Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel heterocyclic compounds of general formula (I) or enantiomers, diastereomers or pharmaceutically acceptable salts thereof, where Y is: phenyl or a heteroaryl selected from thiazolyl, pyridyl, pyrimidinyl, 1,3,5-triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and 1,3,4-thiadiazolyl; wherein the phenyl or heteroaryl is optionally substituted with one substitute selected from fluorine, chlorine, bromine, iodine, C1-4alkyl, trifluoromethyl, C1-4alkoxy, C1-4alkylthio, nitro and cyano; r=1-2; R2 is absent or is an oxo-group; Z is: (a) phenyl substituted with NRaRb; where Ra is: H or C1-4alkyl; where Rb is: C1-4alkyl, cycloalkyl, phenyl, furanylmethyl, or phenyl(C1-2alkyl); and wherein the phenyl or the furanyl are optionally substituted with iodine; alternatively, Ra and Rb are taken together with the nitrogen atom to which they are bonded to form a 5-8 member heterocyclyl, which is optionally condensed to a benzene ring; (b) biphenyl-3-yl or biphenyl-4-yl; where the interior phenyl ring, attached to the carbonyl in formula (I) is optionally substituted with a fluorine atom; and where the terminal phenyl ring is optionally substituted with a substitute selected from trifluoromethyl, C1-4alkoxy, chlorine, dichloro, fluorine, and iodine; (c) phenyl substituted with a substitute selected from C5-8cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbonyl, phenyl(C1-3)alkyl, phenyl(C1-3)alkoxy, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-l,3-dione, 2,3-dihydro-isoindol-2-yl; l-(tert- butoxycarbonyl)piperidin-4-yloxy, and 1-(tert-butoxycarbonyl)piperidin-4-yl; (d) phenyl substituted with 1-2 substitutes independently selected from: C1-6alkyl, C1-4alkoxy, iodine, chlorine and nitro; (e) phenyl(C1-2)alkyl; where the phenyl is optionally substituted with 1 or 2 substitutes independently selected from iodine, fluorine, C1-6alkyl, phenyl and NRcRd; where Rc: H or C1-4alkyl; where Rd is: C1-4alkyl or C1-6cycloalkyl(C1-4)alkyl; and where the C1-2alkyl of phenyl(C1-2)alkyl is optionally substituted with phenyl; (f) phenyl(C2-4)alkenyl; where the phenyl is optionally substituted with a substitute selected from C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethylthio and phenyl; (g) naphthyl; where the naphthyl is optionally substituted with one C1-4alkoxy substitute; (h) fluorenyl or xanthenyl; where the fluorenyl or xanthenyl is optionally substituted with an oxo group; (i) C5-8cycloalkyl; where the C5-8cycloalkyl is optionally substituted with one C1-6alkyl substitute; (j) benzene ring-condensed C5-8cycloalkyl or benzene ring-condensed C5-8cycloalkyl(C1-4)alkyl; where said C5-8cycloalkyl fragment is optionally substituted with 1-4 methyl groups; (k) bicyclo[2.2.2]octyl-1-yl; where the bicyclo[2.2.2]octyl-l-yl is optionally substituted with C1-6alkyl; (1) a heteroaryl or benzene ring-condensed heteroaryl selected from benzooxazolyl, quinolinyl, benzimidazolyl, pyridinyl, indolyl, thienyl, furanyl, pyrazolyl, oxazolyl, benzothienyl and benzofuranyl; where the heteroaryl or benzene ring-condensed heteroaryl is optionally substituted with 1 or 2 substitutes independently selected from C1-4alkyl, trifluoromethyl, C5-8cycloalkyl, phenyl, phenyl(C1-2)alkoxy, phenyl(C2-4)alkynyl and dichlorophenoxy; and where the phenyl substitute in the heteroaryl is further optionally substituted with C1-4alkyl, C1-4alkoxy or trifluoromethyl; (m) l,5-diphenyl-lH-pyrazol-3-yl; where the pyrazol-3-yl is optionally substituted with a methyl group; and where each of the phenyl groups of the 1,5-diphenyl substitutes is also optionally substituted with substitutes selected from chlorine, dichloro or aminosulphonyl; (n) 1,2,3,4-tetrahydroquinolin-6-yl; where the 1,2,3,4-tetrahydroquinolin-6-yl is optionally substituted with phenyl or trifluoromethyl-substituted phenyl; and (o) benzene ring-condensed heterocyclyl(C2-4)alkenyl; where the benzene ring-condensed heterocyclyl is attached to the C2-4alkenyl via the benzene ring; and where benzene ring-condensed heterocyclyl is further optionally substituted with C5-6cycloalkyl; taking into account constraining conditions indicated in claim 1. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of producing said pharmaceutical composition, a method of treating said pathological conditions and use of the compound of formula (I).

EFFECT: obtaining novel heterocyclic compounds having MGL inhibiting activity.

21 cl, 5 tbl, 11 ex

 

CROSS-REFERENCES TO RELATED INVENTIONS

This application claims the priority claimed in provisional patent application U.S. 61/171660 filed April 22, 2009, which is fully included in the present document by reference.

This application relates to provisional application entitled "Heteroaromatic and aromatic piperazineethanesulfonic as inhibitors of monoacylglycerides" (Heteroaromatic and Aromatic Piperazinyl Azetidinyl Amides as Monoacylglycerol Lipase Inhibitors), US provisional application No. 61/171661 filed April 22, 2009

Did THIS STUDY FEDERAL FUNDING

For research and development of the invention described below was not involved Federal funding.

Field of the INVENTION

The present invention relates to new inhibitors of monoacylglycerol (MGL), containing their pharmaceutical compositions and their use for treating, alleviating or preventing disorders associated with the activity of MGL, including mammalian and/or human MGL activity influences the course of the disease, syndrome, or condition.

Background of the INVENTION

Cannabis sativaused as a painkiller for many years. Δ9-THC is the main active ingredientCannabis sativa(hemp) and a�aniston cannabinoid receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Was cloned two cannabinoid receptor associated with G-protein: the cannabinoid receptor type 1 (CB1, Matsuda et al., Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB2, Munro et al., Nature, 1993, 365, 61-5). CB1is expressed in the Central nervous system, particularly in the areas of the brain like the hypothalamus and adjoining the core, as well as in peripheral organs: liver, gastrointestinal tract, pancreas, adipose tissue and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, 2007, 18, 129-140). CB2mainly expressed in immune cells such as monocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134), and, under certain conditions, also in the brain (Benito et al.,Brit J Pharmacol, 2008, 153, 277-285), skeletal (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364, 105-110 and heart (Hajrasouliha et al.,Eur J Pharmacol , 2008, 579, 246-252) muscles. A large number of pharmacological, anatomical and electrophysiological data on the use of synthetic agonists indicates that the increase in the intensity of signals of cannabinoids via CB1/CB2contributes to pain in experiments with acute nociceptive pain and suppresses hyperalgesia and allodynia in models of chronic neuropathic and inflammatory pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60; Guindon et al., Brit J Pharmacol, 2008, 153, 319-334).

The effectiveness of synthetic agonists of cannabinoid receptors �it is well documented. Moreover, studies using antagonists of cannabinoid receptor knock-out mice also confirmed the importance of the system of endocannabinoids as modulators of nociception. Anandamide (AEA) (Devane. et al., Science, 1992, 258, 1946-9) and 2-arachidonoylglycerol (2-AG) (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995, 215, 89-97) are the two main endocannabinoid. AEA hydrolase hydrolyses of amides of fatty acids (FAAH) and 2-AG is hydrolyzed by monoacylglycerol (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). Genetic ablation of FAAH increases the concentration of endogenous AEA and leads to CB1-dependent analgesia in models of acute and inflammatory pain (Lichtman et al., Pain, 2004, 109, 319-27), on what basis we can assume that the endocannabinoid system naturally suppresses nociception (Cravatt et al., J Neurobiol, 2004, 61, 149-60). Unlike the continuous growth of the concentrations of endocannabinoids in mice with an inactive gene FAAH, the use of specific inhibitors of FAAH temporarily increases the concentration of AEA and leads to antinociception in vivo (Kathuria et al., Nat Med, 2003, 9, 76-81). Another indication caused by endocannabinoids antinociceptive tone of the nervous system is the formation of AEA in periaqueductal gray matter known as the pain center, pain after peripheral stimulation (Walker et al., Proc Natl Acad Sci USA, 1999, 96, 12198-2033) and, conversely, in�ukcia of hyperalgesia after administration of antisense RNA CB 1in the spinal cord (Dogrul et al., Pain, 2002, 100, 203-9).

As 2-AG, intravenous injection causes analgesia in tests "OTDELENIE tail" (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90) and hot plate (Lichtman et al., J Pharmacol Exp Ther, 2002, 302, 73-9). On the other hand, it was shown that 2-AG alone is not an analgesic in the test "hot plate", when administered in combination with other 2-monoacylglycerides (i.e. 2-linoleoyl of glycerol and 2-Palmitoyl glycerol) achieved significant analgesia; this phenomenon is known as "effect" (Ben-Shabat et al., Eur J Pharmacol, 1998, 353, 23-31). These 2-monoacylglycerides "environment" is the endogenous lipids that are released in conjunction with 2-AG and potentiating signaling of endocannabinoids, in particular, by inhibiting the decomposition of 2-AG is likely due to competition for the active site on MGL. This suggests that synthetic MGL inhibitors have a similar effect. Indeed, URB602, a relatively weak synthetic inhibitor of MGL, had antinociceptive effects in models of acute inflammation in mice (Comelli et al., Brit J Pharmacol, 2007, 152, 787-794).

Although the use of synthetic cannabinoid agonists have demonstrated that increased cannabinoid signaling has analgesic and anti-inflammatory effects have been difficult to separate put�further the effects of these compounds against unwanted side effects. An alternative approach is to increase the alarm system of endocannabinoids by raising the level of 2-AG, the most common in the Central nervous system (CNS) and gastrointestinal tract of endocannabinoid, which can be achieved by the inhibition of MGL. Thus, MGL inhibitors may be useful for reducing pain, treating inflammation and disorders of the Central nervous system (Di Marzo et al., Curr Pharm Des, 2000, 6, 1361-80; Jhaveri et al., Brit J Pharmacol, 2007, 152, 624-632; McCarberg Bill et al., Amer J Ther, 2007, 14, 475-83), as well as glaucoma and disease States associated with elevated intraocular pressure (Njie, Ya Fatou; He, Fang; Qiao, Xhuanhong; Song, Zhoa-Hui, Exp. Eye Res., 2008, 87(2):106-14).

The SUMMARY of the INVENTION

The present invention relates to the compound of formula (I)

or its enantiomer, diastereoisomer, solvate and pharmaceutically acceptable salts;

Y is a phenyl or heteroaryl from the following group: thiazolyl, pyridyl, pyrimidyl, 1,3,5-triazinyl, benzoxazolyl, benzisoxazole, benzothiazole and 1,3,4-thiadiazolyl;

wherein the phenyl or heteroaryl can be completed with one of the following substituents: fluorine, chlorine, bromine, iodine, C1-4alkyl, trifluoromethyl, C1-4alkoxy, C1-4alkylthio, nitro and cyano group;

r is an integer from 1 to 2;

R2is absent or is f�Xia oxo-group;

Z represents any of the following problems:

(a) phenyl, substituted NRaRb;

where Rarepresents hydrogen or C1-4alkyl; where Rbrepresents C1-4alkyl, cycloalkyl, phenyl, furylmethyl or phenyl(C1-2alkyl); and where the phenyl in the group Rbthe phenyl group of phenyl(C1-2alkyl in Rbor furanyl group furylmethyl in Rbcan be replaced by iodine;

alternatively, Raand Rbcan be connected via the nitrogen atom with the formation of a 5-8-membered heterocyclyl, which in some cases may condense with anthropoi;

(b) biphenyl-3-yl or biphenyl-4-yl; where the internal phenyl ring connected to the carbonyl of a compound of formula (I) may be substituted with one fluorine, and where terminal phenyl ring may be substituted with the following substituents: trifluoromethyl, C1-4alkoxy, chloro, dichloro, fluoro and iodo;

(c) phenyl, substituted by any of the following substituents: C5-8cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbamoyl, phenyl(C1-3)alkyl, phenyl(C1-3)alkoxy, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-1,3-dione, 2,3-dihydroindol-2-yl; 1-(tert-butoxycarbonyl)piperidine-4-yloxy and 1-(tert-butoxycarbonyl)piperidine-4-yl;

(d) phenyl, substituted by one or two independent substituents from shadowshappy: C 1-6alkyl, C1-4alkoxy, iodine, chlorine and the nitro group;

(e) phenyl(C1-2)alkyl, where phenyl may be independently substituted with one or two substituents from the following group: iodine, fluorine, C1-6alkyl, phenyl and NRcRd; where Rcrepresents hydrogen or C1-4alkyl; and where Rdrepresents C1-4alkyl or C3-6cycloalkyl(C1-4)alkyl; and where C1-2alkyl or phenyl(C1-2)alkyl may be substituted by phenyl;

(f) phenyl(C2-4)alkenyl; where phenyl may be substituted with the following substituents: C1-4alkyl, C1-4alkoxy, trifluoromethyl, triptoreline and phenyl;

(g) naphthyl; where the naphthyl may be substituted with one C1-4alkoxy-Deputy;

(h) fluorenyl or xantinol; where fluorenyl or xantinol may be substituted with oxo group;

(i) C5-8cycloalkyl; where C5-8cycloalkyl may be substituted with one C1-6alkyl Deputy;

(j) cycloalkyl C5-8condensed with a benzene ring, or a C5-8cycloalkyl(C1-4)alkyl, is condensed with benzene ring; where the specified C5-8cycloalkyl may be substituted with 1-4 methyl groups;

(k) bicyclo[2.2.2]octyl-1-yl; bicyclo[2.2.2]octyl-1-yl may be substituted C1-6by alkyl;

(l) heteroaryl or heteroaryl, condensed to the benzene ring, represents something of no�perechislennogo: benzoxazolyl, chinoline, benzimidazolyl, pyridinyl, indole, thienyl, furanyl, pyrazolyl, oxazolyl, benzothiazyl and benzofuranyl;

where heteroaryl or heteroaryl, condensed to the benzene ring may independently be substituted with one or two of the following substituents: C1-4alkyl, trifluoromethyl, C5-8cycloalkyl, phenyl, phenyl(C1-2)alkoxy, phenyl(C2-4)alkynyl and dichlorophenoxy; and where the phenyl substituent in the molecule of heteroaryl also may substituted C1-4the alkyl, C1-4alkoxy or trifluoromethyl sulfide;

(m) 1,5-biphenyl-1H-pyrazol-3-yl; pyrazol-3-yl may be substituted substituting methyl group; and when each of the phenyl groups, the substituents 1,5-biphenyl may also be substituted with groups chloro, dichloro or amino-sulfonyl;

(n) 1,2,3,4-tetrahydroquinolin-6-yl; 1,2,3,4-tetrahydroquinolin-6-yl may be substituted by phenyl or triftormetilfullerenov by phenyl; and

(o) heteroaryl (C2-4)alkenyl, condensed with benzene ring; where condensed heteroaromatic structure connected with C2-4alkenyl through the benzene ring; and where heterocyclyl, condensed to the benzene ring may further be substituted C5-6cycloalkyl;

provided that the compound of Formula (I) is not

the compound in which Y represents a 3-methylpyridine-2-yl, r=1, and R2no, a is 4-biphenyl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent and Z is 2-(phenylcarbamoyl)phenyl;

the compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2is absent, and Z is a 4-cyclohexylphenol;

the compound in which Y is pyridin-2-yl, r=1, R2is absent and Z is a 3-cyclohexylcarbodiimide)phenyl;

the compound in which Y represents a 5-cyanopyridine-2-yl, r=1, R2absent and Z is 4-biphenyl;

the compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2absent and Z is 4-biphenyl;

the compound in which Y represents pyrimidine-2-yl, r=2, R2absent and Z is 2-(4-triftormetilfullerenov)vinyl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a 2-phenylphenyl;

the compound in which Y is pyridin-2-yl, r=1, R2absent and Z is 2-phenylethyl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a 2-tert-butylbenzothiazole-6-yl;

the compound in which Y is pyridin-2-yl, r=1, R2absent and Z is 2-(4-methoxyphenyl)benzox�Zol-7-yl

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a 2-cyclohexylbenzothiazole-6-yl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z represents a 1,2-Diisobutyl-1H-indol-5-yl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z represents a 1-methyl-2-propyl-1H-indol-5-yl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a 1-isobutyl-2-phenyl-1H-indol-5-yl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a 1-isobutyl-2-(4-methylphenyl)-1H-indol-5-yl;

the compound in which Y is pyridin-2-yl, r=1, R2absent and Z is 2-(3-methoxyphenyl)benzoxazol-5-yl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a 2-benzylphenol;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a (1R)-1,2,3,4-tetrahydronaphthalen-1-yl

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z represents a (1S)-1-[4-(2-methylpropyl") phenyl]ethyl;

the compound in which Y is pyridin-2-yl, r=1, R2no, � Z represents a (1S)-1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a 2,3-dihydro-1H-indene-2-yl;

the compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is 2,2-biphenylyl; or

the compound in which Y represents a 3-triptoreline, r=1, R2is absent, and Z represents a 1,2,3,4-tetrahydroquinolin-6-yl.

Further, the present invention relates to the use of a compound of formula (I) as specified herein, as of the MGL inhibitor for the treatment, relief or prevention of disorders, diseases, syndrome, or condition-dependent inhibition of MGL.

In addition, the present invention provides methods of treating, alleviating and/or preventing disorders, diseases, syndrome or condition that is affected by the inhibition of MLG, for example, pain, disease, accompanied by pain, inflammation and CNS disorders comprising or consisting in the introduction to the needy in this subject an effective amount of a compound of Formula (I) as described herein.

In addition, the present invention relates to pharmaceutical compositions containing, consisting of, and/or consisting essentially of a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or FA�matemticas acceptable diluent and a compound of Formula (I), or its pharmaceutically acceptable salt.

In the present application is also proposed a technology for the manufacture of a pharmaceutical composition comprising, consisting of and/or consisting mainly of mixing a compound of Formula (I) and pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.

In addition, the present invention relates to the use of a compound of Formula (I) as specified herein for the preparation of medicaments or pharmaceutical compositions for the treatment, relief and/or prevention of a disease, syndrome, condition or violation that is affected by inhibition of MGL, the needy in this subject.

In addition, the present invention provides production methods of the compounds of Formula (I) as described herein and containing pharmaceutical compositions and medicines.

DETAILED description of the INVENTION

The term "alkyl", used alone or to refer the Deputy, denotes a straight or branched carbon chain comprising from 1 to 8 carbon atoms. Thus, the specified number of carbon atoms (e.g., C1-8) denotes the number of carbon atoms in the alkyl group or the alkyl portion of a larger ultilateral for�of estates. In groups of substituents containing multiple alkyl groups such as 2-amino-C1-6alkyl, 2-amino-C1-6alkyl group dialkylamino may be the same or different.

The term "alkoxy" means-O-alkyl group in which the term "alkyl" corresponds to the definition given above.

The terms "alkenyl" and "alkynyl" refers to straight and branched carbon chain containing 2 or more carbon atoms, where Alchemilla chain contains at least one double bond, and akinlua chain contains at least one triple bond. Specialists in this field it is known that the term "vinyl" and "ethenyl" are used interchangeably and are used to indicate the residual group2alkenyl.

The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic hydrocarbon ring comprising from 3 to 14 carbon atoms. Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.

The term "cycloalkyl, condensed with benzene ring" means a 5-8-membered monocyclic cycloalkyl ring fused with benzene ring. The carbon atoms forming cycloalkyl ring can be fully or partially saturated.

The term "heterocyclyl" means neurom�political monocyclic or bicyclic ring system, comprising from 3 to 10 atoms and containing carbon atoms and from 1 to 4 heteroatoms, independently selected from the following group: N, O and S. the term "heterocyclyl" also includes non-aromatic ring comprising 5-7 atoms, of which 1-2 atom - nitrogen atoms, or a non-aromatic ring comprising 5-7 atoms, 0, 1, or 2 of which are nitrogen atoms, and up to 2 atoms represent oxygen atoms or sulfur and at least one atom must be an atom of nitrogen, oxygen, or sulfur; where (optional) the ring contains zero to one unsaturated bonds, and, optionally, when the ring is of 6 or 7 atoms, it contains up to two unsaturated bonds. The carbon atoms constituting the heterocyclic ring can be fully saturated or partially saturated. The definition of "heterocyclyl" also includes two 5-membered monocyclic geteroseksualnoe group, the United a bridged connection with the formation of the bicyclic ring. Such groups are not considered to be fully aromatic and are not defined as heteroaryl groups. If heterocyclyl is bicyclic, both rings heterocyclyl and at least one of the rings contains a member heterocyclic nucleus. Examples of heterocyclic groups include, but are not limited to: pyrrolyl (including 2H-pyrrole, 2-�iraini or 3-pyrrolidyl), pyrrolidinyl, imidazolyl, imidazolidinyl ureido, pyrazolyl, pyrazolidine, piperidine, morpholine, thiomorpholine and piperazinyl. Unless otherwise noted, heterocyclyl attached to its side group at any heteroatom or carbon atom to form a stable structure.

The term "heterocyclyl, condensed with benzene ring" means a 5-7-membered monocyclic heterocyclic ring fused with benzene ring. Heterocyclic ring contains carbon atoms and from 1 to 4 heteroatoms, independently selected from the following group: N, O and S. the carbon Atoms constituting the heterocyclic ring can be fully saturated or partially saturated. Unless otherwise specified condensed with benzene ring heterocyclyl attached to its side group on the carbon atom of the benzene ring.

The term "aryl" refers to unsaturated aromatic monocyclic or bicyclic ring comprising from 6 to 10 carbon atoms. Examples of aryl rings include phenyl and naphthyl.

The term "heteroaryl" refers to aromatic monocyclic or bicyclic ring system containing from 5 to 10 atoms ring members and which contains carbon atoms and from 1 to 4 heteroatoms, independently selected from the group comprising N, O and S. the term "heteroaryl" incl�t 5 - or 6-membered aromatic ring, in which the ring consists of carbon atoms and contains at least one heteroatom. Heteroatoms include nitrogen, oxygen and sulfur. In the case of 5-membered rings, the heteroaryl ring preferably contains one nitrogen atom, oxygen or sulfur and, in addition, up to three additional hydrogen atoms. In the case of 6-membered rings, the heteroaryl ring preferably contains 1 to 3 nitrogen atoms. In the case where the specified 6-membered ring contains three nitrogen atom, two nitrogen atoms are in adjacent positions. If heteroaryl is bicyclic, each ring is present, at least one heteroatom. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Unless otherwise noted, heteroaryl attached to its side group at any heteroatom or carbon atom to form a stable structure.

Unless otherwise indicated, the term "heteroaryl, condensed with a benzene ring", denotes a 5-6-membered monocyclic heteroaryl ring fused with benzene ring. Heteroaryl ring contains carbon atoms and from 1 to 4 heteroatoms, independently selected from the following group: N, O and S. Examples g�tervailing groups optionally condensed benzene rings include indole, isoindolyl, indolinyl, benzofuran, benzothiazyl, indazoles, benzimidazoles, benzothiazoles, benzoxazoles, benzisoxazoles, benzothiadiazoles, benzotriazolyl chinoline, ethenolysis and chinazoline. Unless otherwise noted, heteroaryl, condensed with a benzene ring attached to its side group at any heteroatom or carbon atom to form a stable structure.

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

The term "formyl" refers to a group-C(=O)H.

The term "oxo" refers to a group (=O).

If the term “alkyl” or “aryl” or either of formed from these roots prefixes appears in the name of Deputy (for example, arylalkyl, alkylamino), this implies that all the above specified limits of the terms “alkyl” and “aryl” are derivatives. Indication of the number of carbon atoms (e.g., C1-C6) applies independently to the number of carbon atoms in the alkyl fragment or the alkyl portion of a larger substituent in which name the root of the alkyl is used as a prefix. For the alkyl and alkoxy-substituents specified number of carbon atoms includes all of the independent atoms (ring members, included in the specified range. For example, C1-6alkyl includes individually methyl, ethyl, propyl, butyl, pentyl � hexyl, and their podnominatsii (for example, C1-2, C1-3, C1-4, C1-5,C2-6, C3-6, C4-6, C5-6, C2-5etc).

In relation to substitution groups, the term “independently” refers to situations when there may be more than one residual group, these substituents may be the same or different.

Unless otherwise specified, it is assumed that the definition of any Deputy or variable at a particular position in the molecule does not depend on the corresponding definitions in other parts of the molecule. It is assumed that substituents and substitution scheme compounds of formula (I) can be selected by the person skilled in the art to provide a chemically stable compounds, which are easy to synthesize by known in the field methods and techniques outlined in this document.

In General, the framework used in disclosing the present invention, the standard nomenclature, the first indicates the end portion of the described side chain, it then lists the following functional groups in the direction toward the point of connection of the Deputy. For example, the description of the Deputy C1-C6alkylcarboxylic belongs to the group of the following formula:

The term "R" in stereocentres means that stereocenter has absolutno� R-configuration as defined adopted in the industry; similarly, the term "S" means that stereocenter has an absolute S configuration. Used in this application, the terms "*R" or "*S" in stereocentres are used to indicate that stereocenter has an absolute, but an unknown configuration. Used in the present application, the term "RS" refers to stereocenter, existing in the form of a mixture of R - and S-configurations. Similarly, the terms "*RS" or "*SR" denote stereocenter, existing in the form of a mixture of R - and S-configurations, and having an unknown configuration relative to another of the stereocenter in the molecule.

Compounds containing one stereocenter no symbol stereobase, are a mixture of the two enantiomers. Compounds containing two stereocenter without marks stereobase for both of them, are a mixture of four diastereomers. Compounds with two stereocenters, both of which are marked "RS" and are labeled stereobase, are a two-component mixture, with the appropriate stereochemical characteristics, as shown in the structural formula. Compounds with two stereocenters, both of which are marked "*RS" and are labeled stereobase, are a two-component mixture with unknown stereochemical characteristics. Unmarked stereocenter, UK�specified in the structural formula without indicating stereobase, are a mixture of R - and S-configurations. For the unmarked stereocentres, structural formula of which is given with the notation stereobase, the absolute stereochemical characteristics as depicted formula.

The following abbreviations used in the specification, particularly the Schemes and Examples:

DCC=N,N-dicyclohexylcarbodiimide

Was held=dichloro methane

DIPEA=Diisopropylethylamine

DMF=N,N-Dimethylformamide

DMSO=dimethyl Sulfoxide

EDTA=Ethylendiaminetetraacetic

EtOAc=Oncosmetology ether

h=hours

GATA=O-(7-asiansuite-1-yl)-N,N,N”,N”-tetramethyluronium hexaflurophosphate

Hbtu=O-benzotriazole-1-yl-N,N,N',N'-tetramethylurea hexaflurophosphate

HEPES=4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

HPLC=high performance liquid chromatography

min=minutes

GHSD=Liquid chromatography medium pressure

mjpbk=m-chloroperoxybenzoic acid

PIPES=piperazine-N,N'-bis(2-econsultancy acid)

sec.=seconds

Tea=triethylamine;

THF=tetrahydrofuran;

As used herein, the term "subject" means an animal, preferably a mammal, most preferably human, that is the object of treatment, observation or experiment.

As used herein, the term "terapeuticas� effective amount" means an amount of active substance or medicinal product, causing the biological or medicinal response in a tissue system, animal or human, which achieves the researcher, veterinarian, medical doctor or other health worker. Such reactions may include the relief or partial relief of symptoms be treatment of the disease, syndrome, condition or disorder.

As used herein, the term "composition" means a product, including prescribed components in therapeutically effective amounts, as well as any product that is a direct or indirect result of combining prescribed components in prescribed amounts.

As used herein, the term "treatment", "relief" and the like include, unless otherwise stated, management of subject or patient (preferably mammal, more preferably human) and care to counteract the disease, pathological condition, or disorder and includes the introduction of compounds of the present invention to prevent the onset of symptoms or complications, alleviate the symptoms or complications, or eliminating the disease, pathological condition, or disorder.

As used herein, the term "preventing" and "prevention" includes, unless otherwise specified, (a) a decrease in the frequency of one or more� symptoms; (b) reducing the severity of one or more symptoms; (c) slowing or preventing the development of additional symptoms; and/or (d) slowing down or preventing the development of disorders or pathological conditions.

The person skilled in the art will be understood that in cases where the present invention relates to methods of prevention, a subject in need (i.e. the subject in need of prevention) should be considered any subject or patient (preferably mammal, more preferably human), who feels or who has observed at least one symptom of the disease, disorder or condition, the development of which is necessary to warn. Moreover, in need of prevention, the subject may be a subject (preferably a mammal, more preferably a human), while not showing any symptoms of the disorder, disease or pathological condition requiring warning, but subject, in the opinion of a physician or other healthcare professional, risk of development of a specified disorder, disease or pathological condition. For example, the subject may be at risk of developing a disorder, disease or condition (and therefore to require the prevention or preventive treatment) given its historical� disease, including, without limitation, heredity, predisposition, comorbid disorder or condition, genetic predisposition, and the like.

The term "MGL inhibitor" refers to compounds that interact with MGL significantly reduce or eliminate its catalytic activity, thereby increasing the concentration of its substrate (substrates). The term "adjustable MGL" is used to denote the state-dependent modulation of the MGL enzyme, including state-dependent inhibition of MGL enzyme, such as, pain, and diseases that lead to such pain, inflammation and CNS disorders.

As used herein, the term "influence" or "under the influence" (when talking about the disease, syndrome, condition or disorder that is affected by inhibition of MGL) means, unless otherwise stated, the reduction in the frequency or severity of one or more symptoms or manifestations of the disease, syndrome, condition or disorder is or involves preventing the development of one or more symptoms or manifestations of the disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.

Compounds of Formula (I) useful for use in the methods of treatment, relief and/or prevention� diseases syndromes, conditions or disorders that depend on the inhibition of MGL. Such methods comprise, consist of and/or consist mainly of destination the patient (including animals, mammals and humans) in need of such treatment, alleviation and/or prevention, a therapeutically effective amount of a compound of Formula (I) specified herein, or its enantiomer, diastereoisomer, solvate or pharmaceutically acceptable salt. In particular, the compounds of formula (I) useful for the treatment, mitigation or prevention of pain, diseases, syndromes, conditions or disorders that cause pain, inflammation or disorders of the Central nervous system. In particular, the compounds of Formula (I) specified herein, useful in the treatment, alleviation and/or prevention of inflammatory pain, hypersensitivity inflammatory and/or neuropathic pain. Such treatment, alleviation and/or prevention includes the appointment of a patient requiring treatment, a therapeutically effective amount of a compound of Formula (I) specified herein.

Examples of inflammatory pain include pain caused by disease, condition, syndrome, disorder or disease state, including inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, re�Matigny arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, fights, diseases of the musculoskeletal system, skin diseases, toothache, heartburn, burn, sunburn, snake bite, snake bite, spider bite, insect bites, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis or hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, headache from tension or arachnoiditis.

One type of inflammatory pain is an inflammatory hyperalgesia or hypersensitivity. Examples of inflammatory hyperalgesia include a disease, syndrome, condition, disorder or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal, musculoskeletal diseases, skin diseases, post operative pain, headaches, toothache, burns, sunburn, insect bites, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infections, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact drmatically, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease, ulcerative colitis, urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis, increased sensitivity of the nose, itch, contact dermatitis and/or skin allergies and chronic obstructive pulmonary disease.

In one embodiment, the implementation of the present invention is directed to the treatment, mitigation or prevention of inflammatory visceral hyperalgesia, which is accompanied by increased visceral irritability, consisting wholly or mainly consisting in the introduction to a patient in need of such treatment, a therapeutically effective amount of a compound, salt or solvate of formula (I). Another variant implementation of the present invention relates to a method for treating inflammatory somatic hyperalgesia, which is accompanied by a hypersensitivity to thermal, mechanical or chemical stimuli, which consists in the introduction in need of such treatment to the mammal a therapeutically effective amount of a compound of formula (I), its enantiomer, diastereoisomer, solvate or pharmaceutically acceptable salt.

A further embodiment of the present invention relates to a method for the treatment, mitigation or pre�prevent neuropathic pain. Examples of neuropathic pain include pain caused by disease, syndrome, condition, disorder, or disease state, including cancer, neurological disorders, surgery on the spinal cord and peripheral nerves, brain tumor, traumatic brain injury (TBI), spinal cord injury, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, Central pain, neuropathy associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (als), Parkinson's disease, multiple sclerosis, inflammation of the sciatic nerve, mandibular joint neuralgia, peripheral neuritis, polyneuritis, pain after amputation, phantom pain in limbs, fractures, neuropathic pain in the mouth, pain, Charcot, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, paresthetic sciatica, syndrome burning mouth, optic neuritis, postpuberty neuritis, migrating neuritis, segmental neuritis, neuritis Gombo, the neurons, cervicobrachial neuralgia, cranial neuralgia, neuralgia of the knee, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, neural�Oia breast, neuralgia Morton, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, neuralgia of Slader, sphenopalatine neuralgia node, supraorbital neuralgia, trigeminal neuralgia, vulvodynia or neuralgia of Widiana.

One type of neuropathic pain is a neuropathic cold allodynia, which is characterized by the presence associated with neuropathy allogennogo condition with hypersensitivity to cold stimuli. Examples of neuropathic cold include the degree allodynia caused by disease, condition, syndrome, disorder, or pain state including neuropathic pain (neuralgia), pain after surgery on the spinal cord and the peripheral nerves or their injury, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, Central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and radiculopathy.

In another embodiment the present invention relates to a method for treating, alleviating and/or preventing neuropathic cold the degree with hypersensitivity to cold stimuli, comprising, consisting�him of and/or consisting mainly of prescribing to the patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) specified herein, or its enantiomer, diastereoisomer, solvate or pharmaceutically acceptable salt.

A further embodiment of the present invention relates to a method for the treatment, mitigation or prevention of disorders of the Central nervous system. Examples of disorders of the Central nervous system include anxiety, such as social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute stress, anxiety disorder caused by separation, and generalized anxiety disorder, and depression, such as major depression, bipolar disorder, winter depression, postpartum depression, manic depression and bipolar depression.

The present invention relates to the compound of formula (I)

or its enantiomer, diastereoisomer, solvate or pharmaceutically acceptable salt (I), suitable for the treatment, alleviation and/or prevention of a disease, syndrome, condition or disturbance-dependent inhibition of MGL.

In one embodiment the present invention relates to any single compound or subset of compounds repre�avicennia examples listed in Tables 1-2 below, or its enantiomers, diastereomers, solvates or pharmaceutically acceptable salts. Additional embodiments of the present invention include compounds of Formula (I) as described herein, or their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein the substituents are selected one or more of these variables (e.g., Y, r, R2, Z, etc.) are independent substituents, or any subset of substituents selected from the full list defined herein. Additional embodiments of the present invention include compounds of Formula (I) as described herein, or their enantiomers, diastereomers, solvates, or pharmaceutically acceptable salt of one or more of the above variables (e.g., Y, r, R2, Z, etc.) - separate independent substituents, or a subgroup of the substituents listed in the lists of Tables 1-2 below.

Representative compounds of Formula (I) of the present invention, as described in this document are listed in Tables 1 and 2 below.

no
Table 1
Examples of compounds of formula (I)
Conn. No.YrR2Z
1pyrid-2-yl1no4-(N-methyl-N-cyclohexylamino) phenyl
2pyrimidine-2-yl1no4-(pyrrolidin-1-yl) phenyl
3pyrid-2-yl1no4-(1-azepane) phenyl
4pyrimidine-2-yl1no4-(3-triptoreline) phenyl
5pyrimidine-2-yl1no4-(4-methoxyphenyl) phenyl
6- thiazol-2-yl1no4-cyclohexylphenol
7 pyrimidine-2-yl1no4-(N-(2-jogbani) amino)phenyl
8pyrimidine-2-yl1no4-(2-chlorophenyl) phenyl
9pyrimidine-2-yl1no4-(4-fluorophenyl) phenyl
11pyrimidine-2-yl1no4-(3,4-dichlorophenyl) phenyl
12pyrimidine-2-yl1nobifen-4-yl
13pyrimidine-2-yl1no4-cyclohexylphenol
15pyrid-2-yl1no4-cyclohexylphenol
18pyrid-2-yl1 no4-(N-methyl-N-phenylamino)phenyl
19pyrimidine-2-yl1no4-(4-itfinal) phenyl
20pyrimidine-2-yl1no4-phenoxyphenyl
213-cyano-pyrid-2-yl1no4-cyclohexylphenol
22pyrimidine-2-yl1no4-(N-(5-jodphur-2-ylmethyl)amino)phenyl
233-cyano-pyrid-2-yl1nobifen-4-yl
24pyrimidine-2-yl1no4-benzylphenol
25pyrimidine-2-yl1no4-(pyrrol-1-�l)phenyl
26pyrimidine-2-yl1no4-(3-fluorophenyl)phenyl
27pyrid-2-yl1no4-(N-cyclohexylcarbodiimide)phenyl
28pyrimidine-2-yl1no4-dimethylaminophenyl
30pyrid-2-yl1no4-benzylphenol
321,3,5-triazine-2-yl1no4-cyclohexylphenol
33benzoxazol-3-yl1no4-cyclohexylphenol
345-trifluoromethyl-1,3,4-thiadiazole-2-yl1no4-cyclohexylphenol
35pyrid-2-yl1no4-butylphenyl
36- thiazol-2-yl1nobifen-4-yl
37pyrid-2-yl1no4-diethylaminophenyl
38pyrimidine-2-yl1no3-iodo-4-methoxyphenyl
42pyrid-2-yl1nobifen-4-yl
43pyrimidine-2-yl1no3-iodo-4-chlorophenyl
44pyrid-2-yl1no4-(1,1-dimethylpropyl)phenyl
45pyrid-2-yl1no 4-(phenyloxy)phenyl
46pyrimidine-2-yl1no4-(pyrazol-1-yl)phenyl
47pyrid-2-yl1no3-(phenyloxy)phenyl
48pyrimidine-2-yl1no3-iodo-4-methylphenyl
50pyrimidine-2-yl1no3-methyl-4-itfinal
52pyrid-2-yl1no3-(4-fluorophenyl)phenyl
53pyrimidine-2-yl1no4-itfinal
565-chloropyrid-2-yl1no4-cyclohexylphenol
pyrid-2-yl1no2-(benzyloxy)phenyl
60pyrid-2-yl1no4-(3-fluorophenyl)phenyl
66benzoxazol-2-yl1no4-cyclohexylphenol
67pyrid-2-yl1nobifen-3-yl
69pyrimidine-2-yl1oxobifen-4-yl
71pyrimidine-2-yl1no4-(imidazol-1-yl)phenyl
73pyrid-2-yl1nobifen-4-yl
74pyrid-2-yl1�et 4-(phenylcarbamoyl) phenyl
754-methylpiperid-2-yl1no4-cyclohexylphenol
76pyrid-2-yl1no2-(isoindole-1,3-dione)phenyl
775-pampered-2-yl1no4-cyclohexylphenol
793-chloropyrid-2-yl1no4-cyclohexylphenol
81pyrid-2-yl1no3-(2,3-dichloro-1H-isoindol-2-yl)phenyl
823-cryptomaterial-2-yl1no4-cyclohexylphenol
83pyrimidine-2-yl2no855-pampered-2-yl1nobifen-4-yl
86pyrid-2-yl1no3-(phenylcarbamoyl) phenyl
87pyrimidine-2-yl2no4-(pyrrolidin-1-yl)-phenyl
88pyrid-2-yl1nobifen-4-yl
892-methoxyphenyl1nobifen-4-yl
90benzoxazol-2-yl1nobifen-4-yl
912-methylthiophenyl1nobifen-4-yl
935-canopied-2-yl 1no4-cyclohexylphenol
94pyrimidine-2-yl1no4-nitrophenyl
983-idered-2-yl1no4-cyclohexylphenol
1003-methylpiperid-2-yl1no4-cyclohexylphenol
1013-cryptomaterial-2-yl1nobifen-4-yl
1024-methylpiperid-2-yl1nobifen-4-yl
104benzothiazol-2-yl1no4-cyclohexylphenol
1052-nitrophenyl1nobi�EN-4-yl
106benzothiazol-2-yl1nobifen-4-yl
109pyrid-2-yl1no3-(phenyloxy)phenyl
110pyrimidine-2-yl2no4-benzylphenol
111pyrimidine-2-yl1no4-benzyloxyphenyl
112pyrid-2-yl1no4-benzyloxyphenyl
1143-idered-2-yl1no4-benzylphenol
1183-idered-2-yl1no4-benzyloxyphenyl
122pyrid-2-yl 1no4-(1-tert-butoxycarbonylmethyl-4-yl)phenyl
124pyrid-2-yl1no4-(1-tert-butoxycarbonylmethyl-4-yl)oxy)phenyl
131pyrimidine-2-yl1no4-benzylphenol
29pyrid-2-yl1no1,1,4,4,tetramethyl-1,2,3,4-tetrahydronaphthyl-6-yl-ethyl
57pyrid-2-yl1no6-metoxia-2-yl
125pyrid-2-yl1no1,2,3,4-tetrahydronaphtyl-2-yl
59pyrid-2-yl1no2-(9-oxipurinol)
96pyrid-2-yl 1nofluoren-2-yl
40pyrid-2-yl1no4-(N-methyl-N-cyclohexylethylamine)phenylethyl
51pyrimidine-2-yl1no4-iodo-phenylethyl
55pyrid-2-yl1no4-(tert-butyl) phenylethyl
64pyrimidine-2-yl1no3-idgenerator
103pyrid-2-yl1no
(also known as 1-(1,2-biphenyl)ethyl)
126pyrid-2-yl1no
41pyrid-2-yl14-(triptoreline) phenylethenyl
65pyrid-2-yl1no4-isopropyl-nilateral
95pyrid-2-yl1no3-triptoreline-nilateral
113pyrid-2-yl1no3-ethoxybenzylidene
54pyrid-2-yl1no4-(n-pentyl) cyclohexyl
78pyrid-2-yl1no4-(tert-butyl) cyclohexyl
128pyrid-2-yl1no4 pentavitin-lo[2.2.2]Oct-1-yl
139pyrimidine-2-yl1no6-�reformative-zo[b]Thien-2-yl

Table 2
Examples of compounds of formula (I)
Conn. No.YrR2Z
10pyrimidine-2-yl1no2-cyclohexylbenzothiazole-6-yl
14pyrimidine-2-yl1no2-methyl-3-phenylbenzimidazole-6-yl
16pyrimidine-2-yl1no1-isopropyl-2-triftormetilfullerenov-4-yl
17pyrimidine-2-yl1no1-cyclohexyl-2-methylbenzimidazole-4-yl
31pyrid-2-yl1no-propional-5-yl
49pyrid-2-yl1no2-phenylbenzimidazol-5-yl
61pyrid-2-yl1no4-phenyl-5-triptorelin-2-yl
62pyrid-2-yl1no5-benzyloxyindole-2-yl
80pyrid-2-yl1no5-(3-triptoreline) furan-2-yl
84pyrid-2-yl1no5-(4-methylphenyl)furan-2-yl
92pyrid-2-yl1no5-(4-methoxyphenyl) furan-2-yl
99pyrid-2-yl1no5-phenylfuro-2-yl
107 pyrid-2-yl1no1-phenylpyrazol-4-yl
108pyrid-2-yl1no2-phenyl-5-cryptomaterial-4-yl
115pyrid-2-yl1noquinoline-6-yl
116pyrid-2-yl1nothe quinolin-2-yl
117pyrid-2-yl1no3-methylbenzofuran-2-yl
119pyrid-2-yl1no5-butalbiral-2-yl
120pyrid-2-yl1no4-benzyloxyindole-2-yl
121pyrid-2-yl1no indol-5-yl
123pyrid-2-yl1no5-(phenylethynyl)furan-2-yl
129pyrid-2-yl1no5-(3,5-dichlorophenoxy)furan-2-yl
130pyrid-2-yl1noXanten-3-yl-9-he
63pyrid-2-yl1no(1-cyclohexylidene-5-yl)ethenyl-
39pyrid-2-yl1no1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazol-3-yl
68pyrid-2-yl1no1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrazol-3-yl
70pyrid-2-yl1no1,5-biphenyl�razol-3-yl
72pyrid-2-yl1no1-(4-aminosulfonyl)-5-(4-chlorophenyl)pyrazol-3-yl
97pyrid-2-yl1no1,2,3,4-tetrahydroquinolin-6-yl
132phenyl1no1-phenyl-1,2,3,4-tetrahydroquinolin-6-yl
1334-triptime-terphenyl1no1,2,3,4-tetrahydro-quinoline-6-yl
1344-triptime-terphenyl1no1-(4-triptoreline)-1,2,3,4-tetrahydroquinolin-6-yl
1353-triforma-terphenyl1no1-(3-triptoreline)-1,2,3,4-tetrahydroquinolin-6-yl

In one embodiment the present invention relates to one or more Conn�the modifications of the Formula (I), as described herein, as well as their enantiomers, solvates or pharmaceutically acceptable salts, wherein r=1. In another embodiment the present invention relates to one or more compounds of Formula (I) as described herein, as well as their enantiomers, solvates or pharmaceutically acceptable salts, wherein r=2.

In one embodiment the present invention relates to one or more compounds of Formula (I) as described herein, as well as their enantiomers, solvates or pharmaceutically acceptable salts, wherein R2missing.In another embodiment the present invention relates to one or more compounds of Formula (I) as described herein, as well as their enantiomers, solvates or pharmaceutically acceptable salts, wherein R2represents an oxo group.

In one embodiment the present invention relates to one or more compounds of Formula (I), as described herein, as well as their enantiomers, stereoisomers, solvation or pharmaceutically acceptable salts, wherein Y represents any of the following: phenyl, pyridyl, pyrimidyl, 1,3,5-triazinyl, thiazolyl, 1,3,4-thiadiazolyl, benzoxazolyl, benzisoxazole and benzothiazolyl; wherein the phenyl pyridyl, pyrimidyl, 1,3,5-triazinyl, thiazolyl, 1,3,4-thiadiazolyl, benzoxazolyl, benzisoxazole, benzothiazole can be replaced by one of the following zamestitelei: CYANOGEN, fluorine, chlorine, bromine, iodine, C1-4alkyl, trifluoromethyl, C1-4alkoxy, C1-4alkylthio and nitro-group.

In another embodiment the present invention relates to one or more compounds of Formula (I), as described herein, as well as their enantiomers, stereoisomers, a solvate or pharmaceutically acceptable salts, wherein Y represents any of the following: phenyl, pyridyl, pyrimidyl, 1,3,5-triazinyl, thiazolyl, 1,3,4-thiadiazolyl, benzoxazolyl, benzisoxazole and benzothiazolyl; wherein the phenyl, pyridyl, pyrimidyl, 1,3,5-triazinyl, thiazolyl, 1,3,4-thiadiazolyl, benzoxazolyl, benzisoxazole, benzothiazole can be replaced by one of the following zamestitelei: CYANOGEN, fluorine, chlorine, bromine, iodine, C1-2alkyl, trifluoromethyl, C1-2alkoxy, C1-2alkylthio and nitro-group.

In another embodiment the present invention relates to one or more compounds of Formula (I) as described herein, as well as their enantiomers, stereoisomers, a solvate or pharmaceutically acceptable salts, wherein Y represents any of the following: phenyl, 3-triptoreline, 4-triptoreline, 2-meth�xifen, 2-methylthiophenyl, 2-nitroaniline-2-yl, 3-canopied-2-yl, 5-canopied-2-yl, 5-pampered-2-yl, 3-chloropyrid-2-yl, 5-chloropyrid-2-yl, 3-jumpered-2-yl, 3-methylpiperid-2-yl, 4-methylpiperid-2-yl, 3-cryptomaterial-2-yl, pyrimidine-2-yl, 1,3,5-triazine-2-yl, benzooxazol-2-yl, benzisoxazol-3-yl, thiazol-2-yl, 5-trifluoromethyl-[1,3,4]-thiadiazole-2-yl and benzothiazol-2-yl.

In another embodiment the present invention relates to one or more compounds of Formula (I) as described herein, as well as their enantiomers, stereoisomers, a solvate or pharmaceutically acceptable salts, wherein Y represents any of the following problems: pyrid-2-yl, 3-canopied-2-yl, 5-canopied-2-yl, 5-pampered-2-yl, 3-chloropyrid-2-yl, 5-chloropyrid-2-yl, 3-jumpered-2-yl, 3-methylpiperid-2-yl, 4-methylpiperid-2-yl, 3-cryptomaterial-2-yl, pyrimidine-2-yl, 1,3,5-triazine-2-yl, benzoxazol-2-yl, benzizoksazola-3-yl, thiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-2-yl and benzothiazol-2-yl. In another embodiment the present invention relates to one or more compounds of Formula (I) and their enantiomers, stereoisomers, solvates or pharmaceutically acceptable salts, wherein Y represents any of the following: phenyl, 3-triptoreline, 4-triptoreline, 2-methoxyphenyl, 2-methylthiophenyl, and 2-nitrophenyl.

In another embodiment �astasia the invention relates to one or more compounds of Formula (I), as indicated in this document, as well as their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Y represents any of the following problems: pyrid-2-yl, 3-canopied-2-yl, 5-chloropyrid-2-yl, pyrimidine-2-yl, thiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-2-yl, 1,3,5-triazine-2-yl and the benzizoksazola-2-yl. In another embodiment the present invention relates to one or more compounds of Formula (I) and their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Y represents any of the following problems: pyrid-2-yl, 3-canopied-2-yl, pyrimidine-2-yl, 1,3,5-triazine-2-yl, thiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-2-yl and the benzizoksazola-3-yl. In another embodiment the present invention relates to one or more compounds of Formula (I) and their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Y represents any of the following problems: pyrid-2-yl, 3-canopied-2-yl, pyrimidine-2-yl and thiazol-2-yl. In another embodiment the present invention relates to one or more compounds of Formula (I), as described herein, as well as their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Y represents any of nieper�numerical: pyrid-2-yl, pyrimidine-2-yl, thiazol-2-yl and the benzizoksazola-2-yl.

In another embodiment the present invention relates to one or more compounds of Formula (I) as described herein, as well as their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Y represents any of the following problems:

(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; and Rbrepresents C1-4alkyl, cycloalkyl, phenyl, furylmethyl or phenyl(C1-2alkyl); and where the phenyl group, Rbthe phenyl group of phenyl(C1-2alkyl), or Rbor furanyl group furylmethyl or Rbcan be replaced by one atom of iodine; alternatively, Raand Rbare connected through the nitrogen atom with the formation of 5-6-membered heterocyclyl, which can condense with anthropoi;

(b) biphenyl-3-yl or biphenyl-4-yl; with the ending of the phenyl ring may be substituted with the following substituents: trifluoromethyl, C1-4alkoxy, chloro, dichloro, fluoro and iodo;

(c) phenyl substituted with one substituents from the following group: C5-8cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbamoyl, phenyl(C1-3)alkoxy, benzyl, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-1,3-dione, 2,3-dihydroindol-2-yl; 1-(tert-butoxycarbonyl)p�of peridin-4-yloxy and 1-(tert-butoxycarbonyl)piperidine-4-yl;

(d) phenyl, substituted by one or two independent substituents from the following group: C1-6alkyl, C1-4alkoxy, iodine, chlorine and the nitro group;

(e) phenyl(C1-2)alkyl, where phenyl may be independently substituted with one or two substituents from the following group: iodine, fluorine, C1-6alkyl, phenyl and NRcRd; where Rcrepresents hydrogen or C1-4alkyl; and where Rdrepresents C1-4alkyl or C3-6cycloalkyl(C1-4)alkyl; and where C1-2alkyl or phenyl(C1-2)alkyl may be substituted by phenyl;

(f) phenyl(C2-4)alkenyl; wherein the phenyl may be substituted with one substituents from the following group: triftormetilfullerenov, C1-4alkyl, C1-4alkoxy, phenyl and trifluoromethyl;

(g) naphthyl; where the naphthyl may be substituted with one C1-4alkoxy-Deputy;

(h) fluorenyl or xantinol; where fluorenyl or xantinol may be substituted with oxo group;

(i) C5-6cycloalkyl; while (C5-6cycloalkyl may be substituted with one C1-5by alkyl;

(j) C5-6cycloalkyl or C5-6cycloalkyl(C1-4)alkyl, is condensed with benzene ring; where the specified C5-6cycloalkyl may be substituted with 1-4 methyl groups;

(k) bicyclo[2.2.2]octyl-1-yl; bicyclo[2.2.2]octyl-1-yl may be substituted C1-6by alkyl;

(l) heteroaryl or heteroaryl, condensive�tion with benzene ring, from the following group: benzooxazole, chinoline, benzimidazolyl, pyridinyl, indole, thienyl, furanyl, pyrazolyl, oxazolyl, benzothiazyl and benzofuranyl; heteroaryl or heteroaryl, condensed to the benzene ring may independently be substituted with one or two substituents from the following group: C5-6cycloalkyl, C1-4alkyl, phenyl, trifluoromethyl, phenyl(C1-2)alkoxy, diclofenac and phenylethynyl; and where the phenyl substituent of heteroaryl can also be substituted with the following substituents: methyl, methoxy or trifluoromethyl;

(m) 1,5-biphenyl-1H-pyrazol-3-yl; wherein the pyrazole-3-yl may be substituted with a methyl group; wherein each of the phenyl groups of the Vice-1,5-biphenyl may also be substituted with groups chloro, dichloro or amino-sulfonyl;

(n) 1,2,3,4-tetrahydroquinolin-6-yl; 1,2,3,4-tetrahydroquinolin-6-yl may be substituted by phenyl or triftormetilfullerenov by phenyl; and

(o) heterocyclyl(C2-4)alkenyl, condensed with benzene ring; where condensed heteroaromatic structure connected with C2-4alkenyl through the benzene ring; and where heterocyclyl, condensed to the benzene ring may further be substituted C5-6cycloalkyl.

In another embodiment the present invention relates to one or more compounds of Formula (I) as uka�ANO herein as well as their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Z represents any of the following problems:

(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; and Rbrepresents C1-4alkyl, cycloalkyl, phenyl, furylmethyl or benzyl; and where the phenyl or benzyl, Rbor furanyl group furylmethyl in Rbcan be replaced by one atom of iodine; alternatively, Raand Rbare connected through the nitrogen atom with the formation of 1-pyrrolidinyl or 1-azepane;

(b) biphenyl-3-yl or biphenyl-4-yl; with the ending of the phenyl ring may be substituted with the following substituents: trifluoromethyl, C1-4alkoxy, chloro, dichloro, fluoro and iodo;

(c) phenyl substituted with one substituents from the following group: cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbinol, benzyloxy, benzyl, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-1,3-dione, 2,3-dihydroindol-2-yl; 1-(tert-butoxycarbonyl)piperidine-4-yloxy and 1-(tert-butoxycarbonyl)piperidine-4-yl;

(d) phenyl, substituted by one or two independent substituents from the following group: C1-6alkyl, C1-4alkoxy, iodine, chlorine and nitro-group;

(e) phenyl(C1-2)alkyl, where phenyl may be independently substituted with one or two substituents from the following group: iodine, f�'or C1-6alkyl, phenyl and NRcRd; where Rcrepresents hydrogen or C1-4alkyl; and where Rdrepresents C1-4alkyl or C3-6cycloalkyl(C1-4)alkyl; and where C1-2alkyl or phenyl(C1-2)alkyl may be substituted by phenyl;

(f) phenyl(C2-4)alkenyl; wherein the phenyl may be substituted with one substituents from the following group: triptoreline, C1-4alkyl, C1-4alkoxy and trifluoromethyl;

(g) naphthyl; where the naphthyl may be substituted with one C1-4alkoxy-Deputy;

(h) fluorenyl or xantinol; where fluorenyl or xantinol may be substituted with oxo group;

(i) cyclohexyl; wherein cyclohexyl can be substituted with one C1-6by alkyl;

(j) C5-6cycloalkyl or C5-6cycloalkyl(C1-4)alkyl, is condensed with benzene ring; where the specified C5-6cycloalkyl may be substituted with 1-4 methyl groups;

(k) bicyclo[2.2.2]octyl-1-yl; bicyclo[2.2.2]octyl-1-yl may be substituted C1-6by alkyl;

(l) heteroaryl or heteroaryl, condensed with a benzene ring, from the following group: benzoxazolyl, chinoline, benzimidazolyl, pyridinyl, indole, thienyl, furanyl, pyrazolyl, oxazolyl, benzothiazyl and benzofuranyl; heteroaryl or heteroaryl, condensed to the benzene ring may independently be substituted with one or two for�estately from the following group: cyclohexyl, C1-4alkyl, phenyl, trifluoromethyl, benzoxa, diclofenac and phenylethynyl; and where the phenyl substituent of heteroaryl can also be substituted with the following substituents: methyl, methoxy or trifluoromethyl;

(m) 1,5-biphenyl-1H-pyrazol-3-yl; wherein the pyrazole-3-yl may be substituted with a methyl group; wherein each of the phenyl groups of the Vice-1,5-biphenyl may also be substituted with groups chloro, dichloro or amino-sulfonyl;

(n) 1,2,3,4-tetrahydroquinolin-6-yl; 1,2,3,4-tetrahydroquinolin-6-yl may be substituted by phenyl or triftormetilfullerenov by phenyl; and

(o) heterocyclyl(C2-4)alkenyl, condensed with benzene ring; where condensed heteroaromatic structure connected with C2-4alkenyl through the benzene ring; and where heterocyclyl, condensed to the benzene ring may further be substituted by cyclohexyl.

In another embodiment the present invention relates to one or more compounds of Formula (I) as described herein, or their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Z represents any of the following: 4-(N-methyl-N-cyclohexylamino)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(1-azepane)phenyl, 4-(3-triptoreline)phenyl, 4-(4-methoxyphenyl)phenyl, 4-cyclohexylphenol, 4-(N-(2-jogbani)amino)phenyl, 4(2-chlorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl, bifen-4-yl, 4-(N-methyl-N-phenylamino)phenyl, 4-(4-itfinal)phenyl, 4-phenoxyphenyl, 4-(N-(5-jodphur-2-ylmethyl)amino)phenyl, 4-benzylphenol, 4-(pyrrol-1-yl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-dimethylaminophenyl, 4-butylphenyl, 4-diethylaminophenyl, 3-iodo-4-methoxyphenyl, 3-iodo-4-chlorophenyl, 4-(1,1-dimethylpropyl)phenyl, 4-(pyrazol-1-yl)phenyl, 3-(phenyloxy)phenyl, 3-iodo-4-methylphenyl, 3-methyl-4-itfinal, 3-(4-fluorophenyl)phenyl, 4-itfinal, 2-(benzyloxy)phenyl, bifen-3-yl, 4-(imidazol-1-yl)phenyl, 4-(phenylcarbamoyl)phenyl, 2-(isoindole-1,3-dione)phenyl, 3-(2,3-dihydro-1H-isoindol-2-yl)phenyl, 3-(phenylcarbamoyl)phenyl, 4-nitrophenyl, 4-benzyloxyphenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)phenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)oxy)phenyl, 1,1,4,4,tetramethyl-1,2,3,4-tetrahydronaphtyl-6-yl, 6-metoxia-2-yl, 1,2,3,4-tetrahydronaphtyl-2-yl, 2-(9-oxipurinol), fluoren-2-yl, 4-(N-methyl-N-cyclohexylethylamine)phenylethyl, 4-idenity, 4-(tert-butyl)phenylethyl, 3-idenity,,, 4-(triptoreline)phenylethenyl, 4-isopropylbenzylamine, 3-triftormetilfullerenov, 3-ethoxybenzylidene, 4-(n-pentyl)cyclohexyl, 4-(tert-butyl)cyclohexyl, 4-interdecile[2.2.2]Oct-1-yl, 2-cyclohexylbenzothiazole-6-yl, 2-methyl-3-phenylbenzimidazole-6-yl, 1-isopropyl-2-triftormetilfullerenov-4-yl, 1-cyclohex�l-2-methylbenzimidazole-4-yl, 1-propional-5-yl, 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazol-3-yl, 2-phenylbenzimidazol-5-yl, 4-phenyl-5-triptorelin-2-yl, 5-benzyloxyindole-2-yl, 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrazol-3-yl, 1,5-biphenylmethanol-3-yl, 1-(4-aminosulfonyl)-5-(4-chlorophenyl)pyrazol-3-yl, 5-(3-triptoreline)furan-2-yl), 5-(4-methylphenyl)furan-2-yl, 5-(4-methoxyphenyl)furan-2-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 5-phenylfuro-2-yl, 1-phenylpyrazol-4-yl, 2-phenyl-5-cryptomaterial-4-yl, quinolin-6-yl, the quinolin-2-yl, 3-methylbenzofuran-2-yl, 5-butalbiral-2-yl, 4-benzyloxyindole-2-yl, indol-5-yl, 5-(phenylethynyl)furan-2-yl, 5-(3,5-dichlorophenoxy)furan-2-yl, Xanten-3-yl-9-it, 1-phenyl-1,2,3,4-tetrahydroquinolin-6-yl,1-(4-triptoreline)-1,2,3,4-tetrahydroquinolin-6-yl, 1-(3-triptoreline)-1,2,3,4-tetrahydroquinolin-6-yl, (1-cyclohexylidene-5-yl)ethenyl and 6 triptoreline[b]Tien-2-yl.

In another embodiment the present invention relates to one or more compounds of Formula (I), or their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Z represents any of the following: 4-(N-methyl-N-cyclohexylamino)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(1-azepane)phenyl, 4-(3-triptoreline)phenyl, 4-(4-methoxyphenyl)phenyl, 4-cyclohexylphenol, 4-(N-(2-jogbani)amino)phenyl, 4-(2-chlorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl,bifen-4-yl, 4-(N-methyl-N-phenylamino)phenyl, 4-(4-itfinal)phenyl, 4-phenoxyphenyl, 4-(N-(5-jodphur-2-ylmethyl)amino)phenyl, 4-benzylphenol, 4-(pyrrol-1-yl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-dimethylaminophenyl, 4-butylphenyl, 4-diethylaminophenyl, 3-iodo-4-methoxyphenyl, 3-iodo-4-chlorophenyl, 4-(1,1-dimethylpropyl)phenyl, 4-(pyrazol-1-yl)phenyl, 3-(phenyloxy)phenyl, 3-iodo-4-methylphenyl, 3-methyl-4-itfinal, 3-(4-fluorophenyl)phenyl, 4-itfinal, 2-(benzyloxy)phenyl, 4-benzyloxyphenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)phenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)oxy)phenyl, 1,1,4,4,tetramethyl-1,2,3,4-tetrahydronaphtyl-6-retil, 6-metoxia-2-yl, 2-(9-oxipurinol), 4-(N-methyl-N-cyclohexylethylamine)phenylethyl, 4-idenity, 4-(tert-butyl)phenylethyl, 4-(triptoreline)phenylethenyl, 4-(n-pentyl)cyclohexyl, 2-cyclohexylbenzothiazole-6-yl, 2-methyl-3-phenylbenzimidazole-6-yl, 1-isopropyl-2-triftormetilfullerenov-4-yl, 1-cyclohexyl-2-methylbenzimidazole-4-yl, 1-propional-5-yl, 2-phenylbenzimidazol-5-yl, 4-phenyl-5-triptorelin-2-yl, Xanten-3-yl-9-it, 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazol-3-yl and 6-triptoreline[b]Tien-2-yl.

In another embodiment the present invention relates to one or more compounds of Formula (I), or their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein Z is a�because of the following: 4-(N-methyl-N-cyclohexylamino)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(1-azepane)phenyl, 4-(3-triptoreline)phenyl, 4-(4-methoxyphenyl)phenyl, 4-cyclohexylphenol, 4-(N-(2-jogbani)amino)phenyl, 4-(2-chlorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl, bifen-4-yl, 4-(N-methyl-N-phenylamino)phenyl, 4-(4-itfinal)phenyl, 4-phenoxyphenyl, 4-(N-(5-jodphur-2-ylmethyl)amino)phenyl, 4-benzylphenol, 4-(pyrrol-1-yl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-benzyloxyphenyl, 2-cyclohexylbenzothiazole-6-yl, 2-methyl-3-phenylbenzimidazole-6-yl, 1-isopropyl-2-triftormetilfullerenov-4-yl, 1-cyclohexyl-2-methylbenzimidazole-4-yl, 1-propional-5-yl and 6-triptoreline[b]Tien-2-yl.

In another embodiment the present invention relates to one or more compounds of Formula (I) as described herein, as well as their enantiomers, solvates or pharmaceutically acceptable salts, in this case,

Z represents any of the following: 4-(N-methyl-N-cyclohexylamino)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(1-azepane)phenyl, 4-(3-triptoreline)phenyl, 4-(4-methoxyphenyl)phenyl, 4-(2-chlorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl, bifen-4-yl, 4-(N-methyl-N-phenylamino)phenyl, 4-phenoxyphenyl, 4-cyclohexylphenol, 4-benzylphenol, 4-(pyrrol-1-yl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-dimethylamino�Anil, 4-butylphenyl, 4-diethylaminophenyl, 3-(4-fluorophenyl)phenyl, 4-benzyloxyphenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)phenyl, 1,1,4,4,tetramethyl-1,2,3,4-tetrahydronaphtyl-6-retil, 4-(N-methyl-N-cyclohexylethylamine)phenylethyl, 4-(triptoreline)phenylethenyl, 2-methyl-3-phenylbenzimidazole-6-yl, 1-isopropyl-2-triftormetilfullerenov-4-yl, 1-cyclohexyl-2-methylbenzimidazole-4-yl, 1-propional-5-yl and 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazol-3-yl.

In another embodiment the present invention relates to one or more compounds of Formula (I) as specified herein, or their enantiomers, solvates or pharmaceutically acceptable salts, wherein Z represents any of the following problems: 4-cyclohexylphenol, bifen-4-yl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-benzylphenol, 4-diethylaminophenyl, 3-iodo-4-methoxyphenyl, 3-(4-fluorophenyl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-methyl-N-cyclohexylethylamine)phenyl, 9-octafluoro-2-yl and 2-cyclohexylmethoxy-6-yl.

In the following embodiments, the present invention relates to compounds of Formula (I) as specified herein, or their enantiomers, diastereomers, solvates or pharmaceutically acceptable salts, wherein r is an integer from 1 to 2; R2is absent; Y represents any of the groups (Y-a) (Y-b), as specified in the future; and/or Z �predstavljaet a any of the groups (Z-a) (Z-f), as indicated in the future; provided that the compound of Formula (I), as described in this document is not:

Compound No. 200: a compound in which Y represents a 3-methylpyridine-2-yl, Z is 4-biphenyl, r=1 and R2no;

Compound No. 201: a compound in which Y is pyridin-2-yl, Z is 2-(phenylcarbamoyl)phenyl, r=1 and R2no;

Compound No. 202: compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2is absent, and Z is a 4-cyclohexylphenol;

Compound No. 203: compound in which Y is pyridin-2-yl, Z is 3-(cyclohexylcarbonyl)phenyl, r=1 and R2no;

Compound No. 204: the compound in which Y represents a 5-cyanopyridine-2-yl, Z is 4-biphenyl, r=1, and R2no;

Compound No. 205: a compound in which Y represents a 5-cryptomaterial-2-yl, Z is 4-biphenyl, r=1 and R2no;

Compound No. 206: a compound in which Y represents pyrimidine-2-yl, Z is 2-(4-triftormetilfullerenov)vinyl, r=2 and R2no;

Compound No. 207: a compound in which Y is pyridin-2-yl, Z is 2-phenylphenyl, r=1 and R2no;

Link�m No. 208: link, in which Y represents pyridin-2-yl, Z is 2-phenylethyl, r=1 and R2no;

Compound No. 209: a compound in which Y is pyridin-2-yl, Z is 2-tert-butylbenzothiazole-6-yl, r=1 and R2no;

Compound No. 210: a compound in which Y is pyridin-2-yl, Z is 2-(4-methoxyphenyl)benzoxazole-7-yl, r=1 and R2no;

Compound No. 211: compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z is a 2-cyclohexylbenzothiazole-6-yl;

Compound No. 212: a compound in which Y is pyridin-2-yl, r=1, R2is absent, and Z represents a 1,2-Diisobutyl-1H-indol-5-yl;

Compound No. 213: compound in which Y is pyridin-2-yl, Z is 1-methyl-2-propyl-1H-indol-5-yl, r=1 and R2no;

Compound No. 214: a compound in which Y is pyridin-2-yl, Z is 1-isobutyl-2-phenyl-1H-indol-5-yl, r=1 and R2no;

Compound No. 215: a compound in which Y is pyridin-2-yl, Z is 1-isobutyl-2-(4-methylphenyl)-1H-indol-5-yl, r=1 and R2no;

Compound No. 216: a compound in which Y is pyridin-2-yl, Z is 2-(3-methoxyphenyl)benzoxazol-5-yl, r=1 and R 2no;

Compound No. 217: compound in which Y is pyridin-2-yl, r=1 and R2is absent, and Z is a 2-benzylphenol;

Compound No. 218: a compound in which Y is pyridin-2-yl, r=1 and R2is absent, and Z is a (1R)-1,2,3,4-tetrahydronaphthalen-1-yl;

Compound No. 219: a compound in which Y is pyridin-2-yl, r=1 and R2is absent, and Z represents a (1S)-1-[4-(2-methylpropyl") phenyl]ethyl;

Compound No. 220: a compound in which Y is pyridin-2-yl, r=1 and R2is absent, and Z represents a (1S)-1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl;

Compound No. 221: a compound in which Y is pyridin-2-yl, r=1 and R2is absent, and Z is a 2,3-dihydro-1H-indene-2-yl;

Compound No. 222: a compound in which Y is pyridin-2-yl, r=1 and R2is absent, and Z is 2,2-biphenylyl; or

Compound No. 223: a compound in which Y represents a 3-triptoreline, r=1 and R2is absent, and Z represents a 1,2,3,4-tetrahydroquinolin-6-yl.

In this document, (Y-a) means that Y is heteroaryl from the following group: thiazolyl, pyridinyl, pyrimidinyl, 1,3,5-triazinyl, benzoxazolyl, benzo[d]isoxazole and 1,3,4-thiadiazolyl; and that Y can be replaced by one of the following Deputy�of stitely: cyano, trifluoromethyl, fluorine, chlorine, bromine, iodine and C1-4alkyl.

In this document, (Y-b) means that Y is heteroaryl from the following group: thiazolyl, pyridinyl, pyrimidinyl, 1,3,5-triazinyl, benzo[d]izocsazol and 1,3,4-thiadiazolyl; and that Y can be replaced by one of the following substituents: cyano, trifluoromethyl, fluorine, chlorine, bromine, iodine and C1-4alkyl.

In this document (Z-a) means that Z represents any of the following problems:

(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; Rbis a C-4the alkyl, cycloalkyl or phenyl; where phenyl of Rbcan replace one atom of iodine, or Raand Rbare linked together through a nitrogen atom, forming heterocyclyl with 5-8 members;

(b) biphenyl-3-yl or biphenyl-4-yl; where the internal phenyl ring attached to the carbonyl of formula (I) mentioned biphenyl-3-yl and biphenyl-4-yl may be substituted by one forsakenrealm, and where terminal phenyl ring of the above-mentioned biphenyl-3-yl and biphenyl-4-yl may be substituted by one Deputy, selected from the group consisting of trifloromethyl, S1-4alkoxy, chlorine, dichloro, fluorine, and iodine;

(c) phenyl substituted by one of the following substituents: cyclohexyl, phenyloxy, phenyl(C1-3)alkoxy, benzyl, pyrrolyl, pyrazolyl, 1-(tert-butoxycarbonyl)piperidine-4-and�hydroxy, and 1-(tert-butoxycarbonyl)piperidine-4-yl;

(d) phenyl; where phenyl can be independently substituted with the following substituents: C1-4alkoxy, iodine, C1-6alkyl and chlorine;

(e) phenyl(C1-2)alkyl, where phenyl may be substituted with the following substituents: iodine, C1-6alkyl and NRcRd; and where Rcrepresents hydrogen or C1-4alkyl, and Rdrepresents C1-4alkyl, or cyclohexyl(C1-4)alkyl;

(f) phenyl(C2-4)alkenyl; where phenyl may be substituted by one triptoreline, C1-4alkyl or phenyl Deputy;

(g) naphthyl; where the naphthyl may be substituted with one C1-4alkoxy-Deputy;

(h) cyclohexyl; wherein cyclohexyl can be substituted with one C1-6alkim;

(i) benzoannelirovannykh cyclohexyl(C1-4)alkyl; where the cyclohexyl may be substituted with 1-4 methyl groups;

(j) benzoannelirovannykh heterocyclyl(C2-4)alkenyl; where the condensed heteroaromatic structure connected with C2-4alkenyl through the benzene ring; and where heterocyclyl, condensed to the benzene ring may further be substituted C3-6cycloalkyl

(k) heteroaryl or heteroaryl, condensed with a benzene ring, from the following group: benzoxazolyl, benzimidazolyl, pyridinyl, indole and thienyl; heteroaryl or hetero�Rhyl, condensed with a benzene ring may independently be substituted with one or two substituents from the following group: cyclohexyl, C1-4alkyl, phenyl, trifluoromethyl, phenyl(C1-4)alkoxy and phenylethenyl; or

(l) 1,5-biphenyl-1H-pyrazol-3-yl; wherein the group of the pyrazole-3-yl may be substituted with a methyl group; and where each of the 1.5-phenyl substituents may independently be substituted with one or two groups aminosulfonyl.

In this document (Z-b) means that Z represents any of the following:

(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; Rbis a C-4the alkyl, cycloalkyl or phenyl; where phenyl of Rbcan replace one atom of iodine, or Raand Rbare linked together through a nitrogen atom, forming heterocyclyl with 5-8 members;

(b) biphenyl-3-yl or biphenyl-4-yl; where the internal phenyl ring attached to the carbonyl of a compound of Formula (I) biphenyl-3-yl and biphenyl-4-yl may be substituted by one fluorine atom; and where the end of the phenyl ring specified biphenyl-3-yl and biphenyl-4-yl may be substituted with any of the following substituents: trifluoromethyl, C1-4alkoxy, chloro, dichloro, fluoro and iodo;

(c) phenyl, substituted by one Deputy, selected from the following group: cyclohexyl, phenyloxy, phenyl(C1-3)alkoxy, 3 - and�and 4-phenylmethyl and pyrrolyl;

(d) phenyl, substituted with one or two substituents, independently selected from the following groups: alkoxy, iodine and C1-6alkyl;

(e) phenyl(C1-2)alkyl, where phenyl may be substituted with NRcRd; where Rcrepresents hydrogen or C1-4alkyl and Rdrepresents C1-4alkyl or cycloalkyl(C1-4)alkyl;

(f) 2-phenylphenyl, where phenyl may be substituted with triptoreline;

(g), cyclohexyl(C1-4)alkyl, is condensed with a benzene ring, where the cyclohexyl may be substituted by 1-4 methyl Deputy;

(h) heteroaryl or heteroaryl, condensed with benzene ring, selected from the following group: benzoxazole and indole, where heteroaryl or condensed with a benzene ring heteroaryl can be substituted by one Deputy, selected from the following group: cyclohexyl, C1-4alkyl, phenyl and trifluoromethyl;

(i) 1,5-biphenyl-1H-pyrazol-3-yl, where pyrazol-3-yl may be substituted with one methyl group; and where a 1.5-phenyl substituents may be independently substituted by one or two chlorine atoms or groups aminosulfonyl.

In this document (Z-C) means that Z represents any of the following problems:

(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; Rbis a C-4the alkyl,cycloalkyl or phenyl; where the phenyl of Rbmay be substituted with one iodine substituent, or Raand Rbtaken together with the nitrogen atom to which they are both bound in the form heterocyclyl with 5-8 members;

(b) biphenyl-3-yl or biphenyl-4-yl; where the internal phenyl ring attached to the carbonyl of formula (I) mentioned biphenyl-3-yl and biphenyl-4-yl may be substituted by one forsakenrealm, and where terminal phenyl ring of the above-mentioned biphenyl-3-yl and biphenyl-4-yl may be substituted by one Deputy from the following groups: trifluoromethyl, C1-4alkoxy, chlorine, dichloro, fluorine and iodine;

(c) phenyl, substituted by one Deputy, selected from the following group: cyclohexyl, phenyloxy, phenyl(C1-3)alkoxy, 3 - or 4-phenylmethyl and pyrrolyl;

(d) phenyl, substituted with one or two substituents, independently selected from the following groups: alkoxy, iodine and C1-6alkyl;

(e) phenyl(C1-2)alkyl, where phenyl may be substituted with NRcRd; where Rcrepresents hydrogen or C1-4alkyl and Rdrepresents C1-4alkyl or cycloalkyl(C1-4)alkyl; or

(f) 2-phenylphenyl, where phenyl may be substituted by triftormetilfullerenov;

(g), cyclohexyl benzene(C1-4)alkyl, where the cyclohexyl may be substituted by 1-4 methyl Deputy;

(h) heteroaryl or heteroaryl, condensed with a benzene ring, n�ecstasy benzoxazolyl or indole; heteroaryl or condensed heteroaryl can be substituted with any of the following: cyclohexyl, C1-4alkyl, phenyl and trifluoromethyl.

In this document (Z-d) means that Z represents any of the following problems:

(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; Rbis a C-4the alkyl, cycloalkyl or phenyl; where phenyl of Rbmay be substituted with one iodine substituent, or Raand Rbare connected through the nitrogen atom, forming heterocyclyl with 5-8 members;

(b) biphenyl-3-yl or biphenyl-4-yl; where the internal phenyl ring attached to the carbonyl of formula (I) mentioned biphenyl-3-yl and biphenyl-4-yl may be substituted by one forsakenrealm, and where terminal phenyl ring of the above-mentioned biphenyl-3-yl and biphenyl-4-yl may be substituted by one Deputy, selected from the following groups: trifluoromethyl, C1-4alkoxy, chloro, dichloro, fluoro and iodo;

(c) phenyl substituted by one of the following substituents: cyclohexyl, phenyloxy, phenyl(C1-3)alkoxy, 3-phenylmethyl, 4-phenylmethyl, pyrrolyl, pyrazolyl, 1-(tert-butoxycarbonyl)piperidine-4-yloxy, and 1-(tert-butoxycarbonyl)piperidine-4-yloxy and 1 - (tert-ruboxistaurin)piperidine-4-yl;

(d) phenyl independently substituted by one or two substituents from the following gr�PY: alkoxy, iodine, C1-6alkyl and chlorine;

(e) phenyl(C1-2)alkyl; where the specified phenyl may be substituted with the following substituents: iodine, C1-6alkyl and NRcRd; where Rcrepresents hydrogen or C1-4alkyl, and Rdrepresents C1-4alkyl, or cyclohexyl(C1-4)alkyl;

(f) phenyl(C2-4)alkenyl, where the phenyl can be substituted with the following substituents: triftormetilfullerenov, C1-4alkyl or phenyl;

(g) naphthyl may be substituted with one C1-4alkoxy-group;

(h) cyclohexyl may be substituted with one group C1-6alkyl;

(i) benzocycloheptene(C1-4)alkyl, where the cyclohexyl may be substituted by 1-4 methyl Deputy;

(j) heterocyclyl(C2-4)alkenyl, condensed with benzene ring; where condensed heteroaromatic structure connected with C2-4alkenyl through the benzene ring; and where condensed heterocyclyl may further be substituted C3-6cycloalkyl;

(k) heteroaryl or heteroaryl, condensed with a benzene ring, from the following group: benzoxazolyl, benzimidazolyl, pyridinyl, indole and thienyl; heteroaryl or condensed heteroaryl may be independently substituted with one or two substituents from the following group: cyclohexyl, C1-4alkyl, phenyl, trifluoromethyl, phenyl(C1-4)Ala�XI and phenylethynyl; or

(l) 1,5-biphenyl-1H-pyrazol-3-yl, where pyrazol-3-yl may be substituted with one methyl group; and where a 1.5-phenyl substituents may be independently substituted by one or two chlorine atoms or groups aminosulfonyl.

In this document (Z-e) means that Z represents any of the following:

(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; Rbis a C-4the alkyl, cycloalkyl or phenyl; where phenyl of Rbmay be substituted with one iodine substituent, or Raand Rbconnected through the nitrogen atom, forming heterocyclyl with 5-8 members;

(b) biphenyl-3-yl or biphenyl-4-yl; where the internal phenyl ring attached to the carbonyl of formula (I) mentioned biphenyl-3-yl and biphenyl-4-yl may be substituted by one forsakenrealm, and where terminal phenyl ring of the above-mentioned biphenyl-3-yl and biphenyl-4-yl may be substituted by one Deputy, selected from the group consisting of trifloromethyl, S1-4alkoxy, chlorine, dichloro, fluorine, and iodine;

(c) phenyl substituted by one Deputy from the following group: cyclohexyl, phenyloxy, phenyl(C1-3)alkoxy, 3 - or 4-phenylmethyl and pyrrolyl;

(d) phenyl, substituted with one or two substituents, independently selected from the following groups: alkoxy, iodine and C1-6alkyl;

(e) phenyl(C1-2)al�Il; where phenyl may be substituted with NRcRd; where Rcrepresents hydrogen or C1-4alkyl and Rdrepresents C1-4alkyl or C3-6cycloalkyl(C1-4)alkyl;

(f) 2-phenylphenyl, where phenyl may be substituted with triptoreline;

(g), cyclohexyl(C1-4)alkyl, is condensed with a benzene ring, where the cyclohexyl may be substituted by 1-4 methyl Deputy;

(h) heteroaryl or heteroaryl, condensed with benzene ring selected from the group consisting of benzoxazolyl and indolyl where heteroaryl or a benzene heteroaryl can be substituted by one Deputy, selected from the following group: cyclohexyl, C1-4alkyl, phenyl and trifluoromethyl;

(i) 1,5-biphenyl-1H-pyrazol-3-yl, where pyrazol-3-yl may be substituted with one methyl group; and where a 1.5-phenyl substituents may be independently substituted by one or two chlorine atoms or groups aminosulfonyl.

In this document (Z-f) means that Z represents any of the following:

(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; Rbis a C-4the alkyl, cycloalkyl or phenyl; where phenyl of Rbmay be substituted with one iodine substituent, or Raand Rbconnected to the nitrogen atom, forming heterocyclyl with 5-8 members;

<> (b) biphenyl-3-yl or biphenyl-4-yl; where the internal phenyl ring connected to the carbonyl of Formula (I) as specified herein, or specified biphenyl-3-yl and biphenyl-4-yl may be substituted by one fluorine atom; and where the end of the phenyl ring specified biphenyl-3-yl and biphenyl-4-yl may be substituted with the following substituents: trifluoromethyl, C1-4alkoxy, chloro, dichloro, fluoro and iodo;

(c) phenyl substituted by one of the following substituents: cyclohexyl, phenyloxy, phenyl(C1-3)alkoxy, 3-phenylmethyl, 4-phenylmethyl or pyrrolyl;

(d) phenyl substituted by one or two substituents from the following group: C1-4alkoxy, iodine and C1-6alkyl;

(e) phenyl(C1-2)alkyl; wherein the phenyl may be substituted with NRcRd; wherein Rcrepresents hydrogen or C1-4alkyl and Rdrepresents C1-4alkyl or C3-6cycloalkyl(C1-4)alkyl; or

(f) 2-phenylphenyl; where phenyl may be substituted by triftormetilfullerenov;

(g), cyclohexyl(C1-4)alkyl, is condensed with a benzene ring, where the cyclohexyl may be substituted by 1-4 methyl Deputy;

(h) heteroaryl or benzoannelirovannykh heteroaryl from the following group: benzoxazolyl or indole, where heteroaryl or a benzene heteroaryl can be substituted by the following substituents: cyclohexyl, C1-4�lkyl, phenyl and trifluoromethyl.

The following variant of implementation of the present invention relates to a compound of formula (I)

(I)

when the compound of formula (I) represents any of the following problems:

the compound in which Y is pyridin-2-yl, Z is (3-fluoro-4-phenyl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is (2-cyclohexyl)benzoxazol-6-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-phenylmethylene, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is 3-(phenylcarbamoyl)phenyl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is 4-(phenylcarbamoyl)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is biphenyl-4-ylmethyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 3-(4-fluorophenyl)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z represents 9H-fluoren-1-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is represented�is fluoren-9-Oh-2-yl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is biphenyl-3-yl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is a quinoline-6-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 1H-indol-5-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 1,2,3,4-tetrahydroquinolin-6-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 3-methylbenzofuran-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-phenylfuro-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-(3-triptoreline)furan-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-(4-methoxyphenyl)furan-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-(phenylethynyl)furan-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-(4-methylphenyl)furan-2-yl, r=1 and R2no;

compound wherein Y PR�dstanley a pyridin-2-yl, Z represents a biphenyl-4-yl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is 4-(cyclohexylcarbonyl)phenyl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is (4-phenoxy)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 1-propional-5-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(1-cyclohexyl-2,3-dihydro-1H-indol-5-yl)vinyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is (4-azepin-1-yl)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-(cyclohexylethylamine)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-(phenylethylamine)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(4-(cyclohexyldimethylamine)phenyl)ethyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphtyl-6-yl)ethyl, r=1 and R2no;

the compound in which Y p�establet a pyridin-2-yl, Z represents 4-(1,1-dimethylpropyl)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(4-tert-butylphenyl)ethyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(4-triftormetilfullerenov)vinyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-(4-chlorophenyl)-1-(4-aminomethylphenol)-1H-pyrazol-3-yl, r=1, and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-phenyl-5-cryptomaterial-4-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 5-(phenylmethoxy)indol-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-phenylmethoxy-1H-indol-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-n-butylphenyl, r=1 and Rsup> 2no;

the compound in which Y is pyridin-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z represents a (3-phenoxy)phenyl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is (4-phenylmethoxy)phenyl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is (2-phenylmethoxy)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-(isoindol-1,3-Dion-2-yl)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 6-metoxia-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z represents a 1,2-biphenylyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z represents a (3-phenoxy)phenylmethyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-(1-tert-butoxycarbonyl)piperidine-4-yl)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-(1-tert-butoxycarbonyl)piperidine-4-yloxy)phenyl, r=1 and R2OTS�of tstuat;

the compound wherein Y represents pyrimidine-2-yl, Z is biphenyl-4-yl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is (4-phenoxy)phenyl, r=1 and R2no;

the compound wherein Y represents pyrimidine-2-yl, Z is 4-iodo-3-methylphenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is (3-fluoro-4-phenyl)phenyl, r=1 and R2no;

the compound wherein Y represents pyrimidine-2-yl, Z is (4-phenylmethyl)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-tert-butylcyclohexyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-n-pentylcyclohexyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(4-isopropylphenyl)vinyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(3-triptoreline)vinyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(biphenyl-4-yl)vinyl, r=1 and R2no;

the compound in which Y is a u�ridin-2-yl, Z represents a 5-n-butylpyrazine-2-yl, r=1 and R2no;

compound wherein Y is pyridin-2-yl, Z is a quinoline-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-phenyl-5-triptorelin-2-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 3-(1,3-dihydroindol-2-yl)phenyl, r=1 and R2no;

the compound in which Y represents a 3-yodellin-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-itfinal, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is (4-phenylmethoxy)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y represents a 3-yodellin-2-yl, Z is (4-phenylmethoxy)phenyl, r=1 and R2no;

the compound in which Y represents a 3-yodellin-2-yl, Z is (4-phenylmethyl)phenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 1-FeNi�-1H-pyrazol-4-yl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 1,5-biphenyl-1H-pyrazol-3-yl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 4-diethylaminophenyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-(3-ethoxyphenyl)vinyl, r=1 and R2no;

the compound in which Y is pyridin-2-yl, Z is 2-phenyl-1H-benzimidazol-5-yl, r=1 and R2no;

the compound in which Y represents a thiazol-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y represents benzothiazol-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y represents benzoxazol-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y represents a 5-bromopyridin-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound wherein Y represents pyrimidine-2-yl, Z is 3-iodo-4-methylphenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-chloro-3-itfinal, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 3-iodo-4-methoxyphenyl, r=1 and R2no;

the compound wherein Y represents pyrimidine-2-yl, Z is 2-(3-itfinal)ethyl, r=1 and R2no;

the compound wherein Y represents pyrimidine-2-yl, Z is 2-(4-itfinal)ethyl, r=1 and R2no;

compound wherein Y is 3-chloropyridin, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

compound wherein Y is 5-chloropyridin-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y represents a benzo[d]izocsazol-3-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y is 5-trifluoromethyl-1,3,4-thiadiazole-2-yl, Z is 4-cyclohexylphenol, r=1, and R2no;

the compound in which Y represents a 1,3,5-triazine-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

compound wherein Y is 4-methylpyridine-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

compound wherein Y is 3-methylpyridine-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

compound wherein Y repre�provides a 3-cyanopyridine-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

compound wherein Y is 5-cyanopyridine-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y represents a 3-triptorelin-2-yl, Z is (4-cyclohexyl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is biphenyl-4-yl, r=1 and R2represents oxo;

the compound in which Y represents 4-methylpyridine-2-yl, Z is biphenyl-4-yl, r=1 and R2no;

the compound in which Y represents a 3-cyanopyridine-2-yl, Z is biphenyl-4-yl, r=1 and R2no;

the compound in which Y represents a 3-triptorelin-2-yl, Z is biphenyl-4-yl, r=1 and R2no;

the compound in which Y represents a thiazol-2-yl, Z is biphenyl-4-yl, r=1 and R2no;

the compound in which Y represents benzothiazol-2-yl, Z is biphenyl-4-yl, r=1 and R2no;

the compound in which Y represents benzoxazol-2-yl, Z is biphenyl-4-yl, r=1 and R2no;

the compound in which Y represents a 5-bromopyridin-2-yl, Z is biphenyl-4-�l, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-(4-fluorophenyl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-(2-chlorophenyl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-(3,4-dichlorophenyl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-(3-triptoreline)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-(4-methoxyphenyl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-dimethylaminophenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is (4-pyrrol-1-yl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is (4-pyrazol-1-yl)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is (4-imidazol-1-yl)phenyl, r=1 and R2no;

the compound wherein Y represents pyrimidine-2-yl, Z is (4-pyrrolidin-1-yl)phenyl, r=1 and R2OTS�of tstuat;

the compound in which Y represents pyrimidine-2-yl, Z is 1-isopropyl-2-trifluoromethyl-1H-benzimidazol-5-yl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 2-methyl-1-phenyl-1H-benzimidazol-5-yl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-nitrophenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-(2-idfenumeration)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-(5-jodphur-2-ylmethylamino)phenyl, r=1 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 4-(4-itfinal)phenyl, r=1 and R2no;

the compound in which Y represents a 2-methoxyphenyl, Z is biphenyl-4-yl, r=1 and R2no;

the compound in which Y represents a 2-methylthiophenyl, Z represents dienyl-4-yl, r=1 and R2no;

the compound in which Y represents 2-nitrophenyl, Z is biphenyl-4-yl, r=1 � R 2no;

the compound wherein Y represents pyrimidine-2-yl, Z is biphenyl-4-yl, r=2 and R2no;

the compound wherein Y represents pyrimidine-2-yl, Z is (4-pyrrolidin-1-yl)phenyl, r=2 and R2no;

the compound wherein Y represents pyrimidine-2-yl, Z is (4-phenylmethyl)phenyl, r=2 and R2no;

the compound in which Y represents pyrimidine-2-yl, Z is 6-triftorperasin-2-yl, r=1 and R2no;

and their enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

In another embodiment the present invention relates to the compound of formula (I), where Y represents a pyrimidine-2-yl, r=1, R2is absent, and Z is bifen-4-yl; or their pharmaceutically acceptable salts.

In one embodiment the present invention relates to the treatment, relief or prevention of a disease, syndrome, condition or violation that is affected by inhibition of MGL, wherein the disease, syndrome, condition or violation that is affected by inhibition of MGL, represents any of the following problems: inflammatory or neuropathic pain; and includes an introduction to the needy in this subject (including a mammal or a human) a therapeutically effective�objective amount of a compound of Formula (I)

selected from the group defined above; and its enantiomers, diastereomers, solvates and their pharmaceutically acceptable salts.

In one embodiment the present invention relates to the treatment, relief or prevention of inflammatory pain; and includes an introduction to the needy in this subject (including a mammal or a human) a therapeutically effective amount of a compound of Formula (I)

selected from the group defined above; and enantiomers, diastereomers, solvates and their pharmaceutically acceptable salts. In another embodiment of the present invention inflammatory pain represent any of the following problems: visceral pain and inflammatory hyperalgesia (visceral pain preferred).

In one embodiment the present invention relates to the treatment, relief or prevention of inflammatory hyperalgesia and includes an introduction to the needy in this subject (including a mammal or a human) a therapeutically effective amount of a compound of Formula (I)

selected from the group defined above; and its enantiomers, diastereomers, solvates and their pharmaceutically acceptable salts. In another embodiment, the actual�tion of this invention inflammatory hyperalgesia is a ulcerative colitis.

In one embodiment the present invention relates to the treatment, relief or prevention of neuropathic pain and includes an introduction to the needy in this subject (including a mammal or a human) a therapeutically effective amount of a compound of Formula (I),

as indicated in this document; and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts. In another embodiment of this invention the neuropathic pain is neuropathicguy cold allodynia.

For use in medicine the salts of the compounds of formula (I) refer to non-toxic "pharmaceutically acceptable salts". However, to obtain the compounds of formula (I) or their pharmaceutically acceptable salts can be used and other salts. Appropriate pharmaceutically acceptable salts of compounds of Formula (I) specified herein, include salts obtained by adding an acid, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, �instances, when compounds of Formula (I) specified herein, have acid fragment, corresponding pharmaceutically acceptable salts may include alkali metal salts, e.g., salts of sodium or potassium; salts of alkaline earth metals, e.g., calcium or magnesium; and salts formed corresponding organic ligands, e.g. Quaternary ammonium salts. Thus, typical examples of pharmaceutically acceptable salts include the following salts: acetate, benzolsulfonat, benzoates, bicarbonates, bisulfate, bitartrate, borates, bromides, calcium edetate, camsylate, carbonates, chlorides, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glyceryltrinitrate, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodides, isothionate, lactates, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, the muqata, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylates, stearates, sulfates, subacetate, succinates, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids and bases that can IP�to alisovtsy to obtain pharmaceutically acceptable salts, include such acids as acetic acid, 2,2-dichlorooxine acid, acylated amino acids, fatty acids, ascorbic acid, L-aspartic acid, mixture of Benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, Capraia acid, Caprylic acid, cinnamic acid, citric acid, reklamowa acid, modellerna acid, ethane-1,2-disulfonate acid, econsultancy acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactosemia acid, gentisic acid, glucoheptonate acid, D-gluconic acid, D-glucuronic acid, L-glutamina acid, α-oxoglutarate acid, glycolic acid, gourova acid, Hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonate acid, 1-hidroxi-2-naftalina acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamula acid, phosphoric acid, L-Pyroglutamate acid, salicylic acid, 4-aminosalicylic acid, sabotinova acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-succinic acid, titanova acid, p-toluensulfonate acid undecylenoyl acid; and bases including ammonia, L-arginine, benethamine, benzatin, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, Ethylenediamine, N-methylglucamine, geranamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds of Formula (I) specified herein. In General, such prodrugs are functional derivatives of the compounds constituting the subject of the present invention, which in vivo are easily converted into the required compound. Thus, in embodiments of the present invention relating to methods of treatment or prevention, the term "application" ("welcome", "appointment") covers the treatment or prevention of various diseases, conditions, syndromes and disorders mentioned in the description of the compounds which are the subject of the present invention, or compounds which are not women�already listed in this description but converted to the specified compound in vivo after his admission the patient. Conventional procedures for the selection and preparation of suitable derivatives are Pro-drug forms are described, for example, in "Design of Prodrugs", Ed. H. Bundgaard, Elsevier, 1985.

In cases where in certain embodiments of the present invention the compounds have two or more chiral centers, they may accordingly exist in the form of enantiomers. In those cases where the compounds possess two or more chiral centers, they may additionally exist in the form of diastereoisomers. You need to understand that all such isomers and mixtures thereof fall within the scope of the present invention. In addition, some of the crystalline forms of the compounds of the present invention may exist as polymorphs and as such they fall under the scope of the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention. Specialists in this field understand that used in the present application the term "compound" shall be considered to include solvated compounds of Formula I.

In cases where the processes for producing compounds in accordance�accordance with the implementation of the present invention lead to the formation of a mixture of stereoisomers, these isomers can be isolated using standard methods such as preparative chromatography. Compounds can be obtained in the form of racemates, or individual enantiomers may be obtained by enantiospecific synthesis or by separation. Compounds can e.g. be separated into their component enantiomers using standard methods, such as the formation diastereomeric pairs by forming salts with optically active acids, for example, (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and recovery of the free base. The compounds can also be separated by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral partner. Alternatively, such compounds can be separated using chiral HPLC.

One embodiment of the present invention is a composition, including a pharmaceutical composition, containing, or to some extent or mainly consisting of (+)-enantiomer of a compound of formula (I), wherein, in the specified composition is virtually absent (-)-isomer of the compound. In this context, "almost absent" means m�25%, preferably less than 10%, even more preferably less than 5%, even more preferably less than 2% and most preferably less than 1% (-)-isomer content is calculated as

.

Another variant implementation of the present invention is a composition, including a pharmaceutical composition, containing, or to some extent or mainly composed of (-)-enantiomer of a compound of formula (I), wherein, in the specified composition is virtually absent (+)-isomer of the compound. In this context, "almost no" means less than 25%, preferably less than 10%, even more preferably less than 5%, even more preferably less than 2% and most preferably less than 1% of (+)-isomer content is calculated as

.

During the processes for producing compounds in accordance with the implementation of the present invention, it may be necessary to protect sensitive or reactive groups on any of the considered molecules. For these purposes, can be used with standard protecting groups, for example as described in Protective Groups in Organic Chemistry, Second Edition, J. F. W. McOmie, Plenum Press, 1973; T. W. Greene &P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991; and T. W. Greene &P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Introduced protective group can be�ü subsequently removed at any convenient for this stage with the use of well-known specialists of ways.

Although included in the variants of implementation of the present invention compounds (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered to the patient separately, as a rule, they will be introduced in the form of a mixture with a pharmaceutically acceptable carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Consequently, private embodiments of the present invention relate to pharmaceutical and veterinary compositions comprising compounds of Formula (I) specified herein, and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.

For example, in the pharmaceutical compositions in accordance with the variants of implementation of the present invention compounds of Formula (I) specified herein, may be mixed with any suitable binder (binders), a sliding agent (slip agents), suspenders substance (suspendresume substances), substance (substances) for coating, solubilizers substance (solubilizers substances), as well as combinations of these substances.

TV�rdie oral dosage forms such as tablets or capsules containing compounds included in the composition of the present invention, may be introduced as needed in at least one dosage form at a time. The described compounds can also be administered in the form of compositions with delayed release of the active agent.

Compounds included in the composition of the invention can also be administered in such additional oral forms, such as elixirs, solutions, syrups and suspensions; each of them can contain flavourings and colourings.

In another embodiment of the present invention compounds of Formula (I) specified herein, may be used by inhalation (intratracheal or intranasal) or in the form of suppositories or pessaries, and can also be applied topically in the form of lotions, solutions, creams, ointments or powders. For example, you can include them in the cream, including, to some extent or mainly consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated in a concentration of from about 1% to 10% by weight of the cream, ointment, including, to some extent or mainly consisting of a white wax or white soft paraffin basis with any necessary stabilizers and preservatives. To alternative ways of introduction refers percutaneous introduction through�Ohm dermal or transdermal patch.

The pharmaceutical composition of this invention (and its constituent compounds separately) can be administered parenterally, for example, intracavernosa, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In such cases, the composition also includes at least one suitable carrier, one filler and a solvent.

When administered parenterally, the pharmaceutical components of this invention are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or monosaccharides to make the solution was isotonic with blood.

When buccal or sublingual introduction of the pharmaceutical components of this invention can be administered in pill form, which can be in the usual way.

In addition, for example, pharmaceutical compositions containing at least one compound of Formula (I), as described herein, can be manufactured by mixing the compound (compounds) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or pharmaceutically acceptable auxiliary substance in accordance with the methods of making the compositions adopted in the pharmaceutical industry. Carrier, filler and dilute�l can take many forms depending on the desired method of administration (e.g., oral, parenteral, etc.). Thus, for liquid oral dosage forms such as suspensions, syrups, elixirs and solutions, suitable carriers and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, dyes, etc.; for solid oral dosage forms, such as powders, capsules and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulomatous agents, lubricants, binders, additives to improve tablet disintegration, etc. the Solid oral preparations also possible to additionally cover such substances, like sugar, or enteric coating, which allows to modulate the major site of absorption and decay. In parenteral administration, the carrier, excipient and diluent, usually include sterile water; to increase the solubility and the preservation of the composition may be added other ingredients. The injection of suspensions or solutions can also be obtained using an aqueous media together with additives such as solvents or preservatives.

A therapeutically effective amount of a compound of Formula (I) specified herein, or pharmaceutical compositions according to the present invention includes the dose in pre�trusted from about 0.1 mg to about 3000 mg, or any particular amount or range of doses within the specified limits, in particular, from about 1 mg to about 1000 mg, or any particular amount or range of doses within the specified limits, or more specifically, from about 10 mg to about 500 mg, or any particular amount or range of doses within the specified limits for the active ingredient when the reception mode is from about 1 to about 4 times a day for a person with an average body weight (70 kg); however, the industry obviously, a therapeutically effective amount of a compound of Formula (I) specified herein, will vary depending on existing diseases, syndromes, conditions and disorders, for the treatment of which use the connection.

For oral administration the pharmaceutical composition is preferably provided in the form of tablets containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250, or about 500 milligrams of a compound of Formula (I) specified herein.

The compound of Formula (I) specified herein, may preferably be applied in a single daily dosage. Also the total daily dosage may be divided into two, three or four portions a day.

The optimal dosage of a compound of Formula (I), the decree�of fucking in this document easily determined by the expert and vary depending on the particular compounds used, method of application, concentration of drug and the stage of the disease, syndrome, condition or disorder. In addition, these related to a specific patient factors such as age, weight, diet and time of administration of the drug, also lead to the need to adjust the doses to an appropriate therapeutic level and effect. Therefore, the above dosages are exemplary for some average case. There still may be individual circumstances that require higher or lower dosage ranges, which also fall within the scope of the present invention.

The specialist will be obvious that the test, in vivo and in vitro, carried out with suitable, known and generally accepted cell and/or animal models, presumably allow to evaluate the ability of test compounds to provide a therapeutic or prophylactic effect on the disease. The specialist will also be clear that clinical trials in humans, including primary human trials, assessed the effectiveness of doses of the test, the groups of healthy volunteers and/or patients suffering from this disease, can be carried out by methods well known to the public�time in medical and clinical practice.

The compound of Formula (I) specified herein, can be used in any of the above compositions and schemes of admission or in any of the compositions and schemes of admission adopted by the industry, in all cases, when for the treatment of a patient requires the use of a compound of Formula (I) specified herein.

GENERAL SYNTHESIS METHODS

Representative compounds of this invention can be synthesized in accordance with the General methods of synthesis described below and illustrated in the diagrams. Since the schemes are an illustration, you should not consider the invention limited to specific chemical reactions and conditions described in the schemes and examples. Used in the circuits of the starting materials are commercially available or can be obtained by methods that are within the skills of specialists in this field. Variables are defined in the text and are within the skills of specialists in this field.

For example, compounds of formula (I), where R2absent, can be obtained in accordance with the process shown in Scheme 1 below.

Scheme 1

Accordingly, the compound of Formula (V) with suitable substituting groups, known compound or compound obtained by known methods, is reacted with a compound of formula (VI) with suitable Zama�ment groups, in this case R represents either of a suitable protective group for nitrogen, such as-CH(phenyl)2, benzyl, tert-butyl, methyl and the like, preferably-CH(phenyl)2known compound or compound obtained by known methods; in the presence of an organic base, for example, DIPEA, tea, pyridine, and the like; in an organic solvent, such as acetonitrile, THF, was held, and the like; preferably at a temperature from about 50°C to about 90°C; to obtain the corresponding compound of formula (VII).

To obtain the corresponding compound of formula (VIII) of molecules of a compound of formula (VII) protecting groups are removed by known methods. For example, if P represents a-CH(phenyl)2, removal of protective groups from the molecule of a compound of formula (VII) by reaction with 1-claritinclaritin in an organic solvent, e.g. dichloromethane, and subsequently heated to reflux in an organic solvent, such as methanol, to obtain the corresponding compound of formula (VIII).

The compound of formula (VIII) is reacted with a compound of formula (IX) with suitable substituting groups in which LG1represents-C(O)Cl or -- C(O)OH, and in which LG1connected in the desired position to the benzene ring condensed hour�and a compound of formula (IX), known compound obtained by known methods, in the presence of a suitable binding agent, for example, GATA, gbtu, DCC and the like; in the presence of suitable organic bases, for example, DIPEA, tea, pyridine, etc.; in an organic solvent, e.g., acetonitrile, DMF, was held, etc.; to obtain the corresponding compound of formula (Ia).

Compounds of formula (I), where R2represents an oxo group, can be obtained in accordance with the process described in Scheme 2 below.

Scheme 2

Accordingly, the compound of formula (Ia) with suitable substituting groups (if necessary or if desired, with suitable protective groups) is oxidized to obtain the corresponding compound of formula (Ib). More specifically, the compound of formula (Ia) with the corresponding substituents is reacted with a suitable oxidizing agent, for example, m-HPBC, H2O2etc., in a solvent, for example, was held, chloroform, acetic acid, etc.; preferably, at about room temperature; to obtain the corresponding compound of formula (Ib).

The following examples are offered to facilitate understanding of the present invention and in no way are intended to limit in any way the scope of this invention disclosed in the following paragraphs it� formula.

In the following examples, some synthetic products are referred to as allocated in the form of balances. The person skilled in the art will identify that the term “residue” does not limit the physical state in which the product has been received, and may include, for example, a solid product, oil, foam, resin, syrup, etc.

Example 1: Compound No. 12

Biphenyl-4-yl-[3-(4-pyrimidine-2-yl-piperazine-1-yl)azetidin-1-yl]methanon

STAGE A: 2-[4-(1-benzhydrylamine-3-yl)piperazine-1-yl]pyrimidine

To a solution of 2-piperazine-1-yl-pyrimidine (2.48 g, of 15.10 mmol, Alfa) and ester methanesulfonic acid and 1-benzhydrylamine-3-yl (4 g, 12.6 mmol, Oakwood) in CH3CN (40 ml) was added DIPEA (2,63 ml of 15.10 mmol) at room temperature. The mixture was heated to reflux for 2 h. the Solvent was removed by evaporation and the residue was divided between CH2Cl2and an aqueous solution of NaHCO3. The organic layer was washed with aqueous solution of NaHCO3(2 times) and then was extracted with 1N HCl (2 times). The aqueous layer was cooled and pH was adjusted to 1 N. NaOH. The resulting mixture was extracted using CH2C2(2×). The organic layer was dried over MgSO4and concentrated. The obtained residue was purified by the method GHSD to obtain 2-[4-(1-benzhydrylamine-3-yl)piperazine-1-yl]pyrimidine.

Step B: 2-(4-azetidin-3-hilpipre�Zin-1-yl)pyrimidine

To a solution of 2-[4-(1-benzhydrylamine-3-yl)piperazine-1-yl]pyrimidine (2,03 g, of 5.27 mmol) in CH2Cl2(20 ml) was added 1-chloroethylphosphonic (1,704 ml 15,79 mmol) at 0oC under a layer of N2. The resulting mixture was stirred at 0oC for 90 minutes and was added methanol (4 ml). The mixture was heated to reflux for one hour, then cooled. Was then added diethyl ether (40 ml). The solid residue was filtered, and dried to obtain 2-(4-azetidin-3-reparacin-1-yl)pyrimidine, which was used in next step without further purification.

STAGE C: Biphenyl-4-yl-[3-(4-pyrimidine-2-reparation-1-yl)azetidin-1-yl]methanon

To a solution of 2-(4-azetidin-3-reparacin-1-yl)pyrimidine (0.172 g, 0.87 mmol) and GATA (0,347 g, 0,913 mmol) in DMF (4 ml) was added DIPEA (0,607 ml, 3.48 mmol). The mixture was stirred at room temperature and was added biphenyl-4-carboxylic acid (0.87 mmol). The resulting mixture was stirred at room temperature for 5 hours. Was then added H2O (8 ml) and the resulting mixture was extracted with EtOAc (thrice). The organic layer was dried over MgSO4and concentrated. The resulting residue was purified by HPLC to obtain the biphenyl-4-yl-[3-(4-pyrimidine-2-reparation-1-yl)azetidin-1-yl]methanone.

Using the technique described in example 1 above, and replace the corresponding reagents, the source of prophetic�STV and purification methods, known in the art, were obtained the following compounds forming the subject of the present invention.

Conn. No.The name of the connection
The result of determination of physical properties of the prepared sample
1N-cyclohexyl-N-methyl-4-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}aniline
1H NMR (300 MHz, CD3CN) δ 8,12 (d, J=4,9 Hz, 1 H), 8,01 (DDD, J=1,9, 7,2, 9,0 Hz, 1 H), 7,63 (d, J=9,0 Hz, 2 H), 7,22 (d, J=8,7 Hz, 3 H), 7,02 (t, J=6,6 Hz, 1 H), 4,24-of 4.75 (m, 4 H), of 4.00 (t, J=5.1 Hz, 5 H), 3,53-3,73 (m, 1 H), 3,30 (m, 4h), 3,01 (s, 3h), of 1.85 (d, J=9,8 Hz, 4 H), 1,58-1,72 (m, 1 H), 1,24-1,59 (m, 4 H), 1,03-1,24 (m, 1 H); LC/MS m/z (M+H+) 434,4 (calculated for C26H35N5O, 431,56)
22-(4-{1-[(4-pyrrolidin-1-yl-phenyl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (300 MHz, CD3OD) δ 8,32 (d, 2 H), 7,47 (d, 2 H), of 6.65 (t, 1 H), of 6.49 (d, 2 H), 4,25-a 4.64 (m, 4 H), 3,82-4,19 (m, 5 H), 3,16-of 3.32 (m, 8 H), 1,89-2,02 (m, 4 H); LC/MS m/z (M+H+) 393,3 (calculated for C22H28N6O, 392,51)
31-(4-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}phenyl)ASEAN
1H NMR (300 MHz, CD3CN) δ 8,11 (d, J=6,0 Hz, 1 H), 7,91-8,07 (m, 1 H), of 7.48 (d, J=9,0 Hz, 2 H), 7,21 (d, J=9.4 Hz, 1 H), 7,02 (t, J=6,6 Hz, 1 H), 6,71 (d, J=9,0 Hz, 2 H), 4,47 (m, 4 H), 3,99 (d, J=4,5 Hz, 5 H), 3,40-of 3.60 (m, 4 H), and 3.31 (m, 4 H), 1,78 (m, 4 H), of 1.52 (m, 4 H); LC/MS m/z (M+H+) 420,3 (you�isleno for C25H33N5O, 419,57)
42-[4-(1-{[3'-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)piperazine-1-yl]pyrimidine
1H NMR (300 MHz, CD3OD) δ 8,32 (d, 2 H), 7,78-7,91 (m, 2 H), 7,72 (s, 4 H), 7,51-7,67 (m, 2 H), of 6.65 (t, 1 H), 4,51-4.72 in (m, 2 H), 4,28-4,51 (m, 2 H), 3,92-4,18 (m, 5 H), 3,22-3,35 (m, 4 H); LC/MS m/z (M+H+) 468,1 (calculated for C25H24F3N5O, 467,5)
52-(4-{1-[(4'-methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (300 MHz, CD3OD) δ 8,32 (d, 2 H), 7,63 (s, 4 H), 7,52 (d, 2 H), 6,93 (d, 2 H), of 6.65 (t, 1 H), 4,50-4,71 (m, 2 H), 4,25-4,49 (m, 2 H), 3,95-4,20 (m, 5 H), of 3.75 (s, 3 H), 3,22-3,37 (m, 4 H); LC/MS m/z (M+H+) 430,2 (calculated for C25H27N5O2, 429,53)
61-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-yl)piperazine
1H NMR (300 MHz, CD3OD) δ 7,58 (d, J=8,3 Hz, 2 H), 7,21-7,41 (m, 3h), 6,98 (d, J=4,1 Hz, 1 H), 4,19-4,70 (m, 4 H), of 3.91 (m, 1 H), 3,68-of 3.85 (m, 4 H), 3,16 (m, 4 H), 2,58 (m, 1 H), 1,68-of 1.96 (m, 5 H), 1,19-of 1.57 (m, 5 H); LC/MS m/z (M+H+) 411,3 (calculated for C23H30N4OC, 410,59)
7N-(2-jogbani)-4-{[3-(4-pyrimidine-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}aniline
1H NMR (400 MHz, DMSO-d6) δ to 8.45 (d, J=4,9 Hz, 2 H), 7.87 ft-a 7.92 (m, 1 H), 7,44 (d, J=8,8 Hz, 2 H), to 7.33-7,40 (m, 1 H), 7,27-to 7.33 (m, 1 H), 7,01-was 7.08 (m, 1 H), was 6.77 (s, 1 H), 6,55 (d, J=8,8 Hz, 2 H), 4,62-of 4.77 (m, 2 H), 4,31-4,59 (m, 4 H) to 4.26 (s, 2 H), 4,00-4,11 (m, 2 H), only 3.57 (m, 1 H), 3,10-3,35 (m, 2 H), 2,88-3,10 (m, 2 H); MS m/z (M+H+) 555,1
82-(4-{1-[(2'-chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (300 MHz, CD3OD) δ 8,32 (d, 2 H), 7,67 (d, 2 H), value of 7, 37-7,53 (m, 3 H), 7,121-of 7.36 (m, 3 H), of 6.65 (t, 1 H), of 4.54-4.72 in (m, 2 H), 4,27-4,50 (m, 2 H), 3,90-is 4.21 (m, 5 H), 3,22-3,36 (m, 4 H); LC/MS m/z (M+H+) 434,1 (calculated for C24H24ClN5O, 433,94)
92-(4-{1-[(4'-forbiden-4-yl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (300 MHz, CD3OD) δ 8,32 (d, J=4,9 Hz, 2 H), 7,53-of 7.70 (m, 6 H), 7,11 (t, 2 H), of 6.65 (t, 1 H), 4,52-4,69 (m, 2 H), 4,28-4,47 (m, 2 H), 3,89-4,19 (m, 5 H), 3,21-3,36 (m, 4 H); LC/MS m/z (M+H+) 418,1 (calculated for C24H24N5O, 417,49)
102-cyclohexyl-6-{[3-(4-pyrimidine-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}-1,3-benzoxazol
1H NMR (300 MHz, CDCl3): δ 8,31 (d, J=4,9 Hz, 2 H), 7,80 (s, 1 H), of 7.64-7,73 (m, 1 H), 7,53-of 7.64 (m, 1 H), is 6.51 (t, J=4,7 Hz, 1 H), 4,05-4,42 (m, 4 H), a 3.87 (t, J=4,9 Hz, 4 H), 3,18-3,30 (m, 1 H), 2,92-3,06 (m, 1 H), 2,30-of 2.54 (m, 4h), 2,10-of 2.24 (m, 2 H), 1,81-of 1.95 (m, 2 H), 1,67-of 1.81 (m, 2 H), 1.22 m-153 (m, 4 H); LC/MS m/z (M+H+) 447,3 (calculated for C25H30N6O2, 446,56)
112-(4-{1-[(3',4'-dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (300 MHz, CD3OD) δ 8,32 (d, 2 H), 7,76 (s, 1 H), 7,69 (s, 4 H), of 7.46-7,58 (m, 2 H), of 6.65 (t, 1 H), 4,50-4,70 (m, 2 H), 4,25-4,48 (m, 2 H), 3,89-4,13 (m, 5 H), 3,19-3,37 (m, 4 H); LC/MS m/z (M+H+) 468,1(calculated for C24H23Cl2N5O, 468,39)
122-{4-[1-(biphenyl--yl-carbonyl)azetidin-3-yl]piperazine-1-yl}pyrimidine
1H NMR (300 MHz, CD3CN) δ 8,31 (d, J=4.5 Hz, 2 H), 7,54-7,73 (m, 6 H), 7,24-of 7.48 (m, 3 H), 6,62 (t, J=4,7 Hz, 1 H), 4,19-4,69 (m, 4 H), 3,82-4,18 (m, 5 H), 2,84-of 3.42 (m, 4 H); LC/MS m/z (M+H+) 400,2 (calculated for C24H25N5O, 399,5)
132-(4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (400 MHz, DMSO-d6) δ of 8.44 (d, J=4,9 Hz, 2 H), 7,58 (d, J=8,1 Hz, 2 H), 7,34 (d, J=8,3 Hz, 2 H), was 6.77 (t, J=4,8 Hz, 1 H), 4,55 (m, 2 H), 4,25-4,32 (m, 2 H), 3,99-of 4.09 (m, 1 H), 3,65 (user. C, 4 H), 2,92-3,2 (user. C, 4 H), 2,52-2,62 (m, 1 H), to 1.79 (DD, J=3,1, 6,7 Hz, 4 H), 1,67-of 1.75 (m, 1 H), 1,40 (d, J=10.5 Hz, 4 H), of 1.17 to 1.31 (m, 1 H); MS m/z (M+H+) 406,3
142-methyl-1-phenyl-5-{[3-(4-pyrimidine-2-reparation-1-yl)azetidin-1-yl]carbonyl}-1H-benzimidazol
1H NMR (300 MHz, CD3OD) δ 8,31 (d, J=4,9 Hz, 2 H), with 8.05 (s, 1 H), 7.62 mm-7,76 (m, 4 H), 7,49-7,62 (m, 2 H), of 7.36 (d, J=to 8.7 Hz, 1 H), 6,63 (t, J=4,7 Hz, 1 H), 4,55-of 4.75 (m, 2 H), 4,35-a 4.53 (m, 2 H), 3,94-4,20 (m, 5 H), 3,24 (m, 4 H), of 2.66 (s, 3 H); LC/MS m/z (M+H+) 454,2(calculated for C26H27N7O, 453,55)
151-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
1H NMR (300 MHz, CD3CN) δ 8,02 (d, J=4,9 Hz, 1 H), of 7.82 (DDD, J=1,9, 7,2, 9,0 Hz, 1 H), 7,44 (d, J=8,3 Hz, 2 H), 7,22 (d, J=7.9 Hz, 2 H), 7,03 (d, J=9,0 Hz, 1 H), 6,86 (t, J=6,4 Hz, 1 H), 4,12-of 4.54 (m, 4 H), 3,67-3,95 (m, 5 H), 3,11 (d, J=1.9 Hz, 4 H), of 2.50 (m, 1 H), 1,57-of 1.93 (m, 5 H), 1,02-1,49 (m, 5 H); LC/MS m/z (M+H+) 405,3 (calculated for C25H32N4O, 404,56)

161-(1-methylethyl)-5-{[3-(4-pyrimidine-2-reparation-1-yl)azetidin-1-yl]carbonyl}-2-(trifluoromethyl)-1H-benzimidazol
1H NMR (300 MHz, CD3OD) δ 8,32 (d, J=4.5 Hz, 2 H), 7,02 (s, 1 H), 7,94 (d, 1 H), of 7.70 (d, 1 H), of 6.65 (t, 1 H), to 4.92 (m, 1 H), 4,52-4,73 (m, 2 H), 4,28-4,52 (m, 2 H), 3,83-is 4.21 (m, 5 H), 3,23-3,39 (m, 4 H), 1,64 (d, 6 H); LC/MS m/z (M+H+) 474,3 (calculated for C23H26F3N7O, 473,51)
171-cyclohexyl-2-methyl-5-{[3-(4-pyrimidine-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}-1H-benzimidazol
1H NMR (300 MHz, CD3OD) δ 8,31 (d, J=4,9 Hz, 2 H), 8,09 (d, J=to 8.7 Hz, 1 H), 7,97 (s, 1 H), of 7.75 (d, J=1.5 Hz, 1 H), only 6.64 (t, J=4,9 Hz, 1 H), 4,33-4.72 in (m, 4 H), 3,89-4,19 (m, 5 H), 3,21-3,37 (m, 4 H), 2,85 (s, 3h), 2,11-of 2.35 (m, 2 H), 1,86-of 2.06 (m, 4 H), 1,68-to 1.82 (m, 1 H), 1,25-of 1.65 (m, 4 H); LC/MS m/z (M+H+) 460,4 (calculated for C26H33N7O, 459,6)
18N-methyl-N-phenyl-4-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}aniline
1H NMR (300 MHz, CD3CN) δ 8,01 (d, J=4,9 Hz, 1 H), 7,86 (DDD, J=1,9, 7,2, 9,0 Hz, 1 H), 7,25-7,47 (m, 4 H), 7,00-of 7.19 (m, 4 H), 6,89 (t, J=6,6 Hz, 1 H), 6,69 (d, J=9,0 Hz, 2 H), 4,18-4,55 (m, 4H), 3,74 - 3,94 (m, 5 (H), 3,23 (s, 3H), 3,09-3,20 (m, 4 H); LC/MS m/z (M+H+) 428,3
192-(4-{1-[(4'-godbitene-4-yl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (400 MHz, DMSO-d6) δ to 8.45 (d, J=4,9 Hz, 2 H), a 7.87 (d, J=8,6 Hz, 2 H), to 7.77 (kV, J=8,5 Hz, 4 H), 7,54 (d, J=8,3 Hz, 2 H), was 6.77 (s, 1 H), 4,59-4,69 (m, 2 H), 4,50-4,59 (m, 2 H), 4,25-4,36 (m, 3 H), 3,94-4,16 (m, 2 H), 3,17-to 3.41 (m, 2 H), 2,98 (user. s, 2 H) MS m/z (M+H+) 526,1
202-(4-{1-[(4-phenoxyphenyl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (300 MHz, CD3CN) δ 8,31 (d, J=4,9 Hz, 2 H), 7,52 (d, J=to 8.7 Hz, 2 H), 7,34 (t, 2 H), 7,13 (t, 1 H), 6,98 (d, J=7.9 Hz, 2 H), 6,91 (d, J=to 8.7 Hz, 2 H), 6,62 (t, J=4,9 Hz, 1 H), 3.75 to 4.72 in (m, 9 H), 3,12 (m, 4 H); LC/MS m/z (M+H+) 416,2 (calculated for C24H25N5O2, 415,5)
212-(4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine-1-yl)pyridin-3-carbonitril
1H NMR (300 MHz, CD3OD) δ is 8.46 (DD, J=1,9, with 4.9 Hz, 1 H), and 8.04 (DD, J=1,9, of 7.9 Hz, 1 H), members, 7.59 (d, J=8,3 Hz, 2 H), 7,34 (d, J=7.9 Hz, 2 H), 7,06 (DD, J=4,9, 7.5 Hz, 1 H), 4,57-4,78 (m, 2 H), 4,34-4,56 (m, 2 H), 4,22 (m, 1 H), 3,93 (m, 4 H), 3,44 (m, 4h), 2,58 (m, 1 H), 1,69-of 1.96 (m, 5 H), 1,19-1,58 (m, 5 H); LC/MS m/z (M+H+) 430,2 (calculated for C26H31N5O, 429,57)
22N-[(5-jodphur-2-yl)methyl]-4-{[3-(4-pyrimidine-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}aniline
1H NMR (400 MHz, MeOD) δ 8,36-8,43 (m, 2 H), 7,44-7,53 (m, 2 H), 6,63-was 6.77 (m, 3 H), 6,43-is 6.51 (m, 1 H), 6,14-6,21 (m, 1 H), 4,39-4,76 (m, 6 H), 4,37 (s, 2 H), 3,89-4,29 (m, 5 H), 2,74 (user. s, 2 H); MS m/z (M+H+)
232-{4-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazine-1-yl}pyridine-3-carbonitrile
1H NMR (300 MHz, CD3OD) δ is 8.46 (DD, 1 H), and 8.04 (DD, 1 H), 7,76 (s, 4 H), 7.62 mm-7,72 (m, 2 H), 7,31-to 7.55 (m, 3 H), 7,06 (DD, 1 H), 4,35-4,80 (m, 4 H), 4,20 (m, 1 H), 3,81-of 4.04 (m, 4 H), 3,35-3,51 (m, 4 H); LC/MS m/z (M+H+) USD 424.2 (calculated for C26H25N5O, 423,52)
242-(4-{1-[(4-benzoylphenyl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (400 MHz, DMSO-d6) δ of 8.44 (d, J=4,6 Hz, 2 H), 7,58 (d, J=8,3 Hz, 2 H), 7,35 (d, J=8,1 Hz, 2 H), 7,30 (d, J=7,1 Hz, 2 H), 7,27 (d, J=1,7 Hz, 2 H), up 7.17-7.23 percent (m, 1 H), was 6.77 (s, 1 H), a 4.53-4,65 (m, 2 H), 4,43-a 4.53 (m, 2 H), 4,27-4,31 (m, 1 H), 4,04-4,14 (user. C, 4 H), 4,01 (s, 2 H), 2,80-3,13 (m, 4 H); MS m/z (M+H+) 414,3
252-[4-(1-{[4-(1H-pyrrol-1-yl)phenyl]carbonyl}azetidin-3-yl)piperazine-1-yl]pyrimidine
1H NMR (300 MHz, CD3OD) δ 8,32 (d, 2 H), 7,68 (d, 2 H), 7,53 (d, 2 H), 7,20 (m, 2 H), of 6.65 (t, 1 H), 6,23 (t, 2 H), 4,51-4.72 in (m, 2 H), 4,24-4,48 (m, 2 H), 3,93-4,19 (m, 5 H), 3,22-3,18 (m, 4 H); LC/MS m/z (M+H+) 389,2 (calculated for C22H24N6O, 388,48)
262-(4-{1-[(2-forbiden-4-yl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (400 MHz, DMSO-d6) δ to 8.45 (d, J=8,0 Hz, 2 H), 7,66 (d, J=8,0 Hz, 1 H), EUR 7.57-7.62 mm (m, 3 H), 7,49-EUR 7.57 (m, 2 H), 7,47 (d, J=7,3 Hz, 1 H), was 6.77 (t, J=4,6 Hz, 1 H), 4,58-4,73 (m, 2 H), 4,34 (user. s, 2 H), 4,01-3,83 (user. C, 5 H), 2,89-3,35 (m, 4 H); MS m/z (M+H+) 418,3
27N-(4-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}phenyl)cyclohexanecarboxylic
1H NMR (400 MHz, DMSO-d6) δ for 10.08 (s, 1 H), 8,09 - 8,20 (m, 1 H), 7,69-the 7.75 (m, 3 H), of 7.64-7,69 (m, 1 H), 7,61 (d, J=8,8 Hz, 3 H), 6,98-7,06 (m, 1 H), 6.75 in-is 6.81 (m, 1 H), 4,57-of 4.66 (m, 2 H), 4,49-up 4.57 (m, 2 H), 4,04-4,13 (m, 1 H), 3,4-2,8 (user. C, 8 H), 2,29-to 2.40 (m, 1 H), 1,78 (user. C, 4 H), 1,61-to 1.69 (m, 1 H), 1,34-of 1.46 (m, 2 H), 1,12-of 1.34 (m, 3 H); MS m/z (M+H+) 448,3
28N,N-dimethyl-4-{[3-(4-pyrimidine-2-reparation-1-yl)azetidin-1-yl]carbonyl}aniline
1H NMR (300 MHz, CD3OD) δ 8,44 (d, J=4,9 Hz, 2 H), 7,60 (d, J=9,0 Hz, 2 H), 6,72-to 6.88 (m, 3 H), 4,35-4,82 (m, 4 H), 3,95-4,29 (m, 5 H), 3,34-3,47 (m, 4 H), 3,06 (s, 6 H); LC/MS m/z (M+H+) 367,2 (calculated for C20H26N6O, 366,47)

291-pyridin-2-yl-4-{1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphtyl-2-yl)propanol]azetidin-3-yl}piperazine
1H NMR (300 MHz, CD3CN) δ 8,01 (d, J=4,9 Hz, 1 H) to 7.89 (DDD, J=1,9, 7,2, 9,0 Hz, 1 H), 7,05-7,21 (m, 3 H), 6,80-of 6.96 (m, 2 H), 4,32 (DD, 1 H), 3,96-4,24 (m, 3 H), a 3.87 (t, J=5.1 Hz, 4 H), 3,65-3,81 (m, 1 H), 3,13 (m, 4 H), 2,66 (d, J=8,3 Hz, 2 H), 2,27 (d, J=8,3 Hz, 2 H), 1,58 (s, 4 H), 1,15 (d, 12 H); LC/MS m/z (M+H+) 461,4 (calculated for C29H40N4O, 460,67)
301-{1-[(4-benzoylphenyl)carbonyl]azetidin-3-yl}-4-pyridin-2-yl-piperazine
1H NMR (400 MHz, DMSO-d6) δ 8,12-8,17 (m, 1 H), 7,63-of 7.70 (m, 1 H), members, 7.59 (d, J=8,1 Hz, 2 H), 7,35 (d, J=8,1 Hz, 2 H), 7,30 (d, J=7,1 Hz, 2 H), 7,27 (s, 2 H), up 7.17-7.23 percent (m, 1 H), 6,99-7,06 (m, 1 H), The 6.75-is 6.81 (m, 1 H), of 4.54-4,63 (m, 2 H), 4,43-a 4.53 (m, 2 H), 4,19-4,34 (m, 4 H), 4,03-4,12 (m, 1 H), 4,01 (s, 2 H), 3,01-3,19 (m, 4 H); MS m/z (M+H+) 413,3
311-propyl-5-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}-1H-indole
1H NMR (300 MHz, CD3CN) δ 8,02 (d, J=4,9 Hz, 1 H), 7,72-of 7.88 (m, 2 H), 7,35 (s, 2 H), 7,22 (d, J=3.0 Hz, 1 H), 7,02 (d, J=9,0 Hz, 1 H), of 6.85 (t, J=6,2 Hz, 1 H), 6,45 (�, J=3,4 Hz, 1 H), 4,16-4,59 (m, 4 H), of 4.04 (t, J=7,0 Hz, 2 H), 3,71-3,92 (m, 5 H), 3,13 (m, 4h), 1,61-of 1.81 (m, 2 H), 0,78 (t, 3 H); LC/MS m/z (M+H+) 404,2 (calculated for C24H29N5O, 403,53)
322-(4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine-1-yl)-1,3,5-triazine
1H NMR (300 MHz, CD3OD) δ 8,64 (s, 2 H), 7,60 (d, 2 H), 7,35 (d, 2 H), 4,25-4,69 (m, 4 H), 4,07-of 4.25 (m, 4 H), 3,97 (m, 1 H), 3,09-3,26 (m, 4h), 2,59 (m, 1 H), 1,69-of 1.97 (m, 5 H), of 1.17 to 1.60 (m, 5 H); LC/MS m/z (M+H+) 407,3(calculated for C23H30N6O, 406,54)
333-(4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine-1-yl)-1,2-benzizoksazola
1H NMR (300 MHz, CD3OD) δ to 7.89 (d, 1 H), 7,49 - 7,66 (m, 4 H), 7,29-7,41 (m, 3 H), 4,29-to 4.76 (m, 4 H), 4,16 (m, 1 H), 3,74-of 3.91 (m, 4 H), 3,36-3,50 (m, 4 H), 2,59 (m, 1 H), 1,69-1,94 (m, 5 H), 1,21-1,58 (m, 5 (H); LC/MS m/z (M+H+) 445,2 (calculated for C27H32N4O2, 444,58)
341-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}-4-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]piperazine
1H NMR (300 MHz, CD3OD) δ members, 7.59 (d, 2 H), 7,34 (d, 2 H), 4,15-of 4.66 (m, 4 H), 3.75 to-3,95 (m, 5 H), 2,97-3,19 (m, 4h), 2,58 (m, 1 H), 1,68-of 1.95 (m, 5 H), 1,19-1,58(m, 5 H); LC/MS m/z (M+H+) 480,1 (calculated for C23H28F3N5OC, 479,57)
351-{1-[(4-butylphenyl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
1H NMR (300 MHz, CD3CN) δ 8,15 (d, J=4,9 Hz, 1 H), 7,95 (DDD, J=1,9, 7,2, 9,0 Hz, 1 H), 7,54 (d, J=8,3 Hz, 2 H), 7,30 (d, J=7.9 Hz, 2 H), made 7.16 interest (d, J=9,0 Hz, 1 H), 6,98 (t, J=6,6 Hz, 1 H), 4,24-4,73 (m, 4 H), 3,81-4,06(m, 5 (H), 3,25 (d, J=3.8 Hz, 4 H), 2,68 (t, 2 H), 1,51-1,71 (m, 2 H), 1,22-1,47 (m, 2 H), 0,79-of 1.05 (m, 3 H); LC/MS m/z (M+H+) 379,4 (calculated for C23H30N4O, 378,52)
361-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-yl)piperazine
1H NMR (300 MHz, CD3OD) δ 7,76 (s, 4 H), 7,60-7,71 (m, 2 H), to 7.33-7,53 (m, 3h), 7,29 (d, 1 H), of 6.99 (d, 1 H), 4,59-4,71 (m, 1 H), 4,37-4,59 (m, 2 H), 4,23-4,36 (m, 1 H), 3,88 (m, 1 H), 3,68-3,82 (m, 4 H), 2,98-3,20 (m, 4 H); LC/MS m/z (M+H+) 405,1 (calculated for C23H24N4OC, 404,54)
37N,N-diethyl-4-{[3-(4-pyridine-2-reparation-1-yl)azetidin-1-yl]carbonyl}aniline
1H NMR (300 MHz, CD3OD) δ 7,95-8,13 (m, 2 H), 7,63-7,74 (d, 2 H), 7,35 (d, 1 H), 6,98-made 7.16 interest (m, 3 H), 4,24-4,74 (m, 4 H), 3,84-of 4.04 (m, 5 H), 3,47-3,62 (q, 4h), 3,18 (m, 4 H), of 1.16 (t, 6 H); LC/MS m/z (M+H+) 394,4 (calculated for C23H31N5O, 393,54)
382-(4-{1-[(3-iodine-4-methoxyphenyl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
1H NMR (400 MHz, DMSO-d6) δ to 8.45 (d, J=4,9 Hz, 2 H), 8,02 (d, J=2,0 Hz, 1 H), 7,68 (DD, J=2,2, or 8.6 Hz, 1 H), was 7.08 (d, J=8,6 Hz, 1 H), was 6.77 (t, J=4,8 Hz, 1 H), 4,57-a 4.64 (m, 2 H), 4,52 (user. s, 2 H), 4,23-4,31 (m, 5 H), was 4.02-of 4.09 (m, 4 H); MS m/z (M+H+) of 480.2
391-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-pyridin-2-yl-piperazine
1H NMR (300 MHz, CD3CN) δ 8,02 (d, J=6,0 Hz, 1 H), 7,76 (TD, 1 H), 7,50 (t, 1 H), 7.23 percent-value of 7, 37 (m, 4 H), 7,02-7,13 (m, 2 H), 6,97 (d, J=9,0 Hz, 1 H), is 6.81 (t, J=6,2 Hz, 1 H), USD 4.61 (d, J=6,4 Hz, 2 H), 4,12-4,3 (m, 2 (H), of 3.80 (t, J=5.3 Hz, 5 H), is 3.08 (m, 4h), of 2.16 (s, 3 H); LC/MS m/z (M+H+) 581,1/583,1 (calculated for C29H27Cl3N6O, 581,94)
40N-(cyclohexylmethyl)-N-methyl-4-{3-oxo-3-[3-(4-pyridin-2-reparacin-1-yl)azetidin-1-yl]propyl}aniline
1H NMR (300 MHz, CD3CN) δ 8,15 (d, J=4,9 Hz, 1 H), 7,99 (DDD, J=1,9, 7,2, 9,0 Hz, 1 H), to 7.33-7,45 (m, 4 H), 7,21 (d, J=9,0 Hz, 1 H), 7,01 (t, J=6,6 Hz, 1 H), 4,48 (DD, J=4,7, and 9.6 Hz, 1 H), 4,33 (t, 1 H), 4,08-to 4.26 (m, 2 H), 3,79-4,07 (m, 5 H), 3,19-of 3.43 (m, 6 H), 3,15 (s, 3H), of 2.91 (t, J=7,3 Hz, 2 H), 2,43 (t, J=7,7 Hz, 2 H), 1,48-of 1.75 (m, 5 H), 1,27-of 1.47 (m, 1 H), 0.85 to 1.22 m (m, 5 H); LC/MS m/z (M+H+) 476,4
411-pyridin-2-yl-4-{1-[(2E)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3-yl}piperazine
1H NMR (300 MHz, CD3CN) δ 8,15 (d, J=4,9 Hz, 1 H), 7,96 (DDD, J=1,9, 7,2, 9,0 Hz, 1 H), 7,73 (s, 4 H), 7,56 (d, J=15,8 Hz, 1 H), 7,18 (d, J=9.4 Hz, 1 H), of 6.99 (t, J=6,6 Hz, 1 H), 6,71 (d, J=15,8 Hz, 1 H), 4,52-4,70 (m, 2 H), 4,20-4,39 (m, 2 H), 3,88-4,07 (m, 5 H), 3,16-3,37 (m, 4 H); LC/MS m/z (M+H+) 449,2 (calculated for C22H23F3N4OC, 448,51)
421-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-pyridin-2-yl-piperazine
MS m/z (M+H+) 399,3
432-(4-{1-[(4-chloro-3-itfinal)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
MS m/z (M+H+) 484,1
441-(1-{[4-(1,1-dimethylpropyl)phenyl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 393,3
451-{1-[(4-phenoxyphenyl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 415,2
462-[4-(1-{[4-(1H-pyrazol-1-yl)phenyl]carbonyl}azetidin-3-yl)piperazine-1-yl]pyrimidine
LC/MS m/z (M+H+) 390,1
471-{1-[(3-phenoxyphenyl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 415,2
482-(4-{1-[(3-iodo-4-methylphenyl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
MS m/z (M+H+) 464,2
492-phenyl-5-{[3-(4-pyridine-2-reparation-1-yl)azetidin-1-yl]carbonyl}-1H-benzimidazol
LC/MS m/z (M+H+) 439,3
502-(4-{1-[(3-iodo-4-methylphenyl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
MS m/z (M+H+) 464,2
512-(4-{1-[3-(4-iodophenyl)propanoic]azetidin-3-yl}piperazine-1-yl)pyrimidine
LC/MS m/z (M+H+) 478,0
521-{1-[(4'-forbiden-3-yl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 417,3
532-(4-{1-[(4-itfinal)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
MS m/z M+H+) of 450.1
541-{1-[(4-pentylcyclohexyl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 399,3
551-{1-[3-(4-tert-butylphenyl)propanol]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 407,3
561-(5-chloropyridin-2-yl)-4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine
LC/MS m/z (M+H+) 439,2
571-{1-[(6-metoxia-2-yl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 403,2
581-(1-{ [2-(benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 429,3
592-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}-9H-fluoren-9-it
LC/MS m/z (M+H+) 425,2
601-{1-[(2-forbiden-4-yl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
MS m/z (M+H+) 417,3
611-(1-{[4-phenyl-5-(trifluoromethyl)thiophene-2-yl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 473,2
625-(benzyloxy)-2-{[3-(4-pyridine-2-reparation-1-yl)but�lidin-1-yl]carbonyl}-1H-indole
LC/MS m/z (M+H+) 468,3
631-cyclohexyl-5-{(1E)-3-oxo-3-[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]prop-1-EN-1-yl}-2,3-dihydro-1H-indole
LC/MS m/z (M+H+) 472,4
642-(4-{1-[3-(3-iodophenyl)propanoic]azetidin-3-yl}piperazine-1-yl)pyrimidine
MS m/z (M+H+) 478,2
651-(1-{(2E)-3-[4-(1-methylethyl)phenyl]prop-2-enoyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 391,4
662-(4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine-1-yl)-1,3-benzoxazol
LC/MS m/z (M+H+) 445,4
671-[1-(biphenyl-3-yl-carbonyl)azetidin-3-yl]-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 399,3
681-(1-{[5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 567,2/569,1
692-{4-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-oxidability-1-yl}pyrimidine
MS m/z (M+H+) 416,2
701-{1-[(1,5-biphenyl-1H-pyrazol-3-yl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 465,3
71 2-[4-(1-{[4-(1H-imidazol-1-yl)phenyl]carbonyl}azetidin-3-yl)piperazine-1-yl]pyrimidine
LC/MS m/z (M+H+) 390,1
724-[5-(4-chlorophenyl)-3-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}-1H-pyrazol-1-yl]benzolsulfonat
LC/MS m/z (M+H+) 578,3/580,2
731-{1-[(2E)-3-biphenyl-4-yl-prop-2-enoyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 425,2
74Phenyl(4-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}phenyl)methanon
LC/MS m/z (M+H+) 427,4
751-(3-chloropyridin-2-yl)-4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine
LC/MS m/z (M+H+) 439,2
751-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}-4-(4-methylpyridine-2-yl)piperazine
LC/MS m/z (M+H+) 419,2
762-(4-{[3-(4-pyridine-2-reparation-1-yl)azetidin-1-yl]carbonyl}phenyl)-1H-isoindol-1,3(2H)-dione
LC/MS m/z (M+H+) 468,3
771-(5-bromopyridin-2-yl)-4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine
LC/MS m/z (M+H+) 483,1/485,2
781-{1-[(4-tert-butylcyclohexyl)carbonyl]�lidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 385,4
801-pyridin-2-yl-4-[1-({5-[3-(trifluoromethyl)phenyl]furan-2-yl}carbonyl)azetidin-3-yl]piperazine
LC/MS m/z (M+H+) 457,4
812-(3-{[3-(4-pyridine-2-reparation-1-yl)azetidin-1-yl]carbonyl}phenyl)-2,3-dihydro-1H-isoindol
LC/MS m/z (M+H+) 440,2
821-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
LC/MS m/z (M+H+) 473,2
841-(1-{[5-(4-methylphenyl)furan-2-yl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 403,4
851-[1-(biphenyl-4-yl-carbonyl)azetidin-3-yl]-4-(5-bromopyridin-2-yl)piperazine
LC/MS m/z (M+H+) 477,1/479,1
86Phenyl(3-{[3-(4-pyridine-2-reparation-1-yl)azetidin-1-yl]carbonyl}phenyl)methanon
LC/MS m/z (M+H+) 427,4
871-pyridin-2-yl-4-[1-(4-pyrrolidin-1-ylphenyl)azetidin-3-yl]-[1,4]diazepan
MS m/z (M+H+) 407,2
881-[1-(biphenyl-4-ylacetic)azetidin-3-yl]-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 413,3
891-[1-biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(2-methoxyphenyl)piperazine;
LC/MS m/z (M+H+) 428,3
902-{4-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazine-1-yl}-1,3-benzoxazol
LC/MS m/z (M+H+) 439,2
911-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[2-(methylsulfanyl)phenyl]piperazine
LC/MS m/z (M+H+) 444,1
921-(1-{[5-(4-methoxyphenyl)furan-2-yl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 419,2
936-(4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine-1-yl)pyridin-3-carbonitril
LC/MS m/z (M+H+) 430,2
942-(4-{1-[(4-nitrophenyl)carbonyl]azetidin-3-yl}piperazine-1-yl)pyrimidine
MS m/z (M+H+) 369,2
951-pyridin-2-yl-4-(1-{(2E)-3-[3-(trifluoromethyl)phenyl]prop-2-enoyl}azetidin-3-yl)piperazine
LC/MS m/z (M+H+) 417,2
961-[1-(9H-fluoren-1-ylcarbonyl)azetidin-3-yl]-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 411,3
976-{[3-(4-pyridin-2-reparacin-1-yl)azetidin-1-yl]carbonyl}-1,2,3,4-tetrahydroquinolin
LC/MS m/z (M+H+) 378,3
981-{1-[(4-cyclohex�phenyl)carbonyl]azetidin-3-yl}-4-(3-yodellin-2-yl)piperazine
MS m/z (M+H+) 531,2
991-{1-[(5-phenylfuro-2-yl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 398,2
1001-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}-4-(3-methylpyridine-2-yl)piperazine/MS m/z (M+H+) 419,2
1011-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
LC/MS m/z (M+H+) 467,3
1021-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(4-methylpyridine-2-yl)piperazine
LC/MS m/z (M+H+) 413,3
1031-[1-(2,3-biphenylmethanol)azetidin-3-yl]-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 427,4
1042-(4-{1-[(4-cyclohexylphenol)carbonyl]azetidin-3-yl}piperazine-1-yl)-1,3-benzothiazol
LC/MS m/z (M+H+) 461,2
1051-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(2-nitrophenyl)piperazine;
LC/MS m/z (M+H+) 443,2
1062-{4-[1-(biphenyl-4-yl-carbonyl)azetidin-3-yl]piperazine-1-yl}-1,3-benzothiazol
LC/MS m/z (M+H+) 455,1
1071-{1-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]azetidin�-3-yl}-4-pyridin-2-reparacin
MS m/z (M+H+) 389,3
1081-(1-{[2-phenyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 458,3
1091-{1-[(3-phenoxyphenyl)acetyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 429,3
1101-[1-(4-benzyl-phenyl)azetidin-3-yl]-4-pyrimidine-2-yl-[1,4]diazepan
MS m/z (M+H+) 428,2
1112-[4-(1-{[4-(benzyloxy)phenyl]carbonyl}azetidin-3-yl)piperazine-1-yl]pyrimidine
1H NMR (400 MHz, DMSO-d6) δ of 8.44 (d, J=4,9 Hz, 2 H), of 7.64 (d, J=8,8 Hz, 2 H), 7,44-7,49 (m, 2 H), 7,41 (t, J=7,2 Hz, 2 H), 7,32-7,38 (m, 1 H), 7,10 (d, J=8,8 Hz, 2 H), 6,76 (s, 1 H), 5,19 (s, 2 H), Of 4.54 - a 4.64 (m, 2 H), 4,45-of 4.54 (m, 2 H), 4,19-4,29 (m, 1 H), 3,93-4,10 (m, 4 H), 2,99 (user. C, 4 H); MS m/z (M+H+) 430,3
1121-(1-{[4-(benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
1H NMR (300 MHz, CD3CN) δ 8,01 (d, J=4.5 Hz, 1 H), 7,80 (DDD, J=1,9, 7,2, 9,0 Hz, 1 H), 7,44-7,56 (m, 2 H), 7,20-the 7.43 (m, 5 H), 7,02 (d, J=9,0 Hz, 1 H), 6,95 (d, J=7.9 Hz, 2 H), of 6.85 (t, J=6,4 Hz, 1 H), Of 5.06 (s, 2 H), 4,11-4,58 (m, 4 H), 3,72-of 3.91 (m, 5 H), is 3.08 (m, 4 H); LC/MS m/z (M+H+) 429,3 (calculated for C26H28N4O2, 428,54)
1131-{1-[(2E)-3-(3-ethoxyphenyl)prop-2-enoyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 393,3
1141-{1-[(4-benzoylphenyl)carbonyl]azetidin-3-yl}-4-(3-yodellin-2-yl)piperazine
MS m/z (M+H+) 539,2
1156-{[3-(4-pyridin-2-reparacin-1-yl)azetidin-1-yl]carbonyl}quinolin
LC/MS m/z (M+H+) 374,2
1162-{[3-(4-pyridin-2-reparacin-1-yl)azetidin-1-yl]carbonyl}quinolin
LC/MS m/z (M+H+) 374,2
1171-{1-[(3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 377,2
1181-(1-{[4-(benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4-(3-yodellin-2-yl)piperazine MS m/z (M+H+) 555,2
1191-{1-[(5-butylpyrazine-2-yl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) USD 380.2
1204-(benzyloxy)-2-{[3-(4-pyridine-2-reparation-1-yl)azetidin-1-yl]carbonyl}-1H-indole
LC/MS m/z (M+H+) 468,3
1215-{[3-(4-pyridin-2-reparacin-1-yl)azetidin-1-yl]carbonyl}-1H-indole; LC/MS m/z (M+H+) 362,3
122tert-butyl 4-(4-{[3-(4-pyridin-2-yl-piperazine-1-yl)azetidin-1-yl]carbonyl}phenyl)piperidine-1-carboxylate
LC/MS m/z(M+H+) 506,4
1231-(1-{[5-(phenylethynyl)furan-2-yl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 413,3
1244-{4-[3-(4-pyridin-2-yl-[1,4]diazepan-1-yl)azetidin-1-yl]phenoxy}piperidine-1-carboxylic acid tert-butyl ester
MS m/z(M+H+) to 522.3
1251-pyridin-2-yl-4-[1-(1,2,3,4-tetrahydronaphtyl-2-ylcarbonyl)azetidin-3-yl]piperazine
LC/MS m/z (M+H+) 377,2
1261-{1-[(2R)-2-(2-forbiden-4-yl)propanol]azetidin-3-yl}-4-pyridin-2-reparacin
MS m/z (M+H+) 445,3
1281-{1-[(4-interdecile[2,2,2]Oct-1-yl)carbonyl]azetidin-3-yl}-4-pyridin-2-reparacin
LC/MS m/z (M+H+) 425,4
1291-(1-{[5-(3,5-dichlorophenoxy)furan-2-yl]carbonyl}azetidin-3-yl)-4-pyridin-2-reparacin
LC/MS m/z (M+H+) to 473.1/475,2
1303-{[3-(4-pyridin-2-reparacin-1-yl)azetidin-1-yl]carbonyl}-9H-Xanten-9-it
MS m/z (M+H+) 441,3
1312-(3-{4-[(4-benzoylphenyl)carbonyl]piperazine-1-yl}azetidin-1-yl)pyrimidine
MS m/z (M+H+) of 414.2
1321-Fe�Il-6-{[3-(4-phenylpiperazin-1-yl)azetidin-1-yl]carbonyl}-1,2,3,4-tetrahydroquinolin
LC/MS m/z (M+H+) 453,2
1336-[(3-{4-[4-(trifluoromethyl)phenyl]piperazine-1-yl}azetidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinolin
LC/MS m/z (M+H+) 445,2
1341-[4-(trifluoromethyl)phenyl]-6-[(3-{4-[4-(trifluoromethyl)phenyl]piperazine-1-yl}azetidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinolin
LC/MS m/z (M+H+) 589,0
1351-[3-(trifluoromethyl)phenyl]-6-[(3-{4-[3-(trifluoromethyl)phenyl]piperazine-1-yl}azetidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinolin
LC/MS m/z (M+H+) 489,0

Example 2: Compound No. 139

(6 triptoreline[b]Tien-2-yl)-[3-(4-pyrimidine-2-reparation-1-yl)azetidin-1-yl]methanon

STAGE A: 4-(2,2,2-triptorelin)piperazine-1-carboxylic acid tert-butyl ester

To a solution of piperazine-1-carboxylic acid tert-butyl ester (10 g, 53,69 mmol) and pyridine (8,7 ml, 107,57 mmol) in CH2Cl2(100 ml) was added dropwise (CF3CO)2O (10.5 ml, 75,54 mmol) at 0°C. the resulting mixture was stirred at 0°C for 2 h. Then was added 2 N. HCl (60 ml). The organic layer was dried over MgSO4, filtered and concentrated. The obtained residue represented by the specified in the title compound, was used in the next reaction without further purification. MS m/z (M +-Boc) reached 183.1, (MH+-C4H9) 227,1;1H NMR (300 MHz, CDCl3): δ 3.45 m to 3.7 (m, 8H), of 1.5 (s, 9H).

Step B: 2,2,2-Cryptor-1-piperazine-1-ylatason

To a solution of compound 4-(2,2,2-triptorelin)piperazine-1-carboxylic acid tert-butyl ester (15,15 g, 53,69 mmol) in CH2Cl2(60 ml) was added trifluoroacetic acid (18 ml) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed by evaporation. To the residue was added diethyl ether (100 ml). A white solid was collected by filtration, washed with ether and dried under vacuum. The obtained residue represented by the specified in the title compound, was used in the next reaction without further purification. MS m/z (M+H+) Reached 183.1.

Step C: 1-[4-(1-benzhydrylamine-3-yl)piperazine-1-yl]-2,2,2-triptoreline

To a solution of 2,2,2-Cryptor-1-piperazine-1-retanna (6 g, 32,94 mmol) and 1-benzhydrylamine-3-ylmethanone (12.5 g, 39,38 mmol) in CH3CN (60 ml) was added DIPEA (12 ml, 68,89 mmol) at room temperature. The mixture was heated to reflux for 2 hours. The solvent was removed by evaporation and the residue was divided between CH2Cl2and an aqueous solution of NaHCO3. The organic layer was washed with aqueous solution of NaHCO3(2 times) and then was extracted with 1N HCl (2 RA�a). The aqueous layer was cooled, after which the pH was adjusted to basic (pH=10) with 1N NaOH. The resulting mixture was extracted using CH2C2(2×). The organic layer susheela over MgSO4and concentrated. Specified in the title compound was purified by the method of reversed-phase chromatography. MS m/z (M+H+) 404,2.

Step D. 1-(4-azetidin-3-reparacin-1-yl)-2,2,2-triptoreline

To a solution of 1-[4-(1-benzhydrylamine-3-yl)piperazine-1-yl]-2,2,2-triptoreline (2.11 g, 5,23 mmol) in CH2Cl2(60 ml) was added 1-chloroethylphosphonic (2.0 ml, to 18.35 mmol) at 0°C under a layer of N2. The resulting mixture was stirred at 0°C for 90 minutes and then was added ethanol (4 ml). Then the mixture was heated to reflux for one hour. After cooling, was added diethyl ether (50 ml). The obtained solid substance was collected by filtration and dried to obtain specified in the title compound, which was used for next reaction without further purification. MS m/z (M+H+) 238,1.

Step E: 6-(trifluoromethyl)benzo[b]thiophene-2-carbonylchloride

Oxaliplatin (2,29 mmol, 0.20 ml) was added to a solution of 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (2.03 mmol, 500 mg) CH2Cl2(15 ml). Was added DMF (15 μl) and stirred the resulting mixture for 4 h at room temperature. The resulting solution was concentrated to obtain 6-(trift�rmetal)benzo[b]Tiffin-2-carbonylchloride, which was used in next step without further purification.

STAGE F: 2,2,2-Cryptor-1-(4-(1-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)azetidin-3-yl)piperazine-1-yl)alanon

A solution of 6-(trifluoromethyl)benzo[b]thiophene-2-carbonylchloride(2.03 mmol, 537 mg) in CH2Cl2(5 ml) was added to a solution of 1-(4-azetidin-3-reparacin-1-yl)-2,2,2-triptoreline (2,26 mmol, 700 mg) and tea in CH2Cl2(15 ml) at 0ºC. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. After further processing and extraction of the residue was purified by the method of flash chromatography (silica gel, 3% methanol/CH2Cl2) to obtain 2,2,2-Cryptor-1-(4-(1-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)azetidin-3-yl)piperazine-1-yl)ethanone.

STAGE G: (3-(piperazine-1-yl)azetidin-1-yl)(6-(trifluoromethyl)benzo[b]Thien-2-yl)methanon

A solution of 2,2,2-Cryptor-1-(4-(1-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)azetidin-3-yl)piperazine-1-yl)ethanone (1,12 mmol, 520 mg) in 20 ml of methanol and tea (2 ml) was stirred at room temperature for 3 days. The mixture was concentrated to obtain (3-(piperazine-1-yl)azetidin-1-yl)(6-(trifluoromethyl)benzo[b]thiophene-2-yl)methanone, which was used for next step without purification.

STAGE H: (3-(4-(pyrimidine-2-yl)piperazine-1-yl)azetidin-1-yl)(6-(trifluoromethyl)benzo[b]Thien-2-yl)methanon (Compound No. 139)

A mixture of (3-(Pieper�Zin-1-yl)azetidin-1-yl)(6-(trifluoromethyl)benzo[b]thiophene-2-yl)methanone (0.14 mmol, 50 mg), 2-bromopyrimidine (0,23 mmol, 37 mg) and K2CO3(0.34 mmol, 47 mg) in THF (3 ml) and water (1.5 ml) was heated to reflux for 8 h. After treatment and extraction of the residue was purified by the method of flash chromatography (silica gel, 3% methanol/CH2Cl2) to obtain (3-(4-(pyrimidine-2-yl)piperazine-1-yl)azetidin-1-yl)(6-(trifluoromethyl)benzo[b]thiophene-2-yl)methanone in the form of a solid substance of white color.

1H NMR (400 MHz, CDCl3) δ of 8.33 (d, J=4,6 Hz, 2 H), 8,16 (s, 1 H), 7,95 (d, J=8,3 Hz, 1 H), 7,74 (s, 1 H), 7.62 mm (d, J=8,3 Hz, 1 H), a 6.53 (t, J=4,6 Hz, 1 H), 4,55-4,70 (m, 1 H), 4,40-4,55 (m, 1 H), the 4.25 to 4.40 (m, 1 H), 4,17 (m, 1 H), 3,89 (m, 4 H), of 3.33 (m, 1 H), 2.49 USD (m, 4 H); LC/MS m/z (M+H+) 448 (calculated for C21H20F3N5OS, 448,1).

Example 3 (in vitro study): determination of the activity of the enzyme MGL

All kinetic studies were carried out in 384-well black polypropylene microplate for polymerase chain reaction (PCR) production Abgene with a total volume of 30 µl. The substrate, 4-methylumbelliferone (4MU-B; Sigma), and purified mutant MGL enzyme (mut-MGLL 11-313 L179S L186S), or the purified enzyme wild-type MGL (wt-MGLL 6H-11-313) separately dissolved in 20 mmol of buffer solution (pH=7.0) was 1,4-piperazineethanesulfonic acid (PIPES) containing 150 mmol NaCl and 0.001% tween 20, the compounds of formula (I), pre-made (50 nl) in plate wells for analysis using a system of Cartesian Hummingbird (Genomic olutions, Ann Arbor, MI), and then added 4MU-B (25 μl of 1.2 X of the solution to a final concentration of 10 μm) and the enzyme (5 μl of 6X solution to a final concentration of 5 nm) to initiate the reaction. The concentration of the final product ranged from 17 up to 0.0003 μm. The change in fluorescence due to cleavage of 4MU-B was detected by measuring excitation and emission at a wavelength of 335 and 440 nm, respectively, with a bandwidth of 10 nm (Safire2, Tecan) at 37°C for 5 min.

To determine the percentage of inhibition was measured initial velocities in a pre-specified range of the stationary state (< hydrolysis of the substrate is 10%). The percentage inhibition was calculated by the following equation:

% inhibition=[(maximum speed - the speed of the inhibition)×100]/maximum speed.

Value IR50for compounds of formula (I) were determined using the Excel program on the results of the fit of the equation to the graph of the concentration-response fractional activity depending on the concentration of the inhibitor.

Example 4 (in vitro): test system MGL ThermoFluor®

In the test system ThermoFluor (TF) is used 384-well plates for measurement of thermal stability of proteins by binding (Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R., J Diomol Screen 2001, 6, 429-40; Matulis, D., Kranz, J. K., Salemme, F. R. and Todd M. J., Biochemistry 2005, 44, 5258-66). The experiments were carried out using the tools supplied by Johnson & Johnson Pharmaceutical Research & Development, LLC. As a colorant in all the experiments, a 1,8-ANS (Invitrogen: A-47). Final terms TF method for determining the activity of MGL were as follows: 0.07 mg/ ml of purified mutant MGL (mut-MGLL 11-313 L179S L186S), 100 µmol ANS, 200 mmol NaCl and 0.001% Tween-20 in 50 mmol PIPES (pH=7,0).

Tablets for screening compounds contained solutions of compound in 100% DMSO at the same concentration. For further study the dependence of the concentration-response connections are made in plate wells (Greiner Bio-one: 781280), in serial dilutions in 100% DMSO, using 11 rows of holes for each of a series of studies. Rows 12 and 24 were used as the DMSO-control and did not contain compounds. In experiments with single and multiple measurement of the ratio of the concentration-response aliquots, connections are automatically made into black 384-well polypropylene microplates for PCR (Abgene: TF-0384/k) using the machine for dispensing liquids Cartesian Hummingbird (Genomic Solutions, Ann Arbor, MI). After making connections in the wells was added to the protein solutions and the dye to a final volume of 3 µl. On poverhnosti reaction mixture was applied 1 μl of silicone oil (Fluka, type DC 200: 85411) to protect from evaporation.

Tablets with a bar code automatically�Eski loaded in a thermostatic block for PCR and heated to a temperature of from 40 to 90°C at a rate of 1°C/min. for all the experiments. Fluorescence was measured by continuous illumination with UV light (Hamamatsu LC6) via fiber optics and passing through the bandpass filter (380-400 nm; > the cut-off of 6 O. P. units). Fluorescence emission of the entire 384-well plates opredelyali by measuring light intensity using a CCD camera (Sensys, Roper Scientific) using filters 500±25 nm, which allowed for simultaneous and independent read all 384 wells. For each value of the temperature got one shot at exposure time 20 sec., and the sum of pixel intensities in this region of the investigated tablet and substituted into the standard equation, obtaining the value of Tm(Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R., J Biomol Screen 2001, 6, 429-40).

Example 5: Test system for the determination of the accumulation of 2-AG by using HeLa cells

HeLa cells homogenized with a Polytron in 10 ml (about 400 million cells) of buffer HEPES (20 mm HEPES, pH 7.4, 125 mm NaCl, 1 mm EDTA, 5 mm KCl, 20 mm glucose). Homogenate from 20 million cells (0.5 ml) was incubated with MGL inhibitor for 15 min to block the activity of MGL, and then the buffer solution HEPES were incubated with calcium (10 mm) for 20 min. the Total reaction volume was 5 ml. the Reaction was stopped with 6 ml of organic solvent extract (2:1 chloroform/me�anal). As a positive control used methoxyacetophenone (the MUFF). In the absence of the MUFF the content of 2-AG was reached about 3.4 pmol/sample. In the presence of 100 nm in the MUFF 2-AG was increased to 174 pmol/sample. Accumulated in the organic phase 2-AG was determined by the method NRGH/MS and calculated the number from the following equation: %the MUFF=(Compound 2-AG/the MUFF 2-AG)×100.

Representative compounds of formula (I) have been tested in accordance with the procedure described in examples 3, 4 and 5 above, with the results shown in table 3.

tr> td align="left">
Table 3
Conn, No.Example 3
(mutant)
IR50(μm)
Example 3
(wild type)
IR50(μm)
Example 4
Kd (ám)
Example 5
% The MUFF
@ 1 µm
Example 5
% The MUFF
@ 10 µm
1<0,0050,01070,5
2<0,0050,003 105,1
3<0,0050,00867,3
40,0060,002111,5
50,0070,05098,8
60,0080,0160,01424,3A 41.5
70,0090,002
80,0090,01858,3
90,0090,00881,0
10 0,0100,00797,8A total of 115.4
110,0120,00455,2
120,006, 0,009, 0,015, 0,0170,0090,014, 0,025For 63.1107,9
13<0,0130,010
140,0160,012105,9
150,0180,0400,09247,6
16Is 0.019Of 0.02191,5
17Is 0.019 0,00783,9
18Of 0.0210,03866,2
190,0220,018
200,023<0,0050,06271,9
210,0240,0110,02579,5
220,0260,017
230,0270,03696,8
240,0300,042 81,9
250,0320,05987,7
260,032<0,0050,051124,6
270,0340,0600,05566,2110,1
280,0350,08382,2
290,0370,22976,5
300,0400,0380,33334,737,3
310,0480,0150,04269,5
320,0510,029
330,0550,02717,533,0
340,0550,084
350,0550,37366,7
36Of 0.0560.031 inch91,3
370,0620,04432,065,9
380,0630,192
390,07 0,010,18287,6
400,0780,45177,390,4
410,0840,39566,8
420,1040,162Amount of 0.118
430,1040,400
440,1270,556
450,1400,244
460,1520,44
470,1601,021
480,1620,435
490,1690,704
500,1790,284
510,1960,417
520,2000,8231,90028,052,2
530,2390,333
54To 0.2631,319
550,2710,364
560,2790,250
570,2910,577
580,346Distributed among 1.083
590,4002,30010,239,7
60Is 0.4500,31328,257,8
610,462 2,182
620,5134,546
630,5182,500
640,5470,769
650,5490,488
660,6144,731,282
670,6200,794
680,6241,000
690,7351,389
700,7490,952
710,7613,226
720,9670,476
731,0021,782
741,2002,20029,5
751,5361,923
751,283 0,769
761,3623,849
771,3683,030
781,4664,584
801,75012,500
812,0571,161
822,2294,546
832,8022,381
843,1608,333
853,4534,545
863,1022,381
865,30010,20010,4
873,9871,538
884,0007,1012,8
894,5036,250
4,5760,769
914,6646,250
92>5,000344,546
935,1092,857
945,4014,000
955,4514,189
965,60015,1980,0
975,880 3,571
986,0285,556
996,10012,987
1006,5006,667
1016,5156,667
1026,5931,300
1039,42545,646
10410,10922,223
10511,403>in 76.7
10612,48212,500
10712,85011,363
10813,26224,998
10913,33832,255
1101,6872,000
111<0,0130,014106,5
112 0,0240,12079,2
1137,0994,000
1147,97610,000
1158,1306,667
1168,7006,845
11710,66118,180
1182,330>in 76.7
1192,349 4,518
1202,7812,941
1213,0802,500
1220,1310,41367,8
1233,4603,226
124To 0.2630,541
12510,7897,143
12613,240>in 76.7
1285,6119,999
1297,539,806
1300,6530,909
1310,6280,340
1321,2276,049
133Was 0.84415,157
1344,290>31,2
13510,792 >31,2
1390,0060,0250

Compound No. 200-223 investigated in a similar manner according to the methods of analysis described in Examples 3, 4 and 5 above; the results are shown in the following table 4.

Table 4
Conn. No.Example 3 (mutant)
IR50(μm)
Example 4
Kd (ám)
Example 5
% The MUFF @ 1 µm
Example 5
% The MUFF @10 µm
20015,212,5
201Of 15.3>in 76.7
202>15,325
203&t; Of 15.331,2
204>15,3>19
205>15,3>in 76.7
206>16,712,5
207>15,312,5
208>15,316,7
2091,070,17219,947,3
2100,1860,083379,5
2110,0500,13039,7100,8/td>
2120,2200,33072,9
2130,8104,5561,1
2140,4300,03093,5
2150,06040,0020
216To 1.34The 5.56Of 86.9
217>15,3>in 76.7
218>15,3>in 76.7
219>15,3>in 76.7
220>15,3
221>15,317,2
222>15,3>in 76.7
223>17>31,2

Example 6 (in vivo study)

Swelling of the feet, experimentally induced by carrageenan, in mice C57Bl/6

Introduction carrageenan: male mice C57Bl/6 (Taconic) were subjected to a light sedation gas mixture of 30% oxygen and 70% carbon dioxide. With a syringe with a 27G needle in the interdigital space of the ventral surface of the right hind paw was injected with 20 μl of 2% carrageenan solution (wt./about.) in physiological solution. Control group were injected with same volume of saline. After the recovery period, we measured the volume of the paw as an indicator of tissue swelling and inflammation.

Measurement of paw volume: increase the volume after injection of carrageenan is a measure of tissue edema and inflammation. Swelling of the paws was measured by a water plethysmometer (Ugo Basaile) at initial time and after 0.5, 1, 2 and 4 h after injection. We calculated the percentage change in the paw volume compared to the original.

Compound No. 12 was dissolved in 20% solution of hydroxypropyl-beta-cyclodextrin immediately prior to administration at a dose of 30 mg/kg in a volume of 10 ml/kg Dose of Compound No. 12 was administered once orally 30 min before carrageenan injection. The control group media were given a single dose of 20% hydroxypropyl-beta-cyclodextrin in the dose of 10 ml/kg orally.

Introduction compounds before injection (inside)Injection into the interdigital space
20% HPbCDsaline
20% HPbCD2% carrageenan
Compound No. 12, 30 mg/kg2% carrageenan

Results: after 4 h after injection of carrageenan caused an increase in the paw volume compared to the volume of the paws of animals treated with saline (34,5±8.2% and down 10.7±2.4%, respectively; p<0,001). The introduction of Compound No. 12 in a dose of 30 mg/kg n/a 30 minutes before carrageenan injection inhibited the increase in paw volume after 4 h after injection compared with animals treated before injection of carrageenan-only media (17,7±3,3% and 34.5±8.2 per cent, the corresponding�but; p<0,04).

Example 7 (in vivo study): neuropathic pain

Sciatic nerve plays a major role in sensitive-motor innervation (hind) limbs and paws. Damage to the sciatic nerve or spinal nerves forming it is often accompanied by behavior that is characteristic of the pain response. In rats and mice tight ligation of spinal nerve L5 silk thread, partial tight ligation of the sciatic nerve with silk thread or loose ligation of the sciatic nerve chromed catgut causes the behavior that resembles the symptoms of neuropathic pain in humans. These interventions (one for each animal) are carried out surgically under anesthesia. Damage and spinal cord, and sciatic nerve leads to the degree, painful response to normal harmless stimuli and hyperalgesia, enhanced response to mild pain stimulus. In addition to nerve damage resulting from accidental injury or surgical procedures, neuropathic pain may be induced by diabetes (Fox, A et al., Pain 81:307-316, 1999) or treatment with chemotherapeutic drugs, such as paclitaxel or vincristine (Yaksh, TL et al., Pain 93:69-76, 2001).

Drugs to facilitate neuropathic pain in humans, are also effective in experimentally induced pain in rodents. These drugs vklyucheniyav approved tool Cymbalta (Duloxetine, Iyengar, S., et al., JPET 2004 311:576-584), morphine (Suzuki, R et al., Pain 1999 80:215-228) and gabapentin (Hunter, JC et al., Eur J Pharmacol 1997 324:153-160). Dual receptor antagonist TRPV1/TRPM8 BCTC reduced mechanical hyperalgesia and tactile allodynia in neuropathic pain induced by prolonged compression, in experiments on rodents (Pomonis, JD et al., JPET 2003 306:387-393; Behrendt, H et al., Brit J Pharm 2004 141:737). Cold allodynia - especially exhausting symptom for conditions involving neuropathic pain (Jorum E et al. Pain 2003 101: 229-235). The effect of the compounds of Formula (I) as described herein, expressed in the decrease of the degree, in similar experiments on rodents, it is possible to predict the clinical effects of these new drugs in humans.

Example 7a (in vivo study)

Neuropathic pain experimentally induced by chronic compression of the nerve damage; hypersensitivity test induced by acetone

To assess the ability of selected compounds of Formula (I) to pay cold hypersensitivity induced by compression, used male rats Sprague-Dole (225-450 g; n=5-8/experimental group). Around the left sciatic nerve under inhalation anesthesia was placing four loose ligatures chrome catgut 4-0, as described by Bennett et al. (Bennett GJ, Xie YK. Pain 1988, 33(1): 87-107). Through 14-35 days after �of masterstva experimental animal was placed in a raised cage for observation with a wire bottom, then at intervals of about 5 minutes on the plantar portion of the feet are five-inflicted 0.05 ml of acetone using a multi-dose syringe. A positive reaction was considered to be a sharp pulling or lifting of the paw. For each animal recorded the number of positive reactions to 5 doses of acetone. After determining the number of atdelivery paws in initial moment of time the animals were administered compounds of the formula (I) in a suitable medium such as hydroxypropyl-β-cyclodextrin (HP β CD), methylcellulose, Methocel, 10% Solutol, or H2O, etc., appropriate way, in a/b or inside. In 1-4 hours after administration of the compound again determined the number of flick ex paws. The results were reported as percentage reduction reaction, which was calculated for each animal using the formula: [1-(number of flick ex after administration of a compound/the number of flick ex before the introduction of the compound)]×100, and then find the average between the indices of all the animals that received the connection. Compound No. 12 was tested according to the method described above, the results are shown in Table 5.

Table 5
Compound No. 12 (HCl salt); 30 mg/kg orally in 20% HPbCD
BP�mya Wadena before treatment, hThe percentage of suppression
157,1
274,3
380,0
448,6

Example 8 (in vivo study): a model of visceral hyperalgesia

This Protocol is used Isobaric stretching of the rectum and colon as measured by barrele, to assess the effectiveness of the ability of the compounds to facilitate the visceral hyperalgesia. Male rats Sprague-Dole (275-350 g) (Charles River Labs) contained 2-4 animals in a cage in a room with controlled temperature and humidity and a 12-hour light cycle, with unlimited access to feed and water. The day after the end of the quarantine rats acclimatized to elongating (30 min and 4 hours later, 45 min. periods of being in a confined space device made of plexiglass (G-3, rat ECU; Braintree Scientific; Braintree, MA). At night the rats were returned to cages. The next day the rats were placed in the device is made of plexiglass on 60 minutes in the morning and after 4 h; then gave a light anesthesia 70% CO2: 30% O2and inserted into the rectum and distal part of the colon through the anus plastic cylinder of length 4 with�, well corresponding in shape and lubricated with gel brand K-Y®. The balloon is disposed so that its aboral end was located at a distance of 1 cm from the anus, and secured by attaching the balloon catheter to the base of the tail. The catheter was connected to a computerized barrele regulating balloon inflation and, consequently, the stretching of the bowel wall. Continuously checked the cylinder pressure corresponding to the pressure inside the colon.

I renarcotization animals stretching of the rectum and the colon is a reflex visceromotor response (VMR), accompanied by contractions of the muscles of the anterior abdominal wall (Ness TJ, Gebhart GF, Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat, Brain Res 1988, 450: 153-169). Contraction of these muscles increases intra-abdominal pressure and consequently the pressure in the colon. The change in pressure in the colon is passed through the same cylinder used for stretching. Gauge GIR simulates myoelectric response recorded by electrodes placed on the muscles of the anterior abdominal wall of rats (Tammpere A, Brusberg M, Axenborg J, Hirsch I, Larsson H, Lindstrom and E., Evaluation of pseudo-affective responses to noxious colorectal stension in rats by manometric recorngs, Pain 2005, 116: 220-226).

Data on the dependence of stimulus-response was obtained by two series of 20-second experimental method� with stretching, when pressure was increased by stages (20 kPa (15 mm Hg.CT.)) every 4 minutes and recorded gauge the reaction as described below: the signal of the pressure inside the colon was passed through a digital high-pass filter of 1 Hz and adjusted, and from the decimal part of the values of the stretching of the gut in the first 15 seconds subtracted baseline value (15 sec. immediately before the stretching of the cylinder); then we calculated the average gauge GIR after subtracting a base value to get the ratio of stimulus-response for each rat. Then the cylinders were removed and returned to the rats in the cage.

The next morning was induced colitis by bolus injection into the colon of 2.5% (wt./about.) zymosan And Saccharomyces cerevisiae; Sigma Chemical Co., St. Louis) in 30% ethanol under light anaesthesia 70% CO2: 30% O2. Four hours later, under light anaesthesia through the anus injected the bladder to stretch as the previous day. The cylinders pumped to the design of strain gauge and recorded visceromotor response, and then the data were analyzed as described for the control phase of the experiment. After that, rats were injected subcutaneously (s/to) 1 mg/kg with 3, 10 or 30 mg/kg of a compound which was solubilizers 20% hydroxypropyl-β-cyclodextrin (N=14, 10 and 6, respectively). 20 minutes after the introduction caused �asthenia rectum and colon. The tensile pressure of 6.0 kPa (45 mmHg. calendar) evoked peak response in control conditions (before doing zymosan); therefore, reaction cadley rats was calculated as a percentage of the gauge GIR at the same pressure registered on the day before induction of colitis; thus, each rat served as its own control. The measurement results of the BMP at 6.0 kPa (45 mmHg. calendar) after the introduction of zymosan not greater than 100% of control (N=7) were excluded.

Compound No. 12 (30 mg/kg, n/a) caused a reversion hyperalgesia reaction to the tensile pressure of 6.0 kPa (45 mmHg. calendar) in this model of visceral pain (103,8±22.1% of control values compared with 239,6±28,9% of control values in rats treated with solvent (P<0,001 when compared with the control).

Example 9 (in vivo study): hypercapitalist the clutches of the heat radiation induced complete adjuvant of franda

Each rat was placed in the chamber for studies on temperature-controlled glass surface and left for about 10 minutes to get used to new conditions. Then on the plantar surface of each hind paws of rats were operated thermal stimulus (beam of light) through the glass. Thermal effect was automatically stopped photoelectric relay when the paw was moving or if completed PE�iodine exposure (20 sec. thermal radiation). For each of the rats was fixed initial (natural) period of response to thermal stimulus, after which the animals were totally adjuvant freind (CFA). After 24 hours after the administration of adjuvant to the reaction time of animals to thermal stimulus was again measured and compared with the initial one. The analysis was continued only for rats, which occurred at least a 25% reduction in reaction time (i.e. there was hyperalgesia). Immediately after evaluating the reaction time after administration of CFA rats were administered the investigational compound or vehicle (solutol, hydroxypropylmethyl cellulose, hydroxypropyl-beta-cyclodextrin or PEG-400)/b or inside. Then after a certain period of time (usually 30, 60 and 120 min) were assessed by reaction time (straightening legs). The degree of reversion of hypersensitivity in % was calculated by the following formula: % reversal=(reaction time after the introduction of the reaction time before the introduction)/(initial (before the introduction CFA) reaction time before the introduction)×100,

Compound No. 12 (in the form of the corresponding HCl salt) was administered in the form of a solution of 20% HPβCD at a dose of 30 mg/kg/W, the treatment time was 30 minutes. Found that the compound causes 90.3% of the reversion of hypersensitivity and ED50is 0.9 mg/kg.

Example 10: Solid oral form of an example of the possible used�I

As a specific example of the invention in the form of dosage forms for oral delivery, 100 mg of the obtained Example 1 compound No. 12 is stirred with sufficient finely divided lactose to total mass in the range from 580 to 590 mg to obtain a composition for filling hard gelatin capsules of size O.

The above technical description contains information about the principles underlying the present invention, and illustrating his examples, but you should understand that the practical application of the invention extends to all of the usual variations, adaptations and/or modifications in accordance with the following claims and their equivalents.

1. The compound of formula (I)

where
Y is a phenyl or heteroaryl selected from the group consisting of thiazolyl, pyridyl, pyrimidinyl, 1,3,5-triazinyl, benzoxazolyl, benzisoxazole, benzothiazole and 1,3,4-thiadiazolyl;
wherein the phenyl or heteroaryl optionally substituted by one Deputy, selected from the group consisting of fluorine, chlorine, bromine, iodine, C1-4of alkyl, trifloromethyl, S1-4alkoxy, C1-4alkylthio, nitro and cyano;
r is an integer from 1 to 2;
R2is missing or oxo-group;
Z is selected from the following:
(a) phenyl, sameshe�tion NR aRb;
where Rais hydrogen or C1-4by alkyl; where Rbrepresents C1-4alkyl, cycloalkyl, phenyl, furylmethyl or phenyl(C1-2alkyl); and where the phenyl in the group Rbthe phenyl group of phenyl(C1-2alkyl) as Rbor furanyl as part of a group of furylmethyl as Rboptionally substituted with iodine;
alternatively, Raand Rbtogether with the nitrogen atom to which they are connected, form a 5-8-membered heterocyclyl, which is optionally condensed with benzene ring;
(b) biphenyl-3-yl or biphenyl-4-yl; where the internal phenyl ring connected to the carbonyl in formula (I), optionally substituted by a fluorine atom, and where terminal phenyl ring optionally substituted Deputy selected from the group consisting of trifloromethyl, S1-4alkoxy, chlorine, dichloro, fluorine and iodine;
(c) phenyl, substituted Deputy selected from the group consisting of C5-8cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbamoyl, phenyl(C1-3)alkyl, phenyl(C1-3)alkoxy, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-1,3-dione, 2,3-dihydroindol-2-yl; 1-(tert-butoxycarbonyl)piperidine-4-yloxy and 1-(tert-butoxycarbonyl)piperidine-4-silt;
(d) phenyl, substituted by one or two substituents, independently selected from the group Castiadas: C 1-6alkyl, C1-4alkoxy, iodine, chlorine and nitro;
(e) phenyl(C1-2)alkyl, where phenyl optionally substituted by one or two substituents, independently selected from the group consisting of iodine, fluorine, C1-6of alkyl, phenyl and NRcRd; where Rcrepresents hydrogen or C1-4alkyl; where Rdrepresents C1-4alkyl or C3-6cycloalkyl(C1-4)alkyl; and where C1-2alkyl group, phenyl(C1-2)alkyl optionally substituted by phenyl;
(f) phenyl(C2-4)alkenyl; phenyl optionally substituted Deputy selected from the group consisting of C1-4alkyl, C1-4alkoxy, trifloromethyl, triptoreline and phenyl;
(g) naphthyl; naphthyl optionally substituted With one1-
4alkoxy-Deputy;
(h) fluorenyl or xantinol; where fluorenyl or xantinol optionally substituted by oxo group;
(i)5-8cycloalkyl; where C5-8cycloalkyl optionally substituted with one C1-6alkyl Deputy;
(j) condensed with a benzene ring cycloalkyl5-8or condensed with benzene ring C5-8cycloalkyl(C1-4)alkyl, where specified With5-8cycloalkenyl fragment optionally substituted by 1-4 methyl groups;
(k) bicyclo[2.2.2]octyl-1-yl; bicyclo[2.2.2]octyl-1-yl optionally substituted C1-6by alkyl;
(l) heteroaryl or heteroaryl, condensed with a benzene ring selected from the group consisting of benzoxazolyl, chinoline, benzimidazolyl, pyridinyl, indolyl, teinila, furanyl, pyrazolyl, oxazolyl, benzothiazyl and benzofuranyl;
where heteroaryl or heteroaryl, condensed with a benzene ring, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4of alkyl, trifloromethyl, S5-8cycloalkyl, phenyl, phenyl(C1-2)alkoxy, phenyl(C2-4)alkynyl and dichlorophenoxy; and where the phenyl substituent in the composition of heteroaryl additionally optionally substituted C1-4the alkyl, C1-4alkoxy or trifluoromethyl sulfide;
(m) 1,5-biphenyl-1H-pyrazol-3-yl; pyrazol-3-yl optionally substituted with a methyl group; and where each of the phenyl groups of the 1,5-biphenyl substituents are also optionally substituted by substituents selected from chlorine, dichloro or aminosulfonyl;
(n) 1,2,3,4-tetrahydroquinolin-6-yl, where 1,2,3,4-tetrahydroquinolin-6-yl optionally substituted by phenyl or triftormetilfullerenov by phenyl; and
(o) heterocyclyl(C2-4)alkenyl, condensed with benzene ring; where condensed with a benzene heterocyclyl connected With2-4alkenyl through the benzene ring; and where heterocyclyl, condensed with a benzene ring, optionally neobyazatel� substituted C 5-6cycloalkyl;
or its enantiomer, diastereoisomer or pharmaceutically acceptable salts;
provided that the compound of Formula (I) is not
the compound in which Y represents a 3-methylpyridine-2-yl, r=1, R2no, a Z is 4-biphenyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-(phenylcarbamoyl)phenyl;
the compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2no, a Z is a 4-cyclohexylphenol;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z represents 3-(cyclohexylcarbonyl)phenyl;
the compound in which Y represents a 5-cyanopyridine-2-yl, r=1, R2no, a Z is 4-biphenyl;
the compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2absent, a, Z is 4-biphenyl;
the compound in which Y represents pyrimidine-2-yl r=2, R2absent, a, Z is 2-(4 triftormetilfullerenov)vinyl;
the compound in which Y is pyridin-2-yl r=1, R2no, a Z is a 2-phenylphenyl;
the compound in which Y is pyridin-2-yl r=1, R2absent, a, Z is 2-phenylethyl;
a compound in which Predstavljaet a pyridin-2-yl r=1, R2no, a Z is a 2-tert butylbenzoate-6-yl;
the compound in which Y is pyridin-2-yl r=1, R2absent, a, Z is 2-(4 methoxyphenyl)benzoxazole-7-yl;
the compound in which Y is pyridin-2-yl r=1, R2no, a Z is a 2 cyclohexylbenzothiazole-6-yl;
the compound in which Y is pyridin-2-yl r=1, R2no, a Z is a 1,2-Diisobutyl-1H indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z represents a 1-methyl-2-propyl-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 1-isobutyl-2-phenyl-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 1-isobutyl-2-(4-methylphenyl)-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2absent, a, Z is 2-(3-methoxyphenyl)benzoxazol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-benzylphenol;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a (1R)-1,2,3,4-tetrahydronaphthalene-1-yl;
the compound in which Y �predstavljaet a pyridin-2-yl, r=1, R2no, a Z is a (1S)-1-[4-(2-methylpropyl") phenyl]ethyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a (1S)-1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2,3-dihydro-1H-indene-2-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is 2,2-biphenylyl; or
the compound in which Y represents a 3-triptoreline, r=1, R2no, a Z represents a 1,2,3,4-tetrahydroquinolin-6-yl.

2. The compound according to claim 1, where
Y is selected from the group consisting of phenyl, pyridyl, pyrimidyl, 1,3,5-triazinyl, thiazolyl, 1,3,4-thiadiazolyl, benzoxazolyl, benzisoxazole and benzothiazolyl; where the phenyl, pyridyl, pyrimidyl, 1,3,5-triazinyl, thiazolyl, 1,3,4-thiadiazolyl, benzoxazolyl, benzisoxazole, benzothiazole optionally substituted Deputy selected from the group consisting of cyano, fluorine, chlorine, bromine, iodine, C1-4of alkyl, trifloromethyl, S1-4alkoxy, C1-4alkylthio and nitro;
r is an integer from 1 to 2;
R2is missing or oxo-group;
Z is selected from the following group
(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4and�keel; and Rbrepresents C1-4alkyl, cycloalkyl, phenyl, furylmethyl, or phenyl(C1-2alkyl); and where the phenyl in the group Rbthe phenyl group of phenyl(C1-2alkyl in Rbor furanyl in the composition of furylmethyl in Rboptionally substituted with one atom of iodine; alternatively, Raand Rbtogether with the nitrogen atom to which they are attached, form a 5-6-membered heterocyclyl, which is optionally condensed with a benzene ring group;
(b) biphenyl-3-yl or biphenyl-4-yl; wherein the terminal phenyl ring optionally substituted Deputy selected from the group consisting of trifloromethyl, S1-4alkoxy, chlorine, dichloro, fluorine and iodine;
(c) phenyl, substituted Deputy selected from the group consisting of C5-8cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbamoyl, phenyl(C1-3)alkoxy, benzyl, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-1,3-dione, 2,3-dihydroindol-2-yl; 1-(tert-butoxycarbonyl)piperidine-4-yloxy and 1-(tert-butoxycarbonyl)piperidine-4-silt;
(d) phenyl, substituted by one or two substituents, independently selected from the group consisting of C1-6alkyl, C1-4alkoxy, iodine, chlorine and nitro;
(e) phenyl(C1-2)alkyl, where phenyl optionally substituted by one or two substituents, independently selected from the group consisting of iodine, fluorine, C 1-6of alkyl, phenyl and NRcRd; where Rcrepresents hydrogen or C1-4alkyl; and where Rdrepresents C1-4alkyl or C3-6cycloalkyl(C1-4)alkyl; and where C1-2alkyl phenyl(C1-2)alkyl group optionally substituted by phenyl;
(f) phenyl(C2-4)alkenyl; phenyl optionally substituted Deputy selected from the group consisting of triptoreline, S1-4alkyl, C1-4alkoxy, phenyl and trifloromethyl;
(g) naphthyl; naphthyl optionally substituted With one1-4alkoxy-Deputy;
(h) fluorenyl or xantinol; where fluorenyl or xantinol optionally substituted by oxo group;
(i)5-6cycloalkyl;5-6cycloalkyl optionally substituted With one1-5by alkyl;
(j) condensed with a benzene ring cycloalkyl5-6or condensed with benzene ring C5-6cycloalkyl(C1-4)alkyl, where specified With5-6cycloalkenyl fragment optionally substituted by 1-4 methyl groups;
(k) bicyclo[2.2.2]octyl-1-yl; bicyclo[2.2.2]octyl-1-yl optionally substituted C1-6by alkyl;
(1) heteroaryl or heteroaryl, condensed with benzene ring selected from the group consisting of benzoxazolyl, chinoline, benzimidazolyl, pyridinyl, indolyl, teinila, furanyl, pyrazolyl, oxazolyl, b�isotianil and benzofuranyl;
where heteroaryl or heteroaryl, condensed to the benzene ring may independently be substituted with one or two substituents, independently selected from the group consisting of C5-6cycloalkyl, S1-4of alkyl, phenyl, trifloromethyl, phenyl(C1-2)alkoxy, dichlorophenoxy and phenylethynyl; and where the phenyl substituent of heteroaryl additionally optionally substituted Deputy selected from the group consisting of methyl, methoxy or trifloromethyl;
(m) 1,5-biphenyl-1H-pyrazol-3-yl; wherein the pyrazole-3-yl optionally substituted with a methyl group; wherein each of the phenyl substituents 1,5-biphenyl further optionally substituted by one Deputy, selected from the group consisting of chlorine, or dichloro aminosulfonyl;
(n) 1,2,3,4-tetrahydroquinolin-6-yl, where 1,2,3,4-tetrahydroquinolin-6-yl optionally substituted by phenyl or triftormetilfullerenov by phenyl; and
(o) heterocyclyl(C2-4)alkenyl, condensed with benzene ring; condensed heterocyclyl attached to the C2-4alkenyl through the benzene ring; and where condensed heterocyclyl optionally substituted C5-6cycloalkyl or its enantiomer, diastereoisomer or pharmaceutically acceptable salts;
provided that the compound of Formula (I) is not a compound in which Y represents a 3-methylpyridin�-2-yl, r=1 and R2no, a Z is 4-biphenyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-(phenylcarbamoyl)phenyl;
the compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2no, a Z is a 4-cyclohexylphenol;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z represents 3-(cyclohexylcarbonyl)phenyl;
the compound in which Y represents a 5-cyanopyridine-2-yl, r=1, R2no, a Z is 4-biphenyl;
the compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2absent, a, Z is 4-biphenyl;
the compound in which Y represents pyrimidine-2-yl, r=2, R2absent, a, Z is 2-(4-triftormetilfullerenov)vinyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-phenylphenyl;
the compound in which Y is pyridin-2-yl, r=1, R2absent, a, Z is 2-phenylethyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-tert-butylbenzothiazole-6-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is�Oh 2-(4-methoxyphenyl)- benzoxazol-7-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-cyclohexylbenzothiazole-6-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 1,2-Diisobutyl-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z represents a 1-methyl-2-propyl-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 1-isobutyl-2-phenyl-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 1-isobutyl-2-(4-methylphenyl)-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2absent, a, Z is 2-(3-methoxyphenyl)-benzoxazol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-benzylphenol;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a (1R)-1,2,3,4-tetrahydronaphthalen-1-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a (1S)-1-[4-(2-methylpropyl") phenyl]ethyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z isone (1S)-1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2,3-dihydro-1H-indene-2-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is 2,2-biphenylyl; or
the compound in which Y represents a 3-triptoreline, r=1, R2no, a Z represents a 1,2,3,4-tetrahydroquinolin-6-yl.

3. The compound according to claim 1, where
Y is selected from phenyl, pyridyl, pyrimidyl, 1,3,5-triazinyl, thiazolyl, 1,3,4-thiadiazolyl, benzoxazolyl, benzisoxazole and benzothiazolyl; where the phenyl, pyridyl, pyrimidyl, 1,3,5-triazinyl, thiazolyl, 1,3,4-thiadiazolyl, benzoxazolyl, benzisoxazole, benzothiazole optionally substituted Deputy selected from the group consisting of cyano, fluorine, chlorine, bromine, iodine, C1-2of alkyl, trifloromethyl, S1-2alkoxy, C1-2alkylthio and nitro;
r is an integer from 1 to 2;
R2is missing or oxo-group;
Z is selected from the following:
(a) phenyl, substituted NRaRb; where Rarepresents hydrogen or C1-4alkyl; and Rbrepresents C1-4alkyl, cycloalkyl, phenyl, furylmethyl or benzyl; and where the phenyl or benzyl as Rbor furanyl as part of a group of furylmethyl in Rboptionally substituted with one atom of iodine; alter�ative, Raand Rbtogether with the nitrogen atom to which they are connected, form a 1-pyrrolidinyl or 1-azepane;
(b) biphenyl-3-yl or biphenyl-4-yl; wherein the terminal phenyl ring optionally substituted Deputy selected from the group consisting of trifloromethyl, S1-4alkoxy, chlorine, dichloro, fluorine and iodine;
(c) phenyl, substituted Deputy selected from the group consisting of cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbinol, benzyloxy, benzyl, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-1,3-dione, 2,3-dihydroindol-2-yl; 1-(tert-butoxycarbonyl)piperidine-4-yloxy and 1-(tert-butoxycarbonyl)piperidine-4-silt;
(d) phenyl, substituted by one or two substituents, independently selected from the group consisting of C1-6alkyl, C1-4alkoxy, iodine, chlorine and nitro;
(e) phenyl(C1-2)alkyl, where phenyl may be independently substituted with one or two substituents, independently selected from the group consisting of iodine, fluorine, C1-6of alkyl, phenyl and NRcRd; where Rcrepresents hydrogen or C1-4alkyl; and where Rdrepresents C1-4alkyl or C3-6cycloalkyl(C1-4)alkyl; and where C1-2alkyl in phenyl(C1-2)alkyl optionally substituted by phenyl;
(f) phenyl(C2-4)alkenyl; phenyl optionally substituted Deputy selected from group�s, consisting of triptoreline, S1-4alkyl, C1-4alkoxy and trifloromethyl;
(g) naphthyl; naphthyl optionally substituted With one1-4alkoxy-Deputy;
(h) fluorenyl or xantinol; where fluorenyl or xantinol optionally substituted by oxo group;
(i) cyclohexyl, wherein the cyclohexyl optionally substituted with one C1-6by alkyl;
(j) condensed with benzene ring C5-bcycloalkyl or condensed with benzene ring C5-6cycloalkyl (C1-4) alkyl; where the specified C5-6cycloalkenyl fragment optionally substituted by 1-4 methyl groups;
(k) bicyclo[2.2.2]octyl-1-yl; bicyclo[2.2.2]octyl-1-yl optionally substituted C1-6by alkyl;
(l) heteroaryl or heteroaryl, condensed with benzene ring selected from the group consisting of benzoxazolyl, chinoline, benzimidazolyl, pyridinyl, indolyl, teinila, furanyl, pyrazolyl, oxazolyl, benzothiazyl and benzofuranyl;
where heteroaryl or heteroaryl, condensed to the benzene ring may independently be substituted with one or two substituents, independently selected from the group consisting of cyclohexyl, C1-4of alkyl, phenyl, triptoreline, benzyloxy, dichlorophenoxy and phenylethynyl; and where the phenyl substituent of heteroaryl additionally optionally substituted Deputy, selected� from the group consisting of methyl, methoxy or trifloromethyl;
(m) 1,5-biphenyl-1H-pyrazol-3-yl; wherein the pyrazole-3-yl optionally substituted with a methyl group; wherein each of the phenyl groups of the 1,5-biphenyl is also optionally substituted by a group selected from the group consisting of chlorine, or dichloro aminosulfonyl;
(n) 1,2,3,4-tetrahydroquinolin-6-yl; 1,2,3,4-tetrahydroquinolin-6-yl optionally substituted by phenyl or trifluoromethyl-substituted phenyl; and
(o) heterocyclyl(C2-4)alkenyl, condensed with benzene ring; where condensed heterocyclyl connected With2-4alkenyl through the benzene ring; and where condensed heterocyclyl optionally substituted cyclohexyl;
its enantiomer, diastereoisomer or pharmaceutically acceptable salts;
provided that the compound of Formula (I) is not a compound in which Y represents a 3-methylpyridine-2-yl, r=1, and R2no, a Z is 4-biphenyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-(phenylcarbamoyl)phenyl;
the compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2no, a Z is a 4-cyclohexylphenol;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z represents 3-(cyclohexylcarbonyl�)phenyl;
the compound in which Y represents a 5-cyanopyridine-2-yl, r=1, R2no, a Z is 4-biphenyl;
the compound in which Y represents a 5-cryptomaterial-2-yl, r=1, R2absent, a, Z is 4-biphenyl;
the compound in which Y represents pyrimidine-2-yl, r=2, R2absent, a, Z is 2-(4-triftormetilfullerenov)vinyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-phenylphenyl;
the compound in which Y is pyridin-2-yl, r=1, R2absent, a, Z is 2-phenylethyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-tert-butylbenzothiazole-6-yl;
the compound in which Y is pyridin-2-yl, r=1, R2absent, a, Z is 2-(4-methoxyphenyl)-benzoxazol-7-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-cyclohexylbenzothiazole-6-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 1,2-Diisobutyl-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z represents a 1-methyl-2-propyl-1H-indol-5-yl;
connection, to�Thor Y is pyridin-2-yl, r=1, R2no, a Z is a 1-isobutyl-2-phenyl-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 1-isobutyl-2-(4-methylphenyl)-1H-indol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2absent, a, Z is 2-(3-methoxyphenyl)benzoxazol-5-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-benzylphenol;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a (1R)-1,2,3,4-tetrahydronaphthalen-1-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a (1S)-1-[4-(2-methylpropyl") phenyl]ethyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a (1S)-1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2,3-dihydro-1H-indene-2-yl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is 2,2-biphenylyl; or
the compound in which Y represents a 3-triptoreline, r=1, R2no, a Z represents a 1,2,3,4-tetrahydroquinolin-6-yl.

4. The compound according to claim 1, br/> Y is selected from the following: phenyl, 3-triptoreline, 4-triptoreline, 2-methoxyphenyl, 2-methylthiophenyl, 2-nitrophenyl, pyrid-2-yl, 3-canopied-2-yl, 5-canopied-2-yl, 5-pampered-2-yl, 3-chloropyrid-2-yl, 5-chloropyrid-2-yl, 3-jumpered-2-yl, 3-methylpiperid-2-yl, 4-methylpiperid-2-yl, 3-cryptomaterial-2-yl, pyrimidine-2-yl, 1,3,5-triazine-2-yl, benzoxazol-2-yl, benzisoxazol-3-yl, thiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-2-yl and benzothiazol-2-yl;
r is an integer from 1 to 2;
R2is missing or oxo-group;
Z is selected from the following: 4-(N-methyl-N-cyclohexylamino)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(1-azepane)phenyl, 4-(3-triptoreline)phenyl, 4-(4-methoxyphenyl)phenyl, 4-cyclohexylphenol, 4-(N-(2-jogbani)amino)phenyl, 4-(2-chlorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl, bifen-4-yl, 4-(N-methyl-N-phenylamino)phenyl, 4-(4-itfinal)phenyl, 4-phenoxyphenyl, 4-(N-(5-jodphur-2-ylmethyl)amino)phenyl, 4-benzylphenol, 4-(pyrrol-1-yl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-dimethylaminophenyl, 4-butylphenyl, 4-diethylaminophenyl, 3-iodo-4-methoxyphenyl, 3-iodo-4-chlorophenyl, 4-(1,1-dimethylpropyl)phenyl, 4-(pyrazol-1-yl)phenyl, 3-(phenyloxy)phenyl, 3-iodo-4-methylphenyl, 3-methyl-4-itfinal, 3-(4-fluorophenyl)phenyl, 4-itfinal, 2-(benzyloxy)phenyl, bifen-3-yl, 4-(imidazol-1-yl)phenyl, 4-(phenylcarbamoyl)phenyl, 2-(isoindole-1,3-dione)phenyl, 3-(2,3-dihydro-nitinol-2-yl)phenyl, 3-(phenylcarbamoyl)phenyl, 4-nitrophenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)phenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)oxy)phenyl, 1,1,4,4,tetramethyl-1,2,3,4-tetrahydronaphtyl-6-retil, 6-metoxia-2-yl, 1,2,3,4-tetrahydronaphtyl-2-yl, 2-(9-oxipurinol), fluoren-2-yl, 4-(N-methyl-N-cyclohexylethylamine)phenylethyl, 4-idenity, 4-(tert-butyl)phenylethyl, 3-idenity,,, 4-(triptoreline)phenylethenyl, 4-isopropylbenzylamine, 3-triftormetilfullerenov, 3-ethoxybenzylidene, 4-(n-pentyl)cyclohexyl, 4-(tert-butyl)cyclohexyl, 4-interdecile[2.2.2]Oct-1-yl, 2-cyclohexylbenzothiazole-6-yl, 2-methyl-3-phenylbenzimidazole-6-yl, 1-isopropyl-2-triftormetilfullerenov-4-yl, 1-cyclohexyl-2-methylbenzimidazole-4-yl, 1-propional-5-yl, 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazol-3-yl, 2-phenylbenzimidazol-5-yl, 4-phenyl-5-triptorelin-2-yl, 5-benzyloxyindole-2-yl, 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrazol-3-yl, 1,5-biphenylmethanol-3-yl, 1-(4-aminosulfonyl)-5-(4-chlorophenyl)pyrazol-3-yl, 5-(3-triptoreline)furan-2-yl), 5-(4-methylphenyl)furan-2-yl, 5-(4-methoxyphenyl)furan-2-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 5-phenylfuro-2-yl, 1-phenylpyrazol-4-yl, 2-phenyl-5-cryptomaterial-4-yl, quinolin-6-yl, the quinolin-2-yl, 3-methylbenzofuran-2-yl, 5-butalbiral-2-yl, 4-benzyloxyindole-2-yl, indol-5-yl, 5-(phenylethynyl)furan-2-yl, 5-(3,5-diclofenac�)furan-2-yl, Xanten-3-yl-9-it, 1-phenyl-1,2,3,4-tetrahydroquinolin-6-yl, 1-(4-triptoreline)-1,2,3,4-tetrahydroquinolin-6-yl, 1-(3-triptoreline)-1,2,3,4-tetrahydroquinolin-6-yl, (1-cyclohexylidene-5-yl)-ethenyl - and 6-trifluoromethyl-benzo[b]Thien-2-yl;
or its enantiomer, diastereoisomer or pharmaceutically acceptable salts;
provided that the compound of Formula (I) is not:
the compound in which Y represents a 3-methylpyridine-2-yl, r=1, and R2no, a Z is 4-biphenyl;
the compound in which Y represents a 5-cyanopyridine-2-yl, r=1, R2no, a Z is 4-biphenyl;
the compound in which Y represents pyrimidine-2-yl, r=2, R2absent, a, Z is 2-(4-triftormetilfullerenov)vinyl;
the compound in which Y is pyridin-2-yl, r=1, R2no, a Z is a 2-cyclohexylbenzothiazole-6-yl; or
the compound in which Y represents a 3-triptoreline, r=1, R2no, a Z represents a 1,2,3,4-tetrahydroquinolin-6-yl.

5. The compound according to claim 1, where
Y is selected from the following: pyrid-2-yl, 3-canopied-2-yl, 5-chloropyrid-2-yl, pyrimidine-2-yl, thiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-2-yl, 1,3,5-triazine-2-yl and the benzizoksazola-2-yl;
r=1;
R2no;
Z is selected from the following: 4-(N-methyl-N-cyclohexylamino)phenyl, 4-(pyrrolidin-1-yl)�Anil, 4-(1-azepane)phenyl, 4-(3-triptoreline)phenyl, 4-(4-methoxyphenyl)phenyl, 4-cyclohexylphenol, 4-(N-(2-jogbani)amino)phenyl, 4-(2-chlorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl, bifen-4-yl, 4-(N-methyl-N-phenylamino)phenyl, 4-(4-itfinal)phenyl, 4-phenoxyphenyl, 4-(N-(5-jodphur-2-ylmethyl)amino)phenyl, 4-benzylphenol, 4-(pyrrol-1-yl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-dimethylaminophenyl, 4-butylphenyl, 4-diethylaminophenyl, 3-iodo-4-methoxyphenyl, 3-iodo-4-chlorophenyl, 4-(1,1-dimethylpropyl)phenyl, 4-(pyrazol-1-yl)phenyl, 3-(phenyloxy)phenyl, 3-iodo-4-methylphenyl, 3-methyl-4-itfinal, 3-(4-fluorophenyl)phenyl, 4-itfinal, 2-(benzyloxy)phenyl, 4-benzyloxyphenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)phenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)oxy)phenyl, 1,1,4,4,tetramethyl-1,2,3,4-tetrahydronaphtyl-6-retil, 6-metoxia-2-yl, 2-(9-oxipurinol), 4-(N-methyl-N-cyclohexylethylamine)phenylethyl, 4-idenity, 4-(tert-butyl)phenylethyl, 4-(triptoreline)phenylethenyl, 4-(n-pentyl)cyclohexyl, 2-cyclohexylbenzothiazole-6-yl, 2-methyl-3-phenylbenzimidazole-6-yl, 1-isopropyl-2-triftormetilfullerenov-4-yl, 1-cyclohexyl-2-methylbenzimidazole-4-yl, 1-propional-5-yl, 2-phenylbenzimidazol-5-yl, 4-phenyl-5-triptorelin-2-yl, Xanten-3-yl-9-it, 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazol-3-yl and 6-trifluoromethyl-benzo[b]Thien-2-yl;
or its enantiomer, diastereoisomer or farm�citiesi acceptable salts;
provided that the compound of formula (I) is not a compound in which Y represents pyrid-2-yl, r=1, R2no, a Z is a 2-cyclohexylbenzothiazole-6-yl.

6. The compound according to claim 1, where
Y is selected from the following: pyrid-2-yl, 3-canopied-2-yl, pyrimidine-2-yl, 1,3,5-triazine-2-yl, thiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-2-yl and the benzizoksazola-3-yl;
r=1;
R2no;
Z is selected from the following: 4-(N-methyl-N-cyclohexylamino)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(1-azepane)phenyl, 4-(3-triptoreline)phenyl, 4-(4-methoxyphenyl)phenyl, 4-cyclohexylphenol, 4-(N-(2-jogbani)amino)phenyl, 4-(2-chlorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl, bifen-4-yl, 4-(N-methyl-N-phenylamino)phenyl, 4-(4-itfinal)phenyl, 4-phenoxyphenyl, 4-(N-(5-jodphur-2-ylmethyl)amino)phenyl, 4-benzylphenol, 4-(pyrrol-1-yl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-benzyloxyphenyl, 2-cyclohexylbenzothiazole-6-yl, 2-methyl-3-phenylbenzimidazole-6-yl, 1-isopropyl-2-triftormetilfullerenov-4-yl, 1-cyclohexyl-2-methylbenzimidazole-4-yl, 1-propional-5-yl and 6-triptoreline[b]Tien-2-yl;
or its enantiomer, diastereoisomer or pharmaceutically acceptable salts;
provided that the compound of formula (I) is not a compound in which Y represents pyrid-2-yl, r=1, R2

7. The compound according to claim 1, where
Y is selected from the following: pyrid-2-yl, 3-canopied-2-yl, pyrimidine-2-yl and thiazol-2-yl;
r=1;
R2no;
Z is selected from the following: 4-(N-methyl,N-cyclohexylamino)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(1-azepane)phenyl, 4-(3-triptoreline)phenyl, 4-(4-methoxyphenyl)phenyl, 4-(2-chlorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl, bifen-4-yl, 4-(N-methyl-N-phenylamino)phenyl, 4-phenoxyphenyl, 4-cyclohexylphenol, 4-benzylphenol, 4-(pyrrol-1-yl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-cyclohexylcarbodiimide)phenyl, 4-dimethylaminophenyl, 4-butylphenyl, 4-diethylaminophenyl, 3-(4-fluorophenyl)phenyl, 4-benzyloxyphenyl, 4-(1-tert-butoxycarbonylmethyl-4-yl)phenyl, 1,1,4,4,tetramethyl-1,2,3,4-tetrahydronaphtyl-6-retil, 4-(N-methyl-N-cyclohexylethylamine)phenylethyl, 4-(triptoreline)phenylethenyl, 2-methyl-3-phenylbenzimidazole-6-yl, 1-isopropyl-2-triftormetilfullerenov-4-yl, 1-cyclohexyl-2-methylbenzimidazole-4-yl, 1-propional-5-yl and 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazol-3-yl;
or its enantiomer, diastereoisomer or pharmaceutically acceptable salt.

8. The compound according to claim 1, where
Y is selected from pyrid-2-yl, pyrimidine-2-yl, thiazol-2-yl and the benzizoksazola-2-silt;
r=1;
R2no;
Z is selected from the following: 4-cyclohexylphenol, difen-4-yl, 4-(N-cyclohex�carbonylation)phenyl, 4-benzylphenol, 4-diethylaminophenyl, 3-iodo-4-methoxyphenyl, 3-(4-fluorophenyl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(N-methyl-N-cyclohexylethylamine)phenyl, 9-octafluoro-2-yl and 2-cyclohexylbenzothiazole-6-yl;
or its enantiomer, diastereoisomer or pharmaceutically acceptable salts;
provided that the compound of formula (I) is not a compound in which Y represents pyrid-2-yl, r=1, R2no, a Z is a 2-cyclohexylbenzothiazole-6-yl.

9. Pharmaceutical composition possessing inhibitory active against MGL containing a pharmaceutically acceptable carrier and a compound according to claim 1.

10. A method of obtaining a pharmaceutical composition according to claim 9, comprising mixing a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A method of treating or alleviating of a disease, syndrome, condition or disorder dependent inhibition of MGL, including introduction to the needy in this subject a therapeutically effective amount of a compound according to claim 1.

12. A method according to claim 11, where the disease, syndrome, condition or disorder dependent inhibition of MGL selected from the group consisting of pain, inflammatory pain, inflammatory hypersensitivity and neuropathic pain.

13. A method according to claim 11, where the disease, syndrome, condition or disorder dependent inhibition of MGL is with�fight the pain.

14. A method according to claim 13, wherein the disease, syndrome, condition or disorder dependent inhibition of MGL, is an inflammatory pain.

15. A method according to claim 11, where the disease, syndrome, condition or disorder dependent inhibition of MGL, is a visceral pain.

16. A method according to claim 11, where the disease, syndrome, condition or disorder dependent inhibition of MGL, is an ulcerative colitis.

17. A method according to claim 11, where the disease, syndrome, condition or disorder dependent inhibition of MGL, is a neuropathic pain.

18. A method according to claim 11, where the disease, syndrome, condition or disorder dependent inhibition of MGL, is a neuropathic cold allodynia.

19. A method according to claim 11, where the disease, syndrome, condition or disorder dependent inhibition of MGL selected from the group consisting of inflammatory pain or neuropathic pain.

20. Use of a compound according to claim 1 for the manufacture of a drug or pharmaceutical composition for the treatment of a disease, syndrome, condition or disorder dependent inhibition of MGL, the needy in this subject.

21. Use of a compound according to claim 1 for the manufacture of a drug or pharmaceutical composition for the treatment of inflammatory pain or near�piticescu pain of the needy in this subject.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula A-I, where G1 stands for hydrogen atom or R'; G2 stands for halogen atom, CN, CF3, isopropyl or phenyl, where said isopropyl or phenyl is optionally substituted with up to three substituents, independently selected from WRW; G3 stands for isopropyl or (C3-C10)cycloaliphatic ring, where said G3 is optionally substituted with up to three substituents, independently selected from WRW; W stands for bond or (C1-C6)alkylidene chain, where up to two methylene groups of W residue are optionally and independently substituted for -CO2- or -O-; RW stands for R'; and R' is independently selected from hydrogen atom or (C1-C8)alkyl group. Invention also relates to method of obtaining compound of formula FF (stands for bromine atom, fluorine atom or tret-butyl; G3 stands for tret-butyl) by hydrogenation of respective nitrocompound in presence of palladium catalyst and to methods of obtaining C-9 and 433 compounds, which include stage of hydrogenation of respective nitrocompound in presence of palladium catalyst as intermediate stage.

EFFECT: formula A-I compounds, which are intermediate for synthesis of modulators of ATP-binding cassette ("ABC") transporters.

35 cl, 4 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of synthesis of compounds with biological activity, namely to method of obtaining compound 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane. Essence of method consists in interaction of 3,6-dioxaoctane-1,8-diamine with N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine in medium ethanol-chloroform (1:2 volume) in presence of catalyst SmCl3·6H2O with molar ratio 3,6-dioxaoctane-1,8-diamine:N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:SmCl3·6H2O=1:2:(0.03-0.07) at temperature (~20°C) and atmospheric pressure for 2.5-3.5 h. Invention also relates to application of 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane as agent with fungicidal activity for fighting fungal diseases of agricultural crops.

EFFECT: improved method of obtaining 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane, possessing fungicidal activity against Botrytis cinerea.

2 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides of general formula: , where R=5-methyl-1,3-thiazol-2-yl, or 4-ethoxycarbonylmethyl-1,3-thiazol-2-yl, or 6-methylpyridin-2-yl, or 5-chloropyridin-2-yl, or pyrimidin-2-yl. Novel N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide derivatives which exhibit analgesic activity are obtained.

EFFECT: high activity of derivatives.

2 tbl, 7 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic compound, representing cyclo-bis[(1Z)-1-imino -2-methyl-1H-inden-3-yl-1,2,4-thiadiazole-3,5-diamine]

EFFECT: compound as acid dye for silk, wool and polyamide 6.

3 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the general formula (I), R1 is specified in cyano, (2-4C)alkynyl, (1-4C)alkyl, (3-6C)cycloalkyl, (4-6C)cycloalkenyl, (6-8C)bicycloalkyl, (8-10C)bicyclic group, each of which can be substituted by (1-4C)alkyl, phenyl, biphenyl, naphthyl each of which can be substituted by three substitutes independently specified in halogen, (1-4C)alkyl substituted as may be necessary by one or more atoms of fluorine, (2-4C)alkynyl, (1-4C)alkoxy substituted as may be necessary by one or more atoms of fluorine, amino, di(1-4C)alkylamino and (3-6C)cycloalkyl, phenyl substituted by phenoxy, benzyl, benzyloxy, phenylethyl or a monocyclic heterocycle, each of which can be substituted by (1-4C)alkyl, 5-6-merous monocyclic heterocycle containing 1-3 heteroatoms specified in N, O and S substituted as may be necessary by a halogen, (1-4C)alkyl or phenyl substituted as may be necessary by (1-4C)alkyl, and 9-10-merous bicyclic heterocycle containing 1-2 heteroatoms specified in N and O substituted as may be necessary by (1-4C)alkyl; A is specified in -CO-O-, -NH-CO-, -CO-NH, -C=C-, -CCH3-O- and a binding group -Y-(CH2)n-X-, wherein Y is attached to R1 and specified in a bond, -O-, -SO2-, -CH2-O-, -CO-, -CO-O-, -CO-NH-, -NH-CO-, -C=C- and -C≡C-; n means an integer from 1 to 7; and X is attached to a phenylene group and specified in a bond, -O-, -S-, and -NH; the ring structure B represents phenylene; R2 means H, (1-4C)alkyl substituted as may be necessary by one or more atoms of fluorine, (1-4C)alkoxy or halogen; and R3 means (1-4C)alkylene-R5, wherein the alkylene group can be substituted by one or more atoms of a halogen, or R3 means (3-6C)cycloalkylene-R5 or -CO-CH2-R5, wherein R5 means -OH, -PO3H2, -OPO3H2, -COOH or tetrazol-5-yl; R4 means H or (1-4C)alkyl; R6 means one or more substitutes independently specified in H, (1-4C)alkyl or oxo; W means -O- or -S-.

EFFECT: invention refers to (thio)morpholine derivatives of formula (I) possessing the property of a sphingosine-1-phosphate (S1P) modulator, a based pharmaceutical composition and using them.

18 cl, 1 dwg, 237 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula A-I, where G1 stands for hydrogen atom or R'; G2 stands for halogen atom, CN, CF3, isopropyl or phenyl, where said isopropyl or phenyl is optionally substituted with up to three substituents, independently selected from WRW; G3 stands for isopropyl or (C3-C10)cycloaliphatic ring, where said G3 is optionally substituted with up to three substituents, independently selected from WRW; W stands for bond or (C1-C6)alkylidene chain, where up to two methylene groups of W residue are optionally and independently substituted for -CO2- or -O-; RW stands for R'; and R' is independently selected from hydrogen atom or (C1-C8)alkyl group. Invention also relates to method of obtaining compound of formula FF (stands for bromine atom, fluorine atom or tret-butyl; G3 stands for tret-butyl) by hydrogenation of respective nitrocompound in presence of palladium catalyst and to methods of obtaining C-9 and 433 compounds, which include stage of hydrogenation of respective nitrocompound in presence of palladium catalyst as intermediate stage.

EFFECT: formula A-I compounds, which are intermediate for synthesis of modulators of ATP-binding cassette ("ABC") transporters.

35 cl, 4 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, namely, deals with compounds of formula , suitable for reduction of regulation of biological activity of melanocortin-5 receptor (MC5R). Such diseases and/or conditions include, but are not limited by, acne, seborrhoea, seborrheic dermatitis, cancer and inflammatory diseases.

EFFECT: compounds of claimed invention can be applied for treatment of diseases and/or conditions, in which reducing regulation of MC5R is favourable.

3 cl, 109 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-(1,2,5-oxadiazol-3-yl)benzamides of formula , in which R stands for an alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, cyano, nitro, methylsulphenyl, acetylamino, methoxycarbonyl, methylcarbonyl, piperidinylcarbonyl, halogen, amino, or heteroaryl, selected from the group, including 1,2,3-triazolyl, 1,2,4-triazolyl, benzisoxazolyl, thiophenyl, pyridinyl and benzimidazol-2-yl, or heterocyclyl, selected from the group, including piperidinyl, respectively selected with s residues, selected from the group, including methyl, ethyl, methoxy and halogen; X and Z independently on each other respectively stand for nitro, halogen, cyano, alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, OR1, S(O)nR2, alkyl-OR1 with 1-6 carbon atoms in alkyl, or heteroaryl, selected from the group, including 1,2,4-triazolyl; Y stands for nitro, halogen, OR1, S(O)nR2, NR1COR1, O-alkylheterocyclyl with 1-6 carbon atoms in the alkyl, and where heterocyclyl is selected from 1,4-dioxan-2-yl, O-alkyl heteroaryl with 1-6 carbon atoms in the alkyl, and where the heteroaryl is selected from pyrazolyl, alkyl-OR1 with 1-6 carbon atoms in the alkyl, alkyl-NR1SO2R2 with 1-6 carbon atoms in the alkyl, NR1R2, tetrahydrofuranyloxymethyl, tetrahydrofuranylmethoxymethyl, O(CH2)-3,5-dimethyl-1,2-oxazol-4-yl, O(CH2)2-O(3,5-dimethoxypyrimidin-2-yl, O(CH2)-5-pyrrolidin-2-one, O(CH2)-5-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one, or heteroaryl, selected from the group, including 1,2,3-triazolyl and pyrazolyl, or heterocyclyl, selected from the group, including 4,5-dihydro-1,2-oxazol-3-yl and tetrahydropyrimidi-2(1H)-on-1-yl, respectively substituted with s residues, selected from the group, including methyl, methoxy and cyanomethyl; R1stands for hydrogen, alkyl with 1-6 carbon atoms, alkinyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, cycloalkylalkyl with 2-6 carbon atoms in the cycloalkyl and 1-6 carbon atoms in the alkyl, phenyl or phenylalkyl with 1-6 carbon atoms in the alkyl, with six last residues being substituted with s residues, selected from the group, including a halogen, OR3 and CON(R3)2; R2 stands for alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or phenyl with 1-6 carbon atoms alkyl, with the five last residues being substituted with s residues, selected from the group, including a halogen, OR3, OCOR3, CO2R3, COSR3 and CON(R3)2; R3 stands for hydrogen or alkyl with 1-6 carbon atoms; n stands for 0, 1 or 2; s stands for 0, 1, 2 or 3. The invention also relates to the application of N-(1,2,5-oxadiazol-3-yl)benzamides of formula (I), as a herbicidal preparation and for fighting undesirable plants.

EFFECT: N-(1,2,5-oxadiazol-3-yl)benzamides, possessing herbicidal activity.

9 cl, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to azetidine-substituted isoxazoline derivatives of formula (1), where A represents phenyl, naphtyl or heteroaryl, where said heteroaryl represents 5-6-membered aromatic monocyclic ring and contains 1 N heteroatom; each of R1a, R1b and R1c independently represents hydrogen, halogen, cyano, nitro or C1-C6halogenalkyl; R2 represents halogen, cyano or nitro; R3 represents hydrogen, halogen, hydroxyl, cyano, N3 or -NHR4; R4 represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5 or -C(NR7)R5; R5 represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, representing 5-6-membered aromatic monocyclic ring, containing from 1 to 3 heteroatoms, each of which is independently selected from N, O and S, or C0-C6alkylheterocycle, where said heterocycle represents 4-membered monocyclic ring, containing 1 heteroatom, selected from N, O and S; R6 represents C1-C6halogenalkyl; R7 represents cyano; Ra represents hydrogen, C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl; Rb represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; Rc represents C1-C6alkyl, C1-C6halogenalkyl, C1-C6halogenalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl or C0-C3alkylphenyl, each of which is possibly substituted with at least one substituent, selected from cyano or halogen, each of groups C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl ad R5 can be possibly and independently substituted with at least one substituent, selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenalkoxy, C1-C6halogenalkyl, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rc and -C(O)NRaRb; and where grouping C0-C6alkylheteroaryl or C1-C6alkylheterocycle as R5 can be possibly additionally substituted with at least one substituent, selected from halogen, oxo, hydroxyl, C1-C6alkyl and -SH; n represents integer number 0 or 1, and p represents integer number 0, 1 or 2 and its stereoisomers. Invention also relates to pharmaceutical or veterinary composition, possessing parasiticidal activity, containing therapeutic amount of formula (I) derivative and pharmaceutically or veterinarily acceptable excipient, diluents or carrier.

EFFECT: azetidine-substituted isoxazoline derivatives of formula (1), intended for manufacturing means for treatment or control of parasitic infection or invasion in animal.

20 cl, 5 tbl, 225 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining (S)-2-methoxy-3-{4[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl}propionic acid of formula (I) or its salts, in which formula (II) compound or its salt is hydrated in the presence of an iridium-including catalyst, in which the catalyst includes iridium and formula (III) compound, in which R1 stands for hydrogen, isopropyl, phenyl or benzyl and in which R2 stands for phenyl, 3,5-dimethylphenyl or 3,5-di-tert-butylphenyl. The invention also relates to the application of a complex of the catalyst, containing iridium and the formula (III) compound for obtaining the formula (I) compound.

EFFECT: obtaining the formula (I) compound with a high degree of conversion and enantiomeric purity.

6 cl, 4 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidine, represented by the general formula : where X=O or S, Ar=3-nitrophenyl or 2-thienyl. The described method consists in the fact that at the first stage 5-brom-4-(2-thienyl)-2-(thio)morpholylpyrimidine is obtained by interaction with the excess of 2-thienyllithium in the absolute ether at first at a temperature from -20 to -25°C for not less than 1 hour, and then at room temperature for not less than 18 hours, a solution of a mixture of potassium hexacyonoferrate (III) and potassium hydroxide in water are added with further mixing for 4 hours at room temperature, the ether phase is separated and distilled and the obtained remaining part is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate-hexane, 1:3, with (het)arylboric acid and tetrakis(triphenyphosphine)palladium(0) in tetrahydrofurane, a water solution of potassium carbonate is added and the obtained mixture is irradiated by microwave radiation at 155°C for 20 minutes, the solvent is distilled under a reduced pressure, the obtained residual is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate - hexane, 1:2 with obtaining the target product.

EFFECT: claimed is the highly-efficient two-stage method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidines, which can have a wide spectrum of biological activity.

4 ex

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