 (d, 2H), of 7.48-to 7.32 (m, 4H), 7,22-to 7.15 (m, 3H), 3,65-of 3.32 (m, 4H), 2,53 (m, H), 1,86-of 1.45 (m, 4H).

Example 8

(3-Forfinal)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 3(D)using 3-perbenzoate as selected acylchlorides hydrochloride and 3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine (the receipt of which is described in example 7). Yield: 53% (yellow oil); Rf=0,25 (DHM/MeOH:98/2); IHMS (Tr): 4,77 min (method C); MS (ES+) m/z: 352,3.

1H-NMR (CDCl3), δ (ppm): 8,00-7,72 (m, 2H), of 7.48-7,40 (m, 3H), 7,32-7,22 (m, 4H), 3,65-of 3.32 (m, 4H), 2,53 (m, H), 1,86-of 1.45 (m, 4H).

Example 9

(3-Forfinal)-{3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

9(A). N-Hydroxy-3-ferbenstein

To a mixture of 3-fluoro-benzonitrile (1,21 g, 10 mmol) and DIEA (5,20 ml, 30 mmol) in EtOH(20 ml) type of 2.08 g of hydroxylamine hydrochloride (30 mmol), the reaction mixture is heated to 70°C and kept at this temperature for 48 hours. Half of the volume of the solvent is removed under reduced pressure. The mixture is then poured into DHM (100 ml) and water (30 ml). To the mixture is added 2.5 ml of 1 N. NaOH to achieve pH=9-10. The organic phase is separated and the aqueous phase extracted with DHM. The organic layers are combined, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure, obtaining 1.48 g (96%) of N-hydroxy-3-ferbenstein in the form of a white solid, which was used further without additional purification.

9(B). tert-Butyl ester 3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 3(B), using N-hydroxy-3-ferbenstein and 1-Boc-piperidine-3-carboxylic acid (yield: 78%).

9(C). 3-[3-(3-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine

Connection receive in accordance with the procedure described in example 3(C) (yield: 96%).

9(D). (3-Forfinal)-{3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 3(D)using 3-perbenzoate as selected acylchlorides (yield: 54%).

Yield: 53% (yellow oil); Rf=0,31 (DHM/MeOH:98/2); IHMS (Tr): 4,88 min (method C); MS (ES+) m/z: 370,3;

1H-NMR (CDCl3), δ (ppm): of 7.96-7,72 (m, 2H), 7,66(m, H), 7,42-7,30 (m, 2H), 7,30-7,25 (m, 2H), 7,00 (m, 1H), 3,65-of 3.32 (m, 4H), 2,53 (m, H), 1,86-of 1.45 (m, 4H).

Example 10

(4-Forfinal)-{3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 3(D)using 4-perbenzoate as selected acylchlorides hydrochloride and 3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (the receipt of which is described in example 9). Yield: 50% (yellow oil); TPL=86-89°C (powder beige color); Rf=0,28 (DHM/MeOH:98/2); IHMS (Tr): 4,88 min (method C); MS (ES+) m/z: 370,3;

1H-NMR (CDCl3), δ (ppm): 8,05-of 7.90 (m, 2H), 7,30-of 7.23 (m, 2H), 7,25-to 7.15 (m, 3H), 7,00 (m, 1H), 3,65-of 3.32 (m, 4H), 2,53 (m, H), 1,86-of 1.45 (m, 4H).

Example 11

R-(4-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

11(A). tert-Butyl ether R-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 3(B), using 4-fluoro-N-hydroxybenzamide (commercially available) andR-1-Boc-piperidine-3-carboxylic acid (yield: 79%).

11(B).R-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine

Connection receive in accordance with the procedure described in example 3C) (yield: 68%).

11(C).R-(4-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}IU the anon

Connection receive in accordance with the procedure described in example 3(D)using 4-perbenzoate as selected acylchlorides. Yield: 28%; TPL=98°C (white powder); Rf=0,30 (DHM/MeOH:98/2); IHMS (Tr): 4,87 min (method C); MS (ES+) m/z: 370,1;

1H-NMR CDCl3, δ (ppm): with 8.05 (d, 2H), of 7.48 (m, 2H), 7,15-7,03 (m, 4H), 3,63-to 3.34 (m, 4H), 2,48 (m, H), 1,90 of 1.50 (m, 4H).

Example 12

S-(4-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

12(A). tert-Butyl methyl etherS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 3(B), using 4-fluoro-N-hydroxybenzamide (commercially available) andS-1-Boc-piperidine-3-carboxylic acid (yield: 84%)

12(B).S-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine

Connection receive in accordance with the procedure described in example 3(C) (yield: 63%).

12(B).S-(4-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 3(D)using 4-perbenzoate as selected acylchlorides. Yield: 51%; TPL=99°C (white powder); Rf=0,30 (DHM/MeOH:98/2); [α]D20=+103° (c=1, CHCl3); IHMS (Tr): 4,87 min (method C); MS (ES+) m/z: 370,1.

1H-NMR (CDCl3), δ (ppm): with 8.05 (d, 2H), of 7.48 (m, 2H),7,15-7,03 (m, 4H), 3,63-to 3.34 (m, 4H), 2,48 (m, H), 1,90 of 1.50 (m, 4H).

Example 13

S-(thiophene-2-yl)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

To a suspension of the hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (100 mg, 0.52 mmol, receipt of which is described in example 12) in dry dichloromethane (3 ml) was dropwise added triethylamine (123 μl, 0,881 mmol) and thiophene-2-carbonylchloride (79 μl, 0,352 mmol) at 0°C. the Reaction mixture was allow to warm to room temperature and the mixture is stirred overnight under nitrogen atmosphere. After this, the solution is treated with 1 N. HCl (5 ml) and the phases are separated. The organic layer is washed successively 1 N. HCl (5 ml), saturated aqueous NaHCO3(5 ml) and water (5 ml), then dried over Na2SO4and evaporated under reduced pressure. The crude product was passed through a silica gel cartridge (cartridge: VARIAN HF, Mega Bond Elut SI, 5 g; elution with a gradient from DHM 100% to DHM/MeOH 95/5), the solvent is evaporated under reduced pressure, receiving 97 mgS-(thiophene-2-yl)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}methanone in the form of a white solid.

Yield: 78%; TPL=82-83°C; [α]D20=+11° (c=1,08, CHCl3); IHMS (Tr): 9,86 min (method A); MS (ES+) m/z: 358,1.

1H-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): of 8.06 (DD, 2H); the 7.43 (DD, 1H); 7,34 (DD, 1H); 7,14 (DD, 2H);? 7.04 baby mortality (DD, 1H); to 4.62 (m, 1H); 4,24 (m, 1H); of 3.56 (DD, 1H); 3,36-up 3.22 (m, 2H); 2,41-to 2.29 (m, 1H); 2,10-1,89 (m, 2H); 1,81-of 1.65 (m, 1H).

Example 14

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-4-yl}-(4-methyl-2-pyrazin-2-iltiazem-5-yl)methanon

Connection receive in accordance with the procedure described in example 13 using 4-methyl-2-(2-pyrazinyl)-1,3-thiazole-5-carbonylchloride as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 47% (not quite white solid); TPL=147-148°C; [α]D20=+120° (c=0,34, CHCl3); IHMS (Tr): 9,41 min (method A); MS (ES+) m/z: 45H,0.

1H-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): 9,40 (d, 1H); 8,59 (d, 1H); charged 8.52 (DD, 1H); 8,07 (DD, 2H); 7,14 (DD, 2H); of 4.45 (DD ush., 1H); 4.04 the (USD, 1H); 3,62 (DD, 1H); 3,39 is 3.23 (m, 2H); to 2.55 (s, 3H); 2,42-of 2.30 (m, 1H); 2,12 is 1.91 (m, 2H); 1,80-of 1.64 (m, 1H).

Example 15

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-phenylthiazol-4-yl)methanon

Connection receive in accordance with the procedure described in example 13 using 2-phenyl-1,3-thiazole-4-carbonylchloride as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 26% (orange oil); [α]D20=+176° (c=1,13, CHCl3); IHMS (Tr): 10,83 min (the method A); MS (ES+) m/z: 4H5,1.

1H-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): of 8.06 (DD, 2H); of 7.96 (m, 2H); to 7.95 (s, 1H); the 7.43 (m, 3H); 7,14 (DD, 2H); 5,04 (USD, 1H); 4,59 (USD, 1H); 3,70-to 3.38 (m, 2H); 3.27 to (DD, 1H); 2,46-of 2.34 (m, 1H); 2,15-of 1.92 (m, 2H); 1.91 a-1,74 (m, 1H).

Example 16

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-methyl-6-triptorelin-3-yl)methanon

Connection receive in accordance with the procedure described in example 13, using 2-methyl-6-(trifluoromethyl)pyridine-3-carbonylchloride as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Out: 54% (solid waxy yellow substance; [α]D20=+80° (c=1,15, CHCl3); IHMS (Tr): 10,06 min (method A); MS (ES+) m/z: 4H5,1.

1H-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): with 8.05 (m, 2H); 7,63 (d, 1H); 7,52 (d, 1H); to 7.15 (DD, 2H); 4,70 (USM, 1H); 4,22 (USM, 1H); to 3.64 (m, 1H); 3,54 totaling 3.04 (USM, 2H); 2,60 (s, 3H); 2.40 a-and 2.26 (m, 1H); 2,17-2,00 (m, 1H); 2,00-1,81 (USM, 1H); 1,81-1,52 (USM, 1H).

Example 17

(3,5-Dimethylisoxazol-4-yl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 13, using 3,5-dimethylisoxazol-4-carbonylchloride as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained is output in accordance with the method of example 12).

Output: 20% (colorless oil); [α]D20=+82° (c=0,88, CHCl3); IHMS (Tr): 9,10 min (method A); MS (ES+) m/z: 37H,1.

1H-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): of 8.06 (DD, 2H); to 7.15 (DD, 2H); 4,34 (USD, 1H); 3,88 (USD, 1H); 3,59 (DD, 1H); 3,34-3,17 (m, 2H); 2.40 a (s, 3H); 2,33 (m, 1H); and 2.26 (s, 3H); 2,12-1,89 (m, 2H); 1,72-of 1.57 (m, 1H).

Example 18

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-[1,2,3]thiadiazole-4-ylmethanol

Connection receive in accordance with the procedure described in example 13, using 1,2,3-thiadiazole-4-carbonylchloride as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 44% (solid brownish color); TPL=90-91°C; [α]D20=+104° (c=0,67, CHCl3); IHMS (Tr): 7,25 min (method A); MS (ES+) m/z: 36H,0.

1H-NMR (CDCl3, 343 K, 300 MHz), δ (ppm): a 9.09 (s, 1H); 8,04 (m, 2H); 7,14 (DD, 2H); 4,82 (USD, 1H), 4,45 (USD, 1H); 3,78 (USM, 1H); 3,54-to 3.33 (m, 2H), 2,45 is 2.33 (m, 1H); 2,16 is 1.96 (m, 2H); 1.91 a to 1.76 (m, 1H).

Example 19

Benzothiazol-2-yl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 13, using 1,3-benzothiazol-2-carbonylchloride as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperid is on (obtained according to the method of example 12).

Yield: 70% (powder beige color); TPL-131°C; [α]D20=+155° (c=0.8, the CHCl3); IHMS (Tr): 8,11 min (method A); MS (ES+) m/z: 40H,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,15-7,87 (m, 4H); 7,58-7,41 (m, 2H); 7,19-7,05 (DD, 2H); 5,59-3,84 (USM, 2H); 3,78-3,20 (m, 3H); 2,47-of 2.30 (m, 1H); 2,20-of 1.94 (m, 2H); 1,92-of 1.73 (m, 1H).

Example 20

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-methylisoxazol-3-yl)methanon

Connection receive in accordance with the procedure described in example 13, using 5-methylisoxazol-3-carbonylchloride as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 32% (colorless oil); [α]D20=+112° (c=1,2, CHCl3); IHMS (Tr): 7.23 percent min (method A); MS (ES+) m/z: 357,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,14-of 7.96 (m, 2H); 7,20-to 7.09 (m, 2H); of 6.26 (s, 1H); 5,04-4,24 (USM, 2H); 3,97-to 3.58 (USM, 1H); 3.46 in-3,13 (m, 2H); of 2.45 (s, 3H); 2,41-of 2.27 (m, 1H); 2,11-of 1.88 (m, 2H); 1,83-to 1.67 (m, 1H).

Example 21

(1,5-Dimethyl-1H-pyrazole-3-yl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 13, using 1,5-dimethyl-1H-pyrazole-3-carbonylchloride as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (p is obtained according to the method of example 12).

Yield: 69% (white solid); TPL=108-109°C; [α]D20=+128° (c=0,9, CHCl3); IHMS (Tr): 7,00 min (method A); MS (ES+) m/z: 370,2.

1H-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): 8,12-8,02 (m, 2H); 7,20-to 7.09 (m, 2H); 6.42 per (s, 1H); 5,06-of 4.95 (m, 1H); 4,70-4,54 (USM, 1H); of 3.77 (s, 3H); 3,59-3,37 (USM, 1H); 3,36-3,03 (m, 2H), 2.40 a-2,24 (USM, 1H); and 2.27 (s, 3H); 2,08-1,85 (m, 2H); 1,82-to 1.63 (m, 1H).

Example 22

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-triptoreline)metano

Connection receive in accordance with the procedure described in example 13 using 4-cryptomathematical as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 54% (white solid); TPL=109-110°C; [α]D20=+95° (c=0.7 and CHCl3); IHMS (Tr): 7,78 min (method A); MS (ES+) m/z: 42H,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,11-8,0 (m, 2H); to 7.67 (d, 2H); 7,52 (d, 2H); 7,20-to 7.09 (m, 2H); 4,58-4,17 (USM, 1H); 4,07-3,74 (USM 1H); 3,57 (DD, 1H); 3,38-3,17 (m, 2H); 2.40 a was 2.25 (m, 1H); 2,15-of 1.85 (m, 2H); 1,78-1,58 (m, 1H).

Example 23

4-{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-l-carbonyl}benzonitrile

Connection receive in accordance with the procedure described in example 13 using 4-cyanobenzoate as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]OK diazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 61% (white solid); TPL=129-130°C; [α]D20=+127° (c=1,1, CHCl3); IHMS (Tr): 7,25 min (method A); MS (ES+) m/z: 37H,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,10 to 8.0 (m, 2H); of 7.70 (DD, 2H); 7,51 (DD, 2H); 7,21-7,11 (m, 2H); 4,57-4,11 (USM, 1H); 4,05-to 3.73 (USM, 1H); to 3.58 (DD, 1H); 3.40 in-3,17 (m, 2H); 2.40 a-and 2.26 (m, 1H); 2,16-of 1.85 (m, 2H); 1,78-1,58 (m, 1H).

Example 24

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}isoxazol-5-ylmethanol

Connection receive in accordance with the procedure described in example 13, using isoxazol-5-carbonylchloride as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 50% (white solid); TPL=93-94°C; [α]D20=+127° (c=0.8, the CHCl3); IHMS (Tr): 7,00 min (method A); MS (ES+) m/z: 34H,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): of 8.28 (d, 1H); 8,10 to 8.0 (m, 2H); 7,20-to 7.09 (m, 2H); 6.75 in (d, 1H); 4,87-4,27 (USM, 1H); 4.26 deaths-4,06 (m, 1H); 3,86-of 3.46 (USM, 1H); 3.46 in-3,20 (m, 2H); 2,46-of 2.27 (m, 1H); 2,18-of 1.88 (m, 2H); 1,86-to 1.67 (m, 1H).

Example 25

(2,4-Differenl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 13, using 2,4-differentiald as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]the of piperidine (obtained according to the method of example 12).

Yield: 59% (colorless oil); [α]D20=+104° (c=1,1, CHCl3); IHMS (Tr): 7,51 min (method A); MS (ES+) m/z: 38H,1.

1H-NMR (CDCl3, 336 K, 300 MHz), δ (ppm): with 8.05 (DD, 2H); 7,38 (DD, 1H); to 7.15 (DD, 2H); 6,98-to 6.80 (m, 2H); 5,13-3,72 (USM, 2H); 3,57-to 3.41 (m, 1H); 3,32-3,14 (m, 2H); 2,41-of 2.26 (m, 1H); 2,09-of 1.57 (m, 3H).

Example 26

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(3,4,5-tryptophanyl)metano

Connection receive in accordance with the procedure described in example 13, using 3,4,5-triterpenoid as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 63% (white solid); TPL=139-140°C; [α]D20=+81° (c=1,0, CHCl3); IHMS (Tr): to 7.67 min (method A); MS (ES+) m/z: 406,1.

1H-NMR (CDCl3, 336 K, 300 MHz), δ (ppm): 8,10 shed 8.01 (m, 2H); 7,20-7,01 (m, 4H); 4,39-4,20 (m, 1H); 3,92-of 3.77 (m, 1H); 3,61 (DD, 1H); 3,42-3,18 (m, 2H); 2,38 was 2.25 (m, 1H); 2,15-of 1.85 (m, 2H); 1.77 in-1,59 (m, 1H).

Example 27

(3-Chloro-4-forfinal)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 13, using 3-chloro-4-perbenzoate as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the methodology note the RA 12).

Yield: 56% (white solid); TPL=123-124°C; [α]D20=+94° (c=1,1, CHCl3); IHMS (Tr): 8,00 min (method A); MS (ES+) m/z: 404,1.

lH-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): 8,12-of 8.00 (m, 2H); 7,51 (DD, 1H); 7,34-7,27 (m, 1H); 7,21-7,10 (m, 3H); 4,45-of 4.25 (m, 1H); 3,97-of 3.80 (m, 1H); 3,59 (DD, 1H); 3.40 in-3,18 (m, 2H); 2,39-of 2.26 (m, 1H); 2,12-to 1.86 (m, 2H); 1.77 in is 1.58 (m, 1H).

Example 28

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-phenyl-2H-pyrazole-3-yl)methanon

Connection receive in accordance with the procedure described in example 13, using 1-phenyl-1H-pyrazole-5-carbonylchloride as selected acylchlorides hydrochloride and S-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12)).

Yield: 34% (colorless oil); [α]D20=+69° (c=0.5, CHCl3); IHMS (Tr): 7,19 min (method A); MS (ES+) m/z: 418,2.

1H-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): 8,10-7,98 (m, 2H); to 7.68 (d, 1H); to 7.59-7,52 (m, 2H); of 7.48-7,31 (m, 3H); 7,19-to 7.09 (m, 2H); is 6.54 (d, 1H); 5,02-4,03 (USM, 1H); 3,91-2,53 (USM, 4H); 2,42-1,68 (USM, 3H); 1,20-0,78 (USM, 1H).

Example 29

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl)methanon

Connection receive in accordance with the procedure described in example 13, using 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonylchloride as selected acylchlorides hydrochloride and S-3-[3-(4-forfinal)-[,2,4]oxidiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Output: 20% (not quite white oil); [α]D20=+86° (c=0.3, and CHCl3); IHMS (Tr): 8,20 min (method A); MS (ES+) m/z: 433,2.

1H-NMR (CDCl3, 338 K, 300 MHz), δ (ppm): 8,15-to 7.95 (m, 4H); 7,55-7,28 (m, 3H); 7,22-7,07 (m, 2H); of 5.05-4,75 (USM, 1H), 4,57-4,40 (USM, 1H); 3,83-the 3.65 (m, 1H); 3,56 is 3.15 (m, 2H); to 2.54 (s, 3H); 2,47-to 2.29 (m, 1H); 2,23-of 1.66 (m, 3H).

Example 30

(4-fluoro-3-were)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 13, using 3-methyl-4-perbenzoate as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 52% (white solid); TPL=106-107°C; [α]D20=+99° (c=1,2, CHCl3); IHMS (Tr): 7,76 min (method A); MS (ES+) m/z: 384,2.

1H-NMR (CHCl3, 338 K, 300 MHz), δ (ppm): 8,11-of 8.00 (m, 2H); 7,31-was 7.08 (m, 4H); 7,02 (DD, 1H); 4,49-4,32 (m, 1H); 4,06-3,91 (m, 1H); 3,51 (DD, 1H); 3.33 and-3,17 (m, 2H); 2,38-of 2.30 (m, 1H); of 2.28 (s, 3H); 2,10-of 1.84 (m, 2H); 1.77 in-1,58 (m, 1H).

Example 31

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-pyridin-2-althofen-2-yl)methanon

Connection receive in accordance with the procedure described in example 13, using 5-(2-pyridinyl)-2-thiophenecarboxylate as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-and the]piperidine (obtained in accordance with the method of example 12).

Yield: 13% (no white powder); TPL=115-117°C; IHMS (Tr): the 5.25 min (method A); MS (ES+) m/z: 435,2.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 8,59 (USD, 1H); of 8.06 (DD, 2H); 7,73 (DD, 1H); to 7.67 (d, 1H); at 7.55 (d, 1H); 7,37 (d, 1H); 7,22 (m, 1H); to 7.15 (DD, 2H); 4,69 (m, 1H); 4,32 (m, 1H); 3,57 (m, 1H); 3,36-3,24 (m, 2H); is 2.37 (m, 1H); 2,09-1,89 (m, 2H); 1,83-to 1.67 (m, 1H).

Example 32

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(3-methyl-thiophene-2-yl)methanon

Connection receive in accordance with the procedure described in example 13, using 3-methyl-thiophene-2-carbonylchloride as selected acylchlorides and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 54% (white solid); TPL=90-92°C; [α]D20=+75° (c=0.95, and CHCl3); IHMS (Tr): 5,58 min (method A); MS (ES+) m/z: 372,2.

1H-NMR (CDCl3, 300 MHz), δ (ppm): of 8.06 (DD, 2H); 7,27 (d, 1H); to 7.15 (DD, 2H); 6,83 (d, 1H); of 4.49 (m, 1H); 4,10 (m, 1H); 3,47 (DD, 1H); 3,30-3,15 (m, 2H); 2,33 (m, 1H); and 2.27 (s, 3H); 2,04-of 1.85 (m, 2H); 1,80-of 1.62 (m, 1H).

Example 33

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(1-methyl-1H-pyrrol-2-yl)methanon

Connection receive in accordance with the procedure described in example 13, using 1-methyl-1H-pyrrol-2-carbonylchloride as selected acylchlorides hydrochloride and S-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (polucen is in accordance with the method of example 12).

Yield: 64% (powder beige color); TPL=84-85°C; [α]D20=+101° (c=1,2, CHCl3); IHMS (Tr): of 5.53 min (method A); MS (ES+) m/z: 355,2.

1H-NMR (CDCl3, 300 MHz), δ (ppm): of 8.06 (DD, 2H); 7,16 (DD, 2H); 6,70 (DD, 1H); 6,37 (DD, 1H); 6,09 (DD; 1H); 4,69 (m, 1H); 4,32 (m, 1H); of 3.77 (s, 3H); to 3.52 (DD, 1H); 3.24 in (m, 2H); to 3.34 (m, 1H); 2,08 is 1.86 (m, 2H); 1.77 in-1,61 (m, 1H).

Example 34

Cyclopentyl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 13, using cyclopentanecarboxylate as selected acylchlorides and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 91% (thick oil); [α]D20=+95° (c=1,2, CHCl3); IHMS (Tr): 7,41 min (method A); MS (ES+) m/z: 344,2.

1H-NMR (CDCl3, 343 K, 300 MHz), δ (ppm): 8,07 (DD, 2H); to 7.15 (DD, 2H); 4,48 (m, 1H); 4,08 (m, 1H); to 3.38 (m, 1H); 3,21-of 3.07 (m, 2H); 2,96 (m, 1H); 2,36-of 2.24 (m, 1H); 2.05 is-is 1.51 (m, 11H).

Example 35

(3,4-Differenl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 13, using 3,4-differentiald as selected acylchlorides hydrochloride and S-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

In the move: 59% (white solid); TPL=120-121°C; [α]D20=+105° (c=1,0, CHCl3); IHMS (Tr): 7,6 min (method A); MS (ES+) m/z: 388,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): of 8.06 (DD, 2H); 7,28 (m, 1H); 7,22-7,11 (m, 4H); 4,36 (USD, 1H); 2,92 (USD, 1H); 3,57 (DD, 1H); 3,37-3,19 (m, 2H); 2,33 (m, 1H); 2,12-to 1.86 (m, 2H); 1,68 (m, 1H).

Example 36

Benzothiazol-6-yl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

The mixture hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (100 mg, 0.35 mmol, receipt of which is described in example 12), benzothiazole-6-carboxylic acid (70 mg, 0.38 mmol), HOAT (72 mg, 0.52 mmol), PS-DCC (ex Argonaut Technologies, 0,59 g, 0.70 mmol, content = 1.2 mmol/g) and DIEA (90 ml, 0.52 mmol) in dry dichloromethane (6 ml) was incubated for nights on the screen with rotation in one plane (IKA Vibrax VXR). The resin is filtered off and washed several times with dichloromethane; the filtrate is washed with 1 N. HCl (10 ml × 2) and 5% (water) K2CO3(10 ml × 2), dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified flash chromatography (silica gel, eluent: DHM/MeOH 95/5)to give 50 mg benzothiazol-6-yl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-reparacin-1-yl}methanone.

Yield: 35% (white powder); TPL=63-64°C; [α]D20=+105° (c=1,0, CHCl3); IHMS (Tr): 5,39 min (method A); MS (ES+) m/z: 409,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): remaining 9.08 (c, 1H); 8.17 and (d, 1H); 8,07 (d, 1H); with 8.05 (m, 2H); EUR 7.57 (DD, 1H; 7,16 (DD, 2H); 5,00-3,71 (USM, 2H); to 3.58 (m, 1H); and 3.31 (m, 2H); 2,35 (m, 1H); 2,10-to 1.87 (m, 2H); 1,72 (m, 1H).

Example 37

{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}thiazole-2-ylmethanol

Connection receive in accordance with the procedure described in example 36 using 2-diazocarbonyl acid as the selected acid and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 55% (no white powder); TPL=94-95°C; [α]D20=+127° (c=0,9, CHCl3); IHMS (Tr): 5,54 min (method A); MS (ES+) m/z: 359,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 8,05 (USM, 2H); 7,89 (USM, 1H); 7,53 (USM, 1H); to 7.15 (DD, 2H); 5,41, 4,94, to 4.38, Android 4.04 and 3,44 (USM, 3H); 3,34 (USM, 2H); of 2.36 (m, 1H); 2,13-1,92 (USM, 2H); of 1.78 (m, 1H).

Example 38

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-methylthiazole-5-yl)methanon

Connection receive in accordance with the procedure described in example 36 using 4-methylthiazole-5-carboxylic acid as the acid and hydrochlorideS3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 76% (yellow powder); TPL=122-124°C; [α]D20=+101° (c=0,55, CHCl3); IHMS (Tr): 5,08 min (method A); MS (ES+) m/z: 373,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 8,75 (c, 1H); of 8.06 (DD, 2H); and 7.1 (DD, 2H); was 4.42 (m, 1H); of 3.97 (m, 1H); of 3.56 (DD, 1H); 3,35-3,19 (m, 2H); 2.50 each (c, 3H); of 2.34 (m, 1H); 2,08-of 1.88 (m, 2H); to 1.70 (m, 1H).

Example 39

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(6-morpholine-4-espiridion-3-yl)methanon

Connection receive in accordance with the procedure described in example 36, using 6-morpholinothio acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Output: 20% (no white powder); TPL=112-114°C; [α]D20=+111° (c=0,55,

CHCl3); IHMS (Tr): 4,96 min (method A); MS (ES+) m/z: 438,2.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 8,31 (d, 1H); of 8.06 (DD, 2H); the 7.65 (DD, 1H); 7,16 (DD, 2H); 6,63 (d, 1H); 4,51 (m, 1H); 4,11 (m, 1H); 3,81 (DD, 4H); 3,59 (DD, 4H); 3,50 (m, 1H); 3.24 in (m, 2H); 2,35 (m, 1H); 2.05 is is 1.86 (m, 2H); 1.69 in (m, 1H).

Example 40

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(1H-indol-5-yl)methanon

Connection receive in accordance with the procedure described in example 36, using indole-5-carboxylic acid as the selected acid hydrochloride and S-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 44% (white solid); TPL=191-192°C; [α]D20=+107° (c=0,85, CHCl3); IHMS (Tr): 5,44 min (method A); MS (ES+) m/z: 391,2.

1H-NMR (CDClsub> 3, 333 K, 300 MHz), δ (ppm): 8,19 (USS, 1H); of 8.06 (DD, 2H); 7,75 (USS, 1H); 7,39 (d, 1H); 7,28 (DD, 1H); from 7.24 (m, 1H); 7,14 (DD, 2H); 6,59 (m, 1H); 4,56 (m, 1H); 4,15 (m, 1H); 3,50 (DD, 1H); 3.33 and-3,18 (m, 2H); 2,34 (m, 1H); 2,07-of 1.85 (m, 2H); at 1.73 (m, 1H).

Example 41

2-(4-Forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}alanon

Connection receive in accordance with the procedure described in example 36 using 4-florfenicol acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 37% (clear oil); [α]D20=+68° (c=0,6, CHCl3); IHMS (Tr): 5,58 min (method A); MS (ES+) m/z: 384,2.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): of 8.06 (DD, 2H); 7,22 (DD, 2H); 7,16 (DD, 2H); 6,99 (DD, 2H); 4,65, 4,03, and 3,00 3,47 (USM, 4H); 3.75 to (c, 2H); 3,19 (DDD, 1H); of 2.23 (m, 1H); of 1.97 (m, 1H); to 1.79 (m, 1H); for 1.49 (m, 1H).

Example 42

3-(4-Forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}propane-1-he

Connection receive in accordance with the procedure described in example 36 using 3-(4-forfinal)propionic acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 50% (white powder); TPL=83-84°C; [α]D2O=+80° (c=1,32, CHCl3); IHMS (Tr): 5,68 mi the (method A); MS (ES+) m/z: 398,4.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): of 8.06 (DD, 2H); 7,17 (DD, 2H); to 7.15 (DD, 2H); to 6.95 (DD, 2H); 4,71, 3,93 and 3,44 (USM, 2H); 3,17 (m, 1H); 3,06 (USM, 1H); 2,98 (DD, 2H); to 2.67 (DD, 2H); and 2.26 (m, 1H); of 1.97 (m, 1H); to 1.83 (m, 1H); of 1.55 (m, 1H).

Example 43

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-isoquinoline-3-ylmethanol

Connection receive in accordance with the procedure described in example 36, using isoquinoline-3-carboxylic acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12).

Yield: 56% (white oil); [α]D20=+150° (c=0.8, the CHCl3); IHMS (Tr): 5,59 min (method A); MS (ES+) m/z: 403,2.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,23 (d, 1H); to 8.12 (d, 1H); 8,02 (USM, 2H); to 7.84 (d, 1H); 7,76 (d, 1H); 7,74 (m, 1H); to 7.59 (DD, 1H); 7,13 (USD, 2H); 5,01, 4,51 and 4,18 (USM, 2H); of 3.77-3,26 (USM, 3H); 2,39 (m, 1H); 2,18-1,78 (USM, 3H).

Example 44

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}cinoxacin-6-ylmethanol

Connection receive in accordance with the procedure described in example 36, using 6-khinoksalinona acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12). Net {(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine--yl}cinoxacin-6-ylmethanol obtained after purification of the product on silicagel cartridge (eluent: DHM/MeOH/NH 4OH 98/2/0,2).

Yield: 83% (white solid); [α]D20=+120° (c=1,0, CHCl3); IHMS (Tr): 7,0 min (method A); MS (ES+) m/z: 404,0.

1H-NMR (CDCl3, 330 K, 300 MHz), δ (ppm): 8,88 (c, 2H); 8,18 (DD, 2H); of 8.06 (m, 2H); of 7.82 (DD, 1H); to 7.15 (DD, 2H); 4,47 (USM, 1H); was 4.02 (USM, 1H); the 3.65 (DD, 1H); 3,44 is 3.23 (m, 2H); of 2.36 (m, 1H); 2,14-of 1.88 (m, 2H); 1,74 (m, 1H).

Example 45

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-benzimidazole-6-ylmethanol

Connection receive in accordance with the procedure described in example 36, using benzimidazole-5-carboxylic acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12). Net {(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}benzimidazole-6-ylmethanol obtained after purification of the product flash chromatography (silica gel, eluent: DHM/MeOH/NH4OH 98/2/0,2).

Output: 5% (white solid); TPL=110-115°C; [α]D20=+115° (c=1,0, CHCl3); IHMS (Tr): 6,28 min (method A); MS (ES+) m/z: 392,0.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 9,56 and 8.38 (c, 1H); 8,11-of 7.97 (m, 4H); 7,97-of 7.82 (m, 1H); 7,60-7,46 (m, 1H); 7,13 (m, 2H); 4,42 (USM, 1H); of 3.97 (m, 1H); 3,59 (m, 1H); and 3.31 (m, 2H); of 2.34 (m, 1H); 2,11-of 1.84 (m, 2H); 1,72 (m, 1H).

Example 46

(4-Forfinal)-{(S)-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

46(A). tert-Butilovyi S-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

To a solution of 2,4,6-tripersonal (1.5 g, 9.6 mmol) in EtOH (5 ml) at room temperature is added hydroxylamine (50% (mass.) aqueous solution, 2.5 ml, 38 mmol) and the solution refluxed under stirring for 1 hour. The solvent is removed under reduced pressure, obtaining N-hydroxy-2,4,6-triterpenoids, which are immediately used in the next stage.

A mixture of N-hydroxy-2,4,6-triptorelin (9.6 mmol), S-1-Boc-piperidine-3-carboxylic acid (2.3 g, 9.6 mmol), EDCI·HCl (2,87 g, 15 mmol), HOBT (1.35 g, 9.6 mmol) and DIEA (3.4 ml, 20 mmol) in dioxane (10 ml) is stirred overnight at room temperature in a nitrogen atmosphere. Add another portion of HOBT (1.35 g), EDCI·HCl (2,87 g) and DIEA (3.4 ml), after which the reaction mixture is heated to 60°C and maintained at this temperature for 2 hours. Then the reaction mixture is refluxed for 18 hours and the solvent is evaporated under reduced pressure. The residue was diluted with water (50 ml) and ethyl acetate (50 ml), the phases are separated and the organic layer washed successively with water (50 ml × 2) and 1 N. NaOH (50 ml × 2). The organic layer is dried over Na2SO4and concentrate under reduced pressure. Purification of the crude product flash chromatography (silica gel, eluent: DHM/hexane/MeOH 50/50/0,2) leads to receiving the s 0.7 g of tert-butyl methyl ether S-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid.

Output: 20%; IHMS (Tr): 10,10 min (method B); MS (ES+) m/z: 384,4.

1H-NMR (CDCl3, 300 MHz, 333 K), δ (ppm): to 6.80 (m, 2H); 4,29 (USD, 1H); 3,93 (DDD, 1H); of 3.32 (DD, 1H); 3,19 (TT, 1H); to 3.02 (DDD, 1H); and 2.26 (m, 1H); 1,99-to 1.79 (m, 2H); 1.70 to and 1.56 (m, 1H); 1,47 (c, 9H),

46(B). HydrochlorideS-3-[3-(2,4,6-Tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine

tert-Butyl methyl etherS-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid (0.2 g, 0.52 mmol) dissolved in dichloromethane (3 ml) and added dropwise to 5 ml of HCl 4 N. (dioxane solution). The resulting mixture was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, getting 165 mg (yield: 100%) hydrochlorideS-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine in the form of a white solid.

IHMS (Tr): 4,80 min (method B); MS (ES+) m/z: 284,4.

46(C). (4-Forfinal)-{(S)-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

To a suspension of the hydrochlorideS-3-[3-(2,4,6-Tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine (165 mg, 0.52 mmol) in dry dichloromethane (3 ml) dropwise at 0°C. add triethylamine (154 ml, of 1.09 mmol) and 4-perbenzoate (62 ml, 0.52 mmol). The reaction mixture allow to warm to room temperature and stirred overnight under nitrogen atmosphere. Then the solution is treated with 0.5 N. HCl (5 ml) and the phases are separated. The organic layer is washed successively with 0.5 N. HCl (5 ml), 1 N. NaOH (5ml) and water (5 ml), then dried over Na2SO4and evaporated under reduced pressure. The crude product was purified flash chromatography (silica gel, eluent: hexane/ethyl acetate 8:2)to give 50 mg specified in the connection header. Further purification preparative HPLC (column: SymmetryPrep Cl8, 7 μm, 19×300 mm; mobile phase A: water/acetonitrile/TFWC 900/100/0,5, mobile phase B: water/acetonitrile/TFWC 100/900/0,5, flow rate: 20 ml/min) results in 25 mg (4-forfinal)-{(S)-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}methanone.

Output: 12% (thick oil); IHMS (Tr): 7,0 min (method A); MS (ES+) m/z: 406,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): was 7.45 (m, 2H); 7.18 in-7,00 (m, 2H); 6.90 to to 6.75 (m, 2H); 4,40 (USD, 1H); 3,95 (USD, 1H); to 3.52 (DD, 1H); 3,37-3,20 (m, 2H); 2.40 a-2,20 (m, 1H); 2,15-of 1.85 (m, 2H); 1,78-of 1.55 (m, 1H).

Example 47

(4-Forfinal)-[(S)-3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)-piperidine-1-yl]metano

47(A). tert-Butyl ether S-3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 46(A), from 3-cyanopyridine. Pure tert-butyl etherS-3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid is obtained after trituration of the product in a mixture of diethylether/pentane 1:1 (Yield: 29%).

IHMS (Tr): of 6.49 min (method A); MS (ES+) m/z: 331,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): to 9.32 (d,1H); a total of 8.74 (DD, 1H); of 8.37 (DDD, 1H); the 7.43 (DD, 1H); 4,28 (USD, 1H); 3,93 (DDD, 1H); to 3.34 (DD, 1H); 3,18 (TT, 1H); 3,05 (DDD, 1H); and 2.27 (m, 1H); 2,00-of 1.81 (m, 2H); 1,68-of 1.57 (m, 1H).

47(B). The dihydrochlorideS-3-(5-piperidine-3-yl-[1,2,4]oxadiazol-3-yl)pyridine

Connection receive in accordance with the procedure described in example 46(B), starting from tert-butyl ether S-3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): 1,78 min (method B); MS (ES+) m/z: 231,1.

47(C). (4-Forfinal)-[(S)-3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 46(C), based on dihydrochloride S-3-(5-piperidine-3-yl-[1,2,4]oxadiazol-3-yl)pyridine and using 4-perbenzoate as selected acylchlorides. Pure (4-forfinal)-[(S)-3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano obtained after purification of the crude product flash chromatography (silica gel, eluent: DHM/MeOH/NH4OH 99/1/0,1).

Yield: 98% (solid adhesive white); [α]D20=+105° (c=1.05 by CHCl3); IHMS (Tr): 5,8 min (method A); MS (ES+) m/z: 353,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): of 9.30 (c, 1H); and 8.8 (d, 1H); to 8.3 (m, 1H); 7,55-7,35 (m, 3H); 7,20-7,0 (m, 2H); 4,50 (USD, 1H); 4.0 (with USD, 1H); 3,50 (DD, 1H); 3,35 is 3.15 (m, 2H); of 2.45 (m, 1H); 2,15 and 1.80 (m, 2H); 1,80-to 1.60 (m, 1H).

Example 48

(4-Forfinal)-[(S)-3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

48(A). tert-Butyl methyl etherS-3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 46(A), from 4-cyanopyridine. Pure tert-butyl etherS-3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid is obtained after trituration of the crude product in a mixture of hexane/diethylether 1:1 (yield: 68%).

IHMS (Tr): 6,56 min (method A); MS (ES+) m/z: 331,1.

48(B). The dihydrochlorideS-4-(5-piperidine-3-yl-[1,2,4]oxadiazol-3-yl)pyridine

Connection receive in accordance with the procedure described in example 46(B), starting from tert-butyl methyl etherS-3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): the 1.44 min (method B); MS (ES+) m/z: 231,1.

48(C). (4-Forfinal)-[(S)-3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 46(S), based on dihydrochloride S-4(5-piperidine-3-yl-[1,2,4]oxadiazol-3-yl)pyridine and using 4-perbenzoate as selected acylchlorides. Pure (4-forfinal)-[(S)-3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano obtained after purification of the crude product flash chromatography (2 columns connected in series: silica gel, eluent: DHM/MeOH/NH4OH 99/1/0,1).

Yield: 38% (white solid); TPL=113-115°C; [α]D20=+112° c=1,62, CHCl3); IHMS (Tr): 5,55 min (method A); MS (ES+) m/z: 353,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,79 (m, 2H); 7,99 (m, 2H); the 7.43 (DD, 2H); 7,10 (DD, 2H); 4,45 (USD, 1H); of 3.97 (m, 1H); of 3.54 (DD, 1H); 3,35-is 3.21 (m, 2H); 2,35 (m, 1H); 2,11-to 1.86 (m, 2H); to 1.70 (m, 1H).

Example 49

{(S)-3-[3-(2,4-Differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-forfinal)metano

49(A). tert-Butyl methyl etherS-3-[3-(2,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

To a mixture of 2,4-difterential (1.39 g, 10 mmol) and DIEA (5,13 ml, 30 mmol) in EtOH (15 ml) add 2,12 g of hydroxylamine hydrochloride (30 mmol) and the reaction mixture is heated to 70°C and kept at this temperature for 48 hours. Half of the volume of the solvent is removed under reduced pressure. The mixture is then poured into a mixture of DGM (100 ml) and water (30 ml). Add 2.5 ml of 1 N. NaOH to achieve pH=9-10. The organic phase is separated and the aqueous phase extracted with DHM. The organic layers are combined, washed, dried over MgSO4, filtered and evaporated under reduced pressure, obtaining N-hydroxy-2,4-differentley, which is used in the next stage without additional purification.

A mixture of N-hydroxy-2,4-diftorbenzofenon (10 mmol), S-1-Boc-piperidine-3-carboxylic acid (2.3 g, 10 mmol), EDCI·HCl (2,87 g, 15 mmol), HOBT (1.35 g, 10 mmol) and DIEA (3.4 ml, 20 mmol) in dioxane (10 ml) is stirred overnight at room temperature in ATM is the field of nitrogen. Then the reaction mixture is refluxed for 18 hours and the solvent is evaporated under reduced pressure. The residue was diluted with water (50 ml) and ethyl acetate (50 ml), the phases are separated and the organic layer washed successively with water (50 ml × 2) and 1 N. NaOH (50 ml × 2). The organic layer is dried over Na2SO4and concentrate under reduced pressure. Purification of the crude product flash chromatography (silica gel, eluent: DHM/hexane/MeOH 50/50/0,2) leads to obtain 2.4 g of tert-butyl methyl ether S-3-[3-(2,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid.

Yield: 66%; IHMS (Tr): to 7.93 min (method A); MS (ES+) m/z: 366,2.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): with 8.05 (m, 1H); 6,98 (m, 2H); 4,27 (USD, 1H); to 3.92 (m, 1H); and 3.31 (DD, 1H); 3,17 (TT, 1H); 3,03 (DDD, 1H); to 2.25 (m, 1H); 1,95-of 1.78 (m, 2H); 1.77 in-1,53 (m, 1H); 1,46 (c, 9H).

49(B). HydrochlorideS-3-[3-(2,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine

tert-Butyl methyl etherS-3-[3-(2,4-Differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid (0,22 g, 0.6 mmol) dissolved in dichloromethane (3 ml) and the resulting solution was added dropwise 5 ml of 4 N. HCl solution in dioxane). The resulting mixture was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, receiving 180 mg (yield: 100%) hydrochlorideS-3-[3-(2,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine in the form of a white solid. LC is S (Tr): 4,67 min (method B); MS (ES+) m/z: 266,2.

49(C). {(S)-3-[3-(2,4-Differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-forfinal)metano

To a suspension of the hydrochlorideS3-[3-(2,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine (180 mg, 0.6 mmol) in dry dichloromethane (5 ml) dropwise at 0°C. add triethylamine (180 ml) of 1.26 mmol) and 4-perbenzoate (71 ml, 0.6 mmol). The reaction mixture allow to warm to room temperature and stirred it over night under nitrogen atmosphere. Then the solution is treated with 0.5 N. HCl (5 ml) and the phases are separated. The organic layer is washed successively with 0.5 N. HCl (5 ml), 1 N. NaOH (5 ml) and water (5 ml), then dried over Na2SO4and evaporated under reduced pressure. The crude product was purified flash chromatography (silica gel, eluent: DHM/hexane/MeOH 50/50/0,2), receiving 50 mg specified in the connection header.

Yield: 86% (solid adhesive white); [α]D20=+106° (c=1.05 by CHCl3); IHMS (Tr): 7,13 min (method A); MS (ES+) m/z: 388,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,00 (m, 1H); 7,50-7,35 (m, 2H); 7,15-of 6.90 (m, 4H); 4,4 (USD, 1H); 3,95 (USD, 1H); 3,50 (DD, 1H); 3,35 is 3.15 (m, 2H); 2.40 a-2,20 (m, 1H); 2,10-of 1.80 (m, 2H); 1,80-to 1.60 (m, 1H).

Example 50

(4-Forfinal)-[(S)-3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

50(A). tert-Butyl methyl etherS-3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid

The connection is ucaut in accordance with the methodology described in the example 49(A), from tert-butyl methyl ether 1-cyanonaphthalene. Pure tert-butyl etherS3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid is obtained after trituration of the crude product in a mixture of diethylether/hexane 1:1 and sequentially flash chromatography (silica gel, eluent: DHM/MeOH 99,8/0,2) (yield: 66%).

IHMS (Tr): 8,64 min (method A); MS (ES+) m/z: 380,1.

50(B). HydrochlorideS3-(3-Naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine

Connection receive in accordance with the procedure described in example 49(B), starting from tert-butyl methyl etherS3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): 5,42 min (method B); MS (ES+) m/z: 280,1.

50(C). (4-Forfinal)-[(S)-3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 49(C), based on hydrochlorideS3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine and using 4-perbenzoate as selected acylchlorides. Pure (4-forfinal)-[(S)-3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano obtained after purification of the crude product flash chromatography (silica gel, eluent: DHM/hexane/MeOH 50/50/0,2).

Yield: 83% (solid adhesive white); [α]D20=+88° (c=1,28, CHCl3); IHMS (Tr): 7,6 min (method A); MS (ES+) m/z: 402,1.

1H-NMR (CDCl3 , 333 K, 300 MHz), δ (ppm): 8,90 (d, 1H); to 8.20 (d, 1H); of 7.90 (DD, 2H); 7,60-7,40 (m, 5H); 7,15-7,00 (m, 2H); 4,50 (USD, 1H); 4,00 (USD, 1H); of 3.60 (DD, 1H); 3,40 is 3.15 (m, 2H); 2,45-of 2.30 (m, 1H); 2,20-of 1.85 (m, 2H); 1,80-to 1.60 (m, 1H).

Example 51

{(S)-3-[3-(2,6-Differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-forfinal)metano

51(A). tert-Butyl methyl etherS-3-[3-(2,6-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 49(A), from tert-butyl ether 2,6-difterential.S3-[3-(2,6-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid is obtained after purification of the product flash chromatography (silica gel, eluent: DHM/MeOH 99,8/0,2) (Yield: 55%).

IHMS (Tr): 7.68 per min (Method A); MS (ES+) m/z: 366,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 7,44 (TT, 1H); 7,02 (DD, 2H); 4,29 (USD, 1H); of 3.94 (DDD, 1H); of 3.32 (DD, 1H); 3,19 (TT, 1H); 3,01 (DDD, 1H); and 2.27 (m, 1H); 1,99-of 1.78 (m, 2H); 1,74-and 1.54 (m, 1H); 1,46 (c, 9H).

51(B). HydrochlorideS3-[3-(2,6-differenl)-[1,2,4]oxadiazol-5-yl]piperidine

Connection receive in accordance with the procedure described in example 49(B), starting from tert-butyl methyl etherS3-[3-(2,6-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): 4,24 min (method B); MS (ES+) m/z: 266,1.

51(C). {(S)-3-[3-(2,6-Differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-forfinal)metano

Connection receive in accordance with metodiki, described in the example 49(C), based on hydrochlorideS3-[3-(2,6-differenl)-[1,2,4]oxadiazol-5-yl]piperidine and using 4-perbenzoate as selected acylchlorides. Net {(S)-3-[3-(2,6-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-forfinal)methanon obtained after purification of the crude product flash chromatography (2 columns connected in series: silica gel, eluent: DHM/hexane/MeOH 50/50/0,2).

Yield: 60% (thick oil); [α]D20=+97° (c=1,14, CHCl3); IHMS (Tr): 7,10 min (method A); MS (ES+) m/z: 388,1.

1H-NMR (CDCl3, 328 K, 300 MHz), δ (ppm): 7,50-7,39 (m, 3H); 7,12-6,98 (m, 4H); to 4.41 (USD, 1H); 3,99 (USD, 1H); of 3.54 (DD, 1H); 3,35-is 3.21 (m, 2H); 2,35 (m, 1H); 2,11-to 1.87 (m, 2H); 1,75-to 1.60 (m, 1H).

Example 52

(4-Forfinal)-{(S)-3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

52(A). tert-Butyl methyl etherS3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 49(A), from 2-methoxybenzonitrile. Pure tert-butyl etherS3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid is obtained after purification of the crude product flash chromatography (silica gel, eluent: hexane/ethyl acetate 8/2) (yield: 39%).

IHMS (Tr): 7,19 min (method A); MS (ES+) m/z: 360,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): of 7.97 (DD, 1H); 7,45 (DDD, 1H); 7,06 (DD is, 1H);? 7.04 baby mortality (DD, 1H); 4,33 (USD, 1H); of 3.97 (DDD, 1H); 3,95 (c, 3H); or 3.28 (DD, 1H); 3.15 in (TT, 1H); 2,98 (DDD, 1H); and 2.27 (m, 1H); 1,98-to 1.79 (m, 2H); 1,69-of 1.53 (m, 1H); 1,47 (c, 9H).

52(B). HydrochlorideS3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine

Connection receive in accordance with the procedure described in example 49(B), starting from tert-butyl methyl etherS3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): 4,40 min (method B); MS (ES+) m/z: 260,1.

52(C). (4-Forfinal)-{(S)-3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl)methanon

Connection receive in accordance with the procedure described in example 49(C), based on hydrochlorideS3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine and using 4-perbenzoate as selected acylchlorides. Pure (4-forfinal)-{(S)-3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon obtained after purification of the crude product flash chromatography (silica gel, eluent: hexane/ethyl acetate 6/4).

Yield: 47% (gummy solid); [α]D20=+88° (c=0,98, CHCl3); IHMS (Tr): 7,33 min (method A); MS (ES+) m/z: 382,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): to 7.93 (DD, 1H); 7,49-7,39 (m, 3H); 7,12-7,01 (m, 4H); 4,40 (USD, 1H); 4,00 (USD, 1H); 3,94 (c, 3H); to 3.52 (DD, 1H); of 3.25 (m, 2H); of 2.34 (m, 1H); 2,09 is 1.86 (m, 2H); 1,68 (m, 1H).

Example 53

(4-Forfinal)-[(S)-3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)-piperidine-1-yl]metano

53(A). tert-Butyl methyl etherS3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 49(A), from 2-cyanonaphthalene. Pure tert-butyl etherS3-(3-naphthalene-2-yl-[1,2,4-oxadiazol-5-yl)piperidine-1-carboxylic acid is obtained after purification of the crude product flash chromatography (silica gel, eluent: DHM/hexane/MeOH 50/50/0,2) (yield: 58%).

IHMS (Tr): 8,72 min (method A); MS (ES+) m/z: 380,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,61 (USS, 1H); to 8.14 (DD, 1H); 7,97-of 7.82 (m, 3H); EUR 7.57-of 7.48 (m, 2H); 4,32 (USD, 1H); 3,95 (DDD, 1H); to 3.36 (DD, 1H); 3,19 (TT, 1H); 3,05 (DDD, 1H); to 2.29 (m, 1H); 2,02-to 1.82 (m, 2H); 1,71-1,58 (m, 1H).

53(B). HydrochlorideS3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)piperidine

Connection receive in accordance with the procedure described in example 49(B), starting from tert-butyl methyl etherS3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): 5,96 min (method B); MS (ES+) m/z: 280,1.

53(C). (4-Forfinal)-[(S)-3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 49(C), based on hydrochlorideS3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)piperidine and using 4-perbenzoate as selected acylchlorides. Pure (4-forfinal)-[(S)-3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)-piperidine-1-yl]meth is non obtained after purification of the crude product flash chromatography (silica gel, eluent: hexane/ethyl acetate 8/2).

Yield: 14% (white solid); TPL=142-143°C; [α]D20=+123° (c=1,025, CHCl3); IHMS (Tr): 7,97 min (method A); MS (ES+) m/z: 402,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,59 (USS, 1H); to 8.12 (DD, 1H); 7,97-to 7.84 (m, 3H); to 7.59-7,49 (m, 2H); was 7.45 (DD, 2H); 7,10 (DD, 2H); 4,45 (USD, 1H); 4,01 (USD, 1H); to 3.58 (DD, 1H); 3,29 (m, 2H); of 2.38 (m, 1H); 2,14-1,89 (m, 2H); 1,78-of 1.65 (m, 1H).

Example 54

(4-Forfinal)-[(S)-3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

54(A). tert-Butyl methyl etherS3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 49(A), from 4-methylbenzonitrile. Pure tert-butyl etherS3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid is obtained after trituration of the crude product in a mixture of hexane/diethylether 1/1 (Yield: 78%). IHMS (Tr): 11,0 min (method B); MS (ES+) m/z: to 344.4.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): of 7.96 (d, 2H); 7,26 (d, 2H); 4,28 (USD, 1H); 3,93 (DDD, 1H); 3,30 (DD, 1H); 3,13 (TT, 1H); 3,01 (DDD, 1H); 2,41 (c, 3H); to 2.25 (m, 1H); 1,97-of 1.78 (m, 2H); 1,69-of 1.52 (m, 1H); 1,47 (c, 9H).

54(B). HydrochlorideS3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine

Connection receive in accordance with the procedure described in example 49(B), starting from tert-butyl methyl etherS3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): 5,3 min (method B), MS (ES+) m/z: 244,4.

54(C). (4-Forfinal)-[(S)-3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 49(C), based on hydrochlorideS3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine and using 4-perbenzoate as selected acylchlorides. Pure (4-forfinal)-[(S)-3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano obtained after purification of the crude product flash chromatography (silica gel, eluent: hexane/ethyl acetate 8/2).

Yield: 33% (thick oil); [α]D20=+106° (c=1,0, CHCl3); IHMS (Tr): 9,5 min (method B); MS (ES+) m/z: 366,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 7,94 (d, 2H); the 7.43 (DD, 2H); 7,27 (d, 2H); to 7.09 (DD, 2H); 4,40 (USD, 1H); 3,99 (USD, 1H); to 3.52 (DD, 1H); 3,31-3,18 (m, 2H); 2,41 (c, 3H); 2,33 (m, 1H); 2,09 is 1.86 (m, 2H); 1,75-to 1.59 (m, 1H).

Example 55

(4-Forfinal)-{(S)-3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

55(A). tert-Butyl methyl etherS3-[3-(2-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 49(A), from tert-butyl ether 2-perbenzoate. Pure tert-butyl etherS3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid is obtained after trituration of the crude product in a mixture of hexane/diethylether 1/1 (yield: 83%).

IHMS (Tr): 7,79 min (method A); MS (ES+) m/z: 348,1./p>

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,04 (DDD, 1H); 7,47 (m, 1H); to 7.25 (DDD, 1H); 7,21 (m, 1H); 4,30 (USD, 1H); of 3.94 (DDD, 1H); of 3.32 (DD, 1H); 3,18 (TT, 1H); to 3.02 (DDD, 1H); and 2.26 (m, 1H); 1,99-to 1.79 (m, 2H); 1,69-of 1.53 (m, 1H); 1,47 (c, 9H).

55(B). HydrochlorideS3-[3-(2-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine

Connection receive in accordance with the procedure described in example 49(B), starting from tert-butyl methyl etherS3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): 4,7 min (method B); MS (ES+) m/z: 248,1.

55(C). (4-Forfinal)-{(S)-3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 49(C), based on hydrochlorideS3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine and using 4-perbenzoate as selected acylchlorides. Pure (4-Forfinal)-{(S)-3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon obtained after purification of the crude product flash chromatography (silica gel, eluent: hexane/ethyl acetate 8/2).

Output: 22% (thick oil); [α]D20=+102° (c=1,045, CHCl3); IHMS (Tr): 7,31 min (method A); MS (ES+) m/z: 370,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,01 (DDD, 1H); 7,52-7,41 (m, 1H); the 7.43 (DD, 1H); 7,29-to 7.18 (m, 2H); to 7.09 (DD, 2H); to 4.41 (USD, 1H); 3,99 (USD, 1H); of 3.54 (DD, 1H); with 3.27 (m, 2H); of 2.34 (m, 1H); 2,10-to 1.87 (m, 2H); 1,76-1,61 (m, 1H).

Example 56

(4-Forfinal)-[(S)-3-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-

Il)is piperidin-1-yl]metano

56(A). tert-Butyl methyl etherS3-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 49(A)on the basis of 2-cyanopyridine. Pure tert-butyl etherS3-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid is obtained after purification of the crude product flash chromatography (silica gel, eluent: DHM/MeOH/NH4OH 98/2/0,2) (yield: 54%).

IHMS (Tr): 6,87 min (method A); MS (ES+) m/z: 331,2.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,80 (DDD, 1H); 8,11 (DDD, 1H); of 7.82 (DDD, 1H); 7,40 (DDD, 1H); 4,33 (USD, 1H); 3,98 (DDD, 1H); to 3.33 (DD, 1H); 3,20 (TT, 1H); 2,99 (DDD, 1H); 2,28 (m, 1H); 2,03-to 1.79 (m, 2H); 1,69-and 1.54 (m, 1H), 1,48 (c, 9H).

56(B). The dihydrochlorideS-2-(5-piperidine-3-yl-[1,2,4]oxadiazol-3-yl)pyridine

Connection receive in accordance with the procedure described in example 49(B), starting from tert-butyl methyl etherS-3-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid (yield: 100%).

IHMS (Tr): 3,12 min (method B); MS (ES+) m/z: 231,2.

56(C). (4-Forfinal)-[(S)-3-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 49(C), based on dihydrochlorideS-2-(5-piperidine-3-yl-[1,2,4]oxadiazol-3-yl)pyridine and using 4-perbenzoate as selected acylchlorides.

Yield: 78% (thick yellowish oil color is one); [α]D20=+103° (c=1.05 by CHCl3); IHMS (Tr): 6,56 min (method A); MS (ES+) m/z: 353,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,79 (m, 1H); of 8.09 (DDD, 1H); of 7.82 (DDD, 1H); 7,47-7,37 (m, 3H); was 7.08 (DD, 2H); of 4.44 (USD, 1H); 4,05 (USD, 1H); of 3.54 (DD, 1H); 3,29 (TT, 1H); is 3.21 (DDD, 1H); of 2.36 (m, 1H); 2.13 and is 1.86 (m, 2H); 1,76-to 1.61 (m, 1H).

Example 57

S-(4-Forfinal)-{3-[5-(4-forfinal)-4-methyl-4H-1,2,4-triazole-3-yl]piperidine-1-yl}metano

57(A). 1-(4-Perbenzoic)-(S)piperidine-3-carboxylic acid

To a suspension of the hydrochloride of (S)piperidine-3-carboxylic acid (0.75 g, a 4.53 mmol) in dry dichloromethane (30 ml ) dropwise at 0°C. add triethylamine (1.97 ml, 14.0 mmol) and 4-perbenzoate (543 ml, a 4.53 mmol). The resulting solution is stirred over night at room temperature in a nitrogen atmosphere, was added 1 N. HCl (30 ml) and the phases are separated. The organic layer was washed with 1 N. HCl (30 ml), water (30 ml), dried over Na2SO4and evaporated under reduced pressure, obtaining of 1.05 g of 1-(4-perbenzoic)-(S)piperidine-3-carboxylic acid in the form of a yellow oil, which was used in the next stage of the synthesis without further purification. Yield: 92%; IHMS (Tr): 6,55 min (method B); MS (ES+) m/z: 252,3.

57(B). tert-Butyl ether N'-[1-(4-perbenzoic)-(S)piperidine-3-carbonyl]hydrazinecarboxamide acid

A mixture of 1-(4-perbenzoic)-(S)-piperidine-3-carboxylic acid (1,05 g of 4.17 mmol), tert-BUTYLCARBAMATE (0.55 g of 4.17 mmol), HOBT (0,562 g of 4.17 mmol), EDCI·HCl (1.2 g, of 6.25 mmol) in dry dichloromethane (8 ml) is stirred overnight at ambient temperature under nitrogen atmosphere. Then add 1 N. HCl (30 ml) and the phases are separated. The organic layer was washed with 1 N. HCl (30 ml), 1 N. NaOH (30 ml × 2), then water (30 ml). Evaporation of the organic solvent yields a crude yellow oil, which was purified flash chromatography (silica gel, eluent: DHM/MeOH 70/1), receiving 0,715 g tert-butyl ether N'-[1-(4-perbenzoic)-(S)piperidine-3-carbonyl]hydrazinecarboxamide acid.

Yield: 47% (yellow oil); IHMS (Tr): 6,40 min (method A); MS (ES+) m/z: 366,2.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,04 (USS, 1H); 7,47 and 7.36 (m, 2H); 7,12-7,01 (m, 2H); 6.42 per (USS, 1H); 4,12-3,90 (USM, 1H); 3,88-3,51 (USM, 2H); 3,34-3,09 (USM, 1H); 2,62-2,36 (USM, 1H); 2,18-of 1.84 (m, 2H); 1,81-of 1.64 (m, 1H); 1,47 (c, 9H); 1,52 was 1.43 (m, 1H).

57(C). The hydrazide hydrochloride 1-(4-perbenzoic)-(S)piperidine-3-carboxylic acid

0.55 g (1.5 mmol) tert-butyl ether N'-[1-(4-perbenzoic)-(S)piperidine-3-carbonyl]hydrazinecarboxamide acid are suspended in 5 ml of dichloromethane and added dropwise at 0°C with 4 ml of 1 N. HCl solution in dioxane). Solution allow to warm to room temperature and stirred it for 1 hour and 30 minutes. The solvent is evaporated under reduced pressure, getting 0,412 g of hydrazide 1-(4-perbenzoic)-(S)piperidine-3-carboxylic acid as white solid, very hygroscopical substances.

Yield: 91%; IHMS (Tr): 5,4 min (method B); MS (ES+) m/z: 266,2.

1H-NMR (CDCl3, 333 K + D2O, 300 MHz), δ (ppm): 7,41 (DD, 2H); was 7.08 (DD, 2H); of 4.45 (m, 1H); 4,11 (m, 1H); of 3.84 (m, 1H); 3,39 (DD, 1H); 3,13 (m, 1H); 2,39 (m, 1H); 1,95 (m, 2H); 1.85 to about 1.75 (m, 1H).

57(D). 4-fluoro-N-methylbenzeneboronic

A suspension of 4-fluoro-N-methylbenzamide (CAS: 701-49-5, 0,106 g, 0.69 mmol) in thionyl chloride (202 ml, 2,78 mmol) is refluxed for 1 hour and 30 minutes. The solvent is removed under reduced pressure, then added toluene and the solvent is evaporated under reduced pressure, obtaining a yellow oil, which was immediately used in the next stage.

57(E).S-(4-Forfinal)-{3-[5-(4-forfinal)-4-methyl-4H-[1,2,4]triazole-3-yl]piperidine-1-yl}metano

To a solution of 4-fluoro-N-methylbenzimidazole received in accordance with the methodology described in 58(D), in dry toluene (8 ml), under nitrogen atmosphere add hydrazine hydrochloride 1-(4-perbenzoic)-(S)piperidine-3-carboxylic acid (0.21 g, 0.69 mmol) and anhydrous triethylamine (204 ml of 1.46 mmol) and the resulting mixture is refluxed for 2 hours. The solvent is removed under reduced pressure, the residue diluted with dichloromethane and washed with NaHCO3(water). The organic layer is dried over Na2SO4and evaporated under reduced pressure. The crude product was purified flash chromatography (2 columns connected in series (first Colo is CA: silica gel, elution with a gradient from DHM/MeOH 20:1 to DHM/MeOH 4:1; second column: silica gel, elution gradient: acetone/ethyl acetate 1:1 to 2:1)to give 20 mg of S-(4-forfinal)-{3-[5-(4-forfinal)-4-methyl-4H-[1,2,4]triazole-3-yl]piperidine-1-yl}mechanon.

Output: 8% (white solid); IHMS (Tr): 6,26 min (method A); MS (ES+) m/z: 383,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): the 7.65 (DD, 2H); 7,46 (DD, 2H); then 7.20 (DD, 2H); 7,10 (DD, 2H); 4,46 (USM, 1H); 4,01 (USM, 1H); 3,66 (c, 3H); 3,39 (m, 1H); 3,19 (m, 1H); 2,98 (USM, 1H); 2,28-1,89 (m, 3H)and 1.60 (m, 1H).

Example 58

(4-Forfinal)-{(S)-3-[5-(4-forfinal)-[1,3,4]oxadiazol-2-yl]piperidine-1-yl}metano

58(A). N'-[(S)-1-(4-perbenzoic)piperidine-3-carbonyl]hydrazide 4-fermenting acid

A mixture of hydrazide hydrochloride 1-(4-perbenzoic)-(S)-piperidine-3-carboxylic acid, obtained in accordance with the procedure described in example 57(C) (2,97 g, and 11.2 mmol), 4-fermenting acid (1.68 g, and 11.2 mmol), HOBT (1.5 g, and 11.2 mmol), EDCI·HCl (3.2 g, a 16.8 mmol) and dry triethylamine (5,43 ml of 39.5 mmol) in dry dichloromethane (80 ml) is stirred overnight at ambient temperature in nitrogen atmosphere. Then add 1 N. HCl (80 ml) and the phases are separated. The organic layer was washed with 1 N. HCl (80 ml), 1 N. NaOH (80 ml × 2), then water (80 ml). Evaporation of the organic solvent yields a crude product in the form of oil, which was purified flash chromatography (silica compound is a gel, eluent: DHM/MeOH/NH4OH 98/2/0,2). The compound obtained after column chromatography, again purified flash chromatography (silica gel, eluent: DHM/MeOH/NH4OH 98/2/0,2)to give pure N-[(S)-1-(4-perbenzoic)piperidine-3-carbonyl]hydrazide 4-fermenting acid in the form of a white solid (250 mg).

Output: 6%; IHMS (Tr): 5,88 min (method A); MS (ES+) m/z: 388,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,91 (USS, 1H); 8,35 (USS, 1H); 7,83 (DD, 2H); 7,47 (DD, 2H); 7,13 (DD, 2H); to 7.09 (DD, 2H); 4,03 is 3.76 (m, 3H); of 3.32 (m, 1H); 2,61 (m, 1H); 2,22-of 1.93 (m, 2H); 1.77 in (m, 1H); of 1.55 (m, 1H).

58(B). (4-Forfinal)-{3-[5-(4-forfinal)-[1,3,4]oxadiazol-2-yl]piperidine-1-yl}metano

A mixture of N'-[(S)-1-(4-perbenzoic)piperidine-3-carbonyl]hydrazide 4-fermenting acid (100 mg, 0.26 mmol), 4-toluenesulfonamide (60 mg, 0.31 mmol), 2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-datafactory on solid media (PS-BEMP, ex Fluka, 586 mg, 1.3 mmol, filling 2.2 mmol/g) in dry tetrahydrofuran (6 ml) is treated with microwaves in the following conditions: cycle MV: t=1 min, P=100 W, the cooling time = 2 min; after 5 MV cycles, the resin is filtered off and repeatedly washed with dichloromethane. The solvent is evaporated under reduced pressure to give crude product as a solid, which is purified column flash chromatography (silica gel, eluent: hexane/ethyl acetate 1:1). Specified in the title compound obtained as a solid which logo substances (82 mg).

Yield: 85%; IHMS (Tr): 6,75 min (method A); MS (ES+) m/z: 370,1.

1H-NMR (CDCl3, 300 K, 300 MHz), δ (ppm): 8,02 (m, 2H); 7,41 (m, 2H); 7,31-6,93 (m, 4H); 4,96-3,37 (m, 3H); up 3.22 (m, 2H), 2,32 (m, 1H); 2,20-to 1.63 (m, 3H).

Example 59

(2-Forfinal)-{(S)-3-[2-(3,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 49(C), based on hydrochlorideS3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine and using 3,4-differentiald as selected acylchlorides. Pure (2-Forfinal)-{(S)-3-[2-(3,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon obtained after purification of the crude product flash chromatography (silica gel, eluent:DHM//MeOH/NH4OH 99/1/0,1).

Yield: 61% (gummy solid); TPL=115-119°C; [α]D20=+92,2° (c=1,14,

CHCl3); IHMS (Tr): 7,25 min (method A); MS (ES+) m/z: 388,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,01 (DDD, 1H); of 7.48 (m, 1H); 7,33-to 7.15 (m, 5H); 4,37 (m, 1H); 3,93 (m, 1H); 3,59 (DD, 1H); 3,37 is 3.23 (m, 2H); 2,35 (m, 1H); 2,13-to 1.87 (m, 2H); 1,76-to 1.61 (m, 1H).

Example 60

(4-Forfinal)-{2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]morpholine-4-yl}metano

60(A). tert-Butyl ester 2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]morpholine-4-carboxylic acid

A mixture of (R,S)-N-Boc-2-carboxymaltose (0.5 g, of 2.16 mmol), N-hydroxy-4-fermentation (of 0.333 g of 2.16 mmol), EDCI·HCl (0,621 g, 3.2 mmol), HOBT (0,292 g of 2.16 mmol) and anhydrous triethylamine (605 ml, 4,32 mmol) in dioxane (7 ml) is stirred overnight at room temperature in a nitrogen atmosphere. After that, the mixture is refluxed for 4 hours and concentrated under reduced pressure. The residue is diluted with ethyl acetate (15 ml) and water (15 ml) and the phases are separated. The organic layer was washed with 1 N. NaOH (15 ml) and a solution of salt, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified flash chromatography (silica gel, eluent: hexane/ethyl acetate 9/1)to give 325 mg (yield: 43%) of tert-butyl methyl ether 2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]morpholine-4-carboxylic acid as a white oil.

IHMS (Tr): 7,51 min (method A); MS (ES+) m/z: 350,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 8,11 (DD, 2H); 7,16 (DD, 2H); a 4.83 (DD, 1H); 4,27 (USM, 1H); 4.09 to (m, 1H); a 3.87 (m, 1H); 3,74 (DDD, 1H); 3,41 (USM, 1H); 3,23 (DDD, 1H); 1,48 (c, 9H).

60(B). Hydrochloride of 2-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]research

2-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]morpholine-4-carboxylic acid (0,325 g of 0.93 mmol) dissolved in dichloromethane (3 ml) and added dropwise 5 ml of 4 N. HCl solution in dioxane). The resulting mixture was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, getting 265 mg (yield: 100%) of the hydrochloride of 2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]the research in the form of a white solid ve is esta.

IHMS (Tr): 5,68 min (method A); MS (ES+) m/z: 250,1.

1H-NMR (DMSO, 300 MHz), δ (ppm): 9,58 (USS, 1H); of 8.09 (DD, 2H); the 7.43 (DD, 2H); 5,38 (DD, 1H); 4,19-of 3.97 (m, 2H); 3,71 (DD, 1H); of 3.45 (DD, 1H), 3,30-of 3.12 (m, 2H).

60(C). (4-Forfinal)-{2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]morpholine-4-yl}metano

To a suspension of the hydrochloride of 2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]the research (0.15 g, of 0.53 mmol) in anhydrous dichloromethane (6 ml) under nitrogen atmosphere at 0°C. successively added triethylamine (155 ml, 1.1 mmol) and 4-perbenzoate (62 ml of 0.53 mmol). The reaction mixture allow to warm to room temperature and stirred her during the night. To the mixture was added 1 N. HCl (6 ml) and the phases are separated. The organic layer is washed successively 1 N. HCl (6 ml), 1N NaOH (6 ml × 2) and water, then dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified flash chromatography (silica gel, eluent: hexane/ethyl acetate 7/3)to give 120 mg (4-forfinal)-{2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]morpholine-4-yl}methanone in the form of a white solid.

Yield: 61%; TPL=116-117°C; IHMS (Tr): 7,33 min (method A); MS (ES+) m/z: 372,0.

1H-NMR (CDCl3, 300 MHz, 330 K)δ (ppm): 8,08 (DD, 2H); 7,47 (DD, 2H); 7,16 (DD, 2H); for 7.12 (DD, 2H); 4,90 (DD, 1H); 4,39 (USD,1H); 4,12 (DDD, 1H); 3,95 (USD, 1H); 3,79 (DDD, 1H); 3,71 (DD, 1H); of 3.53 (DDD, 1H).

Example 61

(4-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-4-methylpiperazin-1-yl}metano

61(A). tert-Butyl ether piperazine-1,3-dicarboxylic acid

To a solution of dihydrochloride of 2-piperazinecarboxamide acid (1.0 g, to 4.92 mmol) in 20 ml of a mixture of water/dioxane 1:1 add 6 N. NaOH is added to bring the pH to 11. Then to the mixture is added dropwise a solution of BOC-ON® (1,34 g, 5.41 mmol) in dioxane (5 ml) while maintaining while adding pH=11 and the resulting solution is stirred over night at room temperature. Add 0,134 g of BOC-ON® and the reaction mixture is stirred for 2 hours. The solvent is evaporated under reduced pressure and the residue was diluted with a mixture of diethylether/water (60 ml). The phases are separated and the pH of the aqueous layer was adjusted to 7 by slow addition of 1 N. HCl. Evaporation of water under reduced pressure results specified in the connection header in the form of a white solid, which is dried in a vacuum oven at 50°C and used in the next stage without additional purification.

IHMS (Tr): 3.3V min (method B); MS (ES+) m/z: 231,0.

61(B). tert-Butyl ether 4-methylpiperazin-1,3-dicarboxylic acid

Crude 1-tert-butyl ether piperazine-1,3-dicarboxylic acid (4,92 mmol), obtained according to the method of example 62(A)suspended in dry acetonitrile (30 ml) under nitrogen atmosphere and the solution was added formaldehyde (37% aqueous solution, 367 ml, to 4.92 mmol) and Na(OAc)3BH (2.3 g, was 10.82 mmol). The resulting mixture is displaced is more at room temperature for 3 hours, then slowly add saturated aqueous solution of NaHCO3to bring the pH to 7. The mixture is evaporated to dryness under reduced pressure, obtaining a solid yellow color, which is used in the next stage without additional purification. IHMS (Tr): 3,19 min (method B); MS (ES+) m/z: 245,0.

61(C). tert-Butyl ester 3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-4-methylpiperazin-1-carboxylic acid

A mixture of N-hydroxy-4-ferbenstein (0,758 g, to 4.92 mmol), 4-methylpiperazin-1,3-dicarboxylic acid (4,92 mmol), obtained according to the method of example 62(B), EDCI·HCl (1,41 g, 7,38 mmol), HOBT (0,665 g, to 4.92 mmol) and anhydrous triethylamine (1,38 ml, 9,84 mmol) in dioxane (80 ml) was stirred at room temperature under nitrogen atmosphere during the weekend. Then the reaction mixture is refluxed for 7 hours and the solvent is evaporated under reduced pressure. The residue was diluted with water (50 ml) and ethyl acetate (50 ml), the phases are separated and the organic layer washed successively with water (50 ml × 2) and 1 N. NaOH (50 ml × 2). The organic layer is dried over Na2SO4and concentrate under reduced pressure, obtaining a yellow oil. Purification of the crude product flash chromatography (silica gel, elution with a gradient hexane/ethyl acetate from 8/2 to 7/3) results 0.312 g of tert-butyl ester 3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-4-meth is piperazin-1-carboxylic acid in the form of a yellow oil.

The total yield of three stages 22(A)22(B) and 22(C): 18%. IHMS (Tr): 7,34 min (method B); MS (ES+) m/z: 363,1.

1H-NMR (CDCl3, 300 MHz, 328 K), δ (ppm): 8,11 (DD, 2H); 7,16 (DD, 2H); 4,01-3,90 (m, 2H); 3,83-3,62 (m, 3H); 3,17 (m, 1H); to 2.55 (m, 1H); 2,43 (c, 3H); 1.41 to (c, 9H).

61(D). The dihydrochloride of 2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-1-methylpiperazine

4 N. HCl (3 ml of solution in dioxane) are added dropwise to a solution of tert-butyl methyl ether [3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-4-methylpiperazin-1-carboxylic acid (0.312 g, 0.86 mmol) in methanol (8 ml) and the solution stirred overnight at room temperature. Evaporation of volatile components under reduced pressure yields a dihydrochloride of 2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-1-methylpiperazine in the form of a white solid (0,285 g).

Output: 100%; IHMS (Tr): 5,63 min (method A); MS (ES+) m/z: 263,2.

1H-NMR (CDCl3, 300 MHz, 328 K), δ (ppm): 8,11 (DD, 2H); 7,16 (DD, 2H); 4,01-3,90 (m, 2H); 3,83-3,62 (m, 3H); 3,17 (m, 1H); to 2.55 (m, 1H); 2,43 (c, 3H); 1.41 to (c, 9H).

61(E). (4-Forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-4-methylpiperazin-1-yl}metano

To a suspension of the dihydrochloride of 2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-1-methylpiperazine (0,285 g, 0.86 mmol) in anhydrous dichloromethane (6 ml) under nitrogen atmosphere at 0°C. successively added triethylamine (374 ml, 2.7 mmol) and 4-perbenzoate (102 ml, 0.86 mmol). The reaction mixture allow to warm to room temperature and stirred mixture is within 2 hours. Add 1 N. NaOH (6 ml) and the phases are separated. The organic layer is washed successively 1 N. NaOH (6 ml) and water, then dried over sodium sulfate and evaporated under reduced pressure. Purification of the crude product flash chromatography (silica gel, eluent: DHM/MeOH/NH4OH 99/1/0,1) results (4-forfinal)-{3-[3-(4-forfinal)-[1,2,4-oxadiazol-5-yl]-4-methylpiperazin-1-yl}methanone (0.12 g).

Yield: 36%; IHMS (Tr): 6,36 min (method A); MS (ES+) m/z: 385,1.

1H-NMR (CDCl3, 328 K, 300 MHz), δ (ppm): 8,10 (DD, 2H); 7,40 (DD, 2H); 7.18 in (DD, 2H); 7,06 (DD, 2H); 4,14-to 3.92 (m, 3H); 3,91-to 3.73 (m, 2H); 3,17 (m, 1H); of 2.58 (m, 1H); 2,42 (c, 3H).

Example 62

(4-Forfinal)amide (S)-1-(4-Perbenzoic)piperidine-3-carboxylic acid

62(A). Tert-Butyl ether (S)-3-(4-tortenelmebol)piperidine-1-carboxylic acid

The mixture ofS-1-Boc-piperidine-3-carboxylic acid (0.3 g, of 1.30 mmol), EDCI·HCl (0,376 g, a 1.96 mmol), HOBT (0,198 g of 1.30 mmol) in dry dichloromethane (6 ml) was stirred at room temperature for 1 hour in nitrogen atmosphere. Then add 4-ftoranila (124 ml, of 1.30 mmol) and the reaction mixture was stirred over night at ambient temperature. The solvent is evaporated under reduced pressure and the residue diluted with water and ethyl acetate. The phases are separated, the organic layer washed with 2M Na2CO3(water), dried over sodium sulfate and concentrated at below the nom pressure. The crude product is purified by filtration through a cartridge of silica gel (silica gel: 10 g, elution with a gradient: petroleum ether/ethyl acetate from 9/1 to 8/2)to give 0.35 g of tert-butyl methyl ether (S)-3-(4-tortenelmebol)piperidine-1-carboxylic acid.

Yield: 84%; IHMS (Tr): 7,08 min (method A); MS (ES+) m/z: 323,2.

1H-NMR (CDCl3, 300 MHz), δ (ppm): compared to 8.26 (USS, 1H); 7,53 (DD, 2H); 6,98 (DD, 2H); 3,82 (m, 1H); 3,67-of 3.46 (m, 2H); 3,23 (m, 1H); 2.49 USD (m, 1H); to 2.06 (m, 1H); 1,89 (m, 1H); and 1.63 (m, 1H); 1,50 (m, 1H); 1,46 (c, 9H).

62(B). Hydrochloride (4-forfinal)amide (S)-piperidine-3-carboxylic acid

To a cooled solution of tert-butyl methyl ether (S)-3-(4-tortenelmebol)piperidine-1-carboxylic acid (0.34 g, 1.05 mmol) in dichloromethane (5 ml) added dropwise with 5.2 ml of 4 N. HCl solution in dioxane) and the solution stirred at room temperature for 45 minutes. The solvent is evaporated under reduced pressure, obtaining mentioned in the title compound as white solid (0,252 g).

Yield: 92%; IHMS (Tr): 5,39 min (method A); MS (ES+) m/z: 223,2.

1H-NMR (DMSO, 300 MHz), δ (ppm): 10,34 (c, 1H); 8,95 (USS, 2H); 7,63 (DD, 2H); 7,14 (DD, 2H); 3,18 (m, 2H); to 3.02 (DD, 1H); is 2.88 (m, 2H); 2,04 (m, 1H); 1,88-of 1.55 (m, 3H).

62(C). (4-Forfinal)amide (S)-1-(4-Perbenzoic)piperidine-3-carboxylic acid

4-perbenzoate (53 ml, 0.45 mmol) is added at 0°C to a solution of hydrochloride (4-forfinal)amide (S)-piperidine-3-carboxylic acid (0,116 g, 0.45 mmol) and triethylamine (131 is l, to 0.94 mmol) in dichloromethane (3 ml) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 hours, the solvent is evaporated and the residue diluted with water and ethyl acetate. The phases are separated and the organic layer washed with 1 N. HCl (10 ml)and 2M Na2CO3(water) (10 ml) and salt solution (10 ml). The organic layer is dried over sodium sulfate and concentrated under reduced pressure, getting to 0.127 g (4-forfinal)amide (S)-1-(4-perbenzoic)piperidine-3-carboxylic acid as white solid.

Yield: 82%; TPL=163-164°C; [α]D20=+54,7° (c=0,995, CHCl3); IHMS (Tr): 6,68 min (method A); MS (ES+) m/z: 345,0.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 8,28 (USS, 1H); 7,56 (DD, 2H); 7,41 (DD, 2H); to 7.09 (DD, 2H); 7,01 (DD, 2H); 4,05 (USM, 1H); to 3.89 (DD, 1H); 3,65 (USM, 1H); 3.40 in (USM, 1H); 2.63 in (m, 1H); and 2.26 (m, 1H); 1,95 (m, 1H); 1,64 (m, 1H); and 1.56 (m, 1H).

Example 63

(4-Forfinal)methylamide (S)-1-(4-perbenzoic)piperidine-3-carboxylic acid

63(A). tert-Butyl ether (S)-3-[(4-forfinal)methylcarbamoyl]piperidine-1-carboxylic acid

The mixture ofS-1-Boc-piperidine-3-carboxylic acid (0.3 g, of 1.30 mmol), EDCI·HCl (0,376 g, a 1.96 mmol), HOBT (0,198 g of 1.30 mmol) in dioxane (4 ml) was stirred at room temperature for 1 hour in nitrogen atmosphere. To the mixture is added N-methyl-4-ftoranila (164 mg, of 1.30 mmol), the reaction mixture is heated to 80°C and can withstand is at this temperature for 2 hours and then stirred at room temperature for 2 days. The solvent is evaporated under reduced pressure and the residue diluted with water and ethyl acetate. The phases are separated, the organic layer washed with 2M Na2CO3(water), dried over sodium sulfate and concentrate under reduced pressure. The crude product is purified by filtration through a cartridge of silica gel (silica gel: 10 g, elution with a gradient: petroleum ether/ethyl acetate: 9/1 to 7/3)to give 0,209 g tert-butyl ether (S)-3-[(4-forfinal)methylcarbamoyl]piperidine-1-carboxylic acid.

Yield: 47%; IHMS (Tr): 7,0 min (method A); MS (ES+) m/z: 337,2.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 7,22-7,07 (m, 4H); 4,00 (m, 2H); 3,22 (c, 3H); 2,89 (DD, 1H); 2.63 in (m, 1H); and 2.27 (m, 1H); 1,78-of 1.65 (m, 2H); 1,61 of 1.50 (m, 2H); 1,40 (c, 9H).

63(B). Hydrochloride (4-forfinal)methylamide (S)-piperidine-3-carboxylic acid

To a cooled solution of tert-butyl methyl ether (S)-3-[(4-forfinal)methylcarbamoyl]piperidine-1-carboxylic acid (0,205 g, 0.61 mmol) in dichloromethane (4 ml) added dropwise 3 ml of 4 N. HCl solution in dioxane) and the resulting mixture was stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, obtaining mentioned in the title compound as white solid (0.16 g).

Yield: 96%. IHMS (Tr): lower than the 5.37 min (method A); MS (ES+) m/z: 237,1.

1H-NMR (DMSO + TFUK, 333 K, 300 MHz), δ (ppm): 8,98-to 8.45 (m, 2H); the 7.43 (DD, 2H); 7,28 (DD, 2H); and 3.16 (c, 3H); 3,16-to 2.67 (m, 5H); 1,80 is 1.34 (m, 4H).

63(C). (4-Ftoh the Nile)methylamide (S)-1-(4-perbenzoic)piperidine-3-carboxylic acid

4-perbenzoate (47 ml, 0.40 mmol) is added at 0°C to a solution of hydrochloride (4-forfinal)methylamide (S)piperidine-3-carboxylic acid (0.11 g, 0.40 mmol) and triethylamine (112 ml, 0.80 mmol) in dichloromethane (3 ml) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours, the solvent is evaporated and the residue diluted with water and ethyl acetate. The phases are separated and the organic layer washed with 1 N. HCl (10 ml), 1M Na2CO3(water) (10 ml) and salt solution (10 ml). The organic layer is dried over sodium sulfate and concentrated under reduced pressure, getting 0,121 g (4-forfinal)methylamide (S)-1-(4-perbenzoic)piperidine-3-carboxylic acid as a sticky solid.

Yield: 84%; [α]D20=+48,9° (c=1,020, CHCl3); IHMS (Tr): 6,61 min (method A); MS (ES+) m/z: 359,1.

1H-NMR (CDCl3, 333 K, 300 MHz), δ (ppm): 7,28 (DD, 2H); 7,13-7,00 (m, 6H); 4,06 (USM, 2H); 3,20 (c, 3H); 3,17 (m, 1H); 2,89 (m, 1H); 2.40 a (m, 1H); 1,94-of 1.66 (m, 3H); 1.28 (in m, 1H).

Example 64

(E)-3-(4-Forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}propenone

Connection receive in accordance with the procedure described in example 36 using 4-folkorico acid as the selected acid hydrochloride and S-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12). Pure (E)-3-(4-ftoh the Nile)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}propenone obtained after trituration of the crude product with titilation.

Yield: 77% (white solid); TPL=137-139°C; [α]D20=+191,7° (c=1,49, CHCl3); IHMS (Tr): a 7.62 min (method A); MS (ES+) m/z: 396,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): of 8.06 (DD, 2H); 7,63 (d, 1H); to 7.50 (DD, 2H); 7,13 (DD, 2H); 7,06 (DD, 2H); 6.87 in (d, 1H); to 4.52 (m, 1H); 4,08 (DDD, 1H); 3,59 (m, 1H); 3,37 (DDD, 1H); 3.24 in (m, 1H); 2,33 (m, 1H); 2,07 (m, 1H); of 1.93 (m, 1H); 1,78-of 1.62 (m, 1H).

Example 65

1-(4-{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carbonyl}piperidine-1-yl)alanon

Connection receive in accordance with the procedure described in example 36, using 1-acetylpiperidine-4-carboxylic acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12). Pure 1-(4-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carbonyl}piperidine-1-yl)Etalon obtained after purification of the crude product flash chromatography (silica gel, eluent:

DHM/MeOH/NH4OH 98/2/0,2).

Yield: 57% (sticky solid yellow); [α]D20=+88,3° (c=2,23, CHCl3); IHMS (Tr): 6,5 min (method A); MS (ES+) m/z: 401,2.

1H-NMR (CDCl3+D2O, 330 K, 300 MHz), δ (ppm): of 8.06 (DD, 2H); to 7.15 (DD, 2H); 4,68-to 3.73 (m, 5H); 3,65-of 2.97 (m, 3H); 2,80 (m, 2H); to 2.29 (m, 1H); 2,13-of 1.56 (m, 10H).

Example 66

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}thiophene-3-ylmethanol

Soedineniya in accordance with the methodology described in example 36, using thiophene-3-carboxylic acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12). Net {(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}thiophene-3-ylmethanol obtained after purification of the crude product flash chromatography (silica gel, eluent: DHM/MeOH of 99.5/0.5 to).

Yield: 57% (gummy solid); [α]D20=+79,8° (c=0,9, CHCl3); IHMS (Tr): 7,19 min (method A); MS (ES+) m/z: 358,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 8,07 (DD, 2H); rate of 7.54 (DD, 1H); 7,34 (DD, 1H); 7,20 (DD, 1H); to 7.15 (DD, 2H); 4.53-in (m, 1H); 4,11 (m, 1H); 3,51 (DD, 1H); 3,32-3,19 (m, 2H); 2,35 (m, 1H); 2,09-to 1.87 (m, 2H); 1.77 in-to 1.61 (m, 1H).

Example 67

{(S)-3-[3-(4-Forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-imidazol-1-ylphenyl)metano

Connection receive in accordance with the procedure described in example 36 using 4-(1H-imidazol-1-yl)benzoic acid as the selected acid and hydrochlorideS-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine (obtained in accordance with the method of example 12). Net {(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-imidazol-1-ylphenyl)methanon obtained after purification of the crude product flash chromatography (silica gel, eluent: DHM/MeOH/NH4OH 98,5/1,5/0,15).

Yield: 64% (solid no white substance); [α]D20 =+125,7° (c=1,707, CHCl3); IHMS (Tr): 6,66 min (method A); MS (ES+) m/z: 418,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): 8,19 (USM, 1H); 8,07 (DD, 2H); to 7.59 (d, 2H); 7,49 (d, 2H); 7,32 (m, 2H); 7,16 (DD, 2H); was 4.42 (m, 1H); 3,99 (m, 1H); 3,59 (DD, 1H); 3,39-is 3.21 (m, 2H); of 2.36 (m, 1H); 2,14-1,90 (m, 2H); 1,72 (m, 1H).

Example 68

(4-Forfinal)-[3-(5-phenyltetrazol-2-yl)piperidine-1-yl]metano

68(A). (4-Forfinal)-(3-hydroxypiperidine-1-yl)methanon

A mixture of 3-hydroxypiperidine (0.6 g, to 5.93 mmol), 4-fermenting acid (0,83 g, to 5.93 mmol), HOBT (0.8 g, to 5.93 mmol), EDCI·HCl (1.7 g, 8.9 mmol) and dry triethylamine (of 1.66 ml, up 11,86 mmol) in dry dichloromethane (30 ml) is stirred overnight at ambient temperature under nitrogen atmosphere. Then add 1 N. HCl (30 ml) and the phases are separated. The organic layer was washed with 1 N. HCl (30 ml), 1 N. NaOH (30 ml × 2), then water (30 ml). Evaporation of the organic solvent leads to the production of (4-forfinal)-(3-hydroxypiperidine-1-yl)methanone in the form of a white oil (0.7 g).

Yield: 53%; IHMS (Tr): 5,49 min (method A); MS (ES+) m/z: 224,1.

1H-NMR (CDCl3, 300 MHz), δ (ppm): the 7.43 (DD, 2H); was 7.08 (DD, 2H); 3,83 (m, 1H); to 3.73 (m, 1H); of 3.56 (m, 1H); 3.43 points (m, 2H); 1,99-to 1.79 (m, 2H); 1,74-of 1.42 (m, 2H).

68(B). (4-Forfinal)-[3-(5-phenyltetrazol-2-yl)piperidine-1-yl]metano

To a solution of (4-forfinal)-(3-hydroxypiperidine-1-yl)methanone (0.2 g, 0.89 mmol) in dry tetrahydrofuran (8 ml) under nitrogen atmosphere in one portion at 0°C, add triphenylphosphine 0,235 g, 0.89 mmol). To the reaction mixture is added dropwise diisopropylethylamine (DIAD, 175 μl, 0.89 mmol), maintaining the temperature of the reaction mixture at 0°C. the Reaction mixture was allow to warm to room temperature and the mixture is stirred at room temperature for 24 hours. Then at 0°C. to the mixture is added triphenylphosphine (amount of 0.118 g, 0.45 mmol) and diisopropylethylamine (DIAD, 87 μl, 0.45 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent is evaporated under reduced pressure, obtaining a yellow oil, which was purified flash chromatography (silica gel, eluent: hexane/ethyl acetate 6/4). Pure (4-forfinal)-[3-(5-phenyltetrazol-2-yl)piperidine-1-yl]metano receive in the form of a thick oil (132 mg). Yield: 42%; IHMS (Tr):? 7.04 baby mortality min (method A); MS (ES+) m/z: 352,1.

1H-NMR (CDCl3, 300 MHz, 323 K), δ (ppm): to 8.12 (DD, 2H); 7,55-to 7.35 (m, 5H); 7,07 (DD, 2H); of 4.90 (m, 1H); 4,50 (m, 1H); 4,33 at 3.69 (m, 3H); to 3.36 (m, 1H); 2.57 m-2,28 (m, 1H); 2,14 is 1.96 (m, 1H); 1,84-of 1.66 (m, 1H).

Example 69

(4-Forfinal)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

69(A). tert-Butyl ether S-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 46(A), based on benzonitrile. tert-Butyl methyl etherS-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)PIP is ridin-1-carboxylic acid obtained as oil beige which is used in the next stage without further purification (yield: 85%).

IHMS (Tr): 7,83 min (method A); MS (ES+) m/z: 330,2.

69(B). The hydrochloride of S-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine

Connection receive in accordance with the procedure described in example 46(B), starting from tert-butyl ether S-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid (Yield: 100%).

69(C). (4-Forfinal)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the procedure described in example 46(S), based on hydrochlorideS-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine and using 4-perbenzoate as selected acylchlorides. Pure (4-forfinal)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano obtained after purification of the crude product by chromatography on a cartridge of silica gel (elution with a gradient hexane/ethyl acetate from 8/2 to 6/4).

Yield: 60% (white solid); TPL=116-118°C; [α]D20=+99,3° (c=0.64 in, CHCl3); IHMS (Tr): 7,21 min (method A); MS (ES+) m/z: 352,2.

1H-NMR (CDCl3, 300 MHz, 323 K), δ (ppm): of 8.06 (m, 2H); 7,54-7,37 (m, 5H); was 7.08 (m, 2H); was 4.42 (m, 1H); 3,99 (m, 1H); to 3.52 (DD, 1H); 3,26 (DDD, 2H); of 2.34 (m, 1H); 2,12-to 1.59 (m, 3H).

Example 70

(3,4-Differenl)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano

Connection receive in accordance with the methodology described in PR is as 46(C), on the basis of the hydrochloride of S-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine and using 3,4-differentiald as selected acylchlorides. Net (3,4-differenl)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano obtained after purification by chromatography using silicagel cartridge (elution with a gradient hexane/ethyl acetate from 8/2 to 6/4).

Yield: 31% (white solid); TPL=149-151°C; [α]D20=+111,7° (c=0,55, CHCl3); IHMS (Tr): 7,33 min (method A); MS (ES+) m/z: 370,2.

1H-NMR (CDCl3, 300 MHz, 323 K), δ (ppm): of 8.06 (DD, 2H); 7,53-7,42 (m, 3H); 7,35-7,11 (m, 3H); 4,36 (m, 1H); 3,93 (m, 1H); 3,57 (DD, 1H); 3.40 in-and 3.16 (m, 2H); 2,33 (m, 1H); 2,14-of 1.56 (m, 3H).

Example 71

(4-Forfinal)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

71(A). tert-Butyl methyl etherS-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid

Connection receive in accordance with the procedure described in example 46(A), from 4-nitrobenzonitrile. Pure tert-butyl ether S-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid get in a solid yellow color and is used in the next stage without further purification (yield: 83%).

IHMS (Tr): to 7.93 min (method A); MS (ES+) m/z: 375,1.

71(B). The hydrochloride of S-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine

Connection get matched with the accordance with the methodology described in example 46(B), starting from tert-butyl ether S-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-carboxylic acid (yield: 100%).

71(C). (4-Forfinal)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 46(S), on the basis of the hydrochloride of S-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine and using 4-perbenzoate as selected acylchlorides. Pure (4-forfinal)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon obtained after purification of the crude product by chromatography using silicagel cartridge (elution with a gradient hexane/ethyl acetate from 8/2 to 6/4).

Yield: 48% (solid yellow); TPL=162-164°C; [α]D20=+111,5° (c=0,59, CHCl3); IHMS (Tr): 7,29 min (method A); MS (ES+) m/z: 397,1.

1H-NMR (CDCl3, 300 MHz, 323 K), δ (ppm): 8,29 (DD, 4H); the 7.43 (DD, 2H); 7,10 (DD, 2H); 4,47 (m, 1H); 3,98 (m, 1H); of 3.54 (DD, 1H); 3,37-3,19 (m, 2H); of 2.36 (m, 1H); 2,11-of 1.57 (m, 3H).

Example 72

(3,4-Differenl)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}metano

Connection receive in accordance with the procedure described in example 46(S), on the basis of the hydrochloride of S-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine and using 3,4-differentiald as selected acylchlorides. Net (3,4-deltorphin the l)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon obtained after purification of the crude product by chromatography using silicagel cartridge (elution with a gradient hexane/ethyl acetate from 8/2 to 6/4).

Yield: 44% (solid yellow); TPL=138-140°C; [α]D20=+to 112.4° (c=0,50, CHCl3); IHMS (Tr): 7,39 min (method A); MS (ES+) m/z: 415,1.

1H-NMR (CDCl3, 300 MHz, 328 K), δ (ppm): scored 8.38-8,19 (m, 4H); 7,35-7,10 (m, 3H); to 4.41 (m, 1H); to 3.92 (m, 1H); to 3.58 (DD, 1H); of 3.32 (m, 2H); 2,48-to 1.59 (m, 4H).

PHARMACOLOGY

The compounds presented in this invention are positive allosteric modulators of mGluR5. By themselves, these compounds do not exhibit binding orthotricyclen site recognition glutamate and do not activate mGluR5. But in the presence of compounds of the formula I increases response mGluR5

the concentration of glutamate or mGluR5 agonist. It is expected that the compounds of formula I have an impact on mGluR5 due to their ability to expand the function of the receptor.

Example

The study of mGluR5 binding to the membrane preparation of rat brain

The activity of compounds of the invention are examined in accordance with the method of radioligand binding using cortical membranes rats and labeled with radioactive tritium 2-methyl-6-(phenylethynyl)pyridine ([3H]-MPEP) as a ligand according to methods similar to those described in the publications: Gasparini et al. (2002) Bioorg. Med. Chem. Lett 12: 407-409; Anderson et al. (2002) J. Pharmacol. Exp. Ther. 303:1044-1051.

Membrane drug

Cortical layers are excised from the brain of rats Sprague-Dawley(Charles River Laboratories, L Arbresle, France) weighing 200-300 g of Tissue homogenized in 10 volumes (about./wt.) ice-cold 50 mm HEPES-NaOH (pH 7.4) using a grinder transmitter station (Kinematica AG, Luzern, Switzerland) and centrifuged for 30 minutes at 40,000×g (4°C). The supernatant discharged and the pellet washed twice by repeated suspendirovanie in 10 volumes of 50 mm HEPES-NaOH. Then the membranes are collected by centrifugation and washed before the end suspendirovanie in 10 volumes of 20 mm HEPES-NaOH (pH 7.4). The protein concentration determined using the Bradford method (Bradford) protein assay Bio-Rad, Reinach, Switzerland) using bovine serum albumin as the standard.

Experiments [3H]-MPEP binding

Membranes are thawed and again suspended in binding buffer containing 20 mm HEPES-NaOH, 3 mm MgCl2, 3 mm CaCl2, 100 mm NaCl (pH 7.4). Comparative studies carried out by incubation for 1 hour at 4°C: 3 nm [3H]-MPEP (39 Ci/mmol, Tocris, Cookson Ltd, Bristol, UK), 50 μg of membranes and compounds with a concentration in the range from 0.003 nm to 30 μm in a total volume of 300 μl. Non-specific binding determine using 30 μm MPEP. The reaction is complete by rapid filtration through filter plates are made of fiberglass (96-well filter microplates Unifilter GF/B, Perkin-Elmer, Schwerzenbach, Switzerland) using 4×400 μl of ice-cold buffer and cell harvester (Filtermate, erkin-Elmer, Downers Grove, USA). Radioactivity determine liquid scintillation spectrometry using a tablet reader for reading 96-well microplates (TopCount, Perkin-Elmer, Downers Grove, USA).

Data analysis

Curves of inhibition obtained using the software GraphPad Prism (Graph Pad Software Inc, San Diego, USA). IC50identify at least three independent experiments using non-linear regression analysis curves for 8-point concentration response.

Compounds of the present invention have the ability to inhibit [3H]-MPEP binding in cortical membranes of rats with IC50less than about 100 microns, less than about 30 microns and 10 microns, preferably less than about 3 microns.

The example In

When the exposure growth factors (primary growth factor of the fibroblast) culturebound rat astrocytes Express group I-Gq mGluR related transcripts, namely mGluR5, but not split options mGluR1, and the result is a functional expression of mGluR5 receptors. (Miller et al. (1995) J. Neurosci. 15:6103-9). Stimulation of mGluR5 receptor selective agonist CHPG and complete blockade of hydrolysis of glutamate-induced phosphoinositide (PI) and sequential intracellular mobilization of calcium specific antagonist as MRER poduridae unique expression mluR5 receptors in this preparation.

This drug is produced and used to evaluate properties of the compounds of the present invention to enhance the mobilization of CA2+induced by glutamate, without showing any significant activity when applied in the absence of glutamate.

Primary cultures of cortical astrocytes

Primary glial cultures prepared from cerebral cortex of embryos of rats Sprague-Dawley age 15 days using the modified methods described in the publications: Mc Carthy and de Vellis (1980) J. Cell Biol. 85:890-902; Miller et al. (1995) J. Neurosci. 15(9):6103-9. The cerebral cortex excised and then grind in a sterile buffer containing are 5.36 mm KCl, 0.44 mm NaHCO3, to 4.17 mm KH2PO4, 137 mm NaCl, 0,34 mm NaH2PO41 g/l glucose. The obtained cell homogenate is transferred into Kzt75 flasks pre-coated with poly-D-lysine ((BIOCOAT, Becton Dickinson Biosciences, Erembodegem, Belgium), as modified by the method of Dulbecco Wednesday Needle (D-MEM GlutaMAX™ I, Invitrogen, Basel, Switzerland), superherofan 25 mm HEPES and 22.7 mm NaHCO3and equipped with 4.5 g/l glucose, 1 mm pyruvate and 15% fetal calf serum (FCS, Invitrogen, Basel, Switzerland), Penicillinum and streptomycin, and incubated at 37°C With 5% CO2. For subsequent sowing the FCS content is reduced to 10%. After 12 days, the cells are placed using trypsinization 384-well microplates coated with poly-D-what sinom, at a density of 20,000 cells per well, in superyoung culture, equipped with 5 ng/ml β-FGF (basic growth factor fibroblast) (Invitrogen, Basel, Switzerland) and 10 ng/ml EGF (epidermal growth factor) (Invitrogen, Basel, Switzerland).

Research Sa2+mobilization using cortical astrocytes of the rat

After incubation for 2 days, the cells are washed with normal buffer containing 142 mm NaCl, 6 mm KCl, 1 mm Mg2SO4, 1 mm CaCl2, 20 mm HEPES, 1 g/l glucose, 0.125 mm sulfinpirazon (pH of 7.4). After 60 minutes after the addition of 4 μm Fluo-4 (TefLabs, Austin, TX) cells washed three times with 50 μl of PBS buffer and again suspended in 45 ál of the experimental buffer. Then, the microplate is transferred into a tablet reader Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, CA) to assess the intracellular flow of calcium. After monitoring fluorescence for 15 seconds to determine background levels DMSO solutions containing compounds of the present invention in various concentrations, diluted experienced buffer (15 μl 4× dilution), add on the microplate with cells in the absence or in the presence of 1 μm glutamate: used concentration of 1 μm glutamate, which gives 20% of the maximum response to glutamate (EU20in such experimental conditions in accordance with literature data, is the concentration used is for my discovery of the properties of positive allosteric modulators of the compounds of the present invention. The final DMSO concentration in the experience is 0.3%. After that, in each experiment monitoring the fluorescence as a function of time for 3 minutes and the resulting data analyzed using Microsoft Excel and GraphPad Prism. Each data point is determined by two times.

Data analysis

Curve "concentration-response" is represented by compounds of the present invention in the presence of EU20glutamate is obtained using the software GraphPad Prism (Graph Pad Software Lac, San Diego, USA). The curves correspond to the logistic equation with four parameters (Y=Bottom + (Top-Bottom)/(l+10^((LogEC50-X)*HillSlope), allowing to determine the values of the EU50. Each curve is obtained using a three-fold experiment for each data point at 8 concentrations.

The data presented in figure 1 show the ability of the compounds of examples 12, 55 and 56 at a concentration of 3 μm to increase the stimulation induced by 1 μm of glutamate in primary cortical mGluR5-expressing cell culture. The compounds of examples 12, 55 and 56 do not have statistically significant agonistic activity when tested in the absence of glutamate, as shown by comparison with the value obtained for the buffer.

Each bar chart represents the mean and standard error of the points obtained in the triple experiment, and t is aetsa representative indicator of three independent experiments.

The data presented in figure 1 show the increase in the mobilization of CA2+induced by 1 μm of glutamate in the culture of rat astrocytes in the presence of 3 μm of the compounds of examples 12, 55 and 56 of the present invention.

The results obtained in example a and example, show that the compounds described in this invention, as such, have no effect on mGluR5. However, adding connections together with the mGluR5 agonist, such as glutamate or CHPG, the effect is greatly increased in comparison with the effect of one agonist in the same concentration. In addition, the compounds of the present invention have the ability to inhibit the binding of mGluR5 negative allosteric modulator at the cortical membrane preparation of rat, property, previously described for 3,3'-diftorbenzofenon (DFB), another mGluR5 positive allosteric modulator (O'brien J.A. et al. (2003) Mol. Pharmacol. 64:731-40). In addition, the DFB is not able to inhibit the binding of [3H]-hiquality with orthotricyclen glutamic site (O'brien J.A. et al. (2003) Mol. Pharmacol. 64:731-40). These data show that the compounds of the present invention are positive allosteric modulator of mGluR5 receptor when tested in natural product and do not show binding orthotricyclen the binding site of the receptor.

Thus, it is expected that the good allosteric modulators, provided by the present invention increase the efficiency of glutamate or mGluR5 agonists at the mGluR5 receptor. Therefore, it is assumed that positive allosteric modulators can be used for the treatment of various neurological and psychiatric disorders associated with glutamate dysfunction, which, as described, be treated in such diseases, as well as for treatment of other disorders that can be treated with such positive allosteric modulators.

Example

Models of schizophrenia in animals

Phencyclidine (PCP) model of schizophrenia:PCP-induced increase in locomotor movements are a widely used model of schizophrenia in animals. This model is based on the fact that phencyclidine induces schizophrenia-like psychosis syndrome in humans, including patients with increased motor activity, impaired cognitive function and impairment of working memory (Steinpreis RE (1996) Behav Br Res. 74:45-55; Abi-Saab et al. (1998) Pharmacopsychiatry, 31:104-109). It was further shown that antipsychotic drugs are effective in the treatment of schizophrenia, reduced locomotor activating effect of PCP (Gleason & Shannon (1997) Psychopharmacology, 129:79-84). These results indicate that locomotor activation caused by PCP, is a model applicable for screening soybean is ineni, potentially useful for the treatment of schizophrenia.

Amphetamine model of schizophrenia:The amphetamine-induced increase in locomotor movement is well known and widely used as a model of the positive symptoms of schizophrenia. This model is based on the fact that amphetamine increases motor activity and can cause a psychotic state in humans (Yui et al. (2000) Ann NY Acad Sci 914:1-12). Further, it is well known that amphetamine-induced increase in locomotor activity are blocked by antipsychotic drugs, which are effective in the treatment of schizophrenia (Arnt (1995) Eur J Pharmacol 283:55-62). These data show that the locomotor activation induced by amphetamine, is a model applicable for screening of compounds potentially useful for the treatment of schizophrenia.

Subject:These studies are carried out in accordance with the rules of detention and the use of animals Addex Pharmaceuticals and the laws and directives of the government of Switzerland on the content and use of animals. Male mice C57BL6/J (20-30 g) age 7 weeks contain a group under controlled temperature and humidity with a 12-hour cycle of light/dark for at least 7 days before use. Mice had access to food and water, optionally with the exception of time of experiments studies aniu locomotor activity.

Assessment of locomotor (movement) activities: Study on the effects of compounds on PCP or amphetamine-induced locomotor activation carried out on mice. Locomotor activity of the mice study, placing them in a white plastic box with a size of 35 cm × 35 cm in height with a wall 40 see Locomotor activity (movement) control through surveillance system (VideoTrack, Viewpoint, Champagne au Mont d'or, France), which records the movements of mice. Mouse not afraid of the equipment before testing. In the days of the test compounds (10, 30, 50, or 100 mg/kg (IPR)or carrier injected for 120 minutes before the injection of PCP (5 mg/kg subcutaneously), amphetamine (3.0 mg/kg subcutaneously) or saline. Mice are placed in boxes to monitor locomotor activity immediately after the injection of PCP, amphetamine or saline, and their locomotor activity, defined as they traveled distance, expressed in centimeters (cm), fixed for 60 minutes.

Introduction connections: Compounds prepared in the form of microsuspension in sterile water (60% of final volume) and Labrafil M1944 CS (apricot kernel oil - Gattefosse, Saint Priest, France) (40% of final volume) and injected in a volume of 10 ml/kg to Mice, which as medicine get media injected with equivalent volume of a solution of native parenteral the (I.P. Pavlova.) without adding connections. The PCP hydrochloride (Sigma, Switzerland) dissolved in saline and injected at a dose of 5 mg/kg subcutaneously in a volume of 10 ml/kg to Mice treated with PCP, which as medicine get media subcutaneously injected with equal volume of saline media. Sulfate, D-amphetamine (Amino AG, Neuenhof, Switzerland) dissolved in saline and injected at a dose of 3.0 mg/kg subcutaneously in a volume of 10 ml/kg to Mice treated with D-amphetamine, which as medicine get media subcutaneously injected with equivalent volume of saline media.

Statistical analysisStatistical analysis performed using the software statistical analysis GraphPad PRISM (GraphPad, San Diego, CA, USA). Data analyzed using analysis of variants in a single pass (one-way analysis (ANOVA) with subsequent post-hoc, Bonferroni-corrected multiple comparisons (post-hoc Bonferroni-corrected multiple comparisons)when it comes to. The accepted level of significance p<0,05.

The effect of compounds on PCP-induced locomotor activity of mice

The results obtained in the above experiment using typical compounds of the present invention, is presented in figure 2.

The data presented in figure 2 show that the typical connection of the present invention significantly reduces ascending is the growth of motor activity, induced by PCP (f=13,39, df=(2,45), n=16/group)at a dose of 100 mg/kg I.P.

The effect of compounds on amphetamine-induced locomotor activity of mice

The results obtained in the above experiment using typical compounds of the present invention, is presented in figure 3.

The data presented in figure 3 show that the typical connection of the present invention reduces the increase in locomotor activity induced by amphetamine (f=13,04, df=(4,82), n=8-33 mice per group)at doses of 50 and 100 mg/kg I.P.

A brief discussion of the test results in vivo

The above data show that the typical compounds of formula I significantly reduce hyperlocomotion effects of PCP and amphetamine - two widespread models of schizophrenia in animals. These results conrm the potential of the compounds of formula I in the treatment of schizophrenia and related disorders.

Compounds of the present invention are allosteric modulators of mGluR5 receptors, they can be used for the production of medicines, particularly for the prevention or treatment of disorders of the Central nervous system, as well as other disorders modulated by this receptor.

Compounds of the present invention can be administered by themselves or in combination with other pharmaceutical Lakers the governmental funds, effective for the treatment of the conditions listed above.

Examples of drugs

Typical examples of the compounds of preparations of the compounds of the present invention are the following songs:

1) Tablets

The compound of example 12From 5 to 50 mg
Phosphate calcium20 mg
Lactose30 mg
Talc10 mg
Magnesium stearate5 mg
Potato starchup to 200 mg

In this example, the compound of example 12 can be replaced by any compound described examples 1 through 72, taken in the same amount.

2) Suspension:

For oral administration are prepared in aqueous suspension, in which each 1 ml contains from 1 to 5 mg of one of the compounds described examples, 50 mg of sodium carboxymethyl cellulose, 1 mg sodium benzoate, 50 mg of sorbitol and water up to 1 ml

3) Preparation for injection

The composition for parenteral administration is prepared by mixing a 1.5% (wt.) the active ingredient of the present invention with 10% (vol.) Rast is or propylene glycol and water.

4) Ointment

The compound of example 12From 5 to 1000 mg
Stearyl alcohol3 g
Lanolin5 g
White petrolatum15 g
Waterto 100 g

In this example, the compound of example 12 can be replaced by the same quantity of any of the compounds described in examples 1 through 72.

Reasonable modifications should not be considered separately from the scope of the present invention. Thus, a qualified specialist is clear that the described invention may be modified without separating those changes from the scope of this invention.

1. The compound of General formula I

where W represents a 6-membered geteroseksualnoe ring with 1-2 heteroatoms, selected from N, O;
R1and R2independently represent hydrogen, C1-C6-alkyl;
P and Q each independently selected from
,,,,
R3, R4, R 5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
But atenil, -C(=O)NR8or a group of the formula

R3takes the values defined above;
Represents a-C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-;
or pharmaceutically acceptable salts of such compounds,
with the exception of the following compounds:
4-(3-phenyloxazol-5-yl)-N-(4-bromophenyl)aminocarbonylmethyl;
N-benzoyl-3-(3,4-dimethoxyphenylacetone)piperidine-4-one;
N-(3-cyanobenzeneboronic)-4-(3-(2,3-dichlorophenyl)Pirat-5-yl)piperidine.

2. Connect the s according to claim 1 of formula I-A

where R1and R2independently represent hydrogen, C1-C6-alkyl;
P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
But atenil, -C(=O)NR8or a group of the formula

R3takes the values defined above;
Represents a-C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6or pharmaceutically acceptable salts of such compounds.

3. The compound according to claim 1 or 2, formula I-B

where R1and R2independently represent hydrogen, C1-C6-alkyl;
P and Q, each independently, chosen from:
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H in P and Q independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
D, E and G And independently take the meaning as defined in claim 1;
Represents a-C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-;
or pharmaceutically acceptable salt that is wow connection.

4. The compound according to claim 1 or 2, formula I-C

where R1and R2independently represent hydrogen, C1-C6-alkyl;
P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
Represents a-C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-;
or pharmaceutically acceptable salts of such compounds.

5. The compound according to claim 1 or 2, formula I-D

where P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
or pharmaceutically acceptable salts of such compounds.

6. The compound according to claim 1 or 2 of formula I-E

where P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1 -C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
or pharmaceutically acceptable salts of such compounds.

7. The compound according to claim 1 or 2 of formula I-F

where P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
or pharmaceutically acceptable salts of such compounds.

8. The compound according to claim 1 of formula I-G

where R1and R2independently represent hydrogen, C1-C6-alkyl;
P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
But atenil, -C(=O)NR8and is a group of the formula

R3takes the values defined above;
Represents a-C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-;
J represents-O - or-N(R11);
R11represents hydrogen, C1-C6-alkyl;
or pharmaceutically acceptable salts of such compounds.

9. The compound according to claim 1 or 8 of the formula I-H

where R1and R2independently represent hydrogen, C1-C6-alkyl;
P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR7; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected is N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H in P and Q independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
D, E and G And independently take the meaning as defined in claim 1;
Represents a-C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-;
J represents-O - or-N(R11)-;
R11represents hydrogen, C1-C6-alkyl;
or pharmaceutically acceptable salts of such compounds.

10. The compound according to claim 1 or 8 of the formula I-I

where R1and R2independently represent hydrogen, C1-C6-alkyl;
P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic arilje the second or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
Represents a-C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6alkenyl-;
J represents-O - or-N(R11)-;
R11represents hydrogen, C1-C6-alkyl;
or pharmaceutically acceptable salts of such compounds.

11. The compound according to claim 1 or 8 of the formula I-J

where P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H is ezavisimo represent-C(R 3)=, -O-, -N=, -N(R3)- or-S-;
J represents-O - or-N(R11)-;
R11represents hydrogen, C1-C6-alkyl;
or pharmaceutically acceptable salts of such compounds.

12. The compound according to claim 1 or 8 of the formula I-K

where P and Q each independently selected from
,,,,
where R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
J represents-O - or-N(R11)-;
R11represents hydrogen, C1-C6-alkyl;
or pharmaceutically acceptable salt is such a connection.

13. The compound according to claim 1 or 8 of the formula I-L

where P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
J represents-O - or-N(R11)-;
R11represents hydrogen, C1-C6-alkyl;
or pharmaceutically acceptable salts of such compounds.

14. The compound according to claim 1 or 8 of the formula I-M

where P and Q each independently selected from
,, ,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
J represents-O - or-N(R11)-;
R11represents hydrogen, C1-C6-alkyl;
or pharmaceutically acceptable salts of such compounds.

15. The compound according to claim 1 or 8 of the formula I-N

where P and Q each independently selected from
,,,,
R3, R4, R5, R6and R7independently represent hydrogen; halogen; -CN; nitro; C1-C6alkyl; With3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms; 6-membered heterocycle with 2 heteroatoms, represents N, O; phenyl, optionally substituted with halogen; naphthyl; OR8; where optionally two Deputy together with in between the atoms form a 9-10-membered bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S;
R8represents hydrogen, C1-C6-alkyl;
D, E, F, G and H independently represent-C(R3)=, -O-, -N=, -N(R3)- or-S-;
J represents-O - or-N(R11)-;
R11represents hydrogen, C1-C6-alkyl;
or pharmaceutically acceptable salts of such compounds.

16. The compound according to claim 1, which can exist as optical isomers, where the specified compound is a racemic mixture or the individual optical isomers.

17. The compound according to claim 1, where the said compound is selected from the group including
(4-forfinal)-[3-(4-perforating)piperidine-1-yl]metano;
(4-forfinal)-{3-[5-(4-forfinal)-4H-[1,2,4]triazole-3-yl]piperidine-1-yl}meanon;
(S)-(4-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(S)-(thiophene-2-yl)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]shall xavator-5-yl]piperidine-1-yl}-(4-methyl-2-pyrazin-2-iltiazem-5-yl)methanon;
(2,4-differenl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(3,4,5-tryptophanyl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-pyridin-2-althofen-2-yl)methanon;
cyclopentyl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(3,4-differenl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
benzothiazol-6-yl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(3,5-dimethylisoxazol-4-yl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(4-forfinal)-{(S)-3-[3-(2,4,6-tryptophanyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(4-forfinal)-[(S)-3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
(4-forfinal)-[(S)-3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
{(S)-3-[3-(2,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-forfinal)methanon;
(4-forfinal)-[(S)-3-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
(4-forfinal)-{(S)-3-[3-(2-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(4-forfinal)-[(S)-3-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
(4-forfinal)-{S-3-[5-(4-forfinal)-[1,3,4]oxadiazol-2-yl]piperidine-1-yl}meanon;
(2-forfinal)-{(S)-3-[2-(3,4-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(4-forfinal)-{2-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]morpholine-yl}meanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}thiophene-3-ylmethanone;
(4-forfinal)-[3-(5-phenyltetrazol-2-yl)piperidine-1-yl]metano;
(4-forfinal)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
(3,4-differenl)-[(S)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano.

18. The compound according to claim 1, where the said compound is selected from the group including
{3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}phenylmethanone;
{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}phenylmethanone;
(4-forfinal)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
(3-forfinal)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
(4-forfinal)-{3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(3-forfinal)-{3-[3-(3-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(4-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(3-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(R)-(4-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(4-forfinal)-{3-[5-(4-forfinal)-[1,2,4]oxadiazol-3-yl]piperidine-1-yl)methanon;
(4-forfinal)-{3-[5-(4-forfinal)-4-methyl-4H-[1,2,4]triazole-3-yl]piperidine-1-yl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-phenylthiazol-4-yl)methanon;
{{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-methyl-6-triptorelin-yl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-[1,2,3]thiadiazole-4-yl)methanon;
benzothiazol-2-yl-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-methylisoxazol-3-yl)methanon;
(1,5-dimethyl-1H-pyrazole-3-yl)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-triptoreline)methanon;
4-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-carbonyl}benzonitrile;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}isoxazol-5-ylmethanol;
(3-chloro-4-forfinal)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(2-phenyl-2H-pyrazole-3-yl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl)methanon;
(4-fluoro-3-were)-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(3-methylthiophene-2-yl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(1-methyl-1H-pyrrol-2-yl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}thiazole-2-ylmethanone;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-methylthiazole-5-yl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(6-morpholine-4-espiridion-yl)methanon;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(1H-indol-5-yl)methanon;
2-(4-forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl }Etalon;
3-(4-forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}propane-1-he;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}isoquinoline-3-ylmethanone;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}cinoxacin-6-ylmethanol;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}benzimidazole-6-ylmethanol;
(4-forfinal)-[(S)-3-(3-naphthalene-1-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
{(S)-3-[3-(2,6-differenl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-forfinal)methanon;
(4-forfinal)-{(S)-3-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meanon;
(4-forfinal)-[(S)-3-(3-naphthalene-2-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-yl]metano;
(4-forfinal)-{3-[5-(4-forfinal)-[1,2,4]oxadiazol-3-yl]piperidine-1-yl}meanon;
(4-forfinal)-{3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]-4-methylpiperazin-1-yl}meanon;
(4-forfinal)amide(S)-1-(4-perbenzoic)piperidine-3-carboxylic acid;
(4-forfinal)methylamide(S)-1-(4-perbenzoic)piperidine-3-carboxylic acid;
(E)-3-(4-forfinal)-1-{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}propenone;
{(S)-3-[3-(4-forfinal)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}-(4-imidazol-1-ylphenyl)methanon;
(4-forfinal)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}meta is he;
(3,4-differenl)-{(S)-3-[3-(4-nitrophenyl)-[1,2,4]oxadiazol-5-yl]piperidine-1-yl}mechanon.

19. Compounds according to claim 1, where the said compound is selected from the group including
(4-forfinal)-{(S)-3-[5-(4-forfinal)isoxazol-3-yl]piperidine-1-yl}meanon;
(4-forfinal)-{(S)-3-[5-(4-forfinal)-1H-imidazol-2-yl]piperidine-1-yl}meanon;
(4-forfinal)-{(S)-3-(4-(4-forfinal)-1H-imidazol-1-yl]piperidine-1-yl}meanon;
(4-forfinal)-{(S)-3-(4-(4-forfinal)-1H-pyrazole-1-yl]piperidine-1-yl}meanon;
N-(1-(4-perbenzoic)piperidine-3-yl)-4-perbenzoic;
(2-forfinal)-{3-[2-(4-forfinal)oxazol-5-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[5-(4-forfinal)oxazol-2-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[5-(4-forfinal)thiazol-2-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[2-(4-forfinal)thiazol-5-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[5-(4-forfinal)-[1,3,4]thiadiazole-2-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[5-(4-forfinal)-[1,2,4]oxadiazol-3-yl]piperidine-1-yl}meanon;
(2-forfinal)(3-(5-(4-forfinal)isoxazol-3-yl)piperidine-1-yl)methanon;
(2-forfinal)(3-(5-(4-forfinal)-1H-imidazol-2-yl)piperidine-1-yl)methanon;
(2-forfinal)(3-(4-(4-forfinal)-1H-imidazol-1-yl)piperidine-1-yl)methanon;
(2-forfinal)(3-(4-(4-forfinal)-1H-pyrazole-1-yl)piperidine-1-yl)methanon;
N-(1-(4-perbenzoic)piperidine-3-yl)-2-perbenzoic;
(2-forfinal)-{3-[2-(3,4-differenl)oxazol-5-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[5-(3,4-is afterfeel)oxazol-2-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[5-(3,4-differenl)thiazol-2-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[2-(3,4-differenl)thiazol-5-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[5-(3,4-differenl)-[1,3,4]thiadiazole-2-yl]piperidine-1-yl}meanon;
(2-forfinal)-{3-[5-(3,4-differenl)-[1,2,4]oxadiazol-3-yl]piperidine-1-yl}meanon;
(2-forfinal)(3-(5-(3,4-differenl)isoxazol-3-yl)piperidine-1-yl)methanon;
(2-forfinal)(3-(5-(3,4-differenl)-1H-imidazol-2-yl)piperidine-1-yl)methanon;
(2-forfinal)(3-(4-(3,4-differenl)-1H-imidazol-1-yl)piperidine-1-yl)methanon;
(2-forfinal)(3-(4-(3,4-differenl)-1H-pyrazole-1-yl)piperidine-1-yl)methanon;
N-(1-(3,4-differentail)piperidine-3-yl)-2-perbenzoic.

20. Pharmaceutical composition having the properties of a positive allosteric modulator of mGluR5, comprising a therapeutically effective amount of a compound according to claims 1 to 19 and a pharmaceutically acceptable carriers and/or excipients.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I: , their optical isomers or optical isomer mix, and pharmaceutically acceptable salts, where: R1 is independently selected out of group including: aryl, heteroaryl, arylcarboxyamido, heteroarylcarboxyamido, aryloxy, arylalcoxy or arylamino, and where indicated groups of aryl, aryalkyl or heteroaryl can be substituted by 0-3 substitutes R1a, where R1a is independently selected out of group including: halogen, alkyl, alkenyl, alcoxy, alcoxyalkyl, hydroxyalkyl, mono-, di- or trihalogenoalkyl, mono-, di- or trihalogenoalcoxy, mono- or disubstituted aminoalkyl, aminocarbonyl, mono- or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, etherified carboxylic acid residue, arylcarbonylamino, carbamate, R1b-aryl or R1b-heteroaryl where R1b is H, halogen, OH, amino, mono- or disubstituted amino, mono-, di- or trihalogenoalkyl, alkcoxy, mono-, di- or trihalogenoalcoxy, hydroxyalkyl; R2 is independently selected out of group including: H, OH, cyano, halogen or aryl; optionally R1 and R2 can be linked to form spirocyclyl; R3, R4, R5 and R6 are H; optionally R1 and R3 can be cyclised to form carbocycle; optionally R3 and R4 or R5 and R6 are cyclised to form bicyclic bridge system including ethylene bridge; optionally R3 and R6 are cyclised to form bicyclic bridge system including methylene or ethylene group; R7 and R8 are independently selected out of group including hydrogen, OH, C1-C8alkyl, arylalcoxy, heteroarylalcoxy; optionally R7 and R9 can be cyclised to form spirocarbocycle or spiroheterocycle; and m=0-5; where "aryl" term denotes aromatic carbocyclic groups such as phenyl, biphenyl, indenyl, naphthyl, and aromatic groups condensed with heterocycles; where "heterocycle" term denotes aromatic and non-aromatic rings including 3 to 10 atoms in the ring, 1-4 of which are heteroatom selected out of oxygen, sulfur or nitrogen; where "alkyl" term, when used separately or as suffix, denotes branched or non-branched alkyl group including 1 to 8 carbon atoms in chain; where "alkenyl" term denotes non-saturated branched or non-branched alkyl group including 2 to 12 carbon atoms in chain.

EFFECT: compounds applicable as chemokine receptor activity modulators.

15 cl, 1 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazol derivatives of general formula (I) and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and to based medicinal agent. In general formula (I) , R1 represents 1,4-dioxepanyl or tetrahydropyran-4-yl; R2 represents -N(R)-(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with one-two substitutes chosen from group, consisting of C1-C6alkyl or -NR2, or represents -(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 heteroatoms chosen of N, S or O, optionally substituted with group -(CH2)n-OH, C1-C6alkyl, C1-C6alkoxy, or represents -(CH2)n-5-or 6-merous aromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with the following group: C1-C6alkyl, C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), -CH2N(R)(CH2)2OCH3, -N(R)(CH2)2OCH3, - CH2-morpholinyl or -CH2-pyrrolidinyl or represents (CH2)n-C3-C6cycloalkyl optionally substituted with group hydroxy, or represents -N(R)-C3-C6cycloalkyl optionally substituted with group hydroxy or C1-C6alkyl, or represents phenyl optionally substituted with group C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), C1-C6alkyl, -CH2-pyrrolidine-1-yl, CH2N(R)(CH2)2OCH3 or -CH2-N(R)C(O)-(C1-C6alkyl), or represents 1,4-dioxa-8-azaspiro[4,5]decane, or 2-oxa-5-azabicyclo[2,2,1]heptane, or 1-oxa-8-azaspiro[4,5]decane, or -N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or 2-azabicyclo[2,2,2]octane; R represents hydrogen or C1-C6alkyl; n stands for 0 or 1.

EFFECT: compounds can be applied for treatment and prevention of diseases mediated by adenosine A2A and A1 receptors, eg Alzheimer's disease, some depressions, toxicomania, Parkinson's disease.

8 cl, 3 dwg, 61 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: chemistry.

SUBSTANCE: in compound of formula I , R1 is hydrogen; R2 is phenyl substituted by trifluoromethyl and optionally by other substitute selected out of a group including lower hydroxyl alkyl, lower alkylamino, lower hydroxyl alkylamino, dilower alkylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, pyrrolidino, piperazino, lower alkylpiperazino, morpholino, lower alkoxy, trilfuoro-lower alkoxy, phenyl, pyridyl and halogenyl; R4 is methyl; where 'lower' prefix denotes radical with up to 7 carbon atoms. Also invention concerns pharmaceutical composition and method of treatment, as well as application of the claimed compounds in obtaining pharmaceutical composition.

EFFECT: improved proteinkinase inhibition properties.

9 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

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