Pde10 inhibitors and compositions containing them and methods


FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts, wherein A is thiazolyl, oxazolyl, thienyl, furyl, imidazolyl, pyrazolyl or oxadiazolyl (structures of which are presented in cl.1 of the patent claim), R1 represents C1-6alkyl; R2 represents (i) phenyl substituted by halogen; C1-6alkyl optionally substituted by morpholine or C1-6dialkylamino; C1-6alkoxy optionally substituted by halogen; or heterocyclyl, wherein a heterocyclyl substitute is specified in morpholine; pyrazolyl optionally substituted by C1-6alkyl; piperidinyl; pyrrolidinyl; oxadiazolyl substituted by C1-6alkyl; furyl substituted by C1-6alkyl; dioxydoisothiazolidinyl; triazolyl; tetrazolyl substituted by C1-6alkyl, tridiazolyl substituted by C1-6alkyl; thiazolyl substituted by C1-6alkyl; pyridyl; or pyrazinyl; (ii) substituted or unsubstituted heterocyclyl specified in quinolinyl; pyridyl substituted by C1-6alkoxy or morpholinyl; or benzo [d] [1, 2, 3] triazolyl substituted by C1-6alkyl; R3 represents phenyl substituted by 2 or 3 substitutes specified in halogen; C1-6alkyl; C1-6alkoxy optionally substituted by halogen; hydroxy group; cyano; or -C(=O)ORa, wherein Ra represents phenyl; R4 represents hydrogen, C1-6alkyl or C1-6halogenalkyl. The invention also refers to a pharmaceutical composition containing the compounds of formula (I), a method for PDE10 inhibition, a method of treating neurological disorders, and to intermediate compounds: 2-(4-chlor-3,5-dimethoxyphenyl)furan and 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde.

EFFECT: compounds of formula (I) as PDE10 inhibitors.

39 cl, 13 ex, 2 tbl, 77 dwg

 

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U. S. C. §119(e) of provisional patent application U.S. No. 61/313544 filed March 12, 2010, and provisional patent application U.S. No. 61/430841, filed January 7, 2010, the application data included in this description fully by reference.

The LEVEL of TECHNOLOGY

The technical field to which the present invention relates

In General, the present invention relates to compounds having activity as PDE10 inhibitors, and to compositions containing them, and methods for treating various diseases by administration of these compounds to the needy in a warm-blooded animal.

Description of related prior art

Phosphodiesterase of cyclic nucleotides (PDE) is represented by a large superfamily of enzymes. It is known that PDE have a modular structure, with conservative catalytic domain near the carboxyl end, and regulatory domains, or motifs, often near aminocore. Currently the PDE superfamily includes more than twenty different genes, divided into eleven PDE families (Lugnier, C., "Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther. 2006 Mar; 109(3):366-98).

About the recently described PDE, PDE10, at the same time it was reported by three independent g�uppada (Fujishige et al., "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)", J Biol Chem 1999, 274:18438-18445; Loughney et al., "Isolation and characterization of PDE10A, a novel human 3',5'-cyclic nucleotide phosphodiesterase," Gene 1999, 234:109-117; Soderling et al., "Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A", Proc Natl Acad Set USA 1999, 96:7071-7076). PDE10 has the ability to hydrolyze and camp and cGMP; however,Kmto camp is approximately 0.05 microns, whereasKMto camp is 3 μm. In addition,Vmaxfor camp hydrolysis in five times less than for cGMP. Because of the kinetics of cGMP hydrolysis PDE10 effectively inhibited campin vitroassuming that PDE10 can function as a camp-inhibited cGMP phosphodiesterasein vivo. Unlike PDE8 or PDE9, PDE10 IBMX inhibited with IC50(concentration inhibiting 50%) 2.6 mm (see Soderling and Beavo, "Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions", Current Opinion in Cell Biology, 2000, 12:174-179).

PDE10 contains two aminobenzene domain that are similar to the cGMP-binding domains, PDE2, PDE5 and PDE6, which represent the domains conservative for a wide range of proteins. Because of the conservativeness of this domain is currently called the GAF domain (GAF proteins: cGMP-binding phosphodiesterase; adenylyl cyclase cyanobacteriaAnabaena; and a transcription regulator fh1AEscherichia coli). Although PDE2, PDE5 and PDE6 GAF domains bind cGMP, it, ver�vorable, not the main function of this domain in all cases (for example, it is believed thatE. colinot synthesizes cGMP). Interestingly,in vitroresearch associate PDE10 show a dissociation constant (Kdfor cGMP binding which is much more than 9 μm. Because it is believed thatin vivoconcentration of cGMP do not reach such high values in most cells, it seems likely that either the affinity PDE10 to increases cGMP regulation, either the primary function of the GAF domain in PDE10 may be somewhat different from cGMP binding.

Everywhere are searching inhibitors PDE family of enzymes for a wide range of indications therapeutic applications. Described in the literature therapeutic use of PDE inhibitors include allergies, obstructive lung disease, hypertension, kidney cancer, angina, heart failure, depression, and erectile dysfunction (WO 01/41807 A2). Other PDE inhibitors describe for the treatment of ischemic heart disease (U.S. patent No. 5693652). More specifically, the PDE10 inhibitors are described as suitable for the treatment of certain neurological and mental disorders, including Parkinson's disease, Huntington's disease, schizophrenia, delusional disorder, psychosis caused by drug use, and panic and obsessive-compulsive disorder (patent application school� No. 2003/0032579). It was shown that PDE10 is present at high concentrations in neurons in brain areas that are closely associated with many neurological and psychiatric disorders. By inhibiting PDE10 activity concentrations of camp and cGMP are increased in neurons, and the ability of these neurons to function properly through this improves. Thus, it is believed that inhibition of PDE10 is suitable for treating a wide range of diseases or disorders for which it would be useful to increase the concentration of camp and cGMP in neurons, including the neurological, psychotic, anxiety disorders and/or movement disorders mentioned above.

While success has been achieved inhibiting PDE10, there remains a need in the PDE10 inhibitors, as well as the need for treatment of various diseases and/or conditions, which could be useful for this inhibition.

BRIEF DESCRIPTION of the PRESENT INVENTION

Briefly, the present invention is, in General, refers to compounds that have activity as PDE10 inhibitors and methods for their preparation and use, and to contain their pharmaceutical compositions.

In one embodiment, the compounds have the following General structure (I):

including their pharmaceutically acceptable salts, stereoisomers, solvates and prodrug in which A, R1, R2and R3such as defined below.

Compounds of the present invention can be applied in a wide range of therapeutic applications and can be used to treat a wide range of diseases or disorders for which it would be useful for increasing the concentration of camp and cGMP, especially in neurons, including (but not limited to, neurological disorders such as psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobia, epilepsy, aphasia, bell's palsy, cerebral palsy, sleep disorders, pain, Tourette syndrome, schizophrenia, delusional disorder, bipolar disorder, post-traumatic stress disorder, psychosis, caused by drugs, panic disorder, obsessive-compulsive disorder, attention deficit disorder, a disorder of social behavior, autism, depression, dementia, cognitive disorders, epilepsy, insomnia and multiple sclerosis.

The methods of the present invention include the introduction of an effective amount of compounds of the above structure, usually in the wee�e pharmaceutical compositions needy in the mammal, including humans. Thus, in the next version of the implementation describe pharmaceutical compositions containing one or more compounds of the above structure in combination with a pharmaceutically acceptable carrier or diluent.

These and other aspects of the present invention will be apparent with reference to the following detailed description. To this end, in the present description sets forth various links that describe in more detail some background information, methods, compounds and/or compositions, and each link is introduced in the present description fully by reference.

BRIEF description of the DRAWINGS

FIG.1 shows that compound 1-1 of the present invention (Example 1), introduced by intraperitoneal injection, significantly reduces hyperactivity in mice in a model of psychosis caused by stimulant (PCP), when compared with control media.

FIG.2 shows that compound 1-1 of the present invention (Example 1), introduced oral route of administration significantly reduces hyperactivity in mice in a model of psychosis caused by stimulant (PCP), when compared with control media.

FIG.3 shows that the connection 2-1 of the present invention (Example 2), introduced by intraperitoneal injection, significantly reduces g�perceivest in mice in a model of psychosis, caused by stimulant (PCP), when compared with control media.

FIG.4 shows that the connection 2-1 of the present invention (Example 2), introduced by the oral route of administration significantly reduces hyperactivity in mice in a model of psychosis caused by stimulant (PCP), when compared with control media.

FIG.5 shows that the connection 2-1 of the present invention (Example 2) significantly reduces the conditional avoidance response (CAR) in mice prepared in CAR models of psychosis when compared with control media.

FIG.6 shows that compound 11-1 of the present invention (Example 11), introduced by intraperitoneal injection, significantly reduces hyperactivity in mice in a model of psychosis caused by stimulant (PCP), when compared with control media.

FIG.7 shows that the connection 34-1 of the present invention (Example 34) significantly reduces the conditional avoidance response (CAR) in mice prepared in CAR models of psychosis when compared with control media.

FIG.8 shows that compound 36-1 of the present invention (Example 36) significantly reduces the conditional avoidance response (CAR) in mice prepared in CAR models of psychosis when compared with control media.

FIG.9 shows that the compound 47-1 of the present invention (Example 47) significantly reduces the conditional response is shunned�I (CAR) in mice prepared in CAR models of psychosis when compared with control media.

FIG.10 shows that the connection 61-1 of the present invention (Example 61) significantly reduces the conditional avoidance response (CAR) in mice prepared in CAR models of psychosis when compared with control media.

FIG.11 shows that the connection 63-1 of the present invention (Example 63) significantly reduces the conditional avoidance response (CAR) in mice prepared in CAR models of psychosis when compared with control media.

FIG.12 shows that the connection 49-1 of the present invention (Example 49) significantly reduces the conditional avoidance response (CAR) in mice prepared in CAR models of psychosis when compared with control media.

FIG.13 shows that the connection 65-10 of the present invention (Example 65, table 1) significantly reduces the conditional avoidance response (CAR) in mice prepared in CAR models of psychosis when compared with control media.

DETAILED DESCRIPTION

As mentioned above, in General, the present invention relates to compounds suitable as PDE10 inhibitors and methods for their preparation and use and containing pharmaceutical compositions.

In one embodiment of the PDE10 inhibitors have the following structure (I):

or their pharmaceutically acceptable Sol�, stereoisomer, solvate or prodrug,

in which:

A represents:

or

R1represents a C1-6alkyl, C1-6halogenated, C1-6aralkyl, aryl, -(CH2)nO(CH2)mCH3or -(CH2)nN(CH3)2;

R2represents (i) substituted or unsubstituted aryl or (ii) substituted or unsubstituted heterocyclyl;

R3is a substituted or unsubstituted aryl;

R4represents hydrogen, C1-6alkyl or C1-6halogenated;

n is 1, 2, 3, 4, 5 or 6; and

m is 0, 1, 2, 3, 4, 5 or 6.

As used in the present description, the terms above have the following meanings:

"Amino" refers to-NH2the radical.

"Cyano" refers to-CN radical.

"Hydroxy" or "hydroxyl" refers to an-OH radical.

"Imino" refers to =NH Deputy.

"Nitro" refers to-NO2the radical.

"Oxo" refers to =O the Deputy.

"Thioxo" refers to =S Deputy.

"C1-6alkyl" refers to linear or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon radical containing from 1 to 6 carbon atoms. Examples of saturated Akilov with direct TSE�of them include methyl, ethyl,n-propyl,n-butyl,n-pentyl,n-hexyl and the like; while saturated branched alkali include isopropyl,Deut-butyl, isobutyl,tert-butyl, isopentyl and the like. Examples of saturated cyclic Akilov include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; while unsaturated cyclic alkali include cyclopentenyl and cyclohexenyl and the like. Unsaturated alkali contain at least one double or triple bond between adjacent carbon atoms (referred to as "alkenyl" or "alkynyl" respectively). Examples of alkenyl with a straight or branched chain include ethylenic, propylene, 1-butenyl, 2-butenyl, isobutylene, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl and the like; while examples of alkinyl with a straight or branched chain include acetylenyl, PROPYNYL, 1-butynyl, 2-butynyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butynyl and the like.

"C1-6alkylene" or "C1-6Allenova chain" refers to a straight or branched divalent hydrocarbon chain attaching the remainder of the molecule to the radical containing only carbon atoms and hydrogen, which is saturated or unsaturated (i.e. contains one or more double and/or triple bonds), and containing from one to six carbon atoms, nab�emer methylene, ethylene, propylene,n-butylene, ethenylene, propylen,n-butylen, propylen,n-Butyrin and the like. Alkylenes chain attached to the remainder of the molecule through a single or double bond and to a side chain via a single or double bond. The provisions of the accession alkalinous chain to the remainder of the molecule and to the radical can be carried out via a carbon atom, or any two carbon atoms in the chain.

"C1-6alkoxy" refers to a radical of the formula-ORawhere Rarepresents an alkyl radical, as defined above, such as methoxy, ethoxy and the like.

"Aryl" refers to a hydrocarbon ring system comprising hydrogen, 6-18 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain a condensed or bridged ring system. Aryl radicals include, but are not limited to, aryl radicals generated from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, Fiorentina, fluorene,as-indacene,s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene and triphenylene.

"C1-6aralkyl" refers to a radical of the formula-Rb-Rcwhere RbPR�dstanley alkylenes chain, as defined above, and Rcrepresents one or more aryl radicals as defined above, e.g. benzyl, diphenylmethyl and the like.

"Cycloalkyl" or "carbocyclic ring" refers to a stable neoromanticism monocyclic or polycyclic hydrocarbon radical consisting solely of carbon atoms and hydrogen, which may contain a condensed or bridged ring system containing three to fifteen carbon atoms, preferably containing from three to ten carbon atoms, and which may be saturated or unsaturated and attached to the remainder of the molecule is a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decaline, 7,7-dimethyl-bicyclo[2,2,1]heptanes and the like.

"Halo" or "halogen" refers to bromine, chlorine, fluorine or iodine.

"C1-6halogenated" refers to C1-6the alkyl radical as defined above which is substituted by one or more halogen radicals, as defined above, for example trifluoromethyl, deformity, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-defloratin, 3-bromo-2-forproper, 1,2-dibromoethyl and the like.

"Heterocycle" or "heterocyclyl" refers to a 4 to 7-membered �Hotelissimo or 7-10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and in which the heteroatoms nitrogen or sulfur may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternization, including bicyclic rings in which any of the above heterocycles condensed with benzene ring. Heterocycle can be attached via any heteroatom or carbon atom. Aromatic heterocycle referred to in the present description "heteroaryl", and it includes (but is not limited to furyl, benzofuranyl, thiophenyl, benzothiophene, pyrrolyl, indole, isoindole, azaindole, pyridyl, chinoline, ethenolysis, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolin, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnoline, phthalazine, oxadiazolyl, thiadiazolyl, benzisoxazole, triazolyl, tetrazolyl, indazoles and hintline. In addition to the above heteroaryl, heterocycles also include morpholinyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, piperazinyl and the like. In addition, heterocycles also include benzothiophen-2-yl, 2,3-dihydrobenzo-1,4-dioxin-6-yl, benzo-1,3-dioxol-5-yl and the like.

The term "�alseny", as used in this description (for example, in the context of substituted heterocyclyl or substituted aryl), indicates that at least one hydrogen atom substituted by a substituent. "Substituents" in the context of the present invention include halogen, hydroxy, oxo, cyano, nitro, imino, thioxo, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, halogenated, aryl, aralkyl, heteroaryl, heteroaromatic, heterocycl and heterocyclyl, and-NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O)2Ra, -OS(=O)2Ra, -S(=O)2ORa, =NSO2Raand-SO2NRaRb. In the above-mentioned substituents Raand Rbin this context, may be the same or different and independently represent hydrogen, alkyl, halogenated, cycloalkyl, aryl, aralkyl, heterocyclyl. In addition, the above substituents may be further substituted by one or more of the above substituents.

In the following embodiments of structure (I) compound has the following structure (I-A):

In other embodiments of structure (I) link� has the following structure (I-B):

In other embodiments of structure (I) compound has the following structure (I-C):

In other embodiments of structure (I) compound has the following structure (I-D):

In other embodiments of structure (I) compound has the following structure (I-E):

In other embodiments of structure (I) compound has the following structure (I-F):

In other embodiments of structure (I) compound has the following structure (I-G):

In other embodiments of structure (I) compound has the following structure (I-H):

In other embodiments of structure (I) compound has the following structure (I-I):

In other embodiments of structure (I), in particular the structures (I-B) and (I-C), R4represents hydrogen or R4represents a C1-6alkyl (such as, for example, methyl).

In other embodiments of structure (I) R1represents a C1-6alkyl (such as, for example, a 1is methyl or ethyl).

In other embodiments of structure (I) R3is a substituted or unsubstituted phenyl (such as, for example, 4-bromo-3,5-dimethoxyphenyl, 4-chloro-3,5-dimethoxyphenyl or 3,4,5-trimethoxyphenyl).

In other embodiments of structure (I) R2is a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. In more specific embodiments, in which R2is a substituted phenyl, R2represents phenyl, substituted C1-6alkoxy, or R2represents phenyl, substituted with substituted or unsubstituted heterocyclyl (such as, for example, 4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl, 4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl or 4-morpholinomethyl).

In other embodiments of structure (I) R2is a substituted or unsubstituted heterocyclyl.

Compounds of the present invention can generally be applied in the form of free acid or free base. Alternatively, compounds of the present invention can be applied in the form of salts of accession acid or base. Salt accession acids free amino compounds of the present invention can be obtained by methods well known in the field technician�, and they can be obtained from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic acid, glycolic acid, glutamic and a mixture of Benzenesulfonic acid. Suitable inorganic acids are hydrochloric, bromomethane, sulfuric, phosphoric and nitric acid. Salt accession bases include those salts that form with the carboxylate anion, and include salts derived from organic and inorganic cations, such as salts selected from salts of alkali and alkaline earth metals (e.g. lithium, sodium, potassium, magnesium, barium and calcium), as well as ammonium ion and its substituted derivatives (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium and the like). Thus, it is assumed that the term "pharmaceutically acceptable salt" of the structure (I) includes any and all acceptable salt forms.

In addition, the prodrug is also included in the context of the present invention. Prodrugs are any covalently-linked carriers which release the compound of structure (I)in vivowith the introduction �ƈ prodrug to the patient. Prodrugs are typically obtained by modification of functional groups in such a way that this modification was cut, or conventional methods orin vivogiving the original connection. Prodrugs include, for example, the compounds of the present invention, in which hydroxy, amino, or sulfhydryl group is connected to any group that, when administered to a patient is cleaved, forming a hydroxy, amino or sulfhydryl groups. Thus, typical examples of the prodrug include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I). Further, in the case of the carboxylic acid (-COOH) can be used ethers such as methyl ether, ethyl ether, and the like.

It is envisaged that the present invention described in the present description, also includes all pharmaceutically acceptable compounds of structure (I), isotope labelled by one or more atoms replaced by atoms having different atomic weight and mass number. Examples of isotopes that can be entered in the described compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N15N15O,17O,18O,31P,32P,35S18F,36Cl23 I and125I accordingly. Data Radiometrie compounds may be suitable in order to help determine or measure the effectiveness of compounds, describing, for example, place or method of operation, or binding capacity of pharmacologically important. Certain isotopically-labeled compounds of structure (I), for example compounds introduced with a radioactive isotope, are suitable for studies of the distribution in the tissues of the drug and/or substrate. The radioactive isotopes tritium, T. E.3H, and carbon-14, T. E.14C, are especially suited for this purpose because of the ease of introduction and ready means of detection. Substitution of heavier isotopes such as deuterium, T. E.2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increasingin vivohalf-life or reduce the required doses, and therefore, it may be preferable in some circumstances. Substitution of a positron-emitting isotopes, such as11C,18F,15O and13N, may be suitable in studies using positron emission tomography (PET) to study the extent of employment of the receptor substrate. Isotopically-labeled compounds of structure (I) it is usually possible to obtain a General�accepted methods, known to those skilled in the art, or by methods similar to the methods described in the examples, as described below, using appropriate isotopically-labeled reagent is unlabeled reagent previously used.

With regard to stereoisomers, the compounds of structure (I) may contain chiral centers and may exist in the form of racemates, racemic mixtures and as individual enantiomers or diastereomers. All these isomeric forms are included in the scope of the present invention, including mixtures thereof. In addition, some of the crystalline forms of compounds of structure (I) may exist as polymorphs, which are included in the scope of the present invention. In addition, some compounds of structure (I) can also form solvates with water or other organic solvents. Similarly, these solvates are included in the scope of the present invention.

In another embodiment of the present invention describe pharmaceutical compositions containing one or more compounds of structure (I). For the purposes of administration of the compounds of the present invention may be formulated in the form of pharmaceutical compositions. Pharmaceutical compositions of the present invention contain one or more of the compounds of the present invention and a pharmaceutically acceptable carrier and/or get so�RER. PDE10 inhibitor is present in the composition in an amount that is effective for treating a particular condition, i.e. in an amount sufficient to achieve the desired PDE10 inhibition, and preferably with acceptable toxicity to warm-blooded animal. Typically, the pharmaceutical compositions of the present invention may contain PDE10 inhibitor in an amount of from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentration and dose can be easily determined by the person skilled in the technical field.

In General terms, the standard daily dose can be between about 1 μg/kg to 100 mg/kg, preferably 0.01 to 100 mg/kg, more preferably 0.1 to 70 mg/kg, depending on the type and severity of the disease, for example, one or more individual doses. For repetitive injection within a few days or more depending on the disease treatment is carried out until a desired suppression of emerging symptoms. However, there may be other suitable dosing regimens. The progress of this therapy can be monitored by standard methods and analyses. Characteristics of single dosage forms of the present invention are defined by and are directly dependent on the unique characteristics of the active compounds and specifically�about therapeutic effect, you want to achieve and the limitations inherent in the preparation of active compound compositions for the treatment of individuals.

Pharmaceutically acceptable carrier and/or diluents are known to those skilled in the art. With regard to the compositions obtained in the form of liquid solutions that are acceptable carriers and/or diluents include saline solution and sterile water, and may optionally contain antioxidants, buffers, bacteriostatic and other standard additives. The compositions can also be formulated in the form of pills, capsules, granules, or tablets which contain, in addition to the PDE10 inhibitor diluents, dispersing agents and surfactants, binders and lubricants. In addition, the specialist in the art may formulate the PDE10 inhibitor suitable manner and according to accepted practice, such as that described in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1990.

In another embodiment of the present invention relates to a method of treating a disease, such as (but not limited to, psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobia, epilepsy, aphasia, bell's palsy�, cerebral palsy, sleep disorders, pain, Tourette syndrome, schizophrenia, delusional disorder, bipolar disorder, post-traumatic stress disorder, psychosis, caused by drugs, panic disorder, obsessive-compulsive disorder, attention deficit disorder, disorders of social behavior, autism, depression, dementia, cognitive disorders, epilepsy, insomnia and multiple sclerosis, as described above. These methods include introducing the compound of the present invention blooded animal in an amount sufficient to treat the disease. In this context, to "treat" includes prophylactic administration. This method comprises the systemic administration of PDE10 inhibitor of the present invention, preferably in the form of pharmaceutical compositions, as discussed above. As used in the present invention, systemic administration includes oral and parenteral methods of administration, including subcutaneous, intramuscular, intracranial, vnutriglaznae, ophthalmic, intraventricular, intracapsular, intra-articular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, intravenous, intradermal, inhalation, transdermal, transmucosal and rectal administration.

As for oral introduction�t, suitable pharmaceutical compositions PDE10 inhibitors include powders, granules, pills, tablets and capsules as well as liquids, syrups, suspensions and emulsions. These compositions can also contain flavorings, preservatives, suspendresume agents, thickeners and emulsifiers and other pharmaceutically acceptable additives and fillers. As for parenteral administration, the compounds of the present invention can be obtained in aqueous injection solutions which may contain, in addition to PDE10 inhibitors, buffers, antioxidants, bacteriostats and other additives and excipients usually used in these solutions. The compositions of the present invention can be delivered to the delivery system to provide a delayed release or increased absorption or activity of a therapeutic compound, such as liposomal or gidrogeleva system for injection, microparticles, nanosystem or micelle system for oral or parenteral delivery, or capsule with a phased release for oral delivery.

As additional advantages of the present invention is expected that compounds of structure (I) will be absent or reduced metabolic side effects associated with conventional protivopsychoticheskogo drugs, in particular in�identification of therapeutically induced obesity. For example, prolonged use of olanzapine (Zyprexa®), the most commonly prescribed drug for the treatment of schizophrenia and related non-standard protopsaltis drugs is associated with significant metabolic side effects, including obesity and related diseases such as diabetes.

In animals subchronic treatment with olanzapine stimulates food intake and increases body weight, as well as in humans. In addition, olanzapine dramatically reduces the concentration of leptin in the blood. Leptin is a satiety hormone produced in adipose tissue, and decreased concentrations of leptin stimulates the appetite. There is a theory that olanzapine may stimulate food intake, at least in part by a decrease in the concentration of leptin. A single administration of olanzapine also alters the response of the animal to the concentration of glucose and insulin in the tests of glucose tolerance that may also be directly related to the effect of olanzapine on food intake and increased body weight. The study of the acute effect of PDE10 inhibitors of the present invention on the metabolism, such as changes associated with leptin, insulin and glucose metabolism in standard animal models and chronic effect of PDE10 inhibitors of the present invention to�the abuse of food, the body weight and energy homeostasis, in comparison with olanzapine should justify the pharmaceutical benefit PDE10 inhibitors as anti-psychotic drugs from the viewpoint of side effects.

The compositions of the present invention can be administered in combination with one or more additional therapeutic agents, in combination with or by simultaneous or successive administration. Suitable additional agents (i.e. excipients) may include standard protivopsychoticheskogo drugs that block dopamine D2receptors and serotonin 5HT2receptors, such as haloperidol, fluphenazine, chlorpromazine and non protivopsychoticheskogo drugs, such as clozapine, olanzapine, risperidone, quetiapine, ziprasido.

Compounds of the present invention can be analyzed to determine their IC50quantities by modifying the two-stage method of Thompson and Appleman (Biochemistry 10; 311 to 316; 1971). In short, camp complement (3(H)cyclic amp and incubated with PDE10 and various concentrations of compounds of structure (I). After a suitable incubation period the reaction is stopped by heating. The mixture is then treated with phosphatase snake venom. Phosphatase hydrolyzes any AMP in the mix, but leaves unreacted camp unaffected. Still�, the release of camp from the mixture, and the determination of its concentration (radiography), you can determine the percentage of inhibition. IC50the values can be calculated by carrying out the experiment at different concentrations using standard graphical methods. A detailed description of the method used for analysis IC50in the following examples. In this regard, PDE10 inhibitors of the present invention have the IC50100 μm or less, typically less than 10 microns, and typically less than 1 micron.

Compounds of the present invention can be obtained by known methods of organic synthesis, including the methods described in detail in the following examples. The following examples are given for illustration and not limitation.

EXAMPLES

EXAMPLE 1

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)THIAZOL-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

In a flask dried in a drying Cabinet, loaded 4-(4-morpholinyl)benzaldehyde (10,1 g, 53 mmol), anhydrous methanol (60 ml) and anhydrous dioxane (60 ml), then was equipped with an addition funnel. In the dropping funnel was loaded with a solution of KOH (14,8 g, 264 mmol) in anhydrous methanol (60 ml) and an aliquot (~2 ml) was added to the reaction mixture. Was added to the reaction mixture bromoform (5,8 ml, 67,1 mmol), then the remaining KOH/MeOH solution was added dropwise within 10 minutes. After per�of masiania within 18 hours the mixture was filtered through celite and washed with methanol. The filtrate is collected and concentrated in vacuo. Then the residue was diluted with saturated aqueous NH4Cl and extracted with EtOAc. Then an additional amount of EtOAc was used for extraction of the aqueous phase, while slowly bringing the pH from ~8 to ~2 using concentrated HCl. In the amount of approximately 1.5 l of EtOAc was used for extraction. The combined EtOAc extracts were dried over Na2SO4and was filtered. Concentration of the filtrate in vacuo gave 2-methoxy-2-(4-morpholinomethyl)acetic acid in the form of a yellowish brown solid (7,25 g, 58%).

To a suspension of 2-methoxy-2-(4-morpholinomethyl)acetic acid (2.97 g, of 11.8 mmol) in anhydrous CH2Cl2(66 ml) in a flask, dried in a drying oven, in an atmosphere of argon was added N-methylmorpholine (3 ml, 27.3 mmol) and the resulting solution was cooled on ice. Was added dropwise isobutylparaben (1.8 ml, 13,76 mmol). After stirring for 50 minutes, was added N,O-dimethylhydroxylamine (1.5 g, of 15.3 mmol) and the mixture was slowly warmed to room temperature. After stirring for 16 hours was added saturated aqueous NaHCO3and the mixture was stirred for >15 minutes. The mixture was diluted with CH2Cl2and the layers were separated. The organic layer was washed with brine, dried over MgSO4/Na2SO4and to�was centered. Purification by chromatography (60-85% EtOAc-hexane) gave N,2-dimethoxy-N-methyl-2-(4-morpholinoethyl)acetamide as an off-white solid (3,15 g, yield 90%).

In a flask dried in a drying oven, in an atmosphere of argon was loaded with 4-bromo-3,5-dimethoxybenzaldehyde (for 10.08 g, 41.1 mmol) and anhydrous THF (70 ml). The mixture was cooled to -78°C bath, was then added dropwise from the dropping funnel over 45 minutes a solution of MeMgBr (3.0 M in diethyl ether, to 17.8 ml of 53.4 mmol). After stirring for 20 minutes the mixture was warmed to room temperature and stirred for 19 hours. After termination of the reaction the aqueous solution of NH4Cl it was diluted with H2O and EtOAc, then cooled on an ice bath. After cooling the mixture, the layers were separated. The organic layer was washed with H2O and brine, then dried over Na2SO4and concentrated in vacuo. The residue was dissolved in dichloromethane and concentrated in vacuo again to obtain 1-(4-bromo-3,5-dimethoxyphenyl)ethanol as a white solid (10.8 g, quantitative yield). The product was used without further purification.

To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanol (10.8 g, 41.1 mmol) in anhydrous CH2Cl2(150 ml) was added MnO2(48 g, 552 mmol). The reaction vessel with a mixture of closed Chlorella� tube and the mixture was stirred at room temperature for 22 hours, was filtered through a layer of celite and silica gel and washed with EtOAc. Concentration of the filtrate in vacuo gave 1-(4-bromo-3,5-dimethoxyphenyl)Etalon in the form of a white solid (10.3 g, yield 97%). The product was used without further purification.

To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0,895 g of 3.45 mmol) in anhydrous CH2Cl2(5 ml) under chlorellaceae tube was added dropwise a freshly prepared solution of Br2in CH2Cl2(1,95 M, 1.9 ml, 3.7 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then neutralized with a saturated aqueous solution of NaHCO3. The mixture was diluted with CH2Cl2and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3and brine, then dried over MgSO4/Na2SO4and concentrated in vacuo. The crude product was applied on silica gel (2.9 g) in the form of CH2Cl2solution. Purification by chromatography (0-20% EtOAc-hexane) gave 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)Etalon in the form of a white solid (0,737 g, yield 63%). Large-scale synthesis of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone carried out without chromatographic purification bromide.

In a flask dried in a drying oven, in an atmosphere of argon was loaded P2S5(0,53 g, 1,2 mmol�), anhydrous dioxane (5 ml) and formamide (0.53 ml, a 13.3 mmol). The reaction flask was equipped with a countercurrent fridge and chlorellaceae tube and heated to reflux in the course of 2.25 hours. In a separate drying flask in an argon atmosphere was loaded with 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)alanon (0,313 g, 0.93 mmol) and anhydrous dioxane (6 ml). Thioformate mixture (above) was decanted into the reaction flask, leaving the solids on the inside. The reaction flask was equipped with a countercurrent fridge, placed under harkaliev tube and heated to reflux for 3 hours, then cooled to room temperature. After stirring over night the mixture was podslushivaet the addition of an aqueous solution of 2 M Na2CO3, diluted with H2O, and then was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The crude solid residue was dissolved in CH2Cl2and applied on silica gel. Purification by chromatography (0-35% EtOAc-hexane) gave 4-(4-bromo-3,5-dimethoxyphenyl)thiazole as a white solid (0.20 g, yield 73%).

To a cooled to -78°C solution of 4-(4-bromo-3,5-dimethoxyphenyl)thiazole (0,096 g, 0,32 mmol) in anhydrous THF (2 ml) in an argon atmosphere was added dropwise a solution of LiHMDS (1.0 MV THF, 0,35 mmol). After stirring for 30 minutes was added dropwise a solution ofN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide (equal to 0,121 g, 0.41 mmol) in anhydrous THF (1.5 ml, 1.0 ml). After stirring for 35 minutes, the ice bath was removed and the reaction mixture was warmed to room temperature. The mixture was quenched with brine and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4and concentrated. Purification by chromatography (25% to 45% EtOAc-hexane) gave 1-(4-(4-bromo-3,5-dimethoxyphenyl)thiazol-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon as a yellow solid (0.050 g, yield 29%). MS: m/z 533,1 [M+H]+.

EXAMPLE 2

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)OXAZOL-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

A solution of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.8 g, 0.96 mmol) in formamide (7 ml) in a flask, dried in a drying oven, in an atmosphere of argon was heated at 100°C for 10 hours, then at 110°C for 5 hours. After cooling to room temperature was carefully added EtOAc and saturated aqueous NaHCO3and the mixture was stirred for 15 minutes. Then it was extracted with EtOAc twice and the combined organic layers were washed with H2O and brine, dried over Na2SO4and concentrated. Purification by chromatography (20-40% EtOAc-GE�Sana) gave 4-(4-bromo-3,5-dimethoxyphenyl)oxazole as a yellow solid (0,387 g, yield 58%).

To the cooled to -20°C a solution of 4-(4-bromo-3,5-dimethoxyphenyl)oxazole (0,158 g, 0,56 mmol) in anhydrous THF (2 ml) in a flask, dried in a drying oven, in an atmosphere of argon was added dropwise a solution of LDA (2.0 M in THF/heptane/ethylbenzene; of 0.37 ml, 0.74 mmol). The mixture was stirred at -20 to -10°C for 50 minutes, then cooled to -20°C. was Added a solution ofN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide (ends 0.245 g, 0.83 mmol) in anhydrous THF (3 ml), then the mixture was slowly warmed to room temperature and stirred for 21 hours. The reaction mixture was quenched with H2O and was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated. Purification by chromatography (50-60% EtOAc-hexane) gave 1-(4-(4-bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon as a yellow solid (0,097 g, yield 34%). MS: m/z 517,1 [M+H]+.

EXAMPLE 3

2-(4-(1H-PYRAZOL-1-YL)PHENYL)-1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)THIAZOL-2-YL)-2-METHOXYETHANOL

To a stirred solution of 4-(1H-pyrazol-1-yl)benzaldehyde (1.3 g, to 7.55 mmol) and bromoform (0,85 ml of 9.75 mmol) in MeOH (10 ml) and dioxane (10 ml) was added dropwise a solution of potassium hydroxide (2.2 g, 39 mmol) in MeOH (10 ml) for 15 minutes. Then the stirring was continued for a period�s 23 hours. The mixture was filtered through celite, washed with EtOAc, and concentrated under reduced pressure to obtain 2-(4-(1-pyrazol-1-yl)phenyl)-2-methoxyacetate potassium in the form of a light yellow solid (3.2 g) which was used without further purification. Cm. U.S. patent No. 7129238.

To a stirred solution of 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate potassium (~to 7.55 mmol) in dry MeOH in argon atmosphere was added dropwise sulfuric acid (2.0 ml). The mixture was heated at 80°C for 17 hours. After cooling to room temperature, water was added, then the mixture was podslushivaet the addition of saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water and brine, then dried over Na2SO4and concentrated in vacuo. Purification by chromatography (20-35% EtOAc-hexane) gave methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate in the form of a colorless oil (0.88 g, yield 47% for two steps).

To a stirred solution of methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate (0,204 g, 0.83 mmol) in dry MeOH (5 ml) in an argon atmosphere was added a solution of KOH in MeOH (1.6 ml of a 0.5 M solution of 8.3 mmol) and the reaction mixture was boiled with reflux for 5 hours. The reaction mixture was cooled to room temperature and volatile to�components were removed under reduced pressure. The residue was diluted with saturated aqueous NH4Cl and extracted with EtOAc. Then applied an additional amount of EtOAc extraction of the aqueous phase, as pH was adjusted from ~8 to ~2 using concentrated HCl. The combined organic layers were dried over Na2SO4, was filtered and the solvent was removed under reduced pressure to obtain 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxybutanol acid (0.18 g, 95%) which was used without further purification.

To a solution of methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxybutanol acid (0.18 g, 0.77 mmol) in dry dichloromethane (5 ml) in an argon atmosphere was added aN-methylmorpholin (of 0.18 ml, 1.7 mmol). The reaction mixture was cooled to 0°C, was added isobutylparaben (of 0.11 ml, 0.85 mmol) and the mixture was stirred for 40 minutes. Was then added in one portionN,O-dimethylhydroxylamine (0,098 g, 1 mmol) and slowly warmed to room temperature and stirred for 18 hours. The mixture was diluted with saturated aqueous NaHCO3and was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (0-80% EtOAc-hexane) gave 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.16 g, yield 76%).

To the cooled to -20°C a solution of 4-(4-bromo-3,5-dimethoxyphenyl)thiazole (0,092 g, 0,305 mmol) in anhydrous THF (2 ml) in an argon atmosphere was added dropwise a solution of LDA (of 0.18 ml of a 2.0 M solution in THF/heptane/ethylbenzene, of 0.37 mmol). After stirring for 30 minutes the reaction mixture was cooled to -78°C and added dropwise a solution of 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.15 g, 0.55 mmol) in anhydrous THF (1.5 ml, 1.0 ml). After stirring for 90 minutes the mixture was quenched with brine and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4and concentrated. Purification by chromatography (0-35% EtOAc-hexane) gave 2-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl)thiazol-2-yl)-2-methoxyethanol as a yellow solid (0.030 g, yield 20%). MS: m/z 514,0 [M+H]+.

EXAMPLE 4

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)-1-METHYL-1H-IMIDAZOL-2-yl)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

In a flask dried in a drying oven, in an atmosphere of argon was added 4-bromo-3,5-dimethoxybenzaldehyde (1.0 g, of 4.08 mmol), absolute EtOH (34 ml), p-toluensulfonate (0.78 g, 4.0 mmol) and KCN (0.035 g of 0.54 mmol). The mixture was stirred for 19 hours at room temperature, then concentrated in vacuum to give 5-(4-bromo-3,5-dimethoxyphenyl)-4-tosyl,5-dihydrooxazolo, which was used in the next stage of the synthesis without purification.

In drying flask that can withstand high pressure, was added 5-(4-bromo-3,5-dimethoxyphenyl)-4-tosyl-4,5-dihydrooxazolo (0.4 g, 0.91 mmol), THF solution of methylamine (1.8 ml of 2.0 M solution of 3.6 mmol) and xylene (5 ml). The flask is sealed closed in the atmosphere of argon, then heated at 135°C for 15 hours. After cooling to room temperature the reaction mixture was transferred and concentrated in vacuo, then partitioned between EtOAc and H2O. the Layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine twice, dried over Na2SO4and concentrated. Purification by chromatography (50-100% EtOAc-hexane, then 2-5% MeOH-EtOAc) gave 4-(4-bromo-3,5-dimethoxyphenyl)-1-methyl-1H-imidazole as a pale yellow solid (of 0.056 g, yield 21%).

Method used for end-stage condensation of example 3 was used with modification. The reaction mixture was warmed at room temperature over night. Purification by chromatography (40-55% EtOAc-hexane) gave 1-(4-(4-bromo-3,5-dimethoxyphenyl)-1-methyl-1H-imidazol-2-yl)-2-methoxy-2-(4-morpholinomethyl)alanon (0,0039 g, yield 4%). MS: m/z 530,1 [M+H]+.

EXAMPLE 5

2-(4-(1H-PYRAZOL-1-YL)PHENYL)-1-(4-(4-BROMO-3,5-dim�TOXIGENIC)OXAZOL-2-YL)-2-METHOXYETHANOL

2-(4-(1H-Pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxyethanol was obtained from 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole in a manner similar to the method used in example 2, except that the amide was added to the reaction mixture at -50°C. MS: m/z 498,1 [M+H]+.

EXAMPLE 6

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)OXAZOL-2-YL)-2-METHOXY-2-(4-(PIPERIDINE-1-YL)PHENYL)ALANON

N,2-Dimethoxy-N-methoxy-2-(4-(piperidine-1-yl)phenyl)acetamide was obtained in two steps from 4-(piperidine-1-yl)benzaldehyde following the method used in example 1. 1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-(piperidine-1-yl)phenyl)Etalon received fromN,2-dimethoxy-N-methoxy-2-(4-(piperidine-1-yl)phenyl)acetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole, following the method used in example 5. MS: m/z 515,1 [M+H]+.

EXAMPLE 7

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)OXAZOL-2-YL)-2-METHOXY-2-(4-(PYRROLIDIN-1-YL)PHENYL)ALANON

N,2-dimethoxy-N-methoxy-2-(4-(pyrrolidin-1-yl)phenyl)acetamide was obtained from 4-(pyrrolidin-1-yl)benzaldehyde following the method used in obtaining the sample 1. 1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-(pyrrolidin-1-yl)phenyl)Etalon �was alocale from 2-dimethoxy- N-methoxy-2-(4-(pyrrolidin-1-yl)phenyl)acetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole, following the method used in example 2, except that the amide was added to the reaction mixture at -45°C. MS: m/z 501,1 [M+H]+.

EXAMPLE 8

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)OXAZOL-2-YL)-2-(4-ISOPROPOXYPHENYL)-2-METHOXYETHANOL

In a flask dried in a drying Cabinet, loaded 4-isopropoxybenzonitrile (4,9 g, a 29.9 mmol), anhydrous methanol (30 ml) and anhydrous dioxane (30 ml), then was equipped with an addition funnel. In the dropping funnel was loaded with a solution of KOH (8.4 g, at 149.5 mmol) in anhydrous methanol (30 ml) and an aliquot (~2 ml) was added to the reaction mixture. Was added to the reaction mixture bromoform (3,4 ml of 38.8 mmol), was then added dropwise over 10 minutes remaining KOH/MeOH solution. After stirring for 18 hours the mixture was concentrated in vacuo. The residue was diluted with water, and the pH was adjusted to ~2 using concentrated HCl, then was extracted with EtOAc. The combined organic layers were dried over Na2SO4and was filtered. Concentration of the filtrate in vacuo gave 2-(4-isopropoxyphenyl)-2-methoxybutanol acid as a light yellow solid (6.8 g) which was used without further purification.

2-(4-Isopropoxyphenyl)-N,2-dimethoxy-N-methylacetate� was obtained from 2-(4-isopropoxyphenyl)-2-methoxybutanol acid, following the method used to produce the example 1. 1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-(4-isopropoxyphenyl)-2-methoxyethanol was obtained from 2-(4-isopropoxyphenyl)-N,2-dimethoxy-N-methylacetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole, following the method used for the production of example 7. MS: m/z 490,1 [M+H]+.

EXAMPLE 9

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)OXAZOL-2-YL)-2-METHOXY-2-(QUINOLIN-5-YL)ALANON

N,2-Dimethoxy-N-methoxy-2-(quinolin-5-yl)acetamide was obtained from quinoline-5-carbaldehyde in two stages, following the method used to produce the example 1. 1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(quinolin-5-yl)Etalon received fromN,2-dimethoxy-N-methoxy-2-(quinolin-5-yl)acetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole, following the method used in example 2. MS: m/z 483,0 [M+H]+.

EXAMPLE 10

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)OXAZOL-2-YL)-2-METHOXY-2-(QUINOLIN-3-YL)ALANON

N,2-Dimethoxy-N-methoxy-2-(quinolin-3-yl)acetamide was obtained from quinoline-3-carbaldehyde in two stages, following the method used to produce the example 1. 1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(quinolin-3-yl)Etalon received fromN,2-dimethoxy-N-methoxy-2-(quinolin-3-yl)acetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole, following the method used�the IOM in example 2. MS: m/z 483,1 [M+H]+.

EXAMPLE 11

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)OXAZOL-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

N,2-Dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide was obtained from 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde in two stages, following the method used to produce the example 1. 1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon received fromN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole, following the method used in example 2, except that the amide was added to the reaction mixture at -30°C. MS: m/z 514,0 [M+H]+.

EXAMPLE 12

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

Into a flask containing a suspension of 4-bromo-3,5-dimethoxyaniline (1,99 g of 8.56 mmol; obtained according US2006/128695) in H2O (60 ml) was slowly added concentrated H2SO4(10 ml). The exothermic effect of controlled cooling on ice, and then the reaction mixture was cooled to -10 to -8°C (temperature of the bath). Was then added dropwise over 6 minutes a solution of NaNO2(0.70 g, 10 mmol) in H2O (3.5 ml) and the mixture was stirred for 70 minutes. Was added dropwise a solution of KI(2.8 g, of 16.9 mmol) in H2O (3.5 ml) and the mixture was stirred at -10 to -5°C for 30 minutes. After removal of the bath with ice and the mixture was stirred for 80 min, then EtOAc was added and the mixture was stirred for an additional 40 minutes. The layers were separated and the aqueous layer was extracted with EtOAc several times. The combined organic layers were washed with 1 M NaOH, twice with 10% Na2S2O3twice and brine, then dried over Na2SO4. Purification by chromatography (0-20% EtOAc-hexane) gave 2-bromo-5-iodo-1,3-dimethoxybenzene (of 1.86 g, yield 63%).

2-(4-Bromo-3,5-dimethoxyphenyl)furan was obtained according to the method described in WO 2008/040669, as follows. In a round bottom flask containing 3,5-dimethoxy-4-bromo-iadanza (7.9 g, 85% purity, at 19.6 mmol), 2-Puilboreau acid (3.4 g, 30.4 mmol), triphenylphosphine (0,358 g, 1.37 mmol), tetrabutylammonium (7,94 g, 14.6 mmol) and Na2CO3(4,9 g, or 46.2 mmol) was added THF (87 ml) and H2O (87 ml). The mixture was degassed by alternating placed under vacuum and argon three times for several minutes each. Added 10% Pd/C (1,36 g), and the mixture was heated at 60°C for 17 hours in an argon atmosphere. After cooling to room temperature the mixture was filtered through celite and washed with THF and EtOAc. Filtrate layers were separated and the organic layer was washed with brine, dried over Na2 4and concentrated. Purification of column chromatography (0-25% Et2O-hexane) gave 2-(4-bromo-3,5-dimethoxyphenyl)furan as a white solid (of 5.06 g, yield 91%). Product TLC Rf0,35 (15% EtOAc-hexane, TLC eluent).

To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0,203 g of 0.72 mmol) in anhydrous THF (2 ml) in an argon atmosphere in the flask, dried in a drying oven, cooled to -78°C, was added dropwise a solution of diisopropylamide lithium (2.0 M in THF/heptane/ethylbenzene; 0.4 ml, 0.8 mmol). After stirring for 35 minutes at -78°C was added dropwise a solution ofN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide (0,315 g, 1.1 mmol) in THF (2 ml). After stirring for 25 minutes the mixture was warmed to room temperature with stirring for 2 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Cl was then added brine and EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. Purification of column chromatography (35-65% EtOAc-hexane) gave an oil which was triturated with ΜeΟΗ-H2O (1:1) when the ultrasound treatment. The solid is collected on a Buchner funnel, washed with MeOH-Et2O (1:1) and dried in vacuum to give 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinomethyl)this�it in the form of a yellow solid substance. The second portion was collected from MeOH-Et2O (~10%) to obtain additional quantities of the product (0,220 g in total, yield 59%). MS: m/z of 516.1 [M+H]+.

EXAMPLE 13

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

To a solution of 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde (5,12 g, to 27.2 mmol) in anhydrous MeOH (27 ml) and anhydrous dioxane (27 ml) at -15 to -10°C (temperature bath) was added a few drops of KOH solution (7.6 g, to 135.4 mmol) in MeOH (27 ml). Added bromoform (3 ml, and 34.4 mmol), was then added to the remaining solution of KOH/MeOH for 20 minutes. The mixture was stirred for 1 hour and the ice bath was removed. After stirring for 30 minutes the reaction mixture was placed in an ice bath and heated slowly to room temperature overnight, then concentrated to dryness. After dissolution in a minimum amount of H2O the residue was acidified using to pH 1 with 6 M HCl. The aqueous mixture was extracted with EtOAc several times when adding a salt solution to the aqueous layer in the extraction process. The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuum to give 2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid in the form of semi-solid substances (6.8 g, quantitative yield). Product ispolzovanie further purification.

To a cooled on ice to a solution of 2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid (6.8 g, to 27.4 mmol) in anhydrous CH2Cl2(270 ml) and diisopropylethylamine (17 ml, 97 mmol) in an argon atmosphere was added dropwise TRIFLUORIDE bis(2-methoxyethyl)uminosity with 5.6 ml of 30.3 mmol). After stirring over an ice bath for 45 minutes addedN,O-dimethylhydroxylamine (3,40 g, 34.8 mmol) in three portions over 15 minutes. The mixture was stirred for 15 minutes, then bath with ice was removed. After 3 hours was added saturated aqueous NaHCO3and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3H2O and brine, dried over MgSO4that was filtered through celite and concentrated in vacuo. Purification by chromatography (75-100% EtOAc-hexane, then 0-5% EtOH-EtOAc) gaveN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide in the form of oil, which became solid on standing (2,06 g, yield 26%).

2-(4-Bromo-3,5-dimethoxyphenyl)furan was condensible withN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the method used for the production of example 12. Purification by chromatography (50-80%EtOAc-hexane) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon as a yellow foam (0,356 g, yield 40%). MS: m/z 513,2 [M+H]+.

EXAMPLE 14

2-(4-(1H-PYRAZOL-1-YL)PHENYL)-1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXYETHANOL

Applied the method used for the final stage of condensation of example 12. Purification by chromatography (20-55% EtOAc-hexane) gave 2-(4-(1H-pyrazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanol in the form of a light yellow solid (of 0.0625 g, yield 37%). MS: m/z 497,2 [M+H]+.

EXAMPLE 15

2-(4-(1H-PYRAZOL-4-YL)PHENYL)-1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXYETHANOL

To a suspension of 4-bromopyrazole (1.5 g, 10.2 mmol) and 4,4',4"-trimethoxytrityl (4.5 g, 12.2 mmol) in anhydrous DMF (20 ml) in an argon atmosphere was added triethylamine (3 ml, 21.5 mmol) and the mixture was cooled on an ice bath. After stirring for 10 minutes the bath with ice was removed, and the reaction mixture was stirred for 2.5 hours. The mixture was diluted with H2O and was extracted with EtOAc. The combined organic fractions were washed with H2O three times, then with saturated aqueous NaHCO3and salt solution. The solution was dried over Na2SO4and concentrated in vacuo. The crude oil was recrystallized from isopropanol to obtain 4-bromo-1-(Tris(4-methoxyphenyl)methyl)-1H-pyrazole in the form of a dirty-white crystals (two portions; 2.55 g, o�d 52%).

A mixture of 4-bromo-1-(Tris(4-methoxyphenyl)methyl)-1H-pyrazole (1.47 g, 3.1 mmol), (4-formylphenyl)Bronevoy acid (0,94 g, 6.3 mmol) and K2CO3(0.65 g, 4.7 mmol) in DME-H2O (25 ml, 4:1) was degassed by alternating her room in vacuum and in an atmosphere of argon three times for several minutes each. Was then added tetrakis(triphenylphosphine)palladium (0.35 g, 0.3 mmol), the mixture was again degassed. After heating for 16.5 hours at 80°C and cooling to room temperature was added H2O. the Mixture was extracted with EtOAc and the combined organic layers were washed with H2O, saturated aqueous NaHCO3and brine, then dried over Na2SO4and concentrated in vacuo. Purification by chromatography (20-30% EtOAc-hexane; EtOAc containing 1% Et3N) gave 4-(1-(Tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)benzaldehyde (1.31 g, obtained from two reactions, 33%).

Applied the method used for the production of example 1, except that the allocated potassium salt. Conducting the reaction at room temperature, EtOAc was added and the mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in EtOAc, filtered through celite and concentrated in vacuo. The product was dissolved in a mixture of EtOAc-toluene and concentrated to give 2-methoxy-2-(4-(1-(Tris(4-methods�Setenil)methyl)-1 H-pyrazol-4-yl)phenyl)potassium acetate (1.75 g, quantitative yield) which was used without further purification.

To a cooled on ice to a solution of 2-methoxy-2-(4-(1-(Tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)potassium acetate (1.25 g, 2.1 mmol) in anhydrous DMF (10 ml) in an argon atmosphere was added dropwise diisopropylethylamine (0.54 ml, 3.1 mmol) and TRIFLUORIDE bis(2-methoxyethyl)aminocore (0.46 ml, 2.5 mmol). The reaction mixture was stirred for 30 minutes, then added theN Ο-dimethylhydroxylamine (to 0.303 g, 3.1 mmol). After stirring for an additional 15 minutes on an ice bath, the mixture was warmed to room temperature and stirred for 3.5 hours. Added H2O and the mixture was extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NH4Cl, saturated aqueous NaHCO3and brine, then dried over Na2SO4and concentrated in vacuo. Purification by chromatography (45-90% EtOAc-hexane; EtOAc containing 1% Et3N) gaveN,2-dimethoxy-N-methyl-2-(4-(1-(Tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)acetamide (0,478 g of two reactions, the total yield 32%).

Applied the method used for the final stage of condensation of example 12, except for a shorter reaction time �ri room temperature for 70 minutes. Purification by chromatography (35-90% EtOAc-hexane; EtOAc containing 1% Et3N) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(1-(Tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)Etalon in the form of a solid (0.10 g, yield 18%).

To a suspension of 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(1-(Tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)ethanone (0.10 g, 0.12 mmol) in MeOH-H2O (22 ml, 10:1) addedpair-toluensulfonate pyridinium (0,046 g, 0.16 mmol). After stirring for 18 hours at room temperature was added a saturated aqueous NaHCO3and volatile components were removed under vacuum. The residue was diluted with a small amount of H2O, and then was extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (50-100% EtOAc-hexane) gave 2-(4-(1H-pyrazol-4-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanol as a yellow foam (0,010 g, yield 17%). MS: m/z 497,0 [M+H]+.

EXAMPLE 16

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYLFURAN-2-YL)PHENYL)ALANON

2-Methoxy-2-(4-(5-methylfuran-2-yl)phenyl)acetic acid was obtained from 4-(5-methylfuran-2-yl)benzaldehyde using the method described in example 1 (3.3 g, th� - state output). The product was used without further purification.

N,2-Dimethoxy-N-methoxy-2-(4-(5-methylfuran-2-yl)phenyl)acetamide was obtained from 2-methoxy-2-(4-(5-methylfuran-2-yl)phenyl)acetic acid, following the method used in example 13. The product was isolated as an orange oil (0,693 g, yield 18%).

2-(4-Bromo-3,5-dimethoxyphenyl)furan was condensible withN,2-dimethoxy-N-methoxy-2-(4-(5-methylfuran-2-yl)phenyl)acetamide following the method used for the final stage of condensation of example 12. Purification by chromatography (30-60% EtOAc-hexane) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methylfuran-2-yl)phenyl)Etalon in the form of a pale orange solid (0.172 g, yield 47%). MS: m/z 511,0 [M+H]+.

EXAMPLE 17

2,3-DIMETHOXY-5-(5-(2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ACETYL)FURAN-2-YL)BENZONITRILE

To a mixture of 5-bromo-2,3-dimethoxybenzonitrile (0,958 g, 4.0 mmol), 2-Puilboreau acid (0.53 g, 4.7 mmol), dioxane (24 ml), H2O (8 ml) and Na2CO3(1.1 g, 10.4 mmol) was added tetrakis(triphenylphosphine)palladium (0,23 g, 0.2 mmol). The mixture was degassed by alternating placement in a vacuum and in an atmosphere of argon three times for several minutes each, then heated at 85°C in argon atmosphere for 16.5 hours. After cooling, etc� room temperature, the mixture was diluted with H 2O and was extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (0-20% EtOAc-hexane) gave 5-(furan-2-yl)-2,3-dimethoxybenzonitrile in the form of a white solid (0.85 g, yield 94%).

Followed the method used for the final stage of condensation of example 12, reaction of 5-(furan-2-yl)-2,3-dimethoxybenzonitrile andN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide, except that the reaction was carried out at from -40 to -25°C, then heated to room temperature. Purification by chromatography (20-100% EtOAc-hexane) gave 2,3-dimethoxy-5-(5-(2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetyl)furan-2-yl)benzonitrile (0,040 g, yield 13%). MS: m/z 460,2 [M+H]+.

EXAMPLE 18

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-(4-(5-ETHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)-2-METHOXYETHANOL

To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzhydrazide (6.0 g, 21.4 mmol; Tanaka, A. et al. J. Med. Chem. 1998, 41, 2390) and adipodinitrile (3.5 g, of 25.7 mmol; receipt described in WO2007/73299 A1) in EtOH (120 ml) was added Et3N (2,59 g of 25.7 mmol). The mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was distributed between� EtOAc and H 2O and the organic layer was washed with H2O and brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (EtOAc-hexane) gave 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-ethyl-1,3,4-oxadiazol in the form of a brown oil (3.0 g, yield 44%).

To a cooled on ice to a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-ethyl-1,3,4-oxadiazole (3.0 g, 9.4 mmol) in MeOH (30 ml) was added dropwise 1 M HCl (20 ml, 20 mmol). The reaction mixture was stirred on ice for 1 hour, then concentrated. The residue was quenched with saturated aqueous NaHCO3and was extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuum to give (4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)methanol as an off-white solid (1.92 g, yield 93%).

To a solution of (4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)methanol (1.8 g, 8.8 mmol) in CH2Cl2(50 ml) was added molecular sieves (1.5 g, 4 Å) and the mixture was cooled to 0°C. was Added in portions to the reaction mixture chlorproma pyridinium (2.27 g, 10.5 mmol), then it was heated to room temperature. After stirring for 2 hours the mixture was filtered through celite and washed with additional amount of CH2Cl2. The filtrate was concentrated in vacuo. Clear�and chromatography (EtOAc-hexane) gave 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde as an off-white solid (1.3 g, 70%).

To a solution of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde (1.6 g, 7.9 mmol) in anhydrous DMF (7 ml) was added CHCl3(2.13 g, of 17.8 mmol). After cooling to -10°C was added dropwise over 20 minutes a solution of KOH (0.31 g, 5.5 mmol) in anhydrous MeOH (1.5 ml). After stirring at -10°C for 1 hour the reaction was quenched with 1 M HCl. The formed solid was collected on a Buchner funnel, washed with H2O and dried in vacuum to yield 2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol as a white solid (2.0 g, yield 80%).

To a solution of 2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol (2.0 g, 6.25 mmol) in anhydrous 1,4-dioxane (12.5 ml) and anhydrous MeOH (15 ml) was added a solution of NaOH (1.25 g, of 31.3 mmol) in anhydrous MeOH (15 ml). After stirring for 4 hours at 55°C the mixture was cooled to room temperature and concentrated in vacuo. The residue was neutralized with a saturated aqueous NH4Cl, was carefully acidified with 1 M HCl and was extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuo. The residue was triturated with Et2O obtaining 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybutanol acid as an off-white solid (1.2 g, yield 73%).

Followed the way as a result�WMD to obtain example 1 obtaining 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide of 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybutanol acid. Purification by chromatography (20% EtOAc-hexane) gave 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide in the form of an amorphous solid (0.55 g, yield 40%).

Followed the method used for the final stage of condensation of example 12, the reaction of 2-(4-bromo-3,5-dimethoxyphenyl)furan, 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide. Purification by chromatography (20-100% EtOAc-hexane) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyethanol as a yellow foam (0,037 g, yield 12%). MS: m/z 527,1 [M+H]+.

EXAMPLE 19

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-(4-(1,1-DIOXOTHIAZOLIDINE-2-YL)PHENYL)-2-METHOXYETHANOL

Followed the method used for the production of example 1, to obtain 2-methoxy-2-(4-nitrophenyl)acetic acid 4-nitrobenzaldehyde. Acid, selected after extraction, was used without further purification (5.3 g, yield 76%).

2-Methoxy-2-(4-nitrophenyl)acetic acid was atrificial according to procedure for the preparation of example 3. Purification by chromatography (15-22% EtOAc-hexane) gave methyl� 2-methoxy-2-(4-nitrophenyl)acetate as a yellow oil (2.15 g, yield 38%).

A solution of methyl 2-methoxy-2-(4-nitrophenyl)acetate (0.42 g, to 1.87 mmol) in absolute EtOH (15 ml) was degassed by alternating placement in a vacuum and in an atmosphere of argon three times for several minutes each, then added 10% Pd/C (0.19 g). The mixture was stirred in the atmosphere of H2(1 ATM) for 3 hours, then diluted with EtOAc and filtered through a layer of celite and silica gel. The filtrate was concentrated in vacuo. Purification by chromatography (25-40% EtOAc-hexane) gave methyl 2-(4-Dapsone base)-2-methoxyacetate in the form of a yellow oil containing impurities (0.6 g for two servings, yield 77%). The compound was used without further purification.

To a solution of methyl 2-(4-Dapsone base)-2-methoxyacetate (0.6 g, of 3.07 mmol) in anhydrous pyridine (6 ml) in an argon atmosphere was added dropwise 3-chloropropane-1-sulphonylchloride (0.5 ml, of 4.11 mmol). The exothermic reaction rapidly cooled in a bath of ice H2O. After stirring for 1 hour the reaction mixture was diluted with H2O, 1 M HCl and brine and was extracted with EtOAc. The combined organic layers were washed with 1 M HCl, H2O and brine, then dried over Na2SO4and concentrated in vacuum to give methyl 2-(4-(3-chloropropanesulfonyl)phenyl)-2-methoxyacetate in the form of an orange oil (1.03 g, quantitative yield. The product was used without further purification.

To a solution of methyl 2-(4-(3-chloropropanesulfonyl)phenyl)-2-methoxyacetate (1.03 g, of 3.07 mmol) in anhydrous DMF (10 ml) was addedN,N-diisopropylethylamine (2.0 ml, 11.5 mmol). The mixture was heated at 50°C in argon atmosphere for 17 hours. After cooling to room temperature the reaction mixture was diluted with H2O, 1 HCl and brine, then was extracted with EtOAc. The combined organic layers were washed with 1 M HCl, H2O and brine, dried over Na2SO4and concentrated in vacuo. The residue was triturated with Et2O-EtOAc. After stirring overnight the solution was decanted from the solids and then concentrated in vacuo. Purification by chromatography (50-70% EtOAc-hexane) gave methyl 2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)-2-methoxyacetate in the crude oil (0,69 g, 75% yield). The product was used for the next synthesis stage without further purification.

To a solution of methyl 2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)-2-methoxyacetate (of 0.48 g, 1.6 mmol) in MeOH (21 ml) was slowly added 1 M NaOH (7 ml, 7 mmol). After stirring at room temperature for 23 hours, the volatile components were removed under vacuum and the residue was dissolved in H2O. water solution was added EtOAc and saturated aqueous� NH 4Cl and was slowly added 1 M HCl to pH ~3. The mixture was extracted with EtOAc, the aqueous layer was acidified with to pH 1 and was again extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4and concentrated in vacuum to give 2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)-2-methoxybutanol acid as a yellow foam (0,378 g, yield 82%). The product was used for the next synthesis stage without further purification.

2-(4-(1,1-Dioxothiazolidine-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide was obtained from 2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)-2-methoxybutanol acid, following the procedure for obtaining example 13. Purification by chromatography (0-4% EtOH-EtOAc) gave an oil which was triturated with Et2O. the Solid was dried in vacuum to give pure 2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide in the form of a light yellow powder (0,182 g, yield 64%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)-2-methoxyethanol was obtained from 2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide and 2-(4-bromo-3,5-dimethoxyphenyl)furan, following the methodology used for the production of example 12. Purification by chromatography (EtOAc-hexane) gave compound primer as a yellow solid (0,111 g, yield 37%). MS: m/z 550,1 [M+H]+.

EXAMPLE 20

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(QUINOLIN-5-YL)ALANON

To a cooled on ice to a solution of quinoline-5-carbaldehyde (3.5 g, of 22.3 mmol) in anhydrous MeOH (30 ml) and anhydrous dioxane (30 ml) was added a few drops of KOH solution (6.2 g, 113,4 mmol) in MeOH (30 ml). Added bromoform (2.5 ml, 30 mmol) then was added over 10 minutes remaining solution of KOH/MeOH. After stirring for 30 minutes the reaction mixture was slowly warmed to room temperature overnight, then concentrated to dryness. After dissolution in a minimum amount of H2O the residue was acidified using to pH 1 with concentrated HCl. The aqueous mixture was extracted with EtOAc several times, adding the salt solution to the aqueous layer in the extraction process. The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuum to give 2-methoxy-2-(quinolin-5-yl)acetic acid in the form of semi-solid substances (2.8 g, yield 58%). The product was used without further purification.

To a cooled on ice to a solution of 2-methoxy-2-(quinolin-5-yl)acetic acid (2.8 g, 12.9 mmol) in anhydrous CH2Cl2(50 ml) and NMM (3,1 ml, 29 mmol) in an argon atmosphere was added dropwise isobutylparaben (1.9 ml, 14 mmol). �after stirring in an ice bath for 40 minutes was added in three portions N,O-dimethylhydroxylamine (1.63 g, 16.8 mmol) for 15 minutes. The mixture was stirred for 15 minutes, then bath with ice was removed. After 24 hours was added saturated aqueous NaHCO3and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3H2O and brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (0-100% EtOAc-hexane) gaveN,2-dimethoxy-N-methoxy-2-(quinolin-5-yl)acetamide in the form of an oil which crystallized on standing (1.8 g, yield 60%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(quinolin-5-yl)Etalon received fromN,2-dimethoxy-N-methoxy-2-(quinolin-5-yl)acetamide and 2-(4-bromo-3,5-dimethoxyphenyl)furan, following the methodology used for the production of example 12. Purification by chromatography (EtOAc-hexane) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(quinolin-5-yl)Etalon in the form of a light yellow foam (is 0.102 g, yield 46%). MS: m/z 482,1 [M+H]+.

EXAMPLE 21

1-(5-(3,5-dimethoxy-4-METHYLPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

To a solution of 3,5-dimethoxy-4-methylbenzaldehyde (3.0 g, 16.8 mmol) in CH2Cl2(35 ml) was addedmeta-Harper�ximenting acid (purity 77%; 5.8 g, 25.9 per mmol). After stirring at room temperature for 19 hours added an extra numbermeta-chloroperoxybenzoic acid (purity 77%; 3.5 g, 15.6 mmol). After heating for 4 hours at 40°C and cooling to room temperature was added 10% aqueous Na2S2O3and the mixture was stirred for 30 minutes. The mixture was diluted with CH2Cl2and the layers were separated. The organic layer was washed with 10% aqueous Na2S2O3, ~5% aqueous NaHCO3and brine, then dried over MgSO4and concentrated to give 3,5-dimethoxy-4-methylphenylimino as a yellow solid (2.9 g, yield 88%).

To a solution of 3,5-dimethoxy-4-methylphenylamine (2.9 g, 14.8 mmol) in wet MeOH (81 ml) was added K2CO3(8.1 g, or 58.6 mmol). The mixture was stirred for 2 hours at room temperature, was then added H2O (2-3 ml). After stirring for 21 hours, the mixture was diluted with H2O, acidified with 6M HCl to pH 3-4 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (0-35% EtOAc-hexane) gave 3,5-dimethoxy-4-METHYLPHENOL as the crude yellow powder (0.71 g, yield 29%).

To a suspension of 3,5-dimethoxy-4-METHYLPHENOL in anhydrous CH2/sub> Cl2(10 ml) in an argon atmosphere was added dry pyridine (0.4 ml, 4.9 mmol), the mixture is then cooled in an ice bath. Was added dropwise to the anhydride followed (0.52 g, 3.1 mmol) and the reaction mixture was stirred for 1 hour. Was added a saturated aqueous NaHCO3and stirred, and then it was heated to room temperature. The mixture was diluted with CH2Cl2and the layers were separated. The organic layer was washed with H2O and saturated aqueous NaHCO3, then dried over MgSO4and concentrated in vacuum to give 3,5-dimethoxy-4-methylenetetrahydrofolate in the form of a yellow oil (0,508 g, yield 60%). The product was used without further purification.

To a solution of 3,5-dimethoxy-4-methylenetetrahydrofolate (0.50 g, 1.67 mmol) in DME (15 ml) was added 2-Puilboreau acid (ends 0.245 g, 2.2 mmol), LiCl (0,149 g, 3.5 mmol), 2 M aqueous Na2CO3(1.8 ml, 3.6 mmol) and tetrakis(triphenylphosphine)palladium (0,098 g, 0,085 mmol) and the mixture degassed, as described earlier. The reaction mixture was heated at 80°C in argon atmosphere for 22 hours. After cooling to room temperature the reaction mixture was diluted with H2O and was extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NH4Cl, H2O and brine, dried over Na2SO4and end�was narrowly in a vacuum. Purification by chromatography (0-25% Et2O-hexane) gave 2-(3,5-dimethoxy-4-methylphenyl)furan as a white solid (0.28 g, yield 77%).

N2-Dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide interacted with 2-(3,5-dimethoxy-4-methylphenyl)furan according to the methodology used to produce the example 12. Purification by chromatography (EtOAc-hexane) gave 1-(5-(3,5-dimethoxy-4-methylphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon as a yellow foam (0,148 g, yield 29%). MS: m/z 449,2 [M+H]+.

EXAMPLE 22

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-(4-(5-DIHYDRO-1,3,4-OXADIAZOL-2-YL)PHENYL)-2-METHOXYETHANOL

4-(((tert-Butyldimethylsilyl)oxy)methyl)benzhydrazide interacted with the hydrochloride of ethylcyclopropane according to the methodology used to produce the example 18. Purification by chromatography (EtOAc-hexane) gave 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-cycloramic-1,3,4-oxadiazol in the form of a brown oil (3.7 g, yield 40%).

(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)methanol was obtained from 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-cyclopropyl-1,3,4-oxadiazole according to the method of example 18. (4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)methanol was isolated in the form of not�all white solid and used for the next synthesis stage without further purification (2.2 g, yield 84%).

4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)benzaldehyde was obtained from (4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)methanol according to the method of example 18. Purification by chromatography (EtOAc-hexane) gave 4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)benzaldehyde as a white solid (1.8 g, yield 82%).

2,2,2-Trichloro-1-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol was obtained from 4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)benzaldehyde according to the procedure for obtaining example 18. The product was isolated as a white solid and used without further purification (2.5 g, yield 89%).

2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybutanol acid was obtained from 2,2,2-trichloro-1-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol, following the methodology used for the production of example 18. The product was isolated as a yellow semi-solid substances and used for the next synthesis stage without further purification (1.8 g, yield 90%).

2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide was obtained from 2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybutanol acid according to the procedure for obtaining example 18. The product was isolated as a white semi-solid substances (0.56 g, yield 27%).

2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide interacted with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to the methodology for obtaining of example 12. Purification by chromatography (EtOAc-hexane) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyethanol as a yellow foam (0,126 g, yield 31%). MS: m/z 539,2 [M+H]+.

EXAMPLE 23

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(6-(PIPERIDINE-1-YL)PYRIDIN-3-YL)ALANON

2-Methoxy-2-(6-(piperidine-1-yl)pyridin-3-yl)acetic acid was obtained from 6-(piperidine-1-yl)nicotinamide according to the methodology used for the production of example 1 except that the reaction mixture was cooled on ice before adding a solution of KOH-MeOH. The product was isolated in the form of light beige foam and used without further purification (0,569 g, yield 52%).

N,2-Dimethoxy-N-methoxy-2-(6-(piperidine-1-yl)pyridin-3-yl)acetamide was obtained from 2-methoxy-2-(6-(piperidine-1-yl)pyridin-3-yl)acetic acid according to the methodology used to produce the example 13. Purification by chromatography (50-100% EtOAc-hexane) gave the product as an orange oil (0,295 g, yield 46%).

N,2-Dimethoxy-N-methoxy-2-(6-(piperidine-1-yl)pyridin-3-yl)acetamide communication�istubal with 2-(4-bromo-3,5-dimethoxyphenyl)furan in accordance with the method used in example 12. Purification by chromatography (20-75% EtOAc-hexane) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-(piperidine-1-yl)pyridin-3-yl)Etalon in the form of a light yellow solid (0,328 g, yield 65%). MS: m/z 515,4 [M+H]+.

EXAMPLE 24

2,6-dimethoxy-4-(5-(2-METHOXY-2-(4-MORPHOLINOMETHYL)ACETYL)FURAN-2-YL)PHENYLBENZOATE

4-Bromo-2,6-dimethoxyphenol (Lee, H.; et al. Tetrahedron Letters, 2004, 45, 1019) condensible 2 Puilboreau acid according to the methodology used in obtaining the sample 21. Purification by chromatography (20-40% EtOAc-hexane) gave 4-(furan-2-yl)-2,6-dimethoxyphenol in the form of a light yellow solid (1.95 g, yield 79%).

To a solution of 4-(furan-2-yl)-2,6-dimethoxyphenol (1.3 g, 5.9 mmol) in anhydrous CH2Cl2(20 ml) in an argon atmosphere was added Et3N (1.6 ml, 11.5 mmol), the mixture is then cooled in an ice bath. Added the dropwise benzoyl chloride (0.75 ml, 6.4 mmol) and the reaction mixture was stirred for 3 hours. Added 10% aqueous NaHCO3and CH2Cl2, was stirred and the layers were separated. The organic layer was washed with H2O and saturated aqueous NaHCO3, dried over MgSO4and concentrated in vacuo. Purification by chromatography (0-25% EtOAc-hexane) gave 4-(furan-2-yl)-2,6-dimethoxybenzoate in the form of a light yellow solid (0.54 g, et�record after chromatography approximately half of the crude product; yield 57%).

4-(Furan-2-yl)-2,6-dimethoxybenzoate interacted withN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure described for an example 12, except that the reaction mixture was heated only to about 0°C. Purification by chromatography (EtOAc-hexane) gave 2,6-dimethoxy-4-(5-(2-methoxy-2-(4-morpholinomethyl)acetyl)furan-2-yl)phenylbenzoate as a yellow solid (0,257 g, yield 50%). MS: m/z 558,2 [M+H]+.

EXAMPLE 25

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(1-METHYL-1H-BENZO[d][1,2,3]TRIAZOLE-5-YL)ALANON

2-Methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acetic acid was obtained from 1-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde according to the methodology for obtaining of example 23. The product was isolated as a yellow solid (1.5 g, yield 96%).

N,2-Dimethoxy-N-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acetamide was obtained from 2-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acetic acid according to the method used for the production of example 13. Purification by chromatography (60-100% EtOAc-hexane) gaveN,2-dimethoxy-N-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acetamide as a yellow solid (1.02 g, yield 57%).

N,2-D�methoxy- N-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acetamide was condensible with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to the methodology for obtaining of example 13. Purification by chromatography gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)Etalon in the form of a light yellow foam (0,153 g, yield 34%). MS: m/z 486,1 [M+H]+.

EXAMPLE 26

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(MORPHOLINOMETHYL)PHENYL)ALANON

2-Methoxy-2-(4-(morpholinomethyl)phenyl)acetic acid was obtained from 4-(morpholinomethyl)benzaldehyde following the procedure for obtaining example 23. After the reaction, the volatile components were removed under vacuum. The residue was re-dissolved in minimum amount of H2O and acidified with 1 M HCl to pH 3. The aqueous layer was concentrated in vacuo and the residue was suspended in MeOH, treated with ultrasound and slowly heated. The mixture was filtered through celite and concentrated in vacuo to give a white solid (3 g, quantitative yield). The product was used in the next stage of the synthesis without purification.

N,2-Dimethoxy-N-methoxy-2-(4-(morpholinomethyl)phenyl)acetamide was obtained from 2-methoxy-2-(4-(morpholinomethyl)phenyl)acetic acid, following the method used in example 13. Purification by chromatography (0-7% solution of NH3-MeO in CH 2Cl2; 0,7 M NH3-MeOH) gaveN,2-dimethoxy-N-methoxy-2-(4-(morpholinomethyl)phenyl)acetamide as an orange oil (0,743 g, yield 41%).

N,2-Dimethoxy-N-methoxy-2-(4-(morpholinomethyl)phenyl)acetamide was condensible with 2-(4-bromo-3,5-dimethoxyphenyl)furan, following the method of example 12. Purification by chromatography (used 0-9% NH3-MeOH in CH2Cl2; 0,7 M NH3-MeOH) gave a mixture, which was treated with EtOAc at 30-40°C. After cooling to room temperature, the crystals were collected on a Buechner funnel, washed with EtOAc, and dried in vacuum to give 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(morpholinomethyl)phenyl)ethanone in the form of a white solid. Also provided a second portion (0.125 g for two servings, yield 13%). MS: m/z 530,1 [M+H]+.

EXAMPLE 27

1-(5-(3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

1-Bromo-3,5-dimethoxybenzene was condensible 2 Puilboreau acid, following the method of example 21. 2-(3,5-Dimethoxyphenyl)furan was isolated as a colorless liquid (0,746 g, yield 79%).

N,2-Dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide was condensible with 2-(3,5-dimethoxyphenyl)furan, following the method of example 12. 1-(5-(3,5-Dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinomethyl)economically in the form of a yellow oily foam (0,343 g, yield 62%). MS: m/z 438,2 [M+H]+.

EXAMPLE 28

1-(5-(4-(DEFORMEDARSE)-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

5-Bromo-2-(deformedarse)-1,3-dimethoxybenzene were obtained from 4-bromo-2,6-dimethoxyphenol in accordance with the methodology Zafrani, Y. Tetrahedron 2009, 65, 5278 as follows: to a solution of 4-bromo-2,6-dimethoxyphenol (1,08 g, 4.6 mmol) in MeCN (27 ml) was added a solution of KOH (5.0 g, 89 mmol) in H2O (27 ml). The mixture was cooled to -78°C bath and was added diethyl(bromodifluoromethyl)phosphonate (1.6 ml, 8,9 mmol). The flask is sealed closed by septal and bath was removed with ice. The mixture was stirred for amount, 3.5 hours, after which septa was removed from the flask. The reaction mixture was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with 1 M NaOH, H2O and brine, then dried over Na2SO4and concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexane) gave 5-bromo-2-(deformedarse)-1,3-dimethoxybenzene as a white solid (0,808 g, yield 62%).

5-Bromo-2-(deformedarse)-1,3-dimethoxybenzene was condensible 2 Puilboreau acid, following the procedure for obtaining example 21. Purification by chromatography (0-30% EtOAc-hexane) gave 2-(4-(deformedarse)-3,5-dimethoxyphenyl)furan as a white crystalline prophetic�STV (0,555 g, yield 67%).

2-(4-(Deformedarse)-3,5-dimethoxyphenyl)furan was condensible withN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide following the method used for the production of example 12. Purification by chromatography (EtOAc-hexane) gave 1-(5-(4-(deformedarse)-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinomethyl)-Etalon in the form of a brown oil (of 0.021 g, yield 6%). MS: m/z 504,2 [M+H]+.

EXAMPLE 29

1-(5-(4-ETHOXY-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

To a suspension of 4-(furan-2-yl)-2,6-dimethoxyphenol (0,493 g, 2,24 mmol) in anhydrous DMF (10 ml) in an argon atmosphere was added Cs2CO3(1.2 g, 3.7 mmol) and Iodate (of 0.22 ml, 2.7 mmol). The mixture was stirred for 20 minutes, then heated at 80°C for 2 hours. After cooling to room temperature the reaction mixture was diluted with H2O and EtOAc, then it was acidified with the addition of 6 M HCl. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were diluted with hexane and washed with H2O and brine, dried over Na2SO4and was filtered through a layer of silica gel on celite. The filtrate was concentrated in vacuum to give 2-(4-ethoxy-3,5-dimethoxyphenyl)furan in the form of a beige solid (0,513 g, yield 92%). The product was used without additional eyes�tki.

2-(4-ethoxy-3,5-dimethoxyphenyl)furan was condensible withN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure for obtaining example 12. Purification by chromatography (EtOAc-hexane) gave 1-(5-(4-ethoxy-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon as a yellow foam (to 0.263 g, yield 58%). MS: m/z 482,2 [M+H]+.

EXAMPLE 30

2-(4-(2H-1,2,3-TRIAZOLE-2-YL)PHENYL)-1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXYETHANOL

To a solution of 4-(2H-1,2,3-triazole-2-yl)benzaldehyde (1.0 g, 5,77 mmol) in anhydrous MeOH (15 ml) at 0°C (temperature bath) was added bromoform (1,82 g, 7,21 mmol) with stirring. Was added in portions within 10 minutes of solid KOH (1.62 g, of 28.9 mmol). The mixture was stirred for 1 hour and bath with ice was removed. After stirring for 30 minutes the reaction mixture was slowly warmed to room temperature overnight, then concentrated to dryness. After dissolution in a minimum amount of H2O the residue was acidified using to pH 1 with 6 M HCl. The aqueous mixture was extracted with EtOAc several times, adding the salt solution to the aqueous layer in the extraction process. The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuum to give 2-(4-(2H-1,2,3-triazole-2-yl)phenyl)-2-IU�exucuse acid as an oil (1.19 g, yield 88%). The product was used without further purification.

To a solution of 2-(4-(2H-1,2,3-triazole-2-yl)phenyl)-2-methoxybutanol acid (1.19 g, 5.1 mmol) in anhydrous CH2Cl2(15 ml) was added 4-methylmorpholine (1.55 g, of 15.3 mmol) and cooled in an ice bath. Added isobutylparaben (0.84 g, 6,12 mmol) and stirred for 45 minutes. AddedN,O-dimethylhydroxylamine HCl (0,746 g, 7,65 mmol) and the mixture was stirred overnight while warming to ambient temperature. Was added a saturated aqueous NaHCO3(15 ml) and stirred for 5 minutes. The organic layer was dried over Na2SO4and evaporated to dryness. Purification by chromatography (100% EtOAc) gave 2-(4-(2H-1,2,3-triazole-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide in the form of a white solid (0,63 g, yield 44%).

To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0.20 g, 0.71 mmol) in anhydrous THF (10 ml) in an argon atmosphere in the flask, dried in a drying oven, cooled to -78°C, was added dropwise diisopropylamide lithium (2.0 M in THF/heptane/ethylbenzene; and 0.43 ml, 0.85 mmol). After stirring for 1 hour at -78°C was added dropwise a solution of 2-(4-(2H-1,2,3-triazole-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0,195 g, 0.71 mmol) in THF (2 ml). After stirring for 25 minutes the mixture was warmed to �anatoy temperature with stirring for 2 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Cl and EtOAc was added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (30% EtOAc-hexane) gave 2-(4-(2H-1,2,3-triazole-2-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanol as a yellow solid (0.07 g, yield 10%). MS: m/z 497,9 [M+H]+.

EXAMPLE 31

2-(4-(1H-1,2,3-TRIAZOLE-1-YL)PHENYL)-1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXYETHANOL

2-(4-(1H-1,2,3-Triazole-1-yl)phenyl)-2-methoxybutanol acid was obtained from 4-(1H-1,2,3-triazole-1-yl)benzaldehyde according to the procedure used in example 30. The product was obtained as an oil and used without further purification (1.02 g, yield 76%).

2-(4-(1H-1,2,3-Triazole-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide was obtained from 2-(4-(1H-1,2,3-triazole-1-yl)phenyl)-2-methoxybutanol acid according to the procedure used in example 30. Purification by chromatography (60% EtOAc/hexane) gave the product as an oil (0.73 g, yield 58%).

2-(4-(1H-1,2,3-Triazole-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanol was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(4-(1H-1,2,3-triazole-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide in accordance with the method used in example 30. Purification by chromatography (50% EtOAc hexane) gave 2-(4-(1H-1,2,3-triazole-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanol as a yellow solid (0.025 g, yield 7%). MS: m/z 498,2 [M+H]+.

EXAMPLE 32

2-(4-(1H-1,2,4-TRIAZOLE-1-YL)PHENYL)-1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXYETHANOL

2-(4-(1H-1,2,4-Triazole-1-yl)phenyl)-2-methoxybutanol acid was obtained from 4-(1H-1,2,4-triazole-1-yl)benzaldehyde according to the procedure used in example 30. Crude product was obtained as white solid and used without further purification (1.9 g, yield 47%).

2-(4-(1H-1,2,4-Triazole-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide was obtained from 2-(4-(1H-1,2,4-triazole-1-yl)phenyl)-2-methoxybutanol acid according to the procedure used in example 30. Purification by chromatography (100% EtOAc) gave the product as an off-white solid (0.30 g, yield 26%).

2-(4-(1H-1,2,4-Triazole-1-yl)phenyl-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanol was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(4-(1H-1,2,4-triazole-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the method used in example 30. Purification by chromatography (60% EtOAc-hexane), followed by another clean�coy (40% acetone-hexane) gave 2-(4-(1 H-1,2,4-triazole-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanol in the form of a pale yellow solid (0,078 g, yield 11%). MS: m/z 498,2 [M+H]+.

EXAMPLE 33

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(2-METHYL-2H-TETRAZOL-5-YL)PHENYL)ALANON

2-Methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetic acid was obtained from 4-(2-methyl-2H-tetrazol-5-yl)benzaldehyde according to the procedure used in example 30. The crude product was obtained as an oil and used without further purification (0.88 g, yield 86%).

To a solution of 2-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetic acid (0,87 g, 3.5 mmol) in anhydrous CH2Cl2(10 ml) was addedN,N-diisopropylethylamine (1,36 g, 10.5 mmol) under cooling in an ice bath. Added TRIFLUORIDE bis(2-methoxyethyl)aminocore (0,93 g, 4.2 mmol) and stirred for 15 minutes. AddedN,Ο-dimethylhydroxylamine HCl (0,512 g, a 5.25 mmol) and the mixture was stirred overnight while warming to ambient temperature. Was added a saturated aqueous NaHCO3(15 ml) and stirred for 5 minutes. The organic layer was dried over Na2SO4and evaporated to dryness. Purification by chromatography (60% EtOAc-hexane) gaveN,2-dimethoxy-N-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetamide in the form p�ozracing oil (0,425 g, yield 42%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (40% EtOAc/hexane) gave the product as a pale yellow solid (0,106 g, yield 29%). MS: m/z 513,3 [M+H]+.

EXAMPLE 34

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-THIADIAZOLE-2-YL)PHENYL)ALANON

To a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (2.0 g, 11,17 mmol) in dioxane (40 ml) was added 4-formylbenzeneboronic acid (3,35 g, of 22.34 mmol) and 2M Na2CO3(23 ml). The mixture is degassed by a stream of argon for 2 minutes. Added tetrakis(triphenylphosphine)palladium (0,636 g, 0.55 mmol) and the mixture was held at reflux overnight in an argon atmosphere. After cooling to room temperature was added H2O (30 ml) and EtOAc (50 ml) and stirred for 5 minutes. The organic layer was separated and washed with brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (10-20% EtOAc/hexane) gave 4-(5-methyl-1,3,4-thiadiazole-2-yl)benzaldehyde as pale yellow liquid (1.16 g, yield 51%).

2-Methods�si-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)acetic acid was obtained from 4-(5-methyl-1,3,4-thiadiazole-2-yl)benzaldehyde according to the procedure, used in example 30. The crude product was obtained as an oil and used without further purification (1.12 g, 75% yield).

N,2-Dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)acetamide was obtained from 2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)acetic acid according to the method used in example 33. Purification by chromatography (100% EtOAc) gave the product as a pale yellow oil (0,177 g, yield 26%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (70% EtOAc/hexane) gave the product as a pale yellow solid (0,044 g, yield 15%). MS: m/z 529,3 [M+H]+.

EXAMPLE 35

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(2-THIAZOLE-4-YL)PHENYL)ALANON

2-Methoxy-2-(4-(2-thiazole-4-yl)phenyl)acetic acid was obtained from 4-(2-thiazole-4-yl)benzaldehyde according to the procedure used in example 30. The crude product was obtained as an oil and used without further purification (0,972 g, yield 78%).

N,2-Dimethoxy-N-methoxy-2-(4(2-thiazole-4-yl)phenyl)acetamide was obtained from 2-methoxy-2-(4-(2-thiazole-4-yl)phenyl)acetic acid according to method used in example 33. Purification by chromatography (70% EtOAc/hexane) gave the product as an oil (0,516 g, yield 46%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(2-thiazole-4-yl)phenyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-(2-thiazole-4-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc/hexane) gave the product as an off-white solid (0,039 g, yield 10%). MS: m/z 528,2 [M+H]+.

EXAMPLE 36

2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)-1-(5-(3,4,5-TRIMETHOXYPHENYL)FURAN-2-YL)ALANON

2-(3,4,5-Trimethoxyphenyl)furan was obtained from 5-iodo-1,2,3-trimethoxybenzene according to the method used in example 12. Purification by chromatography (10% EtOAc/hexane) gave the product as an off-white solid (1.2 g, yield 60%).

To a solution of 2-(3,4,5-trimethoxyphenyl)furan (1.4 g, 5,98 mmol) in anhydrous THF (70 ml) in an argon atmosphere in the flask, dried in a drying oven, cooled to -78°C, was added dropwisen-butyllithium (2.5 M in hexano; 2,63 ml, 6,28 mmol). After stirring for 1 hour at -78°C was added dropwise a solution ofN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide (1,75 g, 6.0 mmol) in THF (5 ml). After �of remesiana for 25 minutes, the mixture was warmed to room temperature with stirring for 2 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, then brine and EtOAc was added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. Purification of column chromatography (60% EtOAc/hexane) gave 2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)Etalon as a fluffy yellow solid (0,81 g, yield 29%). MS: m/z 465,3 [M+H]+.

EXAMPLE 37

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(PYRIDIN-3-YL)PHENYL)ALANON

2-Methoxy-2-(4-(pyridin-3-yl)phenyl)acetic acid was obtained from 4-(pyridin-3-yl)benzaldehyde according to the procedure used in example 30, except that a pH of 4 was used in the extraction process. The crude product was obtained as an oil and used without further purification (0,415 g, yield 33%).

N,2-Dimethoxy-N-methoxy-2-(4-(pyridin-3-yl)phenyl)acetamide was obtained from 2-methoxy-2-(4-(pyridin-3-yl)phenyl)acetic acid according to the method used in example 33. Purification by chromatography (100% EtOAc) gave the product as an oil (0,232 g, yield 48%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(pyridin-3-yl)phenyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan� and N,2-dimethoxy-N-methoxy-2-(4-(pyridin-3-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (50% EtOAc/hexane) gave the product as an off-white solid (0,126 g, yield 35%). MS: m/z 508,2 [M+H]+.

EXAMPLE 38

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-ETHOXY-2-(4-MORPHOLINOMETHYL)ALANON

2-Ethoxy-2-(4-morpholinomethyl)acetic acid was obtained from 4-morpholinomethyl according to the methodology used for the production of example 1 except that EtOH was used as the solvent. The product was isolated in the form of a pale yellow oil and used without further purification.

2-Ethoxy-N-methoxy-N-methoxy-2-(4-morpholinoethyl)acetamide was obtained from 2-ethoxy-2-(4-morpholinomethyl)acetic acid, following the method used in example 13. Purification by chromatography (EtOAc-hexane) gave the product as a yellow solid (1.0 g, yield 31% for two steps).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-morpholinomethyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure used in example 30. Purification by chromatography (50% EtOAc/hexane) gave the product as a yellow solid prophetic�STV (0,129 g, yield 34%). MS: m/z 530,2 [M+H]+.

EXAMPLE 39

1-(5-(3-BROMO-4,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

3-Bromo-4,5-dimethoxyphenol was obtained from 3-bromo-4,5-dimethoxybenzaldehyde in accordance with the method used in example 21. Crystallization from a mixture of ether/hexane gave the product as a white solid (2,02 g, yield 39%).

3-Bromo-4,5- was obtained from 3-bromo-4,5-dimethoxyphenol in accordance with the method used in example 21. Evaporation to dryness gave the product as a pale yellow oil (3.3 g, yield 100%).

2-(3-Bromo-4,5-dimethoxyphenyl)furan was obtained from 3-bromo-4,5- according to the method used in example 21. Purification by chromatography (10% ether/hexane) gave the product as a pale yellow oil (1.7 g, yield 73%).

1-(5-(3-Bromo-4,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon was obtained from 2-(3-bromo-4,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (70% EtOAc/hexane) gave the product as a pale yellow solid (0,037 g, yield 10%). MS: m/z 513,1 [MH] +.

EXAMPLE 40

1-(5-(3-CHLORO-4,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

3-Chloro-4,5-dimethoxyphenol was obtained from 3-chloro-4,5-dimethoxybenzaldehyde in accordance with the methodology used to produce the example 21. The crude solid was treated with ~10% EtOAc-hexane at 40°C for 1 hour. After cooling to room temperature the solid is collected on a Buchner funnel and dried in vacuum to give beige crystals (1.44 g, yield 38% for two steps).

3-Chloro-4,5- was obtained from 3-chloro-4,5-dimethoxyphenol in accordance with the methodology for obtaining of example 21. The product was isolated as pale yellow liquid and used for the next synthesis stage without further purification (2.33 g, yield 96%).

2-(3-Chloro-4,5-dimethoxyphenyl)furan was obtained from 3-chloro-4,5- according to the methodology used in the example of getting 21. Purification by chromatography (10% Et2O-hexane) gave the product as a pale yellow oil (1.6 g, yield 94%).

l-(5-(3-Chloro-4,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon was obtained from 2-(3-chloro-4,5-dimethoxyphenyl)furan andN2-dimetix�- N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (70% EtOAc/hexane) gave the product as a pale yellow solid (0,051 g, yield 12%). MS: m/z 469,2 [M+H]+.

EXAMPLE 41

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-(CYCLOPROPYLMETHOXY)-2-(4-MORPHOLINOMETHYL)ALANON

To a solution of 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde (5.3 g, to 27.7 mmol) in cyclopropylmethanol (25 ml) and anhydrous dioxane (25 ml) at 0°C (temperature bath) was added a few drops of KOH solution (of 7.77 g of 138.5 mmol) in cyclopropylmethanol (35 ml). Added bromoform (3,1 ml of 35.2 mmol) then was added over 20 minutes remaining solution of KOH/cyclopropylmethanol. After stirring for 30 minutes the reaction mixture was warmed slowly to room temperature overnight, then concentrated to dryness. After dissolution in a minimum amount of H2O the residue was acidified using to pH 1 with concentrated HCl. The aqueous mixture was extracted with EtOAc several times, adding the salt solution to the aqueous layer in the extraction process. The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuum to give 2-(cyclopropylmethoxy)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid in the form of semi-solid substances�and, then it precrystallization of Et2O (0.5 g, yield 7%).

2-(Cyclopropylmethoxy)-N-methoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide was obtained from 2-(cyclopropylmethoxy)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid according to the method used in the example of getting 13. Purification by chromatography (0-70% EtOAc-hexane) gave the product as an oil (of 0.48 g, yield 77%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(cyclopropylmethoxy)-2-(4-morpholinomethyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(cyclopropylmethoxy)-N-methoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure used in example 30. Purification by chromatography (40% EtOAc/hexane) gave the product as a pale yellow solid (0,092 g, yield 23%). MS: m/z 556,3 [M+H]+.

EXAMPLE 42

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(6-METHOXYPYRIDINE-3-YL)ALANON

2-Methoxy-2-(6-methoxypyridine-3-yl)acetic acid was obtained from 6-methoxynicotinate according to the method used in example 37. The crude product was obtained as an oil and used without further purification (5,67 g, yield 79%).

N,2-Dimethoxy-2-(6-methoxypyridine-3-yl)-N-methylacetamide received and� 2-methoxy-2-(6-methoxypyridine-3-yl)acetic acid according to method used in example 33. Purification by chromatography (60% EtOAc/hexane) gave the product as an oil (0,97 g, yield 40%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-methoxypyridine-3-yl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-2-(6-methoxypyridine-3-yl)-N-methylacetamide according to the method used in example 30. Purification by chromatography (50% EtOAc/hexane) gave the product as a pale yellow solid (0,092 g, yield 28%). MS: m/z 462,2 [M+H]+.

EXAMPLE 43

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-(4-((DIMETHYLAMINO)METHYL)PHENYL)-2-METHOXYETHANOL

2-(4-((Dimethylamino)methyl)phenyl)-2-methoxybutanol acid was obtained from 4-((dimethylamino)methyl)benzaldehyde according to the procedure used in example 37. After pH was adjusted to 4, the aqueous solution was evaporated to dryness. Added MeOH (20 ml) with stirring and the product was filtered. Evaporation to dryness gave the crude product which was used without further purification (1.3 g, yield 95%).

2-(4-((Dimethylamino)methyl)phenyl)-N,2-dimethoxy-N-methylacetamide was obtained from 2-(4-((dimethylamino)methyl)phenyl)-2-methoxybutanol acid according to the method used in example 33. Purification by chromatography (100% EtOAc) gave the product as an oil (0,212 g,�speed 14%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-((dimethylamino)methyl)phenyl)-2-methoxyethanol was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(4-((dimethylamino)methyl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the method used in example 30. Purification by chromatography (4% MeOH/CH2Cl2) gave the product as a pale yellow oil (0.004 g, yield 1%). MS: m/z 488,3 [M+H]+.

EXAMPLE 44

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(6-MORPHOLINOPROPAN-3-YL)ALANON

2-Methoxy-2-(6-morpholinopropan-3-yl)acetic acid was obtained from 6-morpholinosydnonimine according to the method used in example 30, except that the aqueous mixture was adjusted to pH 4 in the extraction process. The crude product was obtained as an oil and used without further purification (1.17 g, yield 89%).

N,2-Dimethoxy-N-methoxy-2-(6-morpholinopropan-3-yl)acetamide was obtained from 2-methoxy-2-(6-morpholinopropan-3-yl)acetic acid according to the method used in example 33. Purification by chromatography (80% EtOAc/hexane) gave the product as an oil (0,692 g, yield 51%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-morpholinopropan-3-yl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,Dimethoxy- N-methoxy-2-(6-morpholinopropan-3-yl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc/hexane) gave the product as a pale yellow solid (0.04 g, yield 11%). MS: m/z 517,3 [M+H]+.

EXAMPLE 45

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(PYRAZINE-2-YL)PHENYL)ALANON

2-Methoxy-2-(4-(pyrazine-2-yl)phenyl)acetic acid was obtained from 4-(pyrazine-2-yl)benzaldehyde according to the procedure used in example 30, except that the aqueous mixture was adjusted to pH 4 in the extraction process. The crude product was obtained as an oil and used without further purification (1.21 g, yield 91%).

N,2-Dimethoxy-N-methoxy-2-(4-(pyrazine-2-yl)phenyl)acetamide was obtained from 2-methoxy-2-(4-(pyrazine-2-yl)phenyl)acetic acid according to the method used in example 33. Purification by chromatography (80% EtOAc/hexane) gave the product as an oil (0,493 g, yield 35%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(pyrazine-2-yl)phenyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-(pyrazine-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc/hexane) gave the product as a pale yellow solid (0,060 g, VGA output� 17%). MS: m/z 509,3 [M+H]+.

EXAMPLE 46

2-ETHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)-1-(5-(3,4,5-TRIMETHOXYPHENYL)FURAN-2-YL)ALANON

2-Ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid was obtained from 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde following the method of example 47. The product was isolated in the form of semi-solid substances and used without further purification (2.6 g, yield 93%).

2-Ethoxy-N-methoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide was obtained from 2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid according to the procedure for obtaining example 41. Purification by chromatography (0-60% EtOAc-hexane) gave the product as an oil (1.0 g, yield 30%).

2-Ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)Etalon was obtained from 2-(3,4,5-trimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc/hexane) gave the product as a pale yellow solid (0,060 g, yield 15%). MS: m/z 479,4 [M+H]+.

EXAMPLE 47

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-ETHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

1-(5-(4-Bromo-3,5-dimethoxy�yl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-ethoxy- N-methoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc/hexane) gave the product as a pale yellow solid (0,070 g, yield 19%). MS: m/z 527,3 [M+H]+.

EXAMPLE 48

1-(5-(4-FLUORO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

2-(4-Fluoro-3,5-dimethoxyphenyl)furan was obtained from 5-bromo-2-fluoro-1,3-dimethoxybenzene (US6177154 B1) according to the method used in example 15. Purification by chromatography (10% EtOAc/hexane) gave the product as a white solid (2.1 g, yield 58%).

1-(5-(4-Fluoro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon was obtained from 2-(4-fluoro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc/hexane) gave the product as a pale yellow solid (0,072 g, yield 16%). MS: m/z 456,4 [M+H]+.

EXAMPLE 49

1-(5-(4-CHLORO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-THIADIAZOLE-2-YL)PHENYL)ALANON

1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)Etalon was obtained from 2-(4-chloro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-(5-methyl�-1,3,4-thiadiazole-2-yl)phenyl)acetamide according to the procedure, used in example 30. Purification by chromatography (80% EtOAc-hexane) gave the product as a pale yellow solid (0,106 g, yield 26%). MS: m/z 485,4 [M+H]+.

EXAMPLE 50

1-(5-(4-CHLORO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

2-(4-Chloro-3,5-dimethoxyphenyl)furan was obtained from 5-bromo-2-chloro-1,3-dimethoxybenzene (EP1568691 A1) according to the method used in example 15. Purification by chromatography (10% ether/hexane) gave the product as a white solid (1.24 g, yield 75%).

1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon was obtained from 2-(4-chloro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure used in example 30. Purification by chromatography (70% EtOAc/hexane) gave the product as a pale yellow solid (0,201 g, yield 43%). MS: m/z 472,2 [M+H]+.

EXAMPLE 51

1-(3-(3,4-dimethoxyphenyl)-1H-PYRAZOL-1-YL)-2-(4-FLUOROPHENYL)-2-METHOXYETHANOL

To a solution of 2-(4-fluorophenyl)-2-methoxybutanol acid (0.11 g, 0.61 mmol) in anhydrous THF (2 ml) at room temperature was added in one portion DCC (0,14 g, 0.67 mmol). After stirring for 10 minutes was added one portion of 3-(3,4-dimethoxyphenyl)-1H-pyrazole (0,14 g, 0.67 mmol). After 48 hours p�promotional mixture was diluted with EtOAc and the solids were removed by filtration. The filtrate was concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexane) gave the product as an oil (0.12 g, yield 46%). MS: m/z 371,1 [M+H]+.

EXAMPLE 52

1-(3-(4-BROMO-3,5-DIMETHOXYPHENYL)-1H-PYRAZOL-1-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

1-(3-(4-Bromo-3,5-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon was obtained from 3-(4-bromo-3,5-dimethoxyphenyl)-1H-pyrazole (obtained according to the Journal of Org. Chem., 2003, 68, 5381) and 2-methoxy-2-(4-morpholinomethyl)acetic acid, using a similar procedure as in example 51 to obtain 1-(3-(4-bromo-3,5-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinomethyl)ethanone in the form of a solid substance (of 0.065 g, yield 22%). MS: m/z of 516.1 [M+H]+.

EXAMPLE 53

1-(3-(3,4-dimethoxyphenyl)-1H-PYRAZOL-1-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

To a solution of 2-methoxy-2-(4-morpholinomethyl)acetic acid (0.1 g, 0,42 mmol) and 3-(3,4-dimethoxyphenyl)-1H-pyrazole (0.86 g, 0,42 mmol) in anhydrous DMF (4 ml) at room temperature was added diisopropylethylamine (of 0.22 ml of 1.26 mmol), then hexaphosphate patrimonialization (0,23 g, 0.50 mmol). After 24 hours was added saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried Na 2SO4and concentrated in vacuo. Purification by chromatography (0-60% EtOAc-hexane) gave 1-(3-(3,4-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon in the form of a white solid (0.90 g, yield 50%). MS: m/z 438,2 [M+H]+.

EXAMPLE 54

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)-1,2,4-OXADIAZOL-3-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

To a solution ofN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide (1.5 g, 5.1 mmol) in anhydrous CH2Cl2(12 ml) and anhydrous toluene (6 ml) at -78°C was added a solution of DIBALH (1 M in hexano, and 7.8 ml, 7.8 mmol) dropwise over 5 minutes. After stirring at -78°C for 1 hour, the reaction mixture was quenched by dropwise addition of EtOAc. The mixture was stirred for 2 minutes, then added Εt2Ο and saturated aqueous NH4Cl and the mixture was heated to room temperature. After stirring for 30 minutes the mixture was diluted with EtOAc and H2O and the layers were separated. Was added to the aqueous layer with 10% aqueous potassium sodium tartrate and the product was extracted with EtOAc/Et2O. the combined organic layers were washed with saturated aqueous NH4Cl and dried over Na2SO4obtaining 2-methoxy-2-(4-morpholinomethyl)acetaldehyde as a yellow oil (1,27 g). The product was used for the next synthesis stage without further purification.

To a solution of 2-methoxy-2-(4-morpholinomethyl)acetaldehyde (1,27 g, ~5.1 mmol) in Et2O (35 ml) under chlorellaceae tube was added trimethylsilylacetamide (1 ml, 8 mmol) and zni extension2(50 mg, 0.16 mmol). After stirring at room temperature for a period of 15.5 hours was added saturated aqueous NaHCO3and the mixture was stirred for several hours. The mixture was diluted with EtOAc and H2O and the layers were separated. The organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4and concentrated in vacuum to give 2-hydroxy-3-methoxy-3-(4-morpholinomethyl)propanenitrile as an orange foam (1.26 g). The product was used without further purification.

To a solution of 2-hydroxy-3-methoxy-3-(4-morpholinomethyl)propanenitrile (~5.1 mmol) in anhydrous CH2Cl2(17 ml) in an argon atmosphere was added apair-toluensulfonate pyridinium (0,094 g of 0.37 mmol) and ethylenically ether (17 ml, 178 mmol). The mixture was placed under harkaliev tube and stirred at room temperature for 16 hours. Added more number of etilenovogo ether (4 ml, 42 mmol) andpair-toluensulfonate pyridinium (0.11 g, 0.44 mmol) and the mixture was stirred for 24 hours. Was added to a mixture of saturated aqueous NaHCO3then it was diluted with H2O and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers washed�whether saline, dried over MgSO4and concentrated in vacuo. Purification by chromatography (20-35% EtOAc-hexane containing 1% Et3N) gave 2-(1-ethoxyethoxy)-3-methoxy-3-(4-morpholinomethyl)propanenitrile (0,606 g, 35% for three steps).

To a solution of 2-(1-ethoxyethoxy)-3-methoxy-3-(4-morpholinomethyl)propanenitrile (of 0.60 g, 1.8 mmol) in anhydrous MeOH (10 ml) in an argon atmosphere was added NH2OH·HCl (0.175 g, 2.5 mmol) and NaHCO3(0,234 g, 2.8 mmol). The reaction mixture was rapidly heated to 75°C, then heated at 60°C for 16 hours. After cooling to room temperature the mixture was concentrated in vacuum to give (Z)-2-(1-ethoxyethoxy)-N'-hydroxy-3-methoxy-3-(4-morpholinomethyl)propanimidamide, which was used for the next synthesis stage without further purification (0,777 g).

To a chilled on ice slurry (Z)-2-(1-ethoxyethoxy)-N'-hydroxy-3-methoxy-3-(4-morpholinomethyl)propanimidamide (~1.41 mmol) in anhydrous CH2Cl2in an argon atmosphere was added Et3N (0.8 ml, 5.7 mmol), 4-bromo-3,5-dimethoxybenzoate (0,434 g, 1.6 mmol) and 4-dimethylaminopyridine (0.015 g, 0.12 mmol). The reaction mixture was stirred for 1 hour on an ice bath, then heated to room temperature. After stirring for 3 hours at room temperature was added an additional amount-bromo-3,5-dimethoxybenzaldehyde (0,047 g, 0,17 mmol) and the mixture was stirred for an additional hour. Added a 10% aqueous solution of NaHCO3and stirred for 20 minutes. The layers were separated and the organic layer was washed with H2O, brine, dried over MgSO4and concentrated in vacuum to yield an off-white foam.

This intermediate obtained compound was dissolved in anhydrous DMF (15 ml) in an argon atmosphere, and then heated at 120°C for 7 hours. After cooling to room temperature the reaction mixture was diluted with H2O and was extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (25-35% EtOAc-hexane containing 1% Et3N) gave 4-(4-(2-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-(1-ethoxyethoxy)-1-methoxyethyl)phenyl)morpholine as a pale yellow oil (0,335 g, yield 40%).

To a solution of 4-(4-(2-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-(1-ethoxyethoxy)-1-methoxyethyl)phenyl)morpholine (0,335 g of 0.57 mmol) in MeOH (15 ml) was addedpair-toluensulfonate pyridinium (0.15 g, 0.6 mmol) and the mixture stirred at room temperature for 16.5 hours. Then the reaction mixture was heated at 40°C for 6 hours, cooled to room temperature and concentrated in vacuo. The rest �astoral in EtOAc and washed with H 2O, saturated NaHCO3and brine, then dried over Na2SO4and concentrated in vacuo. Purification by chromatography (50-60% EtOAc-hexane) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methoxy-2-(4-morpholinyl)ethanol as a colorless residue (0,234, yield 79%).

To a solution of 1-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methoxy-2-(4-morpholinyl)ethanol (0.18 g, 0.35 mmol) in anhydrous CH2Cl2(4 ml) in an argon atmosphere was added 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-he (0,198 g, 0.47 mmol). After stirring at room temperature for 50 minutes, the mixture was diluted with Et2O, saturated aqueous NaHCO3and 20% Na2S2O3. The layers were separated and the organic layer was washed with saturated NaHCO3, dried over Na2SO4and concentrated in vacuo. Purification by chromatography (40-50% EtOAc-hexane) gave the product as a bright yellow solid (0,1249 g, yield 70%). MS: m/z 518,1 [M+H]+.

EXAMPLE 55

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)-5-METHOXAZOLE-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

In a flask dried in a drying oven, in an atmosphere of argon was loaded with 4-bromo-3,5-dimethoxybenzaldehyde (5.0 g, of 20.4 mmol) and anhydrous THF (30 ml). The mixture was cooled on ice, was then added dropwise from drip �of oronce for 45 minutes a solution of ethyl magnesium bromide (3.0 M in diethyl ether, of 8.2 ml, 24.5 mmol). After stirring for 20 minutes the mixture was warmed to room temperature and stirred for 19 hours. After termination of the reaction the aqueous solution of NH4Cl the reaction mixture was diluted with H2O and EtOAc, then cooled on an ice bath. After cooling the mixture, the layers were separated. The organic layer was washed with H2O and brine, then dried over Na2SO4and concentrated in vacuo. The residue was dissolved in CH2Cl2and again concentrated in vacuum to give 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-ol as a clear oil (5,43 g, yield 97%). The product was used without further purification.

To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-ol (5.4 g, a 19.6 mmol) in anhydrous CH2Cl2(75 ml) was added MnO2(17 g, 196 mmol). After the mixture was placed under harkaliev tube and stirred at room temperature for 22 hours, it was filtered through a layer of celite and silica gel and washed with EtOAc. Concentration of the filtrate in vacuo gave 1-(4-bromo-3,5-dimethoxyphenyl)propane-1-it is in the form of a white solid (5.4 g, yield 100%). The product was used without further purification.

To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)propane-1-one (1.50 g, 5,49 mmol) in anhydrous THF (20 ml) was added tribromide feast�dine (1,93 g, of 6.04 mmol). The reaction mixture was stirred at room temperature for 2 hours, then neutralized with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc, the combined organic layers were washed with saturated aqueous NaHCO3and brine, then dried over Na2SO4and concentrated in vacuo. Purification by chromatography (10-20% EtOAc-hexane) gave 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)propane-1-it is in the form of an orange oil (1,09 g, yield 56%).

A solution of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)propane-1-one (1,07 g of 3.04 mmol) in formamide (10 ml) in a flask, dried in a drying oven, in an atmosphere of argon was heated at 110°C for 16 hours. After cooling to room temperature was carefully added EtOAc and saturated aqueous NaHCO3and the mixture was stirred for 15 minutes. Then it was extracted with EtOAc twice and the combined organic layers were washed with H2O and brine, dried over Na2SO4and concentrated. Purification by chromatography (30% EtOAc-hexane) gave 4-(4-bromo-3,5-dimethoxyphenyl)-5-methoxazole as a yellow solid (0,496 g, yield 55%).

1-(4-(4-Bromo-3,5-dimethoxyphenyl)-5-methoxazole-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon was obtained from 4-(4-bromo-3,5-dimethoxyphenyl)-5-methoxazole andN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure, used in example 30. Purification by chromatography (40% EtOAc-hexane) gave the product as a yellow solid (0,048 g, yield 13%). MS: m/z 531,1 [M+H]+.

EXAMPLE 56

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)OXAZOL-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

A solution of 4-bromo-3,5-dimethoxybenzaldehyde (to 5.04 g, 20,57 mmol) and toluensulfonate (of 4.22 g, 21.6 mmol) in MeOH (50 ml) was boiled to reflux for 3 hours. After almost evaporation to dryness was added with stirring H2O (50 ml) and EtOAc (200 ml). The organic layer was separated and washed with brine (50 ml), dried over Na2SO4and concentrated in vacuo. Was added with stirring Et2O (50 ml) and product was collected by filtration, washed with Et2O (2×25 ml) and dried, yielding 5-(4-bromo-3,5-dimethoxyphenyl)oxazol in the form of a pale yellow solid (2.25 g, yield 39%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon was obtained from 5-(4-bromo-3,5-dimethoxyphenyl)oxazole andN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure used in example 30. Recrystallization from EtOAc gave the product as a yellow solid (0,308 g, yield 56%). MS: m/z 517,3 [M+H]+.

EXAMPLE 57

1-(5-(4-BROMO-3,5-DIMETHOXYPHENYL)THIOPHENE-2-YL)-2-M�METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

2-(4-Bromo-3,5-dimethoxyphenyl)thiophene was obtained from 2-bromo-5-iodo-1,3-dimethoxybenzene and thiophene-2-Voronovo acid according to the method used in example 12. Purification by chromatography (0-10% EtOAc-hexane) gave a yellow solid (0,624 g, yield 55%).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)thiophene-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)thiophene andN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (70% EtOAc-hexane) gave the product as a yellow foam (0.031 inch g, yield 11%). MS: m/z 529,2 [M+H]+.

EXAMPLE 58

1-(4-(4-BROMO-3,5-DIMETHOXYPHENYL)-5-(TRIFLUOROMETHYL)OXAZOL-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

1-(4-(4-Bromo-3,5-dimethoxyphenyl)-5-(trifluoromethyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon was obtained from 4-(4-bromo-3,5-dimethoxyphenyl)-5-(trifluoromethyl)oxazole (obtained from 4-bromo-3,5-dimethoxybenzaldehyde according to Heterocycles, 1992, 34, 1047), andN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure used in example 30. Purification by chromatography (20-40% EtOAc-hexane) gave the product as a yellow solid (0,032 g, yield 14%). MS: m/z 585,3 [M+H]+.

EXAMPLE 59

1-(5-(4-BROMO-35-DIMETHOXYPHENYL)THIOPHENE-2-YL)-2-METHOXY-2-(4-MORPHOLINOMETHYL)ALANON

1-(5-(4-Bromo-3,5-dimethoxyphenyl)thiophene-2-yl)-2-methoxy-2-(4-morpholinomethyl)Etalon was obtained from 2-(4-bromo-3,5-dimethoxyphenyl)thiophene andN,2-dimethoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure used in example 30. Purification by chromatography (40% EtOAc-hexane) gave the product as a yellow solid (0,122 g, yield 46%). MS: m/z 532,4 [M+H]+.

EXAMPLE 60

2-(4-(5-CYCLOPROPYL-1,3,4-OXADIAZOL-2-YL)PHENYL)-2-METHOXY-1-(5-(3,4,5-TRIMETHOXYPHENYL)FURAN-2-YL)ALANON

2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-1-(5-(3,5-trimethoxyphenyl)furan-2-yl)Etalon was obtained from 2-(3,4,5-trimethoxyphenyl)furan and 2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the method used in example 30. Purification by chromatography (60% EtOAc-hexane) gave the product as a pale yellow solid (0,129 g, yield 42%). MS: m/z 491,1 [M+H]+.

EXAMPLE 61

1-(5-(4-CHLORO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon was obtained from 2-(4-chloro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the methodology used � example 30. Purification by chromatography (60% EtOAc-hexane) gave the product as a pale yellow solid (0,116 g, yield 25%). MS: m/z 469,1 [M+H]+.

EXAMPLE 62

1-(5-(4-FLUORO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-METHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

1-(5-(4-Fluoro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon was obtained from 2-(4-fluoro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc-hexane) gave the product as a pale yellow solid (0.036 g, yield 8%). MS: m/z 453,2 [M+H]+.

EXAMPLE 63

1-(5-(4-CHLORO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-ETHOXY-2-(4-(5-METHYL-1,3,4-OXADIAZOL-2-YL)PHENYL)ALANON

1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon was obtained from 2-(4-chloro-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc-hexane) gave the product as a pale yellow solid (0,122 g, yield 25%). MS: m/z 483,1 [M+H]+.

EXAMPLE 64

1-(5-(4-CHLORO-3,5-DIMETHOXYPHENYL)FURAN-2-YL)-2-ETHOXY-2-(4-MORPHOLINOMETHYL)ALANON

1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-morpholinomethyl)Etalon was obtained from 2-(4-chloro-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methoxy-2-(4-morpholinoethyl)acetamide according to the procedure used in example 30. Purification by chromatography (60% EtOAc-hexane) gave the product as a pale yellow solid (0,127 g, yield 26%). MS: m/z 486,5 [M+H]+.

EXAMPLE 65

ADDITIONAL EXEMPLARY COMPOUNDS

The following exemplary compounds in table 1 were obtained according to (i) the above ways, choosing the suitable basic substance, and (ii) by known methods of organic synthesis.

Table 1

The following exemplary compounds in table 2 were obtained according to (i) the above ways, choosing the proper initial substances�VA, and (ii) by known methods of organic synthesis.

Table 2

EXAMPLE 66

ANALYSIS of CONNECTIONS

PDE 10 biochemical analysis

Fosfodiesterazu (PDE) analysis was performed using recombinant human PDE 1A3, 2A3, 3 catalytic phase, 4 catalytic site, 5 catalytic site, 7A, 8A, 9A2, 10A1 11A1 and the enzymes expressed in a baculovirus system using Sf9 cells. PDE activity was measured using a modification of the two-stage method of Thompson and Appleman, described above, which is adapted to format 96-well plates. The effect of PDE inhibitors was determined by study of a fixed amount of enzyme in the presence of concentrations of the test compounds and concentrations of the substrate is smaller than Kmso that Ki was equal to IC50. The final volume for analysis was 110 μl with buffer (10 mm MgCl2; 40 mm Tris·HCl; pH 7,4). The reaction was started with the enzyme and withstood C (3H)-�stratum and substance for 20 minutes at 30°C. The reaction was stopped by denaturation of the enzyme (heating the reaction mixture at 70°C for 2 minutes). Then the reaction mixture was cooled to 4°C for 10 minutes before adding snake venom (Crotalus atrox, 0.2 mg/ml) for 10 minutes at 30°C, thus providing nonspecific hydrolysis of saturated tritium substrate. The remaining branch not hydrolyzed cyclic nucleotide provided complex binding mixture with the activated anion exchange resin Dowex (200 μl). Anion-exchange resin linked charged nucleotides, leaving only hydrolyzed (3(H) the substrate in the soluble fraction. Then soluble fraction (50 μl) was added to microscint-20 (200 μl) and counted on a tablet reader Top Count. Units of radioactivity deposited on a graph relative to the concentration of the inhibitor and IC50the values were obtained using the software Graph Pad Prism.

Alternatively, the phosphodiesterase activity was measured by scintillation analysis of approximation (SPA) [3H]-cGMP as substrate. Purified PDE10 was diluted and stored in 25 mm Tris-Cl (pH of 8.0)/100 mm NaCl/0.05% of Tween 20/50% glycerol/3 mm DTT. The analysis consisted of (final concentrations): 50 mm Tris-Cl (pH 7,5)/8.3 mm MgCl2/1.7 mm EGTA/0.5 mg/ml BSA/5% DMSO and 2 ng PDE10 in a final volume of 0.1 ml the Inhibition was evaluated at 8 concentrations in duplicate. The reaction was started by adding f�of rment and stopped after 20 minutes at 30°C by adding 50 μl of SPA granules, containing Zn++. The mixture was shaken, allowed to settle for 3 hours and counted on tablet counter Wallac. The results (total units/min) were fitted to the logistic model with four parameters, using Excel Solver®.

Further, inhibition of other PDE enzymes PDE10 inhibitors was evaluated under the same conditions described above for PDE10, except that the amount of added enzyme optimized for each PDE. Partial inhibition was evaluated at four concentrations (0.1, 1, 10 and 100 μm). In cases where inhibition at the highest concentration was less than 50%, the lower limit value in the logistic model were set at 0% activity.

In the above analysis of the compounds of the present invention represented PDE10 inhibitors with IC50100 μm or less, typically less than 10 microns, and typically less than 1 μm. In this regard, it was found that the compounds 1-1, 2-1, 3-1, 4-1, 5-1, 6-1, 7-1, 8-1, 9-1, 10-1, 11-1, 12-1, 13-1, 14-1, 15-1, 16-1, 17-1, 18-1, 19-1, 20-1, 21-1, 22-1, 23-1, 25-1, 26-1, 27-1, 28-1, 29-1, 30-1, 31-1, 32-1, 33-1, 34-1, 35-1, 36-1, 37-1, 38-1, 39-1, 40-1, 41-1, 42-1, 43-1, 44-1, 45-1, 46-1, 47-1, 48-1, 49-1, 50-1, 51-1, 52-1, 53-1, 54-1, 55-1, 56-1, 57-1, 58-1, 59-1, 60-1, 61-1, 62-1, 63-1, 64-1, 65-1, 65-2, 65-3, 65-4, 65-5, 65-6, 65-7, 65-8, 65-9, 65-10, 65-11, 65-12, 65-13, 65-14 and 65-15, for example, have IC50values less than or equal to 1 micron.

EXAMPLES 67-77

The opinions of REPRESENTATIVES of the COMPOUNDS IN MODELS of CONDUCT

Schizophrenia is associated� with impaired dopaminergic, glutamatergic and serotonin neurotransmission. Psychostimulants in these three classes, dopaminergic agonists, such as amphetamine and apomorphine), glutamatergic antagonists such as phencyclidine (PCP) and ketamine) and serotonin agonists (such as LSD and MDMA) all cause psychotomimetic state (for example, hyperactivity and impaired preimposed inhibition) in animals that strongly resemble the symptoms of schizophrenia in humans. Known protivopsychoticheskogo medicines, including standard protivopsychoticheskogo drugs (eg, haloperidol), and non-protivopsychoticheskogo medicines (such as olanzapine), pay data psychotomimetic state of the animals. Examples 67-77, described below, evaluate the representatives of the compounds of the present invention in models of animal behavior that allows you to compare the resulting effect with the effect known protivopsychoticheskogo medicines. The methods used in the examples 67-77, are as follows.

The introduction of a dose of the compounds was carried out by intraperitoneal (i.p.) injection or oral route of administration (p.o.). Intraperitoneal injection is accompanied by retention of the animal, and bare belly and inserting the needle just above the knee on the right storonniki. Oral route of administration is carried out by holding the animal in such a way that his head was tilted back, and the esophagus is in a relatively upright position. Needle for forcing (20G x 1.5", Cadence Science) is inserted into the jaws parallel to the body and gently lowered along the esophagus and into the stomach. If there is resistance, remove the needle and re-insert.

Caused by stimulant hyperactivity was measured by the introduction of animals PCP and tracking the degree of activity of animals in the chambers VersaMax (Accuscan Instruments, Columbus, OH) with dimensions of 40×40 cm Locomotor activity was determined fotoaparatni sensors as soon as the animal crosses each ray. The animal was placed in the center of the field and left untouched for 20 minutes to measure its involuntary activity in a new environment. The measurement used to assess motor activity included: horizontal activity, total distance traveled, vertical activity (lifting up on its hind legs - the animal rises on its hind legs), rotation, maintaining a certain body position and distance traveled in the center, as compared to the total distance (the ratio of the center: the total distance). NMDA antagonist PCP causes the manifestation psychosoprano symptom in the form of hyperactivity and increases Catatan�Yu. Known protivopsychoticheskogo drugs tend to draw caused by stimulant hyperactivity and catatonia.

Conditional avoidance response (CAR) is a behavioral test to assess protivopsychoticheskogo effect of the test compounds. In it is used to Shuttle box (Med Associates, St. Albans, VT) with two identical cameras, separated by a folding door. Each camera is equipped with a floor made from metal mesh, which is capable of independent electric shock. A computer program used to perform the test approach, as well as records of animal movements between two cameras using sensors with infrared rays. The test approach was as follows. The mouse was placed in one cell. Turn on the light (conditioned stimulus, CS). Five seconds later served mild electric shock (0,4 mA; (unconditioned stimulus, US) in the cell where the mouse is (as determined by infrared rays) up to the moment that the mouse will move to the next cell or as held for 10 seconds. US and CS always stop at the same time. With randomized intervals between trials on average 15 seconds spent 30 data CS-US paired trials with each mouse every day. For each test the reaction of the flight record, if the mouse moves to another cell after electric shock (i.e. for 0 seconds US period), and an avoidance response register, if the mouse moves to another cell within the first 5 seconds only CS period. Animals were trained in this approach within 30-40 days, during which the average percentage of avoidance reactions will increase to 80-90%. This shows that animals have learned to avoid impact on the paws of the electric current moving in the opposite chamber upon activation of the CS (light). Then data of trained mice used to test compounds in the same approach. It has been found that known protivopsychoticheskogo medicines suppress conditional avoidance response, and it is believed that the ability of new compounds to inhibit this reaction predicts protivopsychoticheskogo effect on people.

EXAMPLE 67

The DECREASE in PCP-INDUCED HYPERACTIVITY BY connecting 1-1

It was found that the compound 1-1 (example 1) reduces PCP-induced hyperactivity, as shown in Fig.1 and 2. C57BL/6 male individuals of mice were given either a connection 1-1 or media intraperitoneal injection (FIG.1) or oral route of administration (FIG.2). After twenty minutes (for intraperitoneal route of administration) or forty minutes (oral route of administration), the animals were injected with PCP (5 mg/kg, intraperitoneally). Ten minutes later, mice were placed in a chamber for evaluation of the activity and their active motor�industry in the horizontal direction was monitored with infrared sensors for 20 minutes (5 consecutive 4-minute interval (INT), as mentioned). FIG.1 shows that compound 1-1 (10 mg/kg) significantly reduces the hyperactivity caused by PCP, as can be seen when comparing the control with the introduction of media+PCP (p=0,0088, n=8 per group, t-student test for independent samples). FIG.2 shows that compound 1-1 is also effective oral route of administration (p=0,0045, n=8 per group, t-student test for independent samples).

EXAMPLE 68

The DECREASE in PCP-INDUCED HYPERACTIVITY BY connecting 2-1

It was found that the compound 2-1 (Example 2) reduces PCP-induced hyperactivity, as shown in Fig.3 and 4. C57BL/6 male individuals of mice were given either a connection 2-1 or media intraperitoneal injection (FIG.3) or oral route of administration (FIG.4). After twenty minutes (for intraperitoneal route of administration) or forty minutes (oral route of administration), the animals were injected with PCP (5 mg/kg, intraperitoneally). Ten minutes later, mice were placed in a chamber for evaluation of the activity and motor activity in the horizontal direction was monitored with infrared sensors for 20 minutes (5 consecutive 4-minute interval (INT), as indicated). FIG.3 shows that compound 2-1 (10 mg/kg) significantly reduces the hyperactivity caused by PCP, as can be seen when comparing the control with the introduction of media+PCP (p=0,0021, n=8 per group, t-Crete�s t-test for independent samples). FIG.4 shows that compound 2-1 is also effective oral route of administration (p=0,000005 for a dose of 10 mg/kg, n=8 per group, t-student test for independent samples).

EXAMPLE 69

The DECREASE of the CONDITIONAL AVOIDANCE REACTIONS BY connecting 2-1

It was found that the compound 2-1 (Example 2) reduces conditional avoidance response (CAR), as shown in Fig.5. C57BL/6 males coached in the CAR approach for predicting and avoiding pain stimulus (electric shock on the legs), reaching a stable value of approximately 25 avoidance reactions of 30 trials each day. Then, the mice were given either the media, or the connection 2-1 oral route of administration 30 minutes before the test within 30 trials in the CAR approach. Processing the carrier and the connection processing was performed on the same animals through the day and the effect of compounds on the reduction of avoidance reactions were analyzed using intra-group comparisons (two-sided t-student test). Handling the media is not changed avoidance reaction data of trained animals. FIG.5 shows that compound 2-1 (12 mg/kg) significantly reduces the number of avoidance reactions (p=0,0048, n=7 per group, double-sided t-student test).

EXAMPLE 70

The DECREASE in PCP-INDUCED HYPERACTIVITY BY connecting 11-1

It was found that with�connected 11-1 (Example 11) reduces PCP-induced hyperactivity, as shown in Fig.6. C57BL/6 male individuals of mice were given either compound 11-1 or media intraperitoneal injection. Five minutes later, the animals were injected with PCP (5 mg/kg, intraperitoneally). Ten minutes later, mice were placed in a chamber for evaluation of the activity and motor activity in the horizontal direction was monitored with infrared sensors for 20 minutes (5 consecutive 4-minute interval (INT), as indicated). FIG.6 shows that compound 11-1 (10 mg/kg) significantly reduces the hyperactivity caused by PCP, as can be seen when comparing the control with the introduction of media+PCP (p=0,00040, n=8 per group, t-student test for independent samples).

EXAMPLE 71

The DECREASE of the CONDITIONAL AVOIDANCE REACTIONS BY connecting 34-1

It was found that the compound 34-1 (Example 34) reduces conditional avoidance response (CAR), as shown in Fig.7. C57BL/6 males coached in the CAR approach for predicting and avoiding pain stimulus (electric shock on the legs), reaching a stable value of approximately 25-28 avoidance reactions of 30 trials (training plateau") every day. Then, the mice were given either the media, or the compound (25 minutes before the test) oral route of administration and then tested in 30 trials in the CAR approach. Processing the carrier and the connection processing was performed on the same animals chere� day and the effect of compounds on the reduction of avoidance reactions were analyzed using intra-group comparisons (two-sided t-student test). Processing carrier ("carrier") is not changed avoidance reaction data of trained animals. FIG.7 shows that the connection 34-1 significantly reduces the number of avoidance reactions at 10 mg/kg (p=0,0003, n=7 per group).

EXAMPLE 72

The DECREASE of the CONDITIONAL AVOIDANCE REACTIONS BY connecting 36-1

It was found that the compound 36-1 (Example 36) reduces conditional avoidance response (CAR), as shown in Fig.8. C57BL/6 males coached in the CAR approach for predicting and avoiding pain stimulus (electric shock on the legs), reaching a stable value of approximately 25-28 avoidance reactions of 30 trials (training plateau") every day. Then, the mice were given either the media, or the compound (25 minutes before the test) oral route of administration and then tested in 30 trials in the CAR approach. Processing the carrier and the connection processing was performed on the same animals through the day and the effect of compounds on the reduction of avoidance reactions were analyzed using intra-group comparisons (two-sided t-student test). Processing carrier ("carrier") is not changed avoidance reaction data of trained animals. FIG.8 shows that compound 36-1 significantly reduces the number of avoidance reactions at 15 mg/kg (p=0,000014, n=5 per group) and shows a trend that does not reach the level of significance at 5 and 10 m�/kg.

EXAMPLE 73

The DECREASE of the CONDITIONAL AVOIDANCE REACTIONS BY connecting 47-1

It was found that the compound 47-1 (Example 47) reduces conditional avoidance response (CAR), as shown in Fig.9. C57BL/6 males coached in the CAR approach for predicting and avoiding pain stimulus (electric shock on the legs), reaching a stable value of approximately 25-28 avoidance reactions of 30 trials (training plateau") every day. Then, the mice were given either the media, or the compound (55 minutes before the test) oral route of administration and then tested in 30 trials in the CAR approach. Processing the carrier and the connection processing was performed on the same animals through the day and the effect of compounds on the reduction of avoidance reactions were analyzed using intra-group comparisons (two-sided t-student test). Processing carrier ("carrier") is not changed avoidance reaction data of trained animals. FIG.9 shows that the compound 47-1 significantly reduces the number of avoidance reactions at 5 and 10 mg/kg (p=0.0002 and p=3,3 E-10, respectively, n=8 per group) and shows a trend that does not reach the level of significance with 2 mg/kg.

EXAMPLE 74

The DECREASE of the CONDITIONAL AVOIDANCE REACTIONS BY connecting 61-1

It was found that the connection 61-1 (Example 61) reduces conditional avoidance response (CAR), to�to that shown in Fig.10. C57BL/6 males coached in the CAR approach for predicting and avoiding pain stimulus (electric shock on the legs), reaching a stable value of approximately 25-28 avoidance reactions of 30 trials (training plateau") every day. Then, the mice were given either the media, or the compound (55 minutes before the test) oral route of administration and then tested in 30 trials in the CAR approach. Processing the carrier and the connection processing was performed on the same animals through the day and the effect of compounds on the reduction of avoidance reactions were analyzed using intra-group comparisons (two-sided t-student test). Processing carrier ("carrier") is not changed avoidance reaction data of trained animals. FIG.10 shows that the connection 61-1 significantly reduces the number of avoidance reactions at 2, 5 and 10 mg/kg (p=0.015, p=0.00008 inch and p=E 2,1-7, respectively, n=5 per group).

EXAMPLE 75

The DECREASE of the CONDITIONAL AVOIDANCE REACTIONS BY connecting 63-1

It was found that the connection 63-1 (Example 63) reduces conditional avoidance response (CAR), as shown in Fig.11. C57BL/6 males coached in the CAR approach for predicting and avoiding pain stimulus (electric shock on the legs), reaching a stable value of approximately 25-28 avoidance reactions of 30 trials (training plateau") every day. Then �Isham gave any media, either connection (55 minutes before the test) oral route of administration and then tested in 30 trials in the CAR approach. Processing the carrier and the connection processing was performed on the same animals through the day and the effect of compounds on the reduction of avoidance reactions were analyzed using intra-group comparisons (two-sided t-student test). Processing carrier ("carrier") is not changed avoidance reaction data of trained animals. FIG.11 shows that the connection 63-1 significantly reduces the number of avoidance reactions at 2, 5 and 10 mg/kg (p=0,0099, p=0,00011 and p=E 6,6-16, respectively, n=6 per group).

EXAMPLE 76

The DECREASE of the CONDITIONAL AVOIDANCE REACTIONS BY connecting 49-1

It was found that the connection 49-1 (Example 49) reduces conditional avoidance response (CAR), as shown in Fig.12. C57BL/6 males coached in the CAR approach for predicting and avoiding pain stimulus (electric shock on the legs), reaching a stable value of approximately 25-28 avoidance reactions of 30 trials (training plateau") every day. Then, the mice were given either the media, or the compound (55 minutes before the test) oral route of administration and then tested in 30 trials in the CAR approach. Processing the carrier and the connection processing was performed on the same animals through the day and the effect of compounds on the reduction of the reaction� avoidance were analyzed using intra-group comparisons (two-sided t-student test). Processing carrier ("carrier") is not changed avoidance reaction data of trained animals. FIG.12 shows that the connection 49-1 significantly reduces the number of avoidance reactions at 10 mg/kg (p=5,7 E-9, n=8 per group).

EXAMPLE 77

The DECREASE of the CONDITIONAL AVOIDANCE REACTIONS BY connecting 65-10

It was found that the connection 65-10 (Example 65, table 1) reduces the conditional avoidance response (CAR), as shown in Fig.13. C57BL/6 males coached in the CAR approach for predicting and avoiding pain stimulus (electric shock on the legs), reaching a stable value of approximately 25-28 avoidance reactions of 30 trials (training plateau") every day. Then, the mice were given either the media, or the compound (55 minutes before the test) oral route of administration and then tested in 30 trials in the CAR approach. Processing the carrier and the connection processing was performed on the same animals through the day and the effect of compounds on the reduction of avoidance reactions were analyzed using intra-group comparisons (two-sided t-student test). Processing carrier ("carrier") is not changed avoidance reaction data of trained animals. FIG.13 shows that the connection 65-10 significantly reduces the number of avoidance reactions at 5 and 10 mg/kg (p=0,0145 and p=0,00011; n=8 per group).

It should be clear that although a specific embodiment� implementation described in the present invention for the purpose of illustration, it is possible to make various modifications without going beyond the scope and essence of the present invention. Accordingly, the present invention is not limited, except in the attached claims.

1. The compound having the following formula (I):

or its pharmaceutically acceptable salt, where:
But it is a:

R1represents a C1-6alkyl;
R2represents (i) phenyl substituted by halogen; C1-6the alkyl, optionally substituted morpholine or C1-6dialkylamino; C1-6alkoxy, optionally substituted by halogen; or heterocyclyl,
where heterocyclyl Deputy selected from morpholine; pyrazolyl, optionally substituted C1-6the alkyl; piperidinyl; pyrrolidinyl; oxadiazolyl, substituted C1-6the alkyl; Furie, substituted C1-6the alkyl; dioxothiazolidine; triazolyl; tetrazolyl, substituted C1-6the alkyl; thiadiazolyl, substituted C1-6the alkyl; thiazolyl, substituted C1-6the alkyl; pyridyl; or pyrazinyl;
(ii) substituted or unsubstituted heterocyclyl selected from hineline; pyridyl, substituted C1-6alkoxy or morpholino; or benzo [d] [1, 2, 3] triazolyl, substituted C1-6the alkyl;
R3is a �Anil, substituted 2 or 3 substituents selected from halogen; C1-6alkyl; C1-6alkoxy, optionally substituted by halogen; hydroxy-group; cyano; or-C(=O)ORa where Ra represents phenyl;
R4represents hydrogen, C1-6alkyl or C1-6halogenated.

2. The connection of claim 1, wherein the compound has the following structure (I-A):

3. The connection of claim 1, wherein the compound has the following structure (I-B):

4. The connection of claim 1, wherein the compound has the following structure (I-C):

5. The connection of claim 1, wherein the compound has the following structure (I-D):

6. The connection of claim 1, wherein the compound has the following structure (I-E):

7. The connection of claim 1, wherein the compound has the following structure (I-F):

8. The connection of claim 1, wherein the compound has the following structure (I-G):

9. The connection of claim 1, wherein the compound has the following structure (I-H):

10. The connection of claim 1, wherein the compound has the following structure (I-I):

11. The compound according to claim 1, where R4represents hydrogen.

12. The compound according to claim 1, where R4represents a C1-6and�Kil.

13. The compound according to claim 12, where R4is methyl.

14. The compound according to claim 1, where R1is methyl.

15. The compound according to claim 1, where R1represents ethyl.

16. The compound according to claim 1, where R3is a 4-bromo-3,5-dimethoxyphenyl.

17. The compound according to claim 1, where R3represents 4-chloro-3,5-dimethoxyphenyl.

18. The compound according to claim 1, where R3is a 3,4,5-trimethoxyphenyl.

19. The compound according to claim 1, where R2is a substituted phenyl.

20. The compound according to claim 19, where R2represents phenyl, substituted C1-6alkoxy, optionally substituted by halogen.

21. The compound according to claim 19, where R2represents phenyl, substituted with substituted or unsubstituted heterocyclyl.

22. The compound according to claim 21, where R2represents phenyl, substituted with substituted heterocyclyl.

23. The compound according to claim 22, where R2represents a 4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl.

24. The compound according to claim 22, where R2represents a 4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl.

25. The compound according to claim 21, where R2represents phenyl, substituted unsubstituted heterocyclyl.

26. The compound according to claim 25, where R2is a 4-morpholinomethyl.

27. The compound according to claim 1, where R2is a substituted or unsubstituted heterocyclyl./p>

28. The connection of claim 1, wherein the compound is a:
1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)Etalon;
2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)Etalon;
1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon;
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon;
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon;
1-(5-(4-chloro-N,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)Etalon; or
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)Etalon.

29. The connection of claim 1, wherein the compound is a:
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)Etalon.

30. The connection of claim 1, wherein the compound is a:
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)Etalon.

31. The connection of claim 1, wherein the compound is a:
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl)Etalon.

32. Pharmaceutical composition, inhibiting PDE10 in a warm-blooded animal comprising compound according to any one of claims.1-31 in an amount of from 0.1 mg to 250 mg and headlights�asepticheski acceptable carrier or diluent.

33. Method for inhibiting PDE10 in a warm-blooded animal, comprising administering to the animal an effective amount of a compound according to any one of claims.1-31 or a pharmaceutical composition according to claim 29.

34. A method for the treatment of neurological disorders in need of a warm-blooded animal, comprising administering to the animal an effective amount of a compound according to any one of claims.1-31 or a pharmaceutical composition according to claim 29.

35. A method according to claim 34, where a neurological disorder selected from the group consisting of psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobia, epilepsy, aphasia, bell's palsy, cerebral palsy, sleep disorders, pain, Tourette syndrome, schizophrenia, delusional disorder, bipolar disorder, post-traumatic stress disorder, psychosis, caused by drugs, panic disorder, obsessive-compulsive disorder, attention deficit disorder, disorders of social behavior, autism, depression, dementia, cognitive disorders, epilepsy, insomnia and multiple sclerosis.

36. A method according to claim 35, where the neurological disorder is a schizophrenic.

37. A method according to claim 35, where neurologicas�e disorder is a post-traumatic stress disorder.

38. The compound having the following structure:

39. The compound having the following structure:



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which possess the properties of HCV polymerase inhibitors. In formula , is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 and R3 are specified in hydrogen and methyl; R2 represents hydrogen; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkenyloxy, C3-C6alkynyloxy and halo; L represents a bond, and R6 represents a condensed 2-ring carbocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ and RK; or L is specified in a group consisting of a bond, C≡C, C(O)N(RC), N(RD)C(O), C1-C2-alkylene, C(H)2O, OC(H)2, cyclopropyl-1,2-ene, C(H)2N(RL), N(RM)C(H)2, C(O)CH2 and CH2C(O), and R6 is specified in a group consisting of C5-C6-carbocyclyk and 5-6-merous heterocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ, RK, RL and RM; the R4, RE, RF, RG, RH, RI, RJ, RK, RL and RM values are presented in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a drug preparation for HCV RNA polymerase inhibition and hepatitis C treatment, and to a method for preparing the above compounds.

21 cl, 46 dwg, 42 tbl, 140 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrimidine derivatives of structural formula (I-L0) and their crystalline forms possessing the inhibitory activity on the hepatitis C virus (HCV) polymerase. In formula is specified in a single or double carbon-carbon bond; R1, R2 and R3 represent hydrogen; R4 is specified in halo, C1-C6alkyl, C2-C6alkinyl, amino, C1-C6alkylsulphonyl, C3-C10carbocyclyl and 5-6-merous heterocyclyl having a heteroatom specified in a group consisting of O and S, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls, and C1-C6alkyl and C2-C6alkynyl are optionally substituted by one or more substitutes optionally specified in a group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and C3-C10carbocyclyl and 5-6-merous heterocyclyl are optionally substituted by substitutes specified in C1-C6alkyl, halo and amino, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; R6 represents a condensed 2-ring C3-C10carbocyclyl optionally substituted by substitutes specified in RE, RF, RG, RH, RI, RJ and RK, the values of which are specified in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a therapeutic agent for hepatitis C, to an intermediate compound for producing the compound of structural formula (I-L0) and to a method for preparing the above compounds and their crystalline forms.

70 cl, 23 dwg, 9 tbl, 83 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.

EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.

11 cl, 1 dwg, 2 tbl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of controlling infection of useful plants with phytopathogenic microorganisms or prevention thereof, wherein a compound of formula I or a composition thereof, which contains said compound as an active ingredient, is deposited on plants, on a parts thereof or place where said plants grow, where the compound of formula I is substitutes are as defined in claim 1.

EFFECT: obtaining a compound for controlling infection of useful plants with phytopathogenic microorganisms.

26 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,3,5-dithiazinanes of formula (1): wherein diphenylenediamine (diaminodiphenylmethane, diaminodiphenyl oxide) reacts with N-tert-butyl-1,3,5-dithiazinane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine: N-tert-butyl-1,3,5-dithiazinane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system (1:1, by volume) for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as antimicrobial and antifungual agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method for selective production of 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes of formula (1) where R = 4-C6H4-CH2-C6H4-4', 4-C6H4-O-C6H4-4', 4-H3COC6H3-C6H3OCH3-4', where diphenylenediamines (diaminodiphenylmethane, diaminodiphenyl oxide, dimethoxybenzidine) react with 1-oxa-3,6-dithiacycloheptane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine:1-oxa-3,6-dithiacycloheptane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system for 2.5-3.5 hours.

EFFECT: novel method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes, which can be used as antimicrobial, antifungal and anti-inflammatory agents, sorbents and extractants of precious metals and selective complexing agents.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazine derivatives represented by general formula (I): 0, where R1 is a hydrogen atom; C1-C6 alkyl; COR5; SO2R5; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10; m assumes values from 1 to 6; n assumes values from 2 to 6; R2 is phenyl; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenylpyridine or a benzene ring condensed with a saturated or unsaturated monocyclic heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, other than indole, R3 is methyl or ethyl; R4 and R′4 are identical or different and denote a hydrogen atom; a halogen atom; C1-C6 alkyl; NR7R8; SO2Me; as well as stereoisomers, salts and solvates thereof, for therapeutic use and which are capable of inhibiting 11β-HSD1 on an enzymatic and cellular level.

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-[methylenebis(1,4-phenylene)]-, 3,3'-[oxybis(1,4-phenylene)]- and 3,3'-(3,3'-dimethoxybiphenyl-4, 4'-diyl)-bis-1,5,3-dithiazepinanes of general formula (1): R=4-C6H4-CH2-C6H4-4/, 4-C6H4-O-C6H4-4/, 4-H3COC6H3-C6H3OCH3-4/ which consists in the following: arylamines [diaminodiphenylmethane, diaminodiphenyloxide, dimethoxybenzidine] undergo interaction with N-tert-butyl-1,5,3-dithiazepinane in presence of catalyst Sm(NO3)3·6H2O in argon atmosphere with molar ratio arylamine:N-tert-butyl-1,5,3-dithiazeoinane: Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) at temperature ~20°C in system of solvents ethanol-chloroform for 2.5-3.5 h.

EFFECT: increased efficiency of applying compound as antibacterial, antifungal and antiviral agents, biologically active complexants, selective sorbents and extractants of precious metals, special reagents for suppressing bacterial vital activity in different technical media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which possess the properties of HCV polymerase inhibitors. In formula , is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 and R3 are specified in hydrogen and methyl; R2 represents hydrogen; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkenyloxy, C3-C6alkynyloxy and halo; L represents a bond, and R6 represents a condensed 2-ring carbocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ and RK; or L is specified in a group consisting of a bond, C≡C, C(O)N(RC), N(RD)C(O), C1-C2-alkylene, C(H)2O, OC(H)2, cyclopropyl-1,2-ene, C(H)2N(RL), N(RM)C(H)2, C(O)CH2 and CH2C(O), and R6 is specified in a group consisting of C5-C6-carbocyclyk and 5-6-merous heterocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ, RK, RL and RM; the R4, RE, RF, RG, RH, RI, RJ, RK, RL and RM values are presented in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a drug preparation for HCV RNA polymerase inhibition and hepatitis C treatment, and to a method for preparing the above compounds.

21 cl, 46 dwg, 42 tbl, 140 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula I, their pharmaceutically acceptable salts and crystalline forms, which possess the properties of HCV polymerase inhibitor. In formula I is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 represents hydrogen; R2 is specified in a group consisting of hydrogen and halo; R3 represents hydrogen; R4 is specified in a group consisting of halo, C1-C6alkyl, C1-C6alkylsulphonyl and 5-6-merous heteroaryl containing heteroatom specified in N, O and S, wherein alkyl is optionally substituted by one or more hydroxy; R5 is specified in a group consisting of hygrogen, hydroxy, C1-C6alkyloxy and halo; L is specified in a group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene; RA and RB are independently specified in a group consisting of hydrogen, C1-C6alkyl, C1-C6alkyloxy and halo; R6 represents C6aryl optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI and RJ; the substitutes RE, RF, RG, RH, RI and RJ are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compounds, to using the compounds for inhibiting HCV RNA-polymerase and treating hepatitis C and to a method of preparing the above compounds.

40 cl, 23 dwg, 7 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (Ip1) or (Ip3) or its pharmaceutically acceptable salt, where G1 represents (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)halogenalkyl, (C1-C4)halogenalkoxy, halogen, cyano or nitro; n equals 0; G2a represents (C3-C4)cycloalkyl or (C3-C4)cycloalkyl(C1-C2)alkyl; G2b represents hydrogen; R1 represents methyl or ethyl; R2 represents phenyl or fluorophenyl; and R3 represents 2-hydroxy-2-methylpropyl or 2-methyl-2-cyanopropyl.

EFFECT: invention relates to application of compound of formula (Ip1 and Ip3) for manufacturing medication or pharmaceutical composition, intended for treating a person with disease or state, selected from type II diabetes mellitus, obesity, glucose intolerance, hyperglycemias, hyperlipidemis, insulin resistance, decrease of cognitive functions and dyslipidemia.

5 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrimidine derivatives of structural formula (I-L0) and their crystalline forms possessing the inhibitory activity on the hepatitis C virus (HCV) polymerase. In formula is specified in a single or double carbon-carbon bond; R1, R2 and R3 represent hydrogen; R4 is specified in halo, C1-C6alkyl, C2-C6alkinyl, amino, C1-C6alkylsulphonyl, C3-C10carbocyclyl and 5-6-merous heterocyclyl having a heteroatom specified in a group consisting of O and S, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls, and C1-C6alkyl and C2-C6alkynyl are optionally substituted by one or more substitutes optionally specified in a group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and C3-C10carbocyclyl and 5-6-merous heterocyclyl are optionally substituted by substitutes specified in C1-C6alkyl, halo and amino, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; R6 represents a condensed 2-ring C3-C10carbocyclyl optionally substituted by substitutes specified in RE, RF, RG, RH, RI, RJ and RK, the values of which are specified in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a therapeutic agent for hepatitis C, to an intermediate compound for producing the compound of structural formula (I-L0) and to a method for preparing the above compounds and their crystalline forms.

70 cl, 23 dwg, 9 tbl, 83 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a new compound of formula or its pharmaceutically acceptable salt, wherein R1 represents (C1-C6)alkyl; an oxodihydropyridyl ring in the formula is optionally substituted by 1-3 groups optionally specified in fluorine, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkoxy; R2 represents (C1-C6)alkyl, phenyl, or tetrahydropyranyl optionally substituted by a group in the number of up to 1 independently specified in fluorine, hydroxy(C1-C6)alkyl and (C3-C6)cycloalkyl; R3 is specified in (C1-C6)alkyl optionally substituted by groups in the number of up to 3 independently specified in fluorine, cyano, R4, R4O-, (R4)2N-, R4C(=O)NR4-, (R4)2NC(=O)-, R4OC(=O)NR4-, R4S(=O)2NR4- and oxadiazolyl optionally substituted by (C1-C6)alkyl; R4 independently represents H or (C1-C6)alkyl. Also, the invention refers to a method of treating an individual by using the above compound, a method of inhibiting 11β-HSD1, and a compound-based pharmaceutical composition.

EFFECT: there are prepared new compounds effective in treating the diseases related to 11β-HSD1 activity or expression.

15 cl, 6 tbl, 101 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new phenylpyrimidone derivatives of formula I possessing the properties of a phosphodiesterase type 5 (PDE5) inhibitor. The compounds of formula I can be used for treating various vascular disorders, such as erectile dysfunction, pulmonary arterial hypertension, etc. In formula each R1 and R2 independently means H; C1-C10alkyl; halogen; CF3; CN; OR5; NR6R7; NHCOR8; aryl; or C1-C4alkyl optionally substituted by OR5; Z means OR3; R3 means C1-C6alkyl or C1-C3alkyl, substituted by C1-C3alkoxy group; R4 means SO2NR6R7; NR9R10, providing NR9R10 is other than NH2; COR11; OR12; or R4 means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH and C1-C6 alkyl; or R4 means 5- or 6-merous cyclic monosaccharide group; R5 means C1-C6alkyl; C1-C4alkyl optionally substituted by C1-C4alkoxy group; each R6 and R7 independently means H, OH, C1-C6alkyl, C1-C6alkoxy group, C3-C6alkenyl, C3-C6cycloalkyl, adamantyl, C3-C8lactamyl, aryl, Het or (CH2CH2O)jH, wherein j is 1-3; or each R6 and R7 independently means C1-C6alkyl, optionally substituted by OH, C1-C4alkoxy group, SO3H, SO2NR13R14, SO2R16, NR13R14, aryl, Het or 5-6-merous heterocyclyl; or each R6 and R7 independently means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of C1-C6 alkyl and C1-C6alkyl substituted by hydroxyl; or R6 and R7 together with a nitrogen atom attached whereto form 5-7-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH, COOR8, (CH2CH2O)jH, wherein j is 1-3, C1-C4alkoxy group, Het and C1-C6alkyl substituted by aryl; or R6 and R7 together with a nitrogen atom attached whereto form a glucosyl amino group, an amino acid residue, a residue of an amino acid ester or an amino amide residue. The other radical values are specified in the patent claim.

EFFECT: invention refers to pharmaceutical compositions based on the above compounds, using them, methods for preparing the compounds, and intermediate products.

18 cl, 2 tbl, 224 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-substituted-N-phenyl-1,8-naphthalimides which contain in the N-aryl nucleus a crown ether residue (with a different combination of oxygen, nitrogen and sulphur atoms) of general formula (I) , where R1=NO2, Br, NH2, OCH3, NHCOCH3, Ia: Rl=NO2, X=S, n=1; Ib: R1=NO2, x=NCH3, n=1; Ic: R1=NO2, X=NCH3, n=2; Id: R1=Br, X=NCH3, n=2; Ie: R1=NH2, X=S, n=1; If: R1=NHCOCH3, X=S, n=1; Ig: R1=OMe, X=S, n=1; Ih: R1=OMe, X=NCH3, n=1; Ii: R1=OMe, X=NCH3, n=2, where compounds If-Ii exhibit properties of fluorescent sensors on cations of alkali-earth, transition and heavy metals, and compounds Ia-Ie are intermediate compounds in the process of synthesis of compounds If-Ii. The invention also relates to a method of producing a compound of formula (I) and intermediate compounds of formula (II)

EFFECT: obtaining novel sensors on cations of alkali-earth, transition and heavy metals, novel methods of producing compounds of the given formula.

7 cl, 3 tbl, 7 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of controlling infection of useful plants with phytopathogenic microorganisms or prevention thereof, wherein a compound of formula I or a composition thereof, which contains said compound as an active ingredient, is deposited on plants, on a parts thereof or place where said plants grow, where the compound of formula I is substitutes are as defined in claim 1.

EFFECT: obtaining a compound for controlling infection of useful plants with phytopathogenic microorganisms.

26 cl, 2 tbl, 8 ex

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