Method of producing heterocycle-substituted pyridine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing heterocycle-substituted pyridine derivatives of general formula (I) by reacting a compound of general formula (III) with a compound of formula (II) in a solvent and in the presence of a catalyst based on palladium or a base, where R1, R2, X, Y, Q, A, Z, R, R3 and R4 are described in the claim.

EFFECT: method enables to obtain pyridine derivatives on an industrial scale.

7 cl, 27 ex

 

The technical field

The present invention relates to a method for producing substituted heterocycle derivatives of pyridine.

The level of technology

In recent years, the fight against opportunistic infections has become more important than ever because of the increasing number of older people and immunocompromised patients as a result of advanced chemotherapy, etc. the fact that opportunistic infections occur one after the other, as a result of various avirulent pathogens, shows that the problem of infectious diseases will not be solved until there are underlying diseases, which reduce the immune function of patients. Therefore, new strategies to combat infectious diseases, including the problem of drug-resistant pathogen, will be one of the important problems in elderly patients in the near future.

In the field of antifungal agents for the treatment of deep mycosis were previously developed, for example, amphotericin B, which is based on the polyene skeleton, fluconazole, Itraconazole and voriconazole, which is based on azole skeleton, etc. most of the existing drugs already available commercially, has a similar mechanism of action, and now the problem is the appearance of atlanticcity fungi, etc.

In recent years, as inhibitors of 1,3-β-glucosinates with the new mechanism were developed derivatives of natural compounds cyclic Hexapeptide caspofungin and micafungin and the like; however, since these tools exist only in injectable form, they are not sufficiently satisfactory in practice as antifungal agents.

Because in some situations the existing antifungal agents are not fully suitable for the treatment of deep mycoses, there is a demand and a need to develop tools based on a new engine and having high safety.

The quality of materials used that are relevant in relation to antifungal agents based on such a new mechanism, in Patent documents 1 and 2 described derivatives of pyridine, which demonstrate the effects against the emergence, development and persistence of infections by inhibiting the expression of proteins of cell membranes, inhibiting the Assembly of cell membranes, as well as adhesion to the cell surface and preventing the manifestation of pathogens its pathogenicity by inhibiting transport of GPI (glycosylphosphatidylinositol)-anchored proteins to the cell membrane.

In light of this situation, in Patent document 3 as antifungal agents have been proposed substituted heterocycle carried the major pyridine, which have excellent antifungal activity, not observed in the case of conventional antifungal agents, and also exceeds the latter in relation to the properties, safety and metabolic stability.

Patent document 1: WO02/04626

Patent document 2: WO05/033079

Patent document 3: WO07/052615

Disclosure of invention

Tasks solved in accordance with the invention

The object of the present invention is to develop an efficient way to obtain substituted heterocycle derivatives of pyridine and intermediate compounds that can be used in obtaining substituted heterocycle derivatives of pyridine.

Means of solving problems

As a result of intensive research aimed at solving this problem, the authors have carried out the present invention in the discovery of an effective method of obtaining substituted heterocycle derivatives of pyridine using a specific reaction combinations.

In particular, in the first aspect of the present invention relates to

[1] a Method for producing compounds represented by the following formula (I):

includes introduction to the reaction of the compound represented by the following formula (III):

and the connection performance is undertaken by the following formula (II):

in a solvent and in the presence of a catalyst based on palladium and grounds

and

R1denotes a hydrogen atom, halogen atom, amino group, R11-NH- (where R11represents C1-6alkyl, hydroxy, C1-6alkyl, C1-6alkoxy, C1-6alkyl or C1-6alkoxycarbonyl C1-6alkyl), R12-(CO)-NH- (where R12represents C1-6alkyl or C1-6alkoxy, C1-6alkyl), C1-6alkyl, hydroxy, C1-6alkyl, cyano, C1-6alkyl, C1-6alkoxy or C1-6alkoxy, C1-6alkyl;

R2denotes a hydrogen atom, a C1-6alkyl, amino group which may be protected by a protective group, or di-C1-6alkylamino;

one of X and Y represents a nitrogen atom and the other represents a nitrogen atom or an oxygen atom;

Q denotes a group to delete;

ring A represents a 5 - or 6-membered heteroaryl ring or a benzene ring which may have one or two halogen atom or one or two C1-6alkyl groups;

Z represents a simple bond, methylene group, ethylene group, an oxygen atom, a sulfur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S - or-SCH2-;

R denotes a hydrogen atom or a C1-6alkyl, if both groups R represent C1-6alkyl, they can together about Asociate ring;

R3denotes a hydrogen atom or halogen atom, or a C1-6alkyl, C3-8cycloalkyl, C6-10aryl, 5 - or 6-membered heteroaryl, or 5 - or 6-membered non-aromatic heterocyclic group, and these groups may have one or two substituent selected from the group of substituents α; and

R4denotes a hydrogen atom or a halogen atom;

provided that when Z represents a simple bond or when R3denotes a hydrogen atom, then R1, R2and R4may not simultaneously denote a hydrogen atom,

[the group of substituents α]

halogen atom, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, C3-8cycloalkyl, C2-6alkenyl and C2-6quinil.

[2] the Method of receiving according to item [1]above, in which Q in the formula (III) denotes a halogen atom or substituted sulfonyloxy.

[3] the Method of receiving according to item [1] or [2]above, in which a partial structure represented by:

in the formula (I) represents the following partial structure:

[4] a Method for production according to any one of paragraphs [1] - [3]above, in which R2denotes an amino group which may be protected by a protective group, method D. the Executive includes the removal of the protective group.

[5] a Method for production according to any one of paragraphs [1] - [4]above, in which the compound represented by the following formula (III):

obtained by the production method, which includes stages

the introduction of the compounds represented by the following formula (VI):

in the reaction of cyclization;

the implementation of response and recovery

the implementation of the halogenation

(and R1, R2, R4X, Y and Q have the meanings given above,

R10denotes a hydrogen atom or a C1-6alkyl, and

R13denotes a hydrogen atom or a C1-6alkyl).

[6] the Method of receiving according to paragraph [5]above, in which R2denotes an amino group having a protective group, the method further includes removing the protective group after the reaction of recovery.

[7] the Method of receiving according to item [5] or [6]above, in which R2denotes the amino group, the method further comprises protecting the amino group.

In the second aspect of the present invention also applies to

[8] the Compound represented by the following formula (VII)or its salt:

in which

R1denotes a hydrogen atom, halogen atom, amino group, R11-NH- (where R11represents C1-6al the sludge, hydroxy, C1-6alkyl, C1-6alkoxy, C1-6alkyl or C1-6alkoxycarbonyl C1-6alkyl), R12-(CO)-NH- (where R12represents C1-6alkyl or C1-6alkoxy, C1-6alkyl), C1-6alkyl, hydroxy, C1-6alkyl, cyano, C1-6alkyl, C1-6alkoxy or C1-6alkoxy, C1-6alkyl;

R2denotes a hydrogen atom, a C1-6alkyl, amino group which may be protected by a protective group, or di-C1-6alkylamino;

one of X and Y represents a nitrogen atom and the other represents a nitrogen atom or an oxygen atom;

R4denotes a hydrogen atom or a halogen atom; and

R10denotes a hydrogen atom or a C1-6alkyl.

[9] the Compound or its salt according to paragraph [8]above, in which a partial structure represented by:

in this formula (VII) represents the following partial structure:

In the third aspect of the present invention further relates to

[10] the Compound represented by the following formula (X)or its salt:

in which

R1denotes a hydrogen atom, halogen atom, amino group, R11-NH- (where R11represents C1-6alkyl, hydroxy, C1-6alkyl, C1-6alkoxy, C1-6alkyl or C1-6Ala is xianbei C 1-6alkyl), R12-(CO)-NH- (where R12represents C1-6alkyl or C1-6alkoxy, C1-6alkyl), C1-6alkyl, hydroxy, C1-6alkyl, cyano, C1-6alkyl, C1-6alkoxy or C1-6alkoxy, C1-6alkyl;

R2denotes a hydrogen atom, a C1-6alkyl, amino group which may be protected by a protective group, or di-C1-6alkylamino;

one of X and Y represents a nitrogen atom and the other represents a nitrogen atom or an oxygen atom;

W denotes a hydroxyl group, a halogen atom or substituted sulfonyloxy; and

R4denotes a hydrogen atom or a halogen atom.

[11] the Compound or its salt according to paragraph [10]above, in which a partial structure represented by:

in the formula (X) represents the following partial structure:

In the fourth aspect of the present invention further relates to

[12] the Compound represented by the following formula (XI)or its salt:

in which

R1denotes a hydrogen atom, halogen atom, amino group, R11-NH- (where R11represents C1-6alkyl, hydroxy, C1-6alkyl, C1-6alkoxy, C1-6alkyl or C1-6alkoxycarbonyl C1-6alkyl), R12-(CO)-NH- (where R12about the means C 1-6alkyl or C1-6alkoxy, C1-6alkyl), C1-6alkyl, hydroxy, C1-6alkyl, cyano, C1-6alkyl, C1-6alkoxy or C1-6alkoxy, C1-6alkyl;

R14denotes the amino group protected with a protective group;

one of X and Y represents a nitrogen atom and the other represents a nitrogen atom or an oxygen atom;

ring A represents a 5 - or 6-membered heteroaryl ring or a benzene ring which may have one or two halogen atom or one or two C1-6alkyl groups;

Z represents a simple bond, methylene group, ethylene group, an oxygen atom, a sulfur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S - or-SCH2-;

R3denotes a hydrogen atom or halogen atom, or a C1-6alkyl, C3-8cycloalkyl, C6-10aryl, 5 - or 6-membered heteroaryl, or 5 - or 6-membered non-aromatic heterocyclic group, and these groups may have one or two substituent selected from the group of substituents α; and

R4denotes a hydrogen atom or a halogen atom;

provided that when Z represents a simple bond or when R3denotes a hydrogen atom, then R1and R4cannot simultaneously denote hydrogen atoms

[the group of substituents α]

halogen atom, cyano, C1-6alkyl, C1-6alkoxy, 1-6alkoxycarbonyl, C3-8cycloalkyl, C2-6alkenyl and C2-6quinil.

[13] the Compound or its salt according to item [12], described above, in which a partial structure represented by:

in the formula (XI) is the following partial structure:

In the fifth aspect of the present invention further relates to

[14] the Compound represented by the following formula (XII)or its salt:

in which

ring B represents a benzene ring which may have one or two halogen atom or one or two C1-6alkyl groups;

U represents-CH2O-;

R denotes a hydrogen atom or a C1-6alkyl, and when both groups R represent C1-6alkyl, they may together form a ring; and

R15denotes a hydrogen atom or halogen atom, or a pyridine ring which may have one or two substituent selected from the group of substituents α,

[the group of substituents α]

halogen atom, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, C3-8cycloalkyl, C2-6alkenyl and C2-6quinil.

Advantageous effects of invention

According to the method of obtaining the present invention provides an efficient method is Holocene substituted heterocycle derivatives of pyridine and created an intermediate connection, which can be used in obtaining substituted heterocycle derivatives of pyridine. This makes possible the production of substituted heterocycle derivatives of pyridine on an industrial scale.

The best way of carrying out the invention

The following options for implementation are examples to illustrate the present invention but they are not intended to limit the present invention only two versions of the implementation. The present invention can be implemented in various aspects without derogating from its essence.

The present invention relates to a method for producing substituted heterocycle derivatives of pyridine, and the connection represented by:

can be obtained by reaction of the compound represented by the following formula (III):

and compounds represented by the following formula (II):

in a solvent and in the presence of a catalyst based on palladium and grounds

and when R2denotes an amino group which may be protected by a protective group, followed by removal of the protective group.

Ring A, R1, R2, R3, R4X, Y, Z, Q and R in the above formulas (I), (III) and (II) have the meanings given above.

Substituted heterocycle about spodnie pyridine, obtained by the method of receiving according to the present invention, known from WO07/052615, which is specified by the Patent document 3, and include compounds represented by the following formula (I)and their salts:

Ring A, R1, R2, R3, R4X, Y and Z in the formula (I) have the meanings given above.

The present invention is illustrated in more detail below in relation to symbols and terms used in the description and the following examples.

In the framework of the invention, the structural formula of the compound is sometimes represents a certain isomer for convenience of description. However, the compounds obtained according to the method of receiving according to the present invention, can include all possible isomers, such as structurally possible geometric isomers, optical isomers formed due to the presence of asymmetric carbon, stereoisomers, tautomers and mixtures of isomers, and is not limited to the formulas used for convenience of description, and may be either one of the two isomers, or a mixture of both isomers. Thus, the compounds according to the present invention may be either optically active compounds having asymmetric carbon atom in the molecules, or their racemates, and is not limited by any of these options, but include both. Also what about the, compounds according to the present invention may exhibit crystalline polymorphism and similarly not limited to one, but may be in any of these crystalline forms, or may exist as a mixture of two or more crystalline forms. Compounds according to the present invention also include both anhydrous and solvated, such as hydrated form.

The term “C1-6alkyl”used in the present description, refers to an alkyl group with straight chain or branched chain, having from 1 to 6 carbon atoms, which is a monovalent group formed by removing any hydrogen atom from an aliphatic hydrocarbon with 1 to 6 carbon atoms. In particular, examples, “C1-6the alkyl group may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,Deut-butyl,tert-butyl,npencil, isopentyl,second-pencil, neopentyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and the like, preferably methyl, ethyl,n-propyl, isopropyl,n-butyl, isobutyl, butyl ortert-butyl and the like, more preferably methyl, ethyl or propyl.

The term “C2-6alkenyl”used in the present description, refers to alkenylphenol group with straight chain or branched chain, having from 2 to 6 carbon atoms, which may contain 1 or 2 double bonds. In particular, examples, “C2-6alkenyl” may include ethynyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, hexadienyl and the like, preferably ethynyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl etc.

The term “C2-6quinil”used in the present description, refers to alkenylphenol group with straight chain or branched chain, having from 2 to 6 carbon atoms, which may contain 1 or 2 triple bond. In particular, examples, “C2-6alkenylphenol group” may include ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, pentenyl, hexenyl, hexadienyl and the like, preferably ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl etc.

The term “C3-8cycloalkyl”used in the present description, refers to a cyclic aliphatic hydrocarbon group with 3-8 carbon atoms. In particular, examples, “C3-8cycloalkyl” may include cyclopropyl, cyclobutyl is, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term “C1-6alkoxy”used in the present description, refers to a group in which an oxygen atom is attached to the end of the “C1-6alkyl group”defined above. In particular, examples, “C1-6alkoxygroup” may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, sec-pentyloxy, neopentylene, 1 methylbutoxy, 2-methylbutoxy, 1,1-DIMETHYLPROPANE, 1,2-DIMETHYLPROPANE, n-hexyloxy, isohexane, 1 methylpentylamino, 2-methylpentylamino, 3 methylpentane, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 2,2-Dimethylbutane, 1,3-Dimethylbutane, 2,3-Dimethylbutane, 3,3-Dimethylbutane, 1-ethylbutane, 2-ethylbutane, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and the like, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.

The term “hydroxyl-C1-6alkyl”used in the present description, refers to a group in which any hydrogen atoms in the “C1-6alkyl group, as defined above, substituted hydroxyl group. In particular, examples of the “hydroxyl-C1-6alkyl group m which may include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, 1-hydroxyisopropyl, 2-hydroxyisopropyl, 3-hydroxyisopropyl, 1-hydroxy-tert-butyl and the like, preferably hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, etc.

The term "cyano C1-6alkyl"used in the present description, refers to a group in which any hydrogen atom in the "C1-6alkyl group"defined above, substituted by cyano. Examples of a "cyano C1-6alkyl groups include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyano-n-propyl, 2-cyano-n-propyl, 3-cyano-n-propyl, 1-linosopril, 2-linosopril, 3-linosopril and 1-cyano-tert-butyl, preferably cyanomethyl, 1-cyanoethyl, 2-cyanoethyl etc.

The term “C1-6alkoxycarbonyl”used in the present description, refers to a group in which a carbonyl group is attached to the end of the “C1-6alkoxygroup”, defined above. In particular, examples, “C1-6alkoxycarbonyl group” may include methoxycarbonyl, etoxycarbonyl,npropoxycarbonyl, isopropoxycarbonyl etc.

The term “C1-6alkoxycarbonyl C1-6alkyl”used in the present description, refers to a group in which “C1-6alkyl group”defined above, attached to the end of the “C1-6alkoxycarbonyl group”, is definitely higher. In particular, examples, “C1-6alkoxycarbonyl C1-6alkyl group” may include methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl etc.

The term “C6-10aryl”, as used in the present description, refers to an aromatic cyclic hydrocarbon group with 6-10 carbon atoms. In particular, examples, “C6-10aryl” may include phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulene, heptenyl and the like, preferably phenyl, 1-naphthyl, 2-naphthyl, etc.

The term “C1-6alkoxy, C1-6alkyl”used in the present description, refers to a group in which any hydrogen atoms in the “C1-6alkyl group, as defined above, substituted C1-6alkoxygroup”, as defined above. In particular, examples, “C1-6alkoxy, C1-6alkyl group” may include methoxymethyl, ethoxymethyl,npropoxymethyl, methoxyethyl, ethoxyethyl etc.

The term "remove group"used in the present description, refers to a group acting as the deleted group during the reaction of cross-linking, and examples of "delete group" may include halogen atom, substituted sulfonyloxy etc.

The term “halogen atom”used in the present description, refers to fluorine atom, chlorine atom, bromine atom or iodine atom.

The terminology is "substituted sulfonyloxy", used in the present description, refers to sulfonyloxy in which any Deputy attached to sulfonyloxy. Examples of the substituents may include C1-6alkyl and phenyl which may be substituted by a halogen atom, a C1-6alkyl group, a nitro-group or phenyl group. Examples of a "substituted sulfonyloxy" may include p-toluensulfonate, benzylmalonate, methansulfonate, tripterocalyx, chloromethanesulfonyl etc.

The term "heteroatom"as used in the present description, refers to the nitrogen atom, sulfur atom or oxygen atom.

The term “5 - or 6-membered heteroaryl ring”, as used in the present description, refers to an aromatic ring, in which the number of atoms forming the ring is 5 or 6, and 1 or more heteroatoms included in the number of atoms forming the ring. In particular, examples of “5 - or 6-membered heteroaryl ring may include furan, thiophene, pyrrole, pyridine, pyrazin, pyridazine, pyrimidine, triazole (1,2,3-triazole, 1,2,4-triazole, etc.), tetrazole (1H-tetrazole, 2H-tetrazol etc), thiazole, pyrazole, oxazole, isoxazol, isothiazol, oxadiazole, thiadiazole and the like, preferably isoxazol.

The term “5 - or 6-membered heteroaryl”used in the present description, refers to a monovalent group of obrazovan the th removing 1 hydrogen atom from any position in the aromatic ring, in which the number of atoms forming the ring is 5 or 6, and one or more heteroatoms included in the number of atoms forming the ring. In particular, examples of “5 - or 6-membered heteroaryl” may include furyl (2-furyl or 3-furyl, etc.), thienyl (2-thienyl or 3-thienyl etc), pyrrolyl (1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl etc), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyridazinyl (3-pyridazinyl or 4-pyridazinyl etc), pyrimidinyl (2-pyrimidinyl, 4-or pyrimidinyl 5-pyrimidinyl etc), triazolyl (1,2,3-triazolyl or 1,2,4-triazolyl etc), tetrazolyl (1H-tetrazolyl or 2H-tetrazolyl etc), thiazolyl (2-thiazolyl, 4-thiazolyl or 5-thiazolyl etc), pyrazolyl (3-pyrazolyl or 4-pyrazolyl etc), oxazolyl (2-oxazolyl, 4-oxazolyl or 5-oxazolyl etc), isoxazolyl (3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl etc), isothiazole (3-isothiazole, 4-isothiazole or 5-isothiazolin etc), oxadiazolyl, thiadiazolyl etc.

The term “5 - or 6-membered non-aromatic heterocyclic group”used in the present description, refers to a monovalent group formed by removing 1 hydrogen atom from any position in the non-aromatic ring in which the number of atoms forming the ring is 5 or 6, and 1 or more heteroatoms included in the number of atoms forming the ring. In particular, examples of “5 - or 6-membered aeromatic the Russian heterocyclic group” may include pyrrolidinyl, piperidinyl, piperidinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl etc.

The term “di1-6alkylamino”used in the present description, refers to a group in which 2 hydrogen atoms of the amino group is replaced by “C1-6alkyl group”defined above, which may be the same or different. In particular, examples of the term “di1-6alkylamino” may include N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di Isopropylamine, N,N-di-n-butylamino, N,N-isobutylamino, N,N-di-sec-butylamino, N,N-di-tert-butylamino, N-ethyl-N-methylamino, N-n-propylamino-N-methylamino, N-isopropyl-N-methylamino, N-n-butyl-N-methylamino, N-isobutyl-N-methylamino, N-sec-butyl-N-methylamino, N-tert-butyl-N-methylamino and the like, preferably N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino etc.

The term “may have 1 or 2 substituent”used in the description means that there can be 1 or 2 substituent in any combination in areas suitable for substitution.

R1preferably denotes a hydrogen atom, halogen atom, amino group, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, hydroxyl-C1-6alkylamino or C1-6alkoxy, C1-6alkyl and more preferably a hydrogen atom, an amino group or a C1-6alkoxy, C1-6alkyl, preferably is C 1-6alkoxy, C1-6the alkyl is methoxymethyl.

R2preferably denotes a hydrogen atom, an amino group which may be protected by a protective group, or di-C1-6alkylamino, preferably an amino group which may be protected by a protective group. The term "protective group of an amino group which may be protected by a protective group"is not limited to the following, but examples of such groups may include carbamates such as methoxycarbonyl, etoxycarbonyl or tert-butoxycarbonyl; and amide groups such as formyl, acetyl, pivaloyl. When R2denotes an amino group which may be protected by a protective group, then one of the hydrogen atoms of the amino group may be protected by a protective group, or two of the hydrogen atoms of the amino group can be protected by a protective group. The protective group of the amino group used in the method of receiving according to the present invention, preferably represents acetyl, pivaloyl or tert-butoxycarbonyl, and pivaloyl or tert-butoxycarbonyl are more preferred.

One of X and Y represents a nitrogen atom, while the other represents a nitrogen atom or an oxygen atom.

Partial structure represented by the following formula (IV), including X and Y:

is preferably a structure, before the bringing isoxazoline skeleton, shown below

For example, in the case of a partial structure of the formula (V), the structure of the compound obtained by the method of receiving according to the present invention, will be such as represented by the following formula

Ring A represents a 5 - or 6-membered heteroaryl ring or a benzene ring which may have one or two halogen atom or one or two C1-6alkyl group, and preferably represents a pyridine, benzene, furan, thiophene or pyrrole, and pyridine, benzene or thiophene are more preferable, and pyridine or benzene are even more preferred.

Z represents a simple bond, methylene group, ethylene group, an oxygen atom, a sulfur atom, -CH2O-, -OCH2-, -NH-, -NHCH2-, -CH2NH-, -CH2S - or-SCH2-from which a methylene group, oxygen atom, -CH2O -, or-OCH2- are preferred, and an oxygen atom, -CH2O -, or-OCH2- are more preferred.

R3denotes a hydrogen atom or halogen atom, or denotes a C1-6alkyl, C3-8cycloalkyl, C6-10aryl or 5 - or 6-membered heteroaryl, each of which may have one or two substituent selected from the group of substituents α.

[The group of substituents α]

the atom is alogena, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, C3-8cycloalkyl, C2-6alkenyl and C2-6quinil.

Preferred examples of R3may include n-butyl, cyclopropyl, phenyl, forfinal, furyl, chlorphenyl, methylphenyl, thienyl, bromanil, matiltan, pyridyl and methylpyridyl, and n-butyl, cyclopropyl, phenyl, forfinal, pyridyl and methylpyridyl are more preferred.

Z and R3may be, if necessary, combined with the formation of the substituents for ring A. Preferred examples of R3-Z - as the substituents of ring A, formed thereby, may include phenoxy, benzyloxy, 2-forbindelse, 3 fermentelos, 4-forbindelse, pyridine-2-intoximeter, 6-methylpyridin-2-intoximeter, pyridine-2-ylethoxy, 6-methylpyridin-2-ylethoxy, 4-methylpyridin-2-ylethoxy, butoxymethyl, cyclopropylmethoxy.

Preferred examples of the compounds obtained by the method of receiving according to the present invention may include

3-(3-(4-benzyloxybenzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(pyridine-2-ylethoxy)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(4-methylpyridin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(6-benzyloxypyridine-3-ylmethyl)isoxazol-5-yl)PI is one-2-ylamine;

3-(3-(4-benzyloxybenzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(6-methylpyridin-2-intoximeter)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-butoxybenzoyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-phenoxybenzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(4-methylpyridin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(6-benzyloxypyridine-3-ylmethyl)isoxazol-5-yl)pyridine-2,6-diamine;

6-methoxymethyl-3-(3-(4-(pyridine-2-ylethoxy)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(6-phenoxypyridine-3-ylmethyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(5-herperidin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(4-methylpyridin-2-intoximeter)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(6-herperidin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(4-chloropyridin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(6-chloropyridin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(6-phenoxymethylpenicillin-3-ylmethyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(6-herperidin-2-intoximeter)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(6-(4-forbindelse)pyridine-3-ylmethyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-(5-chlorofuran-2-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

3-(3-(4-phenylenedimethylene)itxas is l-5-yl)pyridin-2-ylamine;

3-(3-(4-(4-methylpyridin-2-intoximeter)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(6-herperidin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(5-methylfuran-2-ylmethyl)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(4-chloropyridin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(6-chloropyridin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(6-phenoxymethylpenicillin-3-ylmethyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(5-herperidin-2-ylethoxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(6-herperidin-2-intoximeter)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(1-benzyl-1H-pyrrol-3-ylmethyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(6-(4-forbindelse)pyridine-3-ylmethyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(5-chlorofuran-2-ylmethyl)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(6-(3-pertenece)pyridine-3-ylmethyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-phenylenedimethylene)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(6-(4-pertenece)pyridine-3-ylmethyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(4-(thiazol-2-ylethoxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine;

3-(3-(5-(4-forfunction-2-ylmethyl)isoxazol-5-yl)pyridine-2,6-diamine;

6-methoxymethyl-3-(3-(4-(pyridine-2-ylethoxy)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

6-methyl-3-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridin-2-ylamine;

p> 5-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridin-2-ylamine and

3-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridine.

The compound represented by formula (III) used as starting substances in the method of receiving according to the present invention

can be obtained by the production method, which includes the introduction of compounds represented by the following formula (VI)

in the cyclization reaction; implementation of reduction reaction and then the implementation of the halogenation. When R2denotes an amino group having a protective group, the compound represented by formula (III)can also be obtained by further removing the protective group after the specified reaction recovery. The protective group of the amino group in this case is not limited to the following, but examples may include carbamates such as methoxycarbonyl, etoxycarbonyl or tert-butoxycarbonyl; and amide groups such as formyl, acetyl or pivaloyl. Formyl, acetyl, pivaloyl or tert-butoxycarbonyl are preferred, and pivaloyl is preferred

(and R1, R2, R4X, Y and Q have the same meanings as defined above,

R10denotes a hydrogen atom or a C1-6alkyl, and

R13denotes the volume of hydrogen or C 1-6alkyl).

Specified structural formula of the compound represents a certain isomer for convenience, but the present invention encompasses all geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, rotamer, tautomers and other such isomers and mixtures of isomers that can occur in the connection structure, and is not limited to those shown in formulas for the sake of convenience, and can represent any of these isomers or mixtures thereof.

R10preferably denotes methyl or ethyl, and R13preferably denotes a hydrogen atom. The cyclization reaction of the compound represented by formula (VI), followed by reduction and halogenation reaction will be discussed in more detail for a General method of obtaining, as discussed below.

When R2denotes the amino group, the stage of protection of the amino group may be optionally included if necessary. Protective group, which protects the amino group, preferably represents acetyl, pivaloyl or tert-butoxycarbonyl, and pivaloyl or tert-butoxycarbonyl are more preferred.

Q in the formula (III) preferably represents a halogen atom or substituted sulfonyloxy. When Q denotes a halogen atom, are preferred as the om chlorine or bromine atom, moreover, the chlorine atom is more preferable. When Q represents substituted sulfonyloxy, preferred are p-toluensulfonate or methysulfonylmethane, and p-toluensulfonate is preferable.

Then will be described intermediate compound that can be used in obtaining the compounds represented by formula (I)described above. More specifically, in one aspect the present invention relates to a compound represented by the following formula (VII)or its salt.

In the above formula, R1, R2, R4X and Y have the same meanings as defined above, and R10denotes a hydrogen atom or a C1-6alkyl.

Partial structure represented

in the formula (VII)described above preferably represents a structure having isoxazoline skeleton as shown below

In addition, R10preferably denotes methyl or ethyl, and ethyl is preferred.

Another intermediate compound that can be used in obtaining the compounds represented by formula (I)described above will be described next. More specifically, in another aspect of the present from retina refers to the connection, represented by the following formula (X)or its salt.

In the above formula, R1, R2, R4X and Y have the same meanings as defined above, and W represents a hydroxyl group, a halogen atom or substituted sulfonyloxy.

Partial structure represented

in the formula (X)described above preferably represents a structure having isoxazoline skeleton as shown below

W preferably represents a hydroxyl group, a chlorine atom, a bromine atom or C-toluensulfonate, and a hydroxyl group or a chlorine atom are more preferable.

Another intermediate compound that can be used in obtaining the compounds represented by formula (I)described above will be described next. More specifically, in another aspect the present invention relates to a compound represented by the following formula (XI)or its salt

In the above formula, R1, R3, R4X, Y, Z and ring A have the same meanings as defined above, and R14denotes the amino group protected with a protective group.

When Z represents a simple bond or when R3denotes a hydrogen atom, t is when R 1and R4cannot both simultaneously be hydrogen atoms.

Partial structure represented

in the formula (XI)described above preferably represents a structure having isoxazoline skeleton as shown below

Examples of protective groups, which protects the amino group, R14may include carbamates such as methoxycarbonyl, etoxycarbonyl or tert-butoxycarbonyl; and amide groups such as formyl, acetyl or pivaloyl. When R14denotes the amino group protected with a protective group, then one of the hydrogen atoms of the amino group may be protected by a protective group, or two of the hydrogen atoms of the amino group can be protected by a protective group, and a pivaloyl or tert-butoxycarbonyl are preferred, and tert-butoxycarbonyl is preferable.

Another intermediate compound that can be used in obtaining the compounds represented by formula (I)described above will be described next. More specifically, in another aspect the present invention relates to a compound represented by the following formula (XII), or its salt

In the above formula, the ring B represents a halogen atom or a benzene ring which m which may have one or two C 1-6alkyl groups;

U represents-CH2O-;

R denotes a hydrogen atom or a C1-6alkyl, and when two groups R both denote C1-6alkyl, they may together form a ring; and

R15denotes a hydrogen atom or halogen atom, or a pyridine ring which may have one or two substituent selected from the group of substituents α,

[the group of substituents α]

halogen atom, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, C3-8cycloalkyl, C2-6alkenyl and C2-6quinil.

Ring B preferably represents an unsubstituted benzene ring, and R preferably denotes a hydrogen atom, or two groups R together form a ring as shown below

R15preferably denotes unsubstituted pyridine ring.

Examples of the term "salt"used in the present description, include a salt with inorganic acid, salt with organic acid, salt with inorganic base, a salt with organic base, salt with acidic or basic amino acid, etc. Among these salts preferably, the salt used according to the invention, was pharmaceutically acceptable.

Preferred examples of the salt with inorganic acid include salts with hydrochloric acid, bromilow the portly acid, sulfuric acid, nitric acid, phosphoric acid, etc. are Preferable examples of the salt with organic acid include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, econsultancy acid,p-toluensulfonate acid, etc.

Preferred examples of salts with acidic amino acid include salts with aspartic acid, glutamic acid, etc. are Preferable examples of salts with basic amino acid include salts with arginine, lysine, ornithine and the like,

A common way to obtain

Now will be described the method of obtaining the compound (14)represented by the specified formula (1) and used in the present invention. Abbreviations used below are defined as follows.

BOC: tert-butoxycarbonyl

Piv: pivaloyl

Ac: acetyl

The scheme of obtaining 1

Scheme for 2

In the above scheme, R1, R3, R4ring A, Z, R10and R have the same meanings as defined above.

It should be noted that the compound represented by formula (1), referred to as compound (1)and compounds represented by other formulas which, mentioned similarly. Connection (1), which is a commercially available product may be used as such or it can be obtained by a known method from the commercially available product.

Stage 1

This stage represents the stage of obtaining the compound (2) by introducing into the reaction of the compound 1 and Vos. There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol,tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or from butyronitrile; the solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; and mixtures of these solvents. Di-tert-BUTYLCARBAMATE or similar compounds can be used as a Re-reagent used in this reaction. Vos-reagent can be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on compound (1). The reaction temperature may range from ambient temperature to the boiling point of the solvent, and the reaction time is from 1 to 24 hours.

Stage 2

This stage represents the stage of obtaining compound (4) in the presence of a base via a connection (3) by introducing into the reaction of the compound (2)obtained in stage 1, with W oxalic acid in the presence of a base and then adding hydroxylamine hydrochloride to the reaction solution. There are no specific limitations to the solvent used in this reaction, provided that it will dissolve to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide g is somethingstore acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; and mixtures of these solvents. Fluids oxalic acid used in the present invention, may be dimethyloxalate, diethyloxalate and other Fluids oxalic acid can be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on compound (2). The base used in this reaction may be sodium carbonate, triethylamine and the like, the Base can be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 ek is ivalent per connection (2). Hydroxylamine hydrochloride is used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on compound (2). The reaction temperature may range from ambient temperature to the boiling point of the solvent, and the reaction time is from 1 to 24 hours.

Stage 3

This stage represents the stage of obtaining the compound (5) by restoring the connection (4). There are no specific limitations to the solvent used in this reaction, provided that it will dissolve to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, Oct the ol, the cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; water and mixtures of these solvents. The reducing agent used in this reaction may be an aluminum-lithium hydride, aluminum-lithium hydride-aluminum chloride (aluminum chloride is used in an amount of from 1 to 1.5 equivalent per aluminum-lithium hydride, lithium borohydride, sodium borohydride or other Reducing agent may be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on compound (4). The reaction temperature may be in the range from 0°C to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

Stage 4

This stage represents the stage of obtaining the compound (6) by introducing into the reaction of the compound (1) with the agent Piv. There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, di is malformed, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; and mixtures of these solvents. Agent Piv used in this reaction may be revalorisation etc. and this agent Piv is used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on compound (1). The reaction temperature is in the range from ambient temperature to the boiling point of the solvent, and the reaction time is from 1 to 24 hours.

Stage 5

At this stage the connection is tion (6), obtained in stage 4, is introduced into reaction with fluids of oxalic acid in the presence of a base and then to the resulting reaction solution was added hydroxylamine hydrochloride, obtaining the compound (8) in the presence of a base via a connection (7). There are no specific limitations to the solvent used in this reaction, provided that it will dissolve to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfate the d or sulfolan; the solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; and mixtures of these solvents. Fluids oxalic acid used in the present invention, may be dimethyloxalate, diethyloxalate and other Fluids oxalic acid can be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on the compound (6). The base used in this reaction may be represented as sodium carbonate, triethylamine and the like, the Base can be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on the compound (6). Hydroxylamine hydrochloride is used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on the compound (6). The reaction temperature is in the range from ambient temperature to the boiling point of the solvent, and the reaction time is from 1 to 24 hours.

Stage 6

This stage represents the stage of obtaining the compound (5) by restoring the connection (8). There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include rest ritali-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; water and mixtures of these solvents. The reducing agent used in this reaction may be an aluminum-lithium hydride, aluminum-lithium hydride-aluminum chloride (aluminum chloride is used in an amount of from 1 to 1.5 equivalent per aluminum-lithium hydride, lithium borohydride, sodium borohydride or other Reducing agent may be used in an amount of from 1 to 100 equivalents, and preference is sustained fashion from 1 to 10 equivalents based on compound (8). The reaction temperature is in the range from -20°C to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours. At this stage protective group of the amino group can also be removed after the reaction of recovery. There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvents on the basis of simple ether, such as tetrahydrofuran, dioxane, dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of nitrile, such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; water and mixtures of these solvents. There are no specific restrictions on the acid used in this reaction, provided that it can promote the reaction, but examples may include inorganic acids such as hydrochloric acid or sulfuric acid; and organic acids such as formic acid is, acetic acid or triperoxonane acid. The use of hydrochloric acid, sulfuric acid, formic acid or triperoxonane acid is preferred. There are no specific restrictions in terms of the Foundation, provided that it can promote the reaction, but examples may include inorganic bases such as sodium hydroxide or potassium hydroxide.

These reagents can be used in amounts of from 0.1 to 100 equivalents, and preferably from 1 to 50 equivalents based on the compound (8). The reaction temperature is in the range from -20°C to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

Stage 7

This stage represents the stage of obtaining the compound (9) by introducing into the reaction of the compound (5) with thionyl chloride. There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene,benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; and mixtures of these solvents. Thionyl chloride can be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on compound (5). The reaction temperature is in the range from -20°C to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

Stage 8

This stage represents the stage of obtaining the compound (10) by introducing into the reaction of the compound (9) in the presence of a protective agent to an amino group. There are no specific limitations to the solvent used in this reaction, provided that it dissolves to not what toroi much of the original material and will not impede the reaction, but his examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; and mixtures of these solvents. The protective agent used in this reaction may be acetylchloride, pivaloyloxy, di-tert-BUTYLCARBAMATE etc. Protective agent for the amino group can be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on compound (9). The temperature p of the shares is in the range from -20°C to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

Stage 9

This stage represents the stage of obtaining the compound (12) by introducing into the reaction of the compound (10) with compound (11), which is derived {4-[(pyridine-2-yloxy)methyl]phenyl}Bronevoy acid, in an inert solvent and in the presence of a base and of a catalyst based on palladium(0). There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of nitrification is a, such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; water and mixtures of these solvents. There are no specific limitations to the compound (11)used in this reaction, provided that it can be obtained target compound and does not form an inseparable by-products, but the V in the formula represents-B(OH)2, -B(OR)2or-BF3M (where M denotes sodium or potassium). For example, the compound (11) preferably represents {4-[(pyridine-2-yloxy)methyl]phenyl}Bronevoy acid, 2-{[4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)benzyl]oxy}pyridine, etc. 2-{[4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)benzyl]oxy}pyridine is preferable.

This compound (11) can be used in amounts of from 0.5 to 10 equivalents, and preferably from 0.5 to 3 equivalents based on compound (10). There are no specific restrictions regarding the catalyst based on palladium, used in this reaction, provided that it can be obtained target compound and does not form an inseparable by-products, but it can be a tetrakis(triphenylphosphine)palladium, Tris(dibenzylideneacetone)dip lady, bis(dibenzylideneacetone)palladium, bis(tri-tert-butylphosphine)palladium, palladium black and the like, or it can be a catalyst based on palladium(0), which is produced in the reaction system, combining a variety of the following ligands and various palladium complexes, which are precursors of palladium(0), listed below.

In particular, there are no specific limitations with respect to the various palladium complexes, which are precursors of palladium(0), provided that can be obtained target compound and does not form an inseparable by-products, but their examples may include palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene globally, dichlorobis(three-o-tolylphosphino)palladium and dichlorobis(tricyclohexylphosphine)palladium. There are no specific limitations to the ligand, provided that can be obtained target compound and does not form an inseparable by-products, but examples may include 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos), tri-tert-butylphosphine, three(4-were)phosphine, tri-2-furifosmin, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, tricyclohexylphosphine, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 1,1'-bis(given phosphino)ferrocene, (oxygen-2,1-phenylene)bis(diphenylphosphine), di-tert-butyl phosphonium tetrafluoroborate and 1,3-bis(2,4,6-trimetilfenil)imidazol-2-ilidene.

The specified catalyst based on palladium(0) can be used in amounts of from 0.01 to 5 molar equivalents, and preferably from 0.01 to 0.1 molar equivalentof per mol of compound (10).

In addition, there are no specific restrictions on the base used in this reaction, provided that it can be obtained target compound and does not form an inseparable by-products, but examples may include inorganic bases such as tripotassium phosphate, trinacria phosphate, cesium carbonate, potassium carbonate, sodium carbonate, cesium bicarbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, barium hydroxide, potassium hydroxide, potassium fluoride or cesium fluoride; alkoxides of metals such as ethoxide or sodium tert-piperonyl sodium acetates of alkali metals such as sodium acetate or potassium acetate; and organic bases such as triethylamine, and preferably potassium carbonate, sodium carbonate. The base may be used in quantities of from 0.5 to 100 equivalents, and preferably from 0.5 to 3 equivalents based on compound (10). The reaction temperature is in the range from 0°C to the boiling point process is Italia, and the reaction time is from 10 minutes to 48 hours.

Stage 10

This stage represents the stage of obtaining the compound (14) through the compound (13) by removing the protective group of the amino group of compound (12). There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the Nove of ester, such as methyl acetate, ethyl acetate, propyl or diethylmalonate; water and mixtures of these solvents. Any known reaction of removing the protective group can be used as a method of removal of the protective group of the amino group used in this reaction, but when the protective group is a tert-butoxycarbonyl, can be used, for example, the method described inSynthesispp. 66-68, 1999, etc, and when the protective group is an acetyl, a method described inJ. Org. Chem., PP. 4593, 1978, etc. may be used for removal of the protective group of amino group.

There are no specific restrictions on the used acid, provided that it can promote the reaction, but examples may include inorganic acids such as hydrochloric acid or sulfuric acid; and organic acids such as formic acid, acetic acid, triperoxonane acid. The use of hydrochloric acid, sulfuric acid, formic acid or triperoxonane acid is preferred.

There are no specific restrictions in terms of the Foundation, provided that it can promote the reaction, but examples may include inorganic bases such as sodium hydroxide or potassium hydroxide; and organic bases, such as Hijazi is, the alkylamines followed.

These reagents can be used in amounts of from 0.1 to 100 equivalents, and preferably from 1 to 50 equivalents based on the compound (11). The reaction temperature ranges from -20°C to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

Stage 11

This stage represents the stage of obtaining the compound (10) by introducing into the reaction of the compound (15) with p-toluensulfonate or another such sulphonylchloride. There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvent-based amide, such as formamide, dimethylformamide, dimethylacetamide, triamide hexamethylphosphoric acid, 1,3-dimethyl-2-imidazolidinone or N-organic; based solvents, aromatic hydrocarbon such as toluene, benzene, xylene or musicial; solvents on the basis of simple ester, such as a simple diethyl ether, simple, diisopropyl ether, tetrahydrofuran, dioxane dimethoxyethane or simple dimethyl ether of diethylene glycol; solvents on the basis of alcohol, such as methanol, ethanol,npropanol, isopropanol,nbutanol, Isobutanol, tert-bout the Nol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methoxyethanol; solvents on the basis of a nitrile such as acetonitrile or isobutyronitrile; solvents on the basis of a sulfoxide, such as dimethylsulfoxide or sulfolane; solvents on the basis of ester such as methyl acetate, ethyl acetate, propyl or diethylmalonate; and mixtures of these solvents. p-toluensulfonate can be used in an amount of from 1 to 100 equivalents, and preferably from 1 to 10 equivalents based on compound (15). The reaction temperature is in the range from -20°C to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

Scheme for the preparation of 3

In the above scheme, R3ring , A, Z and R have the same meanings as defined above.

Compound (17), (18) and (19) can be obtained from compound (16) by a known method (such as described inTetrahedronVol. 45, No. 7, pp. 1859-1885, 1989).

Stage 12

This stage represents the stage of obtaining the compound (17) by introducing into the reaction ether Bronevoy acid Uniontown compound obtained by the reaction between the compound (16) and the ORGANOMETALLIC reagent, followed by the addition of acid to neutralize the reaction mixture. This reaction can be carried out in almost the re or in a current of nitrogen gas, argon or other inert gas. There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvents on the basis of simple ether, such as tetrahydrofuran, 1,2-dimethoxyethane, simple methyl tert-butyl ether, simple cyclopentylmethyl ether, simple diethyl ether, simple diisopropyl ether, simple disutility ether or simple dicyclopentyl ether; solvents on the basis of an aromatic hydrocarbon such as benzene or toluene; the solvent based aliphatic hydrocarbon, such as heptane or hexane; and mixtures of these solvents. The use of tetrahydrofuran is preferred. The "ORGANOMETALLIC reagent" refers, for example, to the Grignard reagent, n-butyllithium, second-butyllithium etc. Using n-utility is preferred. Regarding the reaction temperature, the temperature from 30 to 120°C is preferred to obtain a Grignard reagent, from -80 to -50°C is preferred for litvinovna, from -80 to 30°C is preferred for the esterification Bronevoy acid and from -20 to 30°C is preferred for hydrolysis. The specified ether Bronevoy acids include, e.g. the measures to trimethylborane or triisopropylsilane. Using triisopropylsilane is preferred. This acid includes, for example, aqueous solution of ammonium chloride, methanesulfonic acid,p-toluensulfonate acid, hydrochloric acid-ethyl acetate, hydrochloric acid-methanol or dilute hydrochloric acid. An aqueous solution of ammonium chloride or hydrochloric acid are preferred.

Stage 13

This stage represents the stage of obtaining the compound (18) by introducing into the reaction ether Bronevoy acid Uniontown compound obtained by the reaction between the compound (16) and the ORGANOMETALLIC reagent, followed by the addition of acid to neutralize the reaction mixture and the introduction into reaction with the alcohol or with penacola, neopentylglycol or other diola. This reaction can also be accomplished by adding an ORGANOMETALLIC reagent to a mixture of compound (16) and ether Bronevoy acid and carrying out the reaction with ether Bronevoy acid simultaneously with the receipt of the anion of compound (16). This reaction can be carried out in the atmosphere or in a stream of gaseous nitrogen, argon or other inert gas. There are no specific limitations to the solvent used in this reaction is AI, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvents on the basis of simple ether, such as tetrahydrofuran, 1,2-dimethoxyethane, simple methyl tert-butyl ether, simple cyclopentylmethyl ether, simple diethyl ether, simple diisopropyl ether, simple disutility ether or simple dicyclopentyl ether; solvents on the basis of an aromatic hydrocarbon such as benzene or toluene; the solvent based aliphatic hydrocarbon, such as heptane or hexane; and mixtures of these solvents. The use of tetrahydrofuran is preferred. The specified ether Bronevoy acid includes, for example, trimethylborane or triisopropylsilane. Using triisopropylsilane is preferred. The above "ORGANOMETALLIC reagent" refers, for example, to the Grignard reagent, n-butyllithium, second-butyllithium etc. Using n-utility is preferred. Regarding the reaction temperature, the temperature from 30 to 120°C is preferred to obtain a Grignard reagent, from -80 to -50°C is preferred for litvinovna, from -80 to 30°C is preferred for the esterification Bronevoy acid and from -20 to 30°C is preferred for hydrolysis. The specified ether Bronevoy acids which include, for example, to trimethylborane or triisopropylsilane. Using triisopropylsilane is preferred. This acid includes, for example, aqueous solution of ammonium chloride, methanesulfonic acid,p-toluensulfonate acid, hydrochloric acid-ethyl acetate, hydrochloric acid-methanol or dilute hydrochloric acid. An aqueous solution of ammonium chloride or hydrochloric acid are preferred.

Stage 14

This stage represents the stage of obtaining the compound (19) by introducing into the reaction ether Bronevoy acid Uniontown compound obtained by the reaction between the ORGANOMETALLIC reagent and compound (16), with subsequent introduction into the reaction with hydrochoride salt (hydroptere potassium, hydrofloric sodium etc). This reaction can be carried out in the atmosphere or in a stream of gaseous nitrogen, argon or other inert gas. There are no specific limitations to the solvent used in this reaction, provided that it dissolves to some extent the source material and will not impede the reaction, but examples may include solvents on the basis of simple ether, such as tetrahydrofuran, 1,2-dimethoxyethane, simple methyl tert-butyl ether, simple Cyclops is timetravel ether, simple diethyl ether, simple diisopropyl ether, simple disutility ether or simple dicyclopentyl ether; solvents on the basis of an aromatic hydrocarbon such as benzene or toluene; the solvent based aliphatic hydrocarbon, such as heptane or hexane; and mixtures of these solvents. The use of tetrahydrofuran is preferred. The specified ether Bronevoy acid includes, for example, trimethylborane or triisopropylsilane. Using triisopropylsilane is preferred. The "ORGANOMETALLIC reagent" refers, for example, to the Grignard reagent, n-butyllithium, second-butyllithium etc. Using n-utility is preferred. Regarding the reaction temperature, the temperature from 30 to 120°C is preferred to obtain a Grignard reagent, from -80 to -50°C is preferred for litvinovna, from -80 to 30°C is preferred for the esterification Bronevoy acid and from -20 to 30°C is preferred for hydrolysis. The specified ether Bronevoy acid includes, for example, trimethylborane or triisopropylsilane. Using triisopropylsilane is preferred.

EXAMPLES

The present invention will now be specifically described based on examples, but the present invention is not limited to these examples. The specialist may OS which may serve as a basis present invention, adding various modifications to the examples given below, and such modifications are within the scope of the claims of this application. In the following examples for the compounds synthesized according to the above schemes, numbers are used, the data for these schemes, and they'll be called "connection 1" and so on

[Example of obtaining 1] Synthesis of (3-acetylpyridine-2-yl)tert-BUTYLCARBAMATE

A mixture of 1-(2-aminopyridine-3-yl)ethanone (50 g, 368 mmol), di-tert-BUTYLCARBAMATE (120 g, 552 mmol) and tert-butanol (200 ml) was stirred at 90°C for three hours under nitrogen atmosphere. After cooling, the solvent is evaporated under reduced pressure, to the residue was added n-heptane (500 ml) and the precipitated solid was filtered, obtaining the target compound (77 g) in a solid yellow color.

Range1H-NMR (CDCl3) δ (ppm): and 1.54 (9H, s)of 2.64 (3H, s), 7,03 (1H, DD, J=4,8, 8.0 Hz), 8,16 (1H, DD, J=2,0, 8.0 Hz), 8,63 (1H, DD, J=2.0 a, 4,8 Hz), was 10.82 (1H, users).

[Example 1] Synthesis of 5-(2-aminopyridine-3-yl)isoxazol-3-ethylcarboxylate

To a solution of (3-acetylpyridine-2-yl)tert-BUTYLCARBAMATE (600 mg, to 2.29 mmol) and diethyloxalate (669 mg, 4,58 mmol) in toluene (5.0 ml) was added tert-piperonyl potassium (514 mg, 4,58 mmol) at room temperature under nitrogen atmosphere and was stirred for two hours. After adding toluene (5.0 ml) and AC is shivani within one hour was added tert-piperonyl potassium (257 mg, to 2.29 mmol) and the solution was stirred for two hours. To the reaction mixture was added hydroxylamine hydrochloride (477 mg, 6,87 mmol) and ethanol (10 ml), was stirred for one hour, was added water (1.0 ml) and the solution was stirred over night at room temperature. Was added water (30 ml) and the solution was extracted with ethyl acetate. After the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, the solution was concentrated. The concentrated residue was dissolved in N,N-dimethylformamide (5 ml), was added triethylamine (192 mg) and the solution was stirred at 80°C for six hours. After cooling, was added water and the solution was extracted with ethyl acetate. After the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, obtaining the target compound (443 mg) as a solid white color.

Range1H-NMR (CDCl3) δ (ppm): 1,45 (3H, t, J=7.2 Hz), 4,49 (2H, square, J=7,2 Hz), of 5.40 (2H, users), 6,79 (1H, DD, J=5,2, 7,6 Hz)6,91 (1H, s), 7,81 (1H, DD, J=2.0 a, 7,6 Hz), 8,21 (1H, DD, J=2.0 a, 5,2 Hz).

[Example 2] Synthesis of [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanol

To a suspension of 5-(2-aminopyridine-3-yl)isoxazol-3-ethylcarboxylate (381 mg, and 1.63 mmol) in tetrahydrofuran (3.8 ml)and ethanol (3.8 ml) at 0°C under nitrogen atmosphere was added sodium borohydride (201 mg, 4,89 mmol) and stirred at 0°C for one hour and at 20°C for 21 hours. When cooled in a bath with a mixture of ice water to the reaction mixture was added dropwise 2n. hydrochloric acid (2,46 ml, 4,89 mmol), stirred at 0°C for 10 minutes and at room temperature for 30 minutes. When cooled in a bath with a mixture of ice water after adding dropwise an aqueous solution of 5% sodium bicarbonate until the alkaline solution was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue is suspended in tetrahydrofuran (1.4 ml)to the reaction mixture at 0°C was added sodium borohydride (67 mg, and 1.63 mmol)was washed with methanol (1.4 ml). After stirring at room temperature for one hour the solution was stirred at 60°C for five hours. When cooled in a bath with a mixture of ice water to the reaction mixture was added dropwise 1N. hydrochloric acid (1,63 ml of 1.63 mmol), stirred at 0°C for 10 minutes and at room temperature for 30 minutes. When cooled in a bath with a mixture of ice water after adding dropwise 1N. an aqueous solution of sodium hydroxide until alkaline reaction solution was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, dissolve Italy evaporated under reduced pressure, receiving the target compound (258 mg) as a solid pale yellow color.

Range1H-NMR (DMSO-d6) d (ppm): 4,56 (2H, d, J=5.6 Hz), 5,54 (1H, t, J=5.6 Hz), 6,27 (2H, users), 6,72 (1H, DD, J=4,8 and 7.6 Hz), make 6.90 (1H, s), of 7.90 (1H, DD, J=2.0 a, 7,6 Hz), 8,10 (1H, DD, J=2.0 a, 4,8 Hz).

Examples get 2-4 and Examples 3-5 are other synthesis methods, alternative Examples 1 and 2.

[Example getting 2] Synthesis of N-(3-acetylpyridine-2-yl)-2,2-dimethylpropanamide

To a mixture of 1-(2-aminopyridine-3-yl)ethanone (272 mg, 2 mmol), 4-dimethylaminopyridine (24 mg, 0.2 mmol), triethylamine (of 0.64 ml, 4.6 mmol) and toluene (2 ml) dropwise at room temperature was added pivaloate (0,52 ml, 4.2 mmol), stirred at room temperature for one hour and at 60°C for five hours. After confirming the formation of 2-tert-butyl-4-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-revelate* to the reaction mixture were added water (2 ml) and 5N. hydrochloric acid (0.8 ml) and stirred at room temperature for 30 minutes. After separation of the reaction mixture to aqueous layer was added 5N. an aqueous solution of sodium hydroxide (1 ml) and was extracted with toluene. The solvent is evaporated under reduced pressure and the precipitated solid was filtered, obtaining the target compound (415 mg).

Range1H-NMR (CDCl3) δ (ppm): of 1.33 (9H, s)of 2.64 (3H, s), 7,10 (1H, DD, J=4,8, 8.0 Hz), 8,17 (1, DD, J=2.0 a, 7,6 Hz)8,64 (1H, DD, J=2.0 a, 4,8 Hz).

*2-tert-butyl-4-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-revelat

Range1H-NMR (CDCl3) δ (ppm): 1,09 (9H, s)of 1.32 (9H, s), is 2.05 (3H, s), 7,14 (1H, DD, J=4,8 and 7.6 Hz), 7,71 (1H, DD, J=2.0 a, 7,6 Hz), 8,51 (1H, DD, J=2.0 a, 4,8 Hz).

Examples get 3-4 are other synthesis methods, alternative example of getting 2.

[Example of getting 3] Synthesis of 2-tert-butyl-4H-pyrido[2,3-d][1,3]oxazin-4-it

To a mixture of 2-aminonicotinic acid (13.8 g, 100 mmol), 4-dimethylaminopyridine (1.2 g, 10 mmol), triethylamine (55,8 ml, 400 mmol) and N-methylpyrrolidone (140 ml, 42 mmol) was added dropwise at 0°C pivaloate (24,1 g, 200 mmol) and after the addition was stirred over night at room temperature. To the reaction mixture was added ice water, extracted with toluene and the organic layer was washed with water and saturated aqueous sodium chloride. After the solution was dried over anhydrous magnesium sulfate and filtered, the solvent evaporated under reduced pressure. To the residue was added n-heptane, which is suspended and stirred at 0°C, then filtered, obtaining the target compound (16.6 g).

Range1H-NMR (CDCl3) δ (ppm): to 1.45 (9H, s)of 7.48 (1H, DD, J=4,8, 8.0 Hz), charged 8.52 (1H, DD, J=2.0 a, 7,6 Hz), 8,97 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 4] Synthesis of N-(3-acetylpyridine-2-yl)-2,2-dimethylpropanamide

To a mixture of 2-tert-butyl-4H-pyrido[2,3-d][1,3]oxazin-4-she (10.2 g, 50 mmol) and tetrahydrofuran (50 ml) was added dropwise at -78°C methylanisole (0,97M solution in tetrahydrofuran, 100 ml, 97 mmol) and after the addition was stirred at -78°C for 30 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride and ice water, extracted with ethyl acetate and the organic layer was washed with an aqueous solution of ammonium chloride. The solvent is evaporated under reduced pressure and the precipitated solid was filtered, obtaining the target compound (9.1 g).

Range1H-NMR (CDCl3) δ (ppm): of 1.33 (9H, s)of 2.64 (3H, s), 7,10 (1H, DD, J=4,8, 8.0 Hz), 8,17 (1H, DD, J=2.0 a, 7,6 Hz)8,64 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 3] Synthesis of 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate

To a mixture of N-(3-acetylpyridine-2-yl)-2,2-dimethylpropanamide (8,08 grams of 36.7 mmol), diethyloxalate (10.0 ml, 73.4 mmol) and ethanol (36 ml) was added tert-piperonyl potassium (8,23 g, 73.4 mmol) at -25°C and was stirred at -25°C for one hour. To the reaction mixture were added water (72 ml)was stirred at room temperature, was added toluene (36 ml), separated and the resulting aqueous layer was then washed with toluene (36 ml). To the solution was added 5N. hydrochloric acid (14 ml) and hydroxylamine hydrochloride (5.10 g, 73.4 mmol) and displaced ivali at room temperature for 30 minutes. To the reaction mixture was added 5N. an aqueous solution of sodium hydroxide (14 ml), was extracted with toluene, the solvent is evaporated under reduced pressure. To the obtained residue were added ethanol (35 ml) and triethylamine (5 ml), was stirred at a temperature of from 80°C to 85°C for six hours. To the reaction mixture were added n-heptane (105 ml) and the precipitated solid was filtered, obtaining the target compound (6,90 g).

Range1H-NMR (DMSO-d6) δ (ppm): 1,19 (9H, s)of 1.32 (3H, t), 4,37 (4H, square), 7,12 (1H, s), 7,46 (1H, DD, J=4,8, 8.0 Hz), of 8.25 (1H, DD, J=2,0, 8.0 Hz), 8,58 (1H, DD, J=2.0 a, 4,8 Hz), there is a 10.03 (1H, s).

[Example 4] Synthesis of N-{3-[3-(hydroxymethyl)isoxazol-5-yl]pyridine-2-yl}-2,2-dimethylpropanamide

To a mixture of 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate (111 g, 350 mmol), ethanol (110 ml) and tetrahydrofuran (350 ml) at room temperature was added sodium borohydride (13,2 g, 350 mmol) and stirred at room temperature for 6 hours. To the reaction mixture were added water (350 ml) and 5N. hydrochloric acid (90 ml) and stirred at room temperature for 30 minutes, was added 5N. an aqueous solution of sodium hydroxide (110 ml), the solution was extracted with a mixture of ethyl acetate and tetrahydrofuran and the organic layer was washed with water and saturated aqueous sodium chloride. The solvent is evaporated under reduced pressure,obtaining the target compound (83,8 g) as a solid yellow color, partially contaminated [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanol.

Range1H-NMR (DMSO-d6) δ (ppm): 1,20 (9H, s)to 4.52 (2H, d, J=6.0 Hz), of 5.53 (1H, t, J=6.0 Hz), 6,70 (1H, s), 7,44 (1H, DD, J=4,8, 8.0 Hz), 8,19 (1H, DD, J=5,6, and 7.6 Hz), 8,53 (1H, DD, J=2.0 a, 4,8 Hz), of 9.89 (1H, users).

[Example 5] Synthesis of [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanol

To a mixture of N-{3-[3-(hydroxymethyl)isoxazol-5-yl]pyridine-2-yl}-2,2-dimethylpropanamide (82.8 g)obtained in example 4, and methanol (350 ml) at room temperature was added 5N. an aqueous solution of sodium hydroxide (350 ml) and stirred at a temperature of from 57 to 60°C for 14 hours. To the reaction mixture was added acetic acid (100 ml) and the precipitated solid was filtered, obtaining the target compound (42.2 g) as a solid grayish-white color.

Range1H-NMR (DMSO-d6) δ (ppm): of 4.54 (2H, s), to 5.57 (1H, users), and 6.25 (2H, users), of 6.71 (1H, DD, J=4,8, 8.0 Hz), 6.90 to (1H, s), of 7.90 (1H, DD, J=1,6 and 7.6 Hz), of 8.09 (1H, DD, J=1,6, 4,8 Hz).

Example of getting 5 and examples 6 and 7 are other synthesis methods, alternative examples of the preparation 2-4 and 3-5.

[Example of getting 5] Synthesis of N-(3-acetylpyridine-2-yl)-2,2-dimethylpropanamide

After 1-(2-aminopyridine-3-yl)alanon (40,0 kg, 294 mol) was added to the reactor at 1500 l and washed with toluene (approximately 15 kg). Then, after adding Colorado total toluene 347 kg, added pivaloate (53,1 kg, 1.5 M/M). The triethylamine (23,8 kg, 0.8 M/M) was added dropwise at an internal temperature of 30°C or below and the solution was stirred at an internal temperature of from 20 to 30°C for one hour or more. After triethylamine (23,8 kg, 0.8 M/M) was again added dropwise at an internal temperature of 30°C or less, the solution was stirred at an internal temperature of from 20 to 30°C for two hours or more and HPLC confirmed the completion of reaction.

When cooled saline water (100 l) was added dropwise at an internal temperature of 30°C or less, then 35%hydrochloric acid (49,0 kg 1,6 M/M) was added dropwise at an internal temperature of 30°C or less. After the reaction solution was stirred for five minutes, the solution was left for 15 minutes or more and the bottom layer (a) was separated in a polymeric container. After adding water (100 l) and mixing the solution for five minutes the solution was left for 15 minutes or more. After separation of the lower layer (c) in the polymer container and removal of the upper layer (d) bottom layer (a) and bottom layer (c) was returned to the reactor at 1500 HP When cooled salt solution was added ethyl acetate (289 kg), then after 48,7% aqueous sodium hydroxide solution (43,4 kg, 1.8 M/M) was added dropwise at an internal temperature of 30°C or less and the solution premesis is whether within five minutes, using a paper test UNIV confirmed that the lower layer has a pH of 8 to 9. After settling for 15 minutes or more bottom layer (e) and the top layer (f) was separated and the bottom layer (e) was returned to the reactor at 1500 HP After adding ethyl acetate (144 kg) and mixing the solution for five minutes the solution was left for 15 minutes or more and the bottom layer (g) and upper layer (h), each separated. Then the bottom layer (g) was returned to the reactor at 1500 l, was added ethyl acetate (144 kg) and the solution was stirred for five minutes, after which the solution was left for 15 minutes or more. After removal of the lower layer (i) top layer (f) and upper layer (h) returned to the reactor at 1500 l and washed with ethyl acetate (approximately 15 kg).

The organic layer was returned to the reactor at 1500 l, concentrated under reduced pressure (hot water 50°C) and the concentration was stopped at the time when the concentrate reached a volume of approximately 200 L. the Concentrate was removed in containers SUS and the inside of the reactor was rinsed with toluene (17 kg). Approximately half the number of remote concentrate was placed in the reactor at 300 l and washed with toluene (9 kg). The concentrate was then concentrated under reduced pressure (hot water 50°C), and when the amount of the distillate from the condenser is decreased, the remaining concentrate was placed in the reactor at 300 l and washed with toluene (9kg). Re-ran the concentration under reduced pressure (hot water from 50°C to 70°C). At a time when there was almost no distillate began cooling water and toluene (52 kg) was added at an internal temperature of 50°C or less. Re-ran the concentration under reduced pressure (hot water from 50°C to 80°C). The concentration was stopped at the time when the distillation was no longer observed at an external temperature of 80°C and the level of reduced pressure -0,090 MPa or more, and ethanol (61 kg) was added at an internal temperature of from 20 to 30°C.

In nitrogen atmosphere ethanol solution from the reactor was removed to the capacity of the SUS and the reactor was rinsed with ethanol (13 kg). After that remote solution was added to the reactor at 1500 l, washed with ethanol (13 kg), receiving ethanol solution of the target compound (containing 69,4 kg target compounds; output: 107,3%).

The HPLC conditions: column: YMC-Pack Pro C18 (5 μm, 150×4.6 mm inner diameter, YMC), mobile phase: acetonitrile/water/ammonium acetate = 300/700/1-900/100/1 (about./about./weight.).

[Example 6] Synthesis of 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate

In a stream of gaseous nitrogen diethyloxalate (64.4 kg, 1.5 M/M) was added to the ethanol solution of N-(3-acetylpyridine-2-yl)-2,2-dimethylpropanamide (294 mol, provided that the output of the previous stage was 100%) in R is the actor 1500 HP Began circulating salt solution and pre-cooled ethanol solution of 22% tert-butoxide potassium (212,5 kg 1,45 M/M) was added dropwise at an internal temperature of 10°C or less. After stirring at an internal temperature of -5 to 10°C for 30 minutes or more complete reaction was confirmed by HPLC.

Then hydroxylamine hydrochloride (40.8 kg, 2.0 M/M) was added at an internal temperature of 10°C or less and the solution was stirred at an internal temperature of 10°C or less within one hour or more. Then prepared in advance and chilled aqueous solution of ethanol (ethanol (15.3 kg)/water (5.2 kg)) was added dropwise at an internal temperature of 20°C or less, watching heating, and water (582 l) was added dropwise at an internal temperature of 30°C or less. Switching on the circulation of hot water (28°C), 4-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}-2-(hydroxyimino)-4-ethyloctanoic (approximately 10 g) was added at an internal temperature of from 20 to 30°C. After visual confirmation of the deposition of solids suspension was stirred overnight at an internal temperature of from 15 to 25°C. After confirming the completion of the reaction by HPLC aqueous solution of 48.7% sodium hydroxide was added dropwise at internal temperatures of from 10 to 25°C while the pH of the solution was not from 6.50 to 7.00 (using 18,1 kg). After re is eshiwani when the internal temperature of 10 to 20°C for three hours or more, the separation of the solid and liquid phases was carried out six times by centrifugation. At each centrifugation after washing the precipitate with an aqueous solution of ethanol (ethanol (2.4 kg)/water (12 kg), obtained in advance, the precipitate was washed with water until the washings do not become colorless and transparent (approximately 200 l). After separation by centrifugation was continued for 30 minutes or more and the wet solid was removed in polymer package. Then in the dryer at a temperature of from 45°to 50 ° C by circulating hot water wet solid was dried under reduced pressure, obtaining a solid substance (71,52 kg).

Then the solid obtained above (71,45 kg)was added to the reactor at 1500 l and washed with ethanol (about 7 kg). The ethanol is then added to the total number of 226 kg was added triethylamine (21,6 kg, 1 M/M). Started circulation of hot water (75°C), the solution was stirred at an internal temperature of 70 to 75°C for 14-16 hours and by HPLC confirmed the completion of reaction. Then n-heptane (488,7 kg) was added dropwise at internal temperatures of from 55 to 75°C. Then 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate (approximately 5 g) was added at an internal temperature of 50 to 53°C and visually confirmed that the solid was deposited at an internal temperature of 45 to 50°C. Then the temperature of the hot water was gradually lowered until the internal temperature of 15°C or less,when cooled brine or cold water solution was stirred overnight at an internal temperature of 0 ° to 10°C. Using the filter device, the suspension was filtered and washed with a mixed solution of n-heptane/ethanol (n-heptane (70 kg)/ethanol (10 kg)), then n-heptane (80 kg). After drying in nitrogen for 15 minutes or more wet solid was removed to the container SUS. In the dryer at a temperature of from 45°to 50 ° C by circulating hot water wet solid was dried under reduced pressure, obtaining the target compound (54,55 kg; output: 58,6%).

Range1H-NMR (DMSO-d6) δ (ppm): 1,19 (9H, s)of 1.32 (3H, t), 4,37 (4H, square), 7,12 (1H, s), 7,46 (1H, DD, J=4,8, 8.0 Hz), of 8.25 (1H, DD, J=2,0, 8.0 Hz), 8,58 (1H, DD, J=2.0 a, 4,8 Hz), there is a 10.03 (1H, s).

The HPLC conditions: column: YMC-Pack Pro C18 (5 μm, 150×4.6 mm inner diameter, YMC), mobile phase: acetonitrile/water/ammonium acetate = 300/700/1-900/100/1 (about./about./weight.).

[Example 7] Synthesis of [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanol

In the current of nitrogen gas 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate (54,5 kg, 172 mol) was added to the reactor at 1500 l and washed with methanol (4.9 kg). Then added methanol to the total quantity of methanol 108 kg and triethylamine (8,7 kg 0,5 M/M). Then began the circulation of hot water (60°C), the solution was stirred at an internal temperature of 50 to 60°C for two hours or more and the completion of reaction was confirmed by HPLC (Condition 1).

Then began a cooling gap is giving water and tetrahydrofuran (121 kg) was added at an internal temperature of 30°C or less. Then when cooled saline solution in a stream of gaseous nitrogen at an internal temperature of 0 ° to 10°C sodium borohydride (7,15 kg 1,1 M/M) was added for 5 hours or more. After adding sodium borohydride circulation in the jacket was switched to cold water (4.0°C) and the solution was stirred overnight at an internal temperature of 0 ° to 10°C. the next day, when the internal temperature of 0 ° to 10°C sodium borohydride (1,30 kg 0,2 M/M) was added during one hour or more. Circulation in the jacket was switched to cold water, the internal temperature was raised to a temperature of from 20 to 30°C for three hours or more, and further stirring was carried out overnight at an internal temperature of from 20 to 30°C. the next day, the development of the reaction was checked by HPLC, and since the reaction is almost not evolved, the solution was cooled again and sodium borohydride (1,30 kg 0,2 M/M) was added at an internal temperature of 0 ° to 10°C. After stirring at an internal temperature of 0 ° to 10°C for one hour or more circulation the shirt was switched to cold water and heated until the internal temperature between 15 and 25°C for two hours or more. After stirring for one hour or more complete reaction was confirmed by HPLC (Conditions 1) and the solution was stirred over night.

The next day, after adding water what about the solution of 48.7% sodium hydroxide (71 kg, 5 M/M) dropwise at an internal temperature of 50°C or less, water (133 l) was added dropwise at an internal temperature of 50°C or less. Started circulation of hot water (50 to 80°C), after stirring at an internal temperature of 50 to 60°C for 20 hours or more, completion of the reaction was confirmed by HPLC (Condition 2).

Then, upon cooling, water was added dropwise water (73 l). After switching on the cooling with cold water (15°C), add [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanol when the internal temperature between 15 and 30°C and confirm the deposition of solids was added dropwise water (218 l), then, when cooled salt solution, 35%hydrochloric acid (115 kg) was added dropwise at an internal temperature of from 15 to 30°C and washed with water (3 l). After stirring at an internal temperature between 15 and 30°C for five minutes or more using the pH-meter was confirmed that the pH of the reaction solution was from 4.00 to 5.00, and the solution was stirred at an internal temperature between 15 and 30°C for one hour or more. Then an aqueous solution of 48.7% sodium hydroxide (17,1 kg) was added dropwise until the pH of the solution was not from 7.00 to 8.00, and the solution was left to stand over night. The next day, after the start of mixing and low pressure and confirm distillation from the condenser, began circulation of hot in the s (40°C). Concentration was carried out for one hour or more in terms of hot water (from 35 to 45°C), low pressure 68 cm Hg or more and 30°C or higher internal temperature. Negative pressure was released in a stream of nitrogen and particulate matter attached to the wall of the reactor, thoroughly washed with water (approximately 20 liters). The solution was stirred at an internal temperature between 15 and 30°C for three hours or more and left to stand over night. The next day, the internal temperature was confirmed as being within the range from 15 to 25°C, the solid and liquid phase of the suspension was divided using two centrifugation. At each centrifugation, the solid is washed with water (approximately 200 l), after drainage separation by centrifugation was carried out for one hour and then the wet solid was removed in polymer package. Then in the dryer at a temperature of from 45°to 50 ° C by circulation of hot water, the solid was dried under reduced pressure, obtaining the target compound (26,57 kg, yield: 80.9 per cent).

Range1H-NMR (DMSO-d6) δ (ppm): of 4.54 (2H, s), to 5.57 (1H, users), and 6.25 (2H, users), of 6.71 (1H, DD, J=4,8, 8.0 Hz), 6.90 to (1H, s), of 7.90 (1H, DD, J=1,6 and 7.6 Hz), of 8.09 (1H, DD, J=1,6, 4,8 Hz).

Conditions for HPLC 1: column: YMC-Pack Pro C18 (5 μm, 150×4.6 mm inner diameter, YMC), mobile phase: acetonitrile/water is/ammonium acetate = 300/700/1-900/100/1 (about./about./weight.).

Conditions for HPLC 2: column: YMC-Pack ODS-AQ (5 μm, 150×4.6 mm inner diameter, YMC), mobile phase: acetonitrile/water/85%phosphoric acid/1-octanesulfonate sodium = 161,3/838,7/1/1,1 to 900/100/1/1,1 (vol./about./about./weight.).

Examples get 8-9 are other synthesis methods, alternative example 5.

[Example 8] Synthesis of [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanococcales

To a mixture of 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate (3,17 g, 10 mmol), ethanol (3 ml) and tetrahydrofuran (10 ml) at room temperature was added sodium borohydride (0,38 g, 10 mmol) and stirred overnight while cooling with ice to room temperature. The reaction mixture was divided into five aliquot, one of which was added to 5N. aqueous solution of sodium hydroxide (2 ml) and stirred overnight at 55°C. To the reaction mixture was added ice water, extracted with a mixture of simple methyl tert-butyl ether and tetrahydrofuran and the organic layer was added oxalic acid (0.18 g, 2 mmol). The precipitated solid was filtered, obtaining the target compound (0.39 g) as a solid white color.

Range1H-NMR (DMSO-d6) δ (ppm): of 4.54 (2H, s), of 6.31 (2H, users), 6,72 (1H, DD, J=4,8, 8.0 Hz), 6.89 in (1H, s), of 7.90 (1H, DD, J=2,0, 8.0 Hz), of 8.09 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 9] Synthesis of [5-(2-aminopyridine-3-yl)isoxazol-3-yl]IU is anola

To a mixture of [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanococcales (0.39 g) and water (2 ml) at room temperature was added 5 N. aqueous sodium hydroxide solution (0.5 ml) and the precipitated solid was filtered, obtaining the target compound (0.18 g) as a solid white color.

Range1H-NMR (DMSO-d6) δ (ppm): of 4.54 (2H, s), to 5.57 (1H, users), and 6.25 (2H, users), of 6.71 (1H, DD, J=4,8, 8.0 Hz), 6.90 to (1H, s), of 7.90 (1H, DD, J=1,6 and 7.6 Hz), of 8.09 (1H, DD, J=1,6, 4,8 Hz).

[Example 10] Synthesis of 3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-amine

To a mixture of [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanol (0,19 g, 1 mmol) and N,N-dimethylacetamide (1 ml) under ice cooling was added a mixture of thionyl chloride (0.15 ml, 2 mmol), benzotriazole (0.26 g, 2.2 mmol) and tetrahydrofuran (1 ml) and stirred at room temperature for 30 minutes. To the reaction mixture were added water and 5 N. aqueous sodium hydroxide solution to achieve a basic pH, then was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent is evaporated under reduced pressure, obtaining the target compound (0.21 g) as a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 4,84 (2H, s), of 6.31 (2H, users), 6,72 (1H, DD, J=4,8, 8.0 Hz),? 7.04 baby mortality (1H, s), to $ 7.91 (1H, DD, J=1,6 and 7.6 Hz), 8,11 (1H, DD, J=1,2, 4,8 Hz).

[The use of the 11] Synthesis of {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate

To a mixture of 3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-amine (420 mg, a 2.01 mmol), 4-dimethylaminopyridine (to 26.8 mg, 0,220 mmol) and tetrahydrofuran (2.1 ml) at room temperature was added di-tert-BUTYLCARBAMATE (924 mg, 4,24 mmol) and the mixture was stirred. After 25 hours to the reaction solution was added water and was extracted with toluene, and then the organic layer was washed with 5%aqueous solution of sodium chloride and the solvent evaporated under reduced pressure, obtaining the target compound (880 mg) in the form of oil product is a pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,33 (N, C), 4,63 (2H, s), of 6.66 (1H, s), 7,45 (1H, DD, J=4,8, 8.0 Hz), 8,30 (1H, DD, J=2,0, 8.0 Hz), to 8.62 (1H, DD, J=2.0 a, 4,8 Hz).

Examples 12-15 are other synthesis methods, alternative examples examples 4-5 and 10-11.

[Example 12] Synthesis of {3-[3-(hydroxymethyl)isoxazol-5-yl]pyridine-2-yl}tert-BUTYLCARBAMATE

To a mixture of 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate (1,59 g, 5 mmol), di-tert-BUTYLCARBAMATE (1.31 g, 6 mmol) and tetrahydrofuran (5 ml) at room temperature was added 4-dimethylaminopyridine (61 mg, 0.5 mmol) and stirred at room temperature for one hour, and then stirred at 60°C for six hours. To the reaction mixture were added ethanol (2.5 ml) and sodium borohydride (,57 g, 15 mmol)and the mixture was stirred at 0°C for 30 minutes, and then stirred over night at room temperature. To the reaction mixture was added ice water, extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate and filtering, the solvent is evaporated under reduced pressure, obtaining the target compound (1.60 g).

Range1H-NMR (CDCl3) δ (ppm): to 1.47 (9H, s), a 4.83 (2H, s), 6,63 (1H, s), 7,17 (1H, DD, J=4,8, 8.0 Hz), 7,58 (1H, s), of 7.97 (1H, DD, J=2,0, 8.0 Hz), 8,51 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 13] Synthesis of {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}tert-BUTYLCARBAMATE

In the atmosphere of nitrogen benzotriazol (3.55 g, 29.5 mmol) was dissolved in N,N-dimethylacetamide (10 ml) and thionyl chloride (2.06 to ml, 26.8 mmol) was added dropwise while cooling the mixture in ice-water, obtaining a solution of thionyl chloride-benzotriazol (1:1,1) in N,N-dimethylacetamide.

In nitrogen atmosphere {3-[3-(hydroxymethyl)isoxazol-5-yl]pyridine-2-yl}tert-BUTYLCARBAMATE (781 mg, 2.68 mmol) was dissolved in N,N-dimethylacetamide (2.7 ml). To the solution dropwise while cooling the mixture in ice-water was added to this solution thionyl chloride-benzotriazol (1:1,1) in N,N-dimethylacetamide (6 ml, 14.4 mmol) and was stirred at the same temperature for one hour and then stirred at room temperature. After the underwater hours and 20 minutes while cooling the mixture in ice-water was added dropwise a solution of thionyl chloride-benzotriazol (1:1,1) in N,N-dimethylacetamide (2.2 ml, 5,12 mmol) and the solution was stirred at room temperature for one hour. Upon cooling, a mixture of ice-water to the reaction solution was added 1N. an aqueous solution of sodium hydroxide and simple tert-butyl methyl ether to alkaline reaction and then was extracted. The organic layer was washed successively 0,5h. aqueous sodium hydroxide solution and 5%aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure to give crude target compound (953 mg) in the form of oil product is a pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): to 1.47 (9H, s)and 4.65 (2H, s), to 6.67 (1H, s), 7,20 (1H, DD, J=4,8, 8.0 Hz), 7,44 (1H, users), 8,01 (1H, DD, J=2,0, 8.0 Hz), charged 8.52 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 14] Synthesis of {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate

The crude substance {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}tert-BUTYLCARBAMATE (1.13 g, 3,17 mmol) was dissolved in tetrahydrofuran (7.0 ml)was added while cooling the mixture in ice-water di-tert-BUTYLCARBAMATE (761 mg, 3,49 mmol) and washed with THF (3.0 ml). Then, after adding 4-dimethylaminopyridine (39,1 mg, MX 0.317 mmol), the solution was stirred at room temperature. After five hours of stirring while cooling the mixture in ice-water to the reaction solution were added ethyl acetate and 5%wagnerstr of sodium chloride and was extracted. The organic layer was washed with 5%aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent is evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel, obtaining the target compound (1,14 g) as a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,33 (N, C), 4,63 (2H, s), of 6.66 (1H, s), 7,45 (1H, DD, J=4,8, 8.0 Hz), 8,30 (1H, DD, J=2,0, 8.0 Hz), to 8.62 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 15] Synthesis of {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate

In the current of nitrogen gas [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanol (26,00 kg, 136,0 mol) and 1,3-dimethyl-2-imidazolidinone (143 kg, 5.5 weight./weight., the part left for thorough washing) was added into the reactor 1 in 500 l and started mixing. The solution was stirred at an internal temperature of from 35 to 45°C for one hour or more, and cooled after dissolution [5-(2-aminopyridine-3-yl)isoxazol-3-yl]methanol. When the internal temperature between 5 and 25°C was added dropwise thionyl chloride (19,40 kg, to 163.1 mol, 1.2 M/M). When you are finished adding thionyl chloride was carefully stored away portion of 1,3-dimethyl-2-imidazolidinone, the solution was stirred at an internal temperature of 5 to 25°C within 12 hours or more. After completion of the reaction was confirmed by analysis of the m HPLC, an aqueous solution of 36%sodium hydroxide solution (mixed solution between the aqueous solution of 48%sodium hydroxide (15.9 kg; 190,8 mol, 1.4 M/M sodium hydroxide) and water (5.3 kg, 0.2 weight./weight.)) was added dropwise at internal temperatures of from 0 to 25°C and then ethyl acetate (164 kg of 6.31 weight./weight.) and water (74,2 kg 2,85 weight./weight.) was added dropwise at an internal temperature of from 15 to 35°C. in Addition, after adding dropwise an aqueous solution of approximately 8%aqueous sodium hydroxide solution (mixed solution between the solution of 48%sodium hydroxide (13.6 kg; 163,2 mol, 1,20 M/M sodium hydroxide) and water (68,0 kg, 2.6 weight./weight.)) when the internal temperature of 0 to 25°C and bring the internal temperature to a temperature of from 15 to 30°C the solution was stirred at the same temperature range for 30 minutes or more and was left for 30 minutes or more. The bottom layer and the top layer was removed separately and 1/2 the weight of each was added to the reactor 1 in 500 l reactor 2 to 500 liters

Subsequent processing of the reactor 1 in 500 l was carried out as described below. After the start of mixing and adding water (52 kg, 2 wt./weight.) an aqueous solution of approximately 8%aqueous sodium hydroxide solution (mixed solution between the aqueous solution of 48%sodium hydroxide (11.3 kg; 135,6 mol, 1,0 M/M sodium hydroxide) and water (56,5 kg, 2,17 weight./weight.)) was gradually added dropwise at the internal temperature of 0 to 25°C in order to bring the pH of the lower layer from 7.00 to 8.50 (actual value: pH 7,84). At this time, used 35,55 kg of an aqueous solution of approximately 8%sodium hydroxide. Then, after the establishment of the internal temperature between 15 and 30°C and stirring the solution for 30 minutes or more, the solution was left to stand over night. The next day, once again was confirmed to 7.59 pH, the top layer and bottom layer, respectively, separated, only the bottom layer was returned to the reactor 1 in 500 l and then added ethyl acetate (82 kg 3,15 weight./weight.). After stirring at an internal temperature of from 15 to 30°C within five minutes the solution was left for 30 minutes or more and the bottom layer (pH of 7.55) was separated. To the upper layer, which was left in the reactor, was added to the separated upper layer and 5%aqueous sodium chloride solution (mixed solution between sodium chloride (3.3 kg, 0.13 wt./weight.) and water (618 kg of 2.38 wt./weight.)) and stirred at an internal temperature between 15 and 30°C for five minutes, then left for 30 minutes or more and the bottom layer (pH 8,23) was separated. In addition, there was added water (65 kg, 2.5 wt./weight), the solution was stirred at an internal temperature between 15 and 30°C for five minutes and then left to stand overnight, and the bottom layer (pH? 7.04 baby mortality was separated.

Subsequent processing of reactor 2 to 500 l was performed concurrently with operations to reactor 1 in 500 l, carrying out the same procedure. Then the top layer of the reactor 2 n is 500 l was transferred into the reactor 1 in 500 l and the solution was concentrated under reduced pressure while circulating hot water (45 to 55°C) and the level of reduced pressure from -0,070 to -0,085 MPa to obtain a solution volume of approximately 200 HP was Added ethyl acetate (141 kg, 5,42 weight./weight.) and the solution was concentrated again under reduced pressure in the same conditions. After an additional two-fold repetition of this operation, before and after the 4th add ethyl acetate (141 kg, 5,42 weight./weight), the content of 3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-amine in the solution was checked by HPLC analysis and was calculated content of 3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-amine (23,35 kg, byr111.4 mol) in solution and output (81,9%). Then again was carried out by concentration under reduced pressure in the same conditions, as the content of 3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-amine was not from 10.0 to 13.0%, obtaining a solution of 3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-amine in ethyl acetate.

In a stream of gaseous nitrogen a solution of 3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-amine in ethyl acetate (containing the total number obtained in the previous phase, 23,35 kg (byr111.4 mol) was stirred in the reactor 1 in 500 l, di-tert-BUTYLCARBAMATE (53.47 USD kg, 245,0 mol, 2,2 M/M) was added at an internal temperature of from 15 to 25°C and washed with ethyl acetate (2 kg). Solution was added 4-dimethylaminopyridine in ethyl acetate (mixed solution of 4-dimethylaminopyridine (0,409 kg, 3.35 mol, of 0.03 M/M) and ethyl acetate (8 kg), obtained in advance, and after washing with ethyl acetate (1 kg) and the solution was stirred at an internal temperature of 10 to 30°C for 22 hours or more. Pokepower completion of the reaction by HPLC analysis) was added 1,3-dimethyl-2-imidazolidinone (50 kg, 2,12 weight./weight.). The solution was concentrated under reduced pressure while circulating hot water (45 to 55°C), when the level of reduced pressure to -0,092 MPa or more and the weakening of the liquid distillation and after confirmation by GC analysis that the content of ethyl acetate was 7.0%, the reactor was cooled to an internal temperature of 30°C or less and the solution was left to stand over night. The next day, to the residue concentration was added methanol (111 kg, 4,74 weight./weight), was stirred for 10 minutes or more and confirmed the absence of sedimentation of solids, and the solution was divided into two factions. Then the solutions are divided into two factions were added respectively in reactors 1 and 2 at 500 l each) and, accordingly, washed with methanol (9 kg each, 0.4 wt./weight. each). Thus, as a result of HPLC analysis of the solution before the separation of the two fractions (225,65 kg), the content of the target {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate was 19,37%, and the mass contained {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate was 43,71 kg (106,6 mol, yield: 95.7 per cent).

For reactor 1 in 500 l of the processing carried out as described below. After stirring was started when the internal temperature from 35 to 45°C, for 30 minutes or more was added dropwise water (35 kg, 1.5 weight./weight.) and {3-[3-(chloromethyl)isoxazol-5-yl]what iridin-2-yl}di-tert-butylimidazole (0,010 kg) was added at an internal temperature of 35 to 40°C. After stirring at an internal temperature of 35 to 40°C for 30 minutes or more checked the deposition of solids and the solution was further stirred at the same temperature range for one hour or more. Then, after water (three times 35 kg, 1.5 weight./weight. each) was added dropwise for 30 minutes or more when the internal temperature from 35 to 45°C, the reactor was cooled to an internal temperature of 5 to 15°C for 3 hours or more and the solution was stirred at the same temperature range for 12 hours or more. Separation of solid and liquid phases was performed using two centrifugation and the precipitate was washed with an aqueous solution of methanol (a mixed solution of methanol (every 7 kg, 0.3 wt./weight.) and water (each time 27 kg 1,14 weight./weight)). After flushing is complete separation by centrifugation was carried out for 30 minutes or more, obtaining the target compound (25,80 kg) in the form of wet solids. This wet solid was loaded into the drying mixer vacuum type, and dried under vacuum at ambient temperature from 45 to 55°C for 24 hours or more, obtaining the target compound (21,09 kg) in the form of a solid pale yellow color.

The operation for reactor 2 500 l was carried out simultaneously with the specified, performing the same operations, and receiving the target connection (21,22 the g) as a solid pale yellow color.

Accordingly, the received target connection (42,31 kg, yield: 92.7%of).

Range1H-NMR (CDCl3) δ (ppm): 1,33 (N, C), 4,63 (2H, s), of 6.66 (1H, s), 7,45 (1H, DD, J=4,8, 8.0 Hz), 8,30 (1H, DD, J=2,0, 8.0 Hz), to 8.62 (1H, DD, J=2.0 a, 4,8 Hz).

The HPLC conditions: column: YMC-Pack Pro C18 (5 μm, 150×4.6 mm inner diameter, YMC), mobile phase: acetonitrile/water/ammonium acetate = 300/700/1-900/100/1 (about./about./weight.).

The conditions of the gas chromatography (GC): column: DB-624 (30 m, 0.53 mm internal diameter, Film 3 μm, Agilent).

[Example of obtaining 6] 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate

To a mixture of tert-butyl methyl ether 4-methylene-2-oxo-4H-pyrido[2,3-d][1,3]oxazin-1-carboxylic acid (2,71 g, 10,37 mmol)which was synthesized according to the methods described in international publication WO08/136279, Description, Example get 3-3-1, triethylamine (of 4.2 ml, 30 mmol) and tetrahydrofuran (30 ml) at 0°C for two hours was added 2-chloro-2-(hydroxyimino)in ethyl acetate (4.5 g, 30 mmol) and then stirred at room temperature for 14 hours. To the reaction mixture was added ice water, extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride. After drying over magnesium sulfate and filtering, the solvent is evaporated under reduced pressure. The residue is suspended and washed with 1:1 mixture of n-hexane and utilize the ATA, receiving the target compound (1.56 g).

Range1H-NMR (CDCl3) δ (ppm): the 1.44 (3H, t, J=6,8 Hz)of 1.46 (9H, s), 4,47 (4H, square, J=7,2 Hz), to 6.95 (1H, s), 7,22 (1H, DD, J=4,8, 8.0 Hz), 7,42 (1H, users), with 8.05 (1H, DD, J=2,0, 8.0 Hz), charged 8.52 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 16] 5-{2-[bis(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate

To a mixture of ethyl 5-{2-[(2,2-dimethylpropanoyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate (1,46 g of 4.38 mmol), di-tert-BUTYLCARBAMATE (1,46 g, 6,69 mmol) and tetrahydrofuran (25 ml) at room temperature was added 4-dimethylaminopyridine (30 mg, 0.25 mmol) and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added ice water, extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride. After drying over magnesium sulfate and filtering, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate = 3:1, then 1:1), obtaining the target compound (1,96 g).

Range1H-NMR (CDCl3) δ (ppm): 1,36 (N, C)of 1.46 (3H, t, J=6.8 Hz), 4,47 (4H, square, J=6,8 Hz), 6,93 (1H, s), 7,46 (1H, DD, J=4,8 and 7.6 Hz), 8,29 (1H, d, J=7,6 Hz)8,64 (1H, d, J=4,8 Hz).

[Example 17] {3-[3-(hydroxymethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylimidazolium

To a mixture of 5-{2-[bis(2,2-dimethylpropyl dicarbonyl)amino]pyridine-3-yl}isoxazol-3-ethylcarboxylate (1.73 g, 4 mmol), ethanol (5 ml) and tetrahydrofuran (5 ml) at 0°C was added sodium borohydride (0.15 g, 4 mmol) and the mixture was stirred at room temperature for one hour. Then was added sodium borohydride (0.15 g, 4 mmol) and the solution was stirred at room temperature for three hours. To the reaction mixture was added ice water, extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate and filtering, the solvent is evaporated under reduced pressure. To the residue was added a mixture of n-hexane-ethyl acetate (1:1), suspended and stirred, and then filtered, obtaining the target compound (1,02 g).

Range1H-NMR (CDCl3) δ (ppm): 1,33 (N, (C), to 4.81 (2H, s), 6,60 (1H, s), the 7.43 (1H, DD, J=4,8, 8.0 Hz), of 8.27 (1H, DD, J=2,0, 8.0 Hz), at 8.60 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 18] {3-[3-(methyl bromide)isoxazol-5-yl]pyridine-2-yl}di-tert-butylimidazolium

To a mixture of {3-[3-(hydroxymethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate (0,78 g, 2 mmol), triethylamine (of 1.95 ml, 14 mmol) and 1,2-dimethoxyethane (10 ml) dropwise at 0°C was added tribromide phosphorus (from 0.37 ml, 4 mmol)and the mixture was stirred at room temperature for two hours, and then stirred at 50°C for 30 minutes. The reaction mixture was cooled to 0°C, then added in the near and were extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous magnesium sulfate and filtering, the solvent is evaporated under reduced pressure, the residue was purified by chromatography on a column of silica gel, obtaining the target compound (0.14 g).

Range1H-NMR (CDCl3) δ (ppm): 1,33 (N, (C), of 4.45 (2H, s), 6,63 (1H, s), the 7.43 (1H, DD, J=4,8, 8.0 Hz), of 8.28 (1H, DD, J=2,0, 8.0 Hz), 8,61 (1H, DD, J=2.0 a, 4,8 Hz).

[Example 19] (5-{2-[bis(tert-butoxycarbonyl)amino]pyridine-3-yl}isoxazol-3-yl)methyl-4-methylbenzenesulfonate

A mixture of {3-[3-(hydroxymethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmalonate (0,170 g, 0,434 mmol), triethylamine (91 μl, 0,651 mmol), 4-dimethylaminopyridine (5 mg, 0,043 mmol),p-toluensulfonate (0.104 g g 0,543 mmol) and tetrahydrofuran (10 ml) was stirred at room temperature. After 15 hours was added triethylamine (40 μl, 0,287 mmol) and 50 mg (0,262 mmol) p-toluensulfonate (50 mg, 0,262 mmol) and stirred at room temperature. After 5 hours and 30 minutes to the reaction mixture was added water and was extracted with ethyl acetate and the organic layer was washed first with water and then saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate and filtering, the solvent is evaporated under reduced pressure, the residue was purified chromatograph is she on a column of silica gel, receiving the target connection (0,151 g) as a white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,33 (N, (C), of 2.45 (3H, s), 5,14 (2H, s), is 6.61 (1H, s), 7,38 (2H, d, J=8.0 Hz), the 7.43 (1H, DD, J=4,8, 8.0 Hz), 7,83 (2H, d, J=8.0 Hz), by 8.22 (1H, DD, J=2,0, 8.0 Hz), 8,61 (1H, DD, J=2.0 a, 4,8 Hz).

[Example of getting 7] Synthesis of 2-[(4-bromobenzyl)oxy]pyridine

To a solution of 4-bromobenzylamine alcohol (18 g, to 94.3 mmol) in dimethyl sulfoxide (85 ml) slowly under nitrogen atmosphere at room temperature was added tert-piperonyl potassium (11,5 g, 99 mmol) and was stirred for 10 minutes. To this solution is added dropwise over 30 minutes while cooling in a water bath was added 2-herperidin (12.3 g, 123 mmol). After stirring at room temperature for two hours was added ethyl acetate and 5%aqueous solution of sodium chloride and was extracted. After sequential washing of the organic layer with water and 5%aqueous solution of sodium chloride, the solvent evaporated under reduced pressure, obtaining the target compound (24.3 g) in the form of oil product yellow color.

Range1H-NMR (CDCl3) δ (ppm): 5,33 (2H, s), 6.87 in-6,70 (1H, m), 6,98-7,02 (1H, m), 7,38-7,44 (2H, m), 7,55-of 7.60 (2H, m), 7,71-7,76 (1H, m), 8,15-8,18 (1H, m).

Example of getting 8 represents another method of synthesis, an alternative example of receipt 7.

[Example of getting 8] Synthesis of 2-[(4-bromobenzyl)oxy]pyridine

In a nitrogen atmosphere to a solution of 4-bromobenzylamine alcohol (600 g, is 3.21 mol) and 2-herperidin (343 g of 3.53 mol) in tetrahydrofuran (1069 ml) dropwise while cooling at a temperature of 7°C was added a solution of tert-butoxide potassium (396 g of 3.53 mol) in tetrahydrofuran (3208 ml) (63 min, from 9.2 to 20.5°C). After stirring at 22°C for three hours was added dropwise (20 min, 21,0 to 23.9°C) aqueous solution of 5%sodium bicarbonate (derived from sodium bicarbonate: 160 g and water: 3208 ml). Then was added heptane (3220 ml) and was extracted, the organic layer was washed with water (800 ml). The organic layer was concentrated under reduced pressure (approximately 3200 ml), was added ethanol (1604 ml) and concentrated under reduced pressure (approximately 3200 ml). Then to this layer was added heptane (3200 ml), concentrated under reduced pressure, then was added heptane (3200 ml) and concentrated under reduced pressure, obtaining the solution of the target compound in heptane (2603 g containing 789 g of the target product) in the form of oil product brown (output: 93,2%).

Range1H-NMR (CDCl3) δ (ppm): 5,33 (2H, s), 6.87 in-6,70 (1H, m), 6,98-7,02 (1H, m), 7,38-7,44 (2H, m), 7,55-of 7.60 (2H, m), 7,71-7,76 (1H, m), 8,15-8,18 (1H, m).

[Example 20] Synthesis of {4-[(pyridine-2-yloxy)methyl]phenyl}Bronevoy acid

Under nitrogen atmosphere a solution of 2-[(4-bromobenzyl)oxy]pyridine (50 g, 190 mmol who) in tetrahydrofuran (200 ml) was cooled to -78°C and 2,6M solution of hexane nutility (88 ml, 228 mmol) was added dropwise. After stirring for 45 minutes trimethoxysilane boron (29,6 g, 285 mmol) was added dropwise at the same temperature. After 30 minutes, a saturated aqueous solution of ammonium chloride and water extinguished and the solution was extracted with ethyl acetate. After the organic layer was washed with a mixture of saturated aqueous ammonium chloride and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. To the residue was added acetonitrile (200 ml), suspending and stirring at 70°C for 30 minutes, then cooled and stirred overnight at 4°C. the Precipitated solid was filtered, obtaining the target compound (11.2 g) as a solid white color.

Range1H-NMR (CDCl3) δ (ppm): to 4.62 (2H, s), 5,42 (2H, s), 6,83 (1H, d, J=8,4 Hz), 6.87 in-6,92 (1H, m)to 7.50 (2H, d, J=8.0 Hz), EUR 7.57 to 7.62 (1H, m), of 7.75 (2H, d, J=8.0 Hz), 8,16-8,19 (1H, m).

[Example 21] Synthesis of 2-{[4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)benzyl]oxy}pyridine

To a solution of 2-[(4-bromobenzyl)oxy]pyridine (789 g, 2,99 mol) in heptane (2603 g) was added heptane (939 ml) and tetrahydrofuran (1199 ml), then slowly cooled in a bath with a mixture of dry ice/ethanol in a nitrogen atmosphere with stirring. After 45 minutes, the cooling was stopped and was added 2-[(4-bromobenzyl)oxy]pyridi is (0.9 g) when the internal temperature of -12°C. Cooling was resumed with a cooling rate of -20°C/hour, About 3 hours later was added dropwise (80 min, -67,0 up to 61.4°C) 1,66M solution of n-utility in hexane (1980 ml, 3,29 mol). After stirring for 0.5 h at the same temperature was added dropwise (134 min, -68,2 to 60.3°C) triisopropoxide (674 g of 3.56 mol). At the same temperature after stirring for 0.5 h the reaction mixture was cooled in a bath with a mixture of water with ice, the solution was stirred over night (external temperature: 0°C). The next day was added dropwise water (5600 ml), the solution was transferred into a separating vessel and were extracted into the aqueous layer (pH: 11,2). Added ethyl acetate (4800 ml) and concentrated hydrochloric acid (approximately 280 ml) was added dropwise (internal temperature of 20°C or below) under stirring, podkisst solution to a pH of 7.1. The organic layer was separated and washed with 5%aqueous solution of sodium chloride (about 900 g) and then concentrated under reduced pressure. To the residue was added isopropyl alcohol (3300 ml), concentrated under reduced pressure, was added isopropyl alcohol (3300 ml) and concentrated under reduced pressure, obtaining a solution of {4-[(pyridine-2-yloxy)methyl]phenyl}Bronevoy acid (646 g) in isopropyl alcohol (2671 g) (yield: 94,4%). The resulting solution was heated to 60°C, then added to the container, with the containing a series of 2,2-dimethyl-1,3-propandiol (354 g, to 3.41 mol), was separated insoluble substance is suction filtered and then the container was rinsed with isopropyl alcohol (685 ml). After confirmation of dissolution, the solution was stirred at a bath temperature of 20°C and observed precipitation of crystals at an internal temperature of 28.8°C. After 1.5 hours was set the bath temperature -20°C and the solution was stirred over night. The precipitated crystal was filtered and the crystal was washed by a small amount of isopropyl alcohol, cooled to 0°C. the Crystal was dried under reduced pressure, obtaining the target compound (779 g) as a white crystal (yield: 92.2 per cent).

Range1H-NMR (DMSO-d6) δ (ppm): 0,94 (6H, s), 3,74 (4H, s), to 5.35 (2H, s), 6.87 in (1H, d, J=8,4 Hz), of 6.96-7,00 (1H, m), 7,39 (2H, d, J=8.0 Hz), to 7.67-7,74 (3H, m), 8,14-8,17 (1H, m).

[Example 22] Synthesis of [3-(3-{4[(pyridine-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-yl]di-tert-butylmethacrylate

In a nitrogen atmosphere to a mixture of {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate (164 mg, 0.40 mmol), {4-[(pyridine-2-yloxy)methyl]phenyl}Bronevoy acid (138 mg, of 0.60 mmol), cesium carbonate (391 mg, 1.20 mmol), copper iodide(I) (3.9 mg, 5% mol.) and 1,2-dimethoxyethane (2.0 ml) was added to the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane (16.4 mg, 5% mol.) and the mixture was stirred at 80°C for 1.5 hours. Added {4-[(pyridine-2-ILO is si)methyl]phenyl}Bronevoy acid (46 mg, 0.20 mmol) and the solution was further stirred for 4.5 hours. After cooling, was added ethyl acetate and 5%sodium chloride solution, insoluble substance was filtered, then the filtrate was transferred to a separating funnel and separated. After washing the organic layer washed with 5%aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel, obtaining the target compound (173 mg) in the form of oil product is a pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): of 1.23 (9H, s), of 4.05 (2H, s), of 5.34 (2H, s), 6,32 (1H, s), 6,76-6,79 (1H, m), 6,86-of 6.90 (1H, m), 7,28 (2H, d, J=8.0 Hz), 7,38-the 7.43 (3H, m), 7,55-of 7.60 (1H, m), 8,15-8,18 (1H, m), of 8.27 (1H, DD, J=2,0, 8.0 Hz), to 8.57 (1H, DD, J=2.0 a, 7,6 Hz).

[Example 23] 3-(3-(4-pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridin-2-ylamine

[3-(3-{4[(pyridine-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-yl]di-tert-butylimidazole (28.8 mg, 51.6 mmol) was dissolved in acetonitrile (0.6 ml), concentrated hydrochloric acid (60 ml, 690 mmol) was added dropwise while cooling the mixture in ice-water and the mixture was stirred at the same temperature for one hour. Then was added dropwise concentrated hydrochloric acid (140 ml, of 1.61 mmol) and the solution was stirred at the same temperature for one hour and at 20°C in t is an increase of 3.5 hours. Upon cooling, a mixture of ice-water to the reaction solution was added 0,5h. an aqueous solution of sodium hydroxide and ethyl acetate and was extracted. After washing the organic layer with 5%aqueous solution of sodium chloride and drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, obtaining the target compound (18.3 mg) in the form of oil product is a light yellow color.

Range1H-NMR (CDCl3) δ (ppm): 4,07 (2H, s), lower than the 5.37 (2H, s), 5,42 (2H, users), and 6.25 (1H, s)of 6.71 (1H, DD, J=5,2, 7,6 Hz), to 6.80 (1H, d, J=8,4 Hz), 6.87 in-6,91 (1H, m), 7,30 (2H, d, J=7,6 Hz), 7,44 (2H, d, J=7,6 Hz), 7,56-to 7.61 (1H, m,), of 7.70 (1H, DD, J=2.0 a, 7,6 Hz), 8,14 (1H, DD, J=2.0 a, 4,8 Hz), 8,16-8,19 (1H, m).

Examples 24 and 25 are other synthesis methods, alternative example 22.

[Example 24] Synthesis of [3-(3-{4-[(pyridine-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-yl]di-tert-butylmethacrylate

In a nitrogen atmosphere to a mixture of {3-[3-(methyl bromide)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate (68 mg, 0.15 mmol), {4-[(pyridine-2-yloxy)methyl]phenyl}Bronevoy acid (34 mg, 0.15 mmol), potassium phosphate (35 mg, 0,17 mmol), triphenylphosphine (7.9 mg, 0.03 mmol) and toluene (1.0 ml) was added palladium acetate (1.7 mg, 5% mol.) and the mixture was stirred for 16 hours at 90°C. After cooling was added ethyl acetate and water and the mixture transferred to a separating funnel and separated. The organic layer was washed on Ishenim solution of sodium chloride and then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel, receiving a mixture of the target compounds {3-[3-(methyl bromide)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate and [3-(3-methylisoxazol-5-yl)pyridin-2-yl]di-tert-butylmethacrylate (54 mg molar ratio 53:36:11) as a yellow oil.

Range1H-NMR (CDCl3) δ (ppm): of 1.23 (9H, s), of 4.05 (2H, s), of 5.34 (2H, s), 6,32 (1H, s), 6, 76-6,79 (1H, m), 6,86-of 6.90 (1H, m), 7,28 (2H, d, J=8.0 Hz), 7,38-the 7.43 (3H, m), 7,55-of 7.60 (1H, m), 8,15-8,18 (1H, m), 8,25-8,30 (1H, m,), to 8.57 (1H, DD, J=2.0 a, 7,6 Hz).

[Example 25] Synthesis of [3-(3-{4-[(pyridine-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-yl]di-tert-butylmethacrylate

In a nitrogen atmosphere to a mixture of (5-{2-[bis(tert-butoxycarbonyl)amino]pyridine-3-yl}isoxazol-3-yl)methyl-4-methylbenzenesulfonate (82 mg, 0.15 mmol), {4-[(pyridine-2-yloxy)methyl]phenyl}Bronevoy acid (34 mg, 0.15 mmol), potassium phosphate (35 mg, 0,17 mmol), triphenylphosphine (7.9 mg, 0.03 mmol) and toluene (1.0 ml) was added palladium acetate (1.7 mg, 5 mol%) and the mixture was stirred for 16 hours at 90°C. After cooling was added ethyl acetate and water and the mixture transferred to a separating funnel and separated. The organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified is by chromatography on a column of silica gel, receiving a mixture of target compound (45.9%), (5-{2-[bis(tert-butoxycarbonyl)amino]pyridine-3-yl}isoxazol-3-yl)methyl-4-methylbenzenesulfonate (25.7%) and [3-(3-methylisoxazol-5-yl)pyridine-2-yl]di-tert-butylmethacrylate (6.2%) (63 mg molar ratio 59:33:8) as a pale yellow oil.

Range1H-NMR (CDCl3) δ (ppm): 1,23 (N, (C), of 4.05 (2H, s), of 5.34 (2H, s), 6,32 (1H, s), 6,76-6,79 (1H, m), 6,86-make 6.90 (1H, m), 7,28 (2H, d, J=8.0 Hz), 7,38-the 7.43 (3H, m), 7,55-of 7.60 (1H, m), 8,15-8,18 (1H, m), of 8.27 (1H, DD, J=2,0, 8.0 Hz), to 8.57 (1H, DD, J=2.0 a, 7,6 Hz).

Examples 26-27 are other synthesis methods, alternative examples 22-23.

[Example 26] Synthesis of [3-(3-{4[(pyridine-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridine-2-yl]di-tert-butylmethacrylate

The operation with the first loading was carried out as described below. In a stream of gaseous nitrogen after adding {3-[3-(chloromethyl)isoxazol-5-yl]pyridine-2-yl}di-tert-butylmethacrylate (20,80 kg, 50,75 mol), 2-{[4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)benzyl]oxy}pyridine (19,61 kg of 66.00 mol, 1.30 M/M), (oxydi-2,1-phenylene)bis(diphenylphosphine) (1,367 kg, 2.54 mol, 0.05 M/M), potassium carbonate (9,11 kg, 65,91 mol, 1.30 M/M) in the reactor 2 500 l, which was previously purged with nitrogen, the internal environment of the reactor was again purged with nitrogen, was added N,N-dimethylformamide (147 kg, 7,08 weight./weight.) and started mixing. The ZAT is, after the internal temperature of from 15 to 25°C and the level of reduced pressure -0,090 MPa or more was maintained for three to five minutes, the vacuum pressure is released with nitrogen. This operation was repeated five times to Degas the solution. After degassing of the solution was added palladium acetate in N,N-dimethylformamide (mixed solution of palladium acetate (0,570 kg, 2.54 mol, 0,05 M/M) and degassed N,N-dimethylformamide (9,8 kg, 0.5 wt./weight., part of which was retained for thorough washing)and washed saved part of degassed N,N-dimethylformamide. Then, after stirring for 10 minutes, immediately added dropwise at internal temperatures of from 20 to 30°C degassed water (10.4 kg, 0.5 wt./weight.) and the operation of lowering the pressure to -0,087 MPa and release of reduced pressure with nitrogen was repeated three times. Then ran the quick circulation of hot water with a temperature of approximately 60°C to set the internal temperature of from 55 to 65°C, and the solution was stirred for three hours from the start of heating. After the completion of reaction was confirmed by HPLC analysis, was added toluene (90 kg, 4,34 weight./weight.) when the internal temperature of 0 to 25°C and added dropwise water (156 kg, 7.5 wt./weight.) in the same temperature range. Then, after stirring at an internal temperatureof 15 to 30°C for 30 minutes, the solution was left for 30 minutes or more and the bottom layer was separated. To the upper layer in the reactor was added water (104 kg, 5.0 weight./weight), was stirred at an internal temperature between 15 and 30°C for five minutes, then left to stand overnight and was separated only the bottom layer containing no insoluble matter. The top layer and the bottom layer containing the insoluble substance was filtered through Celite 503 RV (2.8 kg, is 0.135 weight./weight.) under pressure through the filter device and the reactor and the filter device was rinsed with toluene (18,0 kg, 0,867 weight./weight., the part left for washing and thorough rinsing). The obtained filtrate and washings were returned to the reactor 2 to 500 l and washed the reactor previously deferred toluene. Then, after the internal temperature was set in the range from 15 to 30°C the solution was left for 30 minutes or more and the bottom layer was separated. After stirring speed was adjusted approximately to the maximum dropwise for one hour or more at an internal temperature between 15 and 30°C was added n-heptane (152 kg, 7,32 weight./weight), then the solution was stirred at the same temperature range for two hours or more. Then, after adding titanoboa acid (0.90 kg, 5.08 mol, 0.1 M/M) in the form of separate fractions for 30 minutes or more when the internal temperature is round from 15 to 30°C, the solution was stirred at the same temperature range for one hour or more. Again added ticinobuy acid (0.90 kg, 5.08 mol, 0.1 M/M) in separate fractions for 30 minutes or more when the internal temperature between 15 and 30°C and the solution was stirred overnight at the same temperature range. After stirring overnight the solution in the reactor was filtered through activated charcoal using a filter device, which is prepared in advance, and the reactor and the filter device is thoroughly washed with a mixed solution of n-heptane-toluene (mixed solution of n-heptane (130 kg) and toluene (83 kg), part of which was retained for moisture activated carbon (Seisei Shirasagi)). After the new addition of titanoboa acid (1.80 kg, 10,16 mol, 0,2 M/M) was carried out by filtration activated carbon, using the same number of Celite RV 503, activated carbon (Seisei Shirasagi) and a mixed solution of n-heptane-toluene. The obtained filtrate and the washings were added to the reactor 1 in 500 l of concentrated under reduced pressure and the circulation of hot water with temperatures ranging from 40 to 70°C until the solution volume was approximately 100 l of a visual assessment. The residue was left to stand in an atmosphere of nitrogen and at an internal temperature of 30°C or below until filtration activated carbon of the second download was not finished.

In quality the ve second load, as described above, was carried out by the same operation. The filtrate and washings from the second download was added into the reactor 1 in 500 l, combined with the remainder of the first boot, and started by concentration under reduced pressure. When the circulation of hot water with a temperature from 60 to 70°C, when the expiration of the distillate weakened, was added toluene (144 kg), then, for the circulation of hot water with a temperature from 60 to 70°C, was carried out by concentration under reduced pressure to weaken the expiration of the distillate. At this point, the residue was analyzed and the ratio of toluene/target product (0,167 weight./weight.) was calculated based on the content of [3-(3-{4[(pyridine-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-yl]di-tert-butylmethacrylate and content of toluene in the residue after concentration. Was added toluene (29,66 kg, corresponding to the ratio of toluene/target product 0,700 weight./weight), the solution was stirred at an internal temperature between 15 and 30°C for 30 minutes or more, obtaining a solution of the target compound in toluene (containing 42,37 kg of the desired product; yield: 74.7 per cent).

The HPLC conditions: column: CAPCELL PAK C18 MGII (5 μm, 150×4.6 mm inner diameter, SHISEIDO), mobile phase: acetonitrile/water/triperoxonane acid = 180/820/1-900/100/1 (about./about./vol.).

[Example 27] 3-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridin-2-ylamine

To a solution of [3-(3-{4[(pyridine-2-yl) - Rev. XI)methyl]benzyl}isoxazol-5-yl)pyridin-2-yl]di-tert-butylmethacrylate in toluene (contents 42,37 kg (75,85 mol)) was added formic acid (181 kg 4,27 weight./weight.) dropwise at an internal temperature of -5 to 20°C and the mixture was stirred at an internal temperature of from 22 to 32°C for 19-20 hours. After the completion of reaction was confirmed by HPLC analysis, the internal temperature was cooled to a temperature of from -5 to 10°C and the solution was divided into two fractions and added to the reactors 1 and 2 at 500 l each, respectively.

For reactor 1 in 500 l of subsequent processing was carried out as described below. Under stirring was added dropwise at an internal temperature of -5 to 20°C water (74 kg 1,75 weight./weight), then added a simple tert-butyl methyl ether (31,4 kg 0,74 weight./weight.) and n-heptane (29,0 kg, 0,684 weight./weight.) when the internal temperature of 0 to 25°C. the Solution was stirred at an internal temperature of from 15 to 25°C for five minutes, leave on for 30 minutes or more to separate the lower layer. The bottom layer was returned to the reactor was again added a simple tert-butyl methyl ether (31,4 kg 0,74 weight./weight.) and n-heptane (29,0 kg, 0,684 weight./weight.) when the internal temperature of 0 to 25°C, the solution was stirred at an internal temperature of from 15 to 25°C for five minutes, then left for 30 minutes or more and the bottom layer was again separated. The bottom layer was returned to the first reactor and an aqueous solution of 48% sodium hydroxide (116 kg; 1392,0 mol, 18,35 M/M sodium hydroxide) was added dropwise at internal temperatures of from 0 to 25°C. C is in the same range as the temperature was added ethyl acetate (96 kg, 2.26 and weight./weight.) and was added dropwise an aqueous solution of 48% sodium hydroxide (20.5 kg; 246,0 mol, 3,24 M/M sodium hydroxide). In addition, in the same temperature range was added dropwise an aqueous solution of approximately 8% aqueous sodium hydroxide solution (mixed solution of aqueous 48% sodium hydroxide (12.7 kg; 152,4 mol, 2,00 M/M sodium hydroxide) and water (64 kg, 1.5 weight./weight)), while the pH of the lower layer was not from 8.00 to 9.00 (actual value: pH 8,58) (using 0.75 kg). After stirring the solution for one hour or more at an internal temperature of from 20 to 30°C and settling in for the night again checked the pH of the lower layer (the actual value: pH 8,29) and the bottom layer was separated. To the upper layer remaining in the reactor was added an aqueous solution of about 5% sodium bicarbonate (mixed solution of sodium bicarbonate (5.3 kg, 63,09 mol) and water (101 kg of 2.375 weight./weight.)) and the mixture was stirred at an internal temperature of from 20 to 30°C for one hour or more and then left for 30 minutes or more. After removal of the lower layer (pH 8,60) to the upper layer was added water (106 kg, 2.5 wt./weight.) and the mixture was stirred at an internal temperature of from 20 to 30°C for one hour or more, then left for 30 minutes or more and the bottom layer (pH 7,17) again separated.

For reactor 2 with a volume of 500 liters of the same post-processing was performed simultaneously with the reactor 1 volume of 50 L.

The solution from the reactor 1 volume of 500 l was transferred into the reactor 2 has a capacity of 500 l and concentrated under reduced pressure while circulating hot water with temperatures ranging from 55 to 65°C until the solution volume was approximately 100 HP Then to the residue after concentration of the solution was added ethanol (42 kg, 1.0 wt./weight.) and ethyl acetate (96 kg weight of 2.26./weight.) and the mixture was stirred for five minutes, then concentrated under reduced pressure by circulating hot water at a temperature of from 55 to 65°C and reduced pressure -0,092 MPa or more and did not observe the expiration of any distillate. At this point, as was observed precipitation of the crystal was gradually added ethyl acetate to dissolve the crystal (using 13,85 kg). After adding an additional amount of ethanol (18.3 kg) and ethyl acetate (6.7kg) internal temperature was set in the range from 50 to 55°C and after visual confirmation of the dissolution of the crystal was added n-heptane (33,5 kg 0,79 weight./weight.) for 30 minutes or more at an internal temperature of 45 to 55°C. Then, after adding an internal temperature of 45 to 50°C 3-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridine-2-ylamine (0,011 kg), can be synthesized according to methods described in international publication WO08/136279, description, example 18, and the observed deposition of the crystal, the solution peremeci the Ali in the same temperature range for one hour or more. After adding dropwise within one hour or more at an internal temperature of 45 to 55°C n-heptane (66,9 kg 1,58 weight./weight.) the internal temperature was lowered to a temperature of from 0 to 10°C for four hours or more and the solution was stirred at the same temperature range for five hours or more. After selection of the solution and confirm that the degree of crystallization of the desired product was 94%, the suspension was filtered under pressure, the crystal is washed with a mixed solution of ethanol-ethyl acetate-n-heptane (a mixed solution of ethanol (3,60 kg 0,085 weight./weight), ethyl acetate (4,15 kg, 0,098 weight./weight.) and n-heptane (18,81 kg, 0,444 weight./weight.)) and a mixed solution of ethanol-n-heptane (a mixed solution of ethanol (7,25 kg, 0,171 weight./weight.) and n-heptane (18,81 kg, 0,444 weight./weight.)) in order, getting wet crystal of the crude target compound (36,52 kg) in the form of a yellowish crystal.

The obtained wet crude crystal of 3-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridine-2-ylamine (36,52 kg) and ethanol (57,9 kg, 2,37 weight./weight.) were added sequentially into a vessel with a volume of 500 l for dissolution, which had previously been purged with nitrogen, and heated to an internal temperature of 70 to 75°C to dissolve the crystal. Maintaining this temperature, the solution was passed through a filter SUS vessel with a volume of 500 l for crystallization and the vessel with a volume of 500 l for dissolution and Phil is Tr SUS thoroughly washed with ethanol (19.3 kg, 0.8 wt./weight), which was kept heated with an external temperature of approximately 65°C. Then set the internal temperature of the filtrate from 55 to 60°C and confirmed the homogeneity of the solution in the vessel. After a slow lowering of the internal temperature to a temperature of from 48 to 51°C besieged crystal. After re-heating to an internal temperature of 55 to 60°C to dissolve the crystal internal temperature was immediately lowered to a temperature of from 48 to 51°C and immediately added 3-(3-(4-(pyridine-2-intoximeter)benzyl)isoxazol-5-yl)pyridin-2-ylamine (0,011 kg), which can be synthesized according to methods described in international publication WO08/136279, description, Example 18. Then, after the deposition of the crystal was confirmed visually when the internal temperature of 45 to 50°C, the suspension was stirred at an internal temperature of 43 to 47°C for from one hour to one hour and 30 minutes and the internal temperature was lowered to a temperature of from 0 to 10°C for four hours or more. At this point, after selecting the precipitated crystal and confirm its crystalline form as identical to the reference sample, the suspension was stirred overnight at the same temperature range. The next day, after confirmation of the crystalline forms as identical to the reference sample, the crystal was subjected to separation of solids and W is dcoi two phases by centrifugation and washed approximately half the number of 19.3 kg of ethanol, getting wet crystal of the target product (24,23 kg). This wet crystal was placed in a vacuum dryer with stirring, and dried under reduced pressure at ambient temperature from 20 to 30°C for 6 hours or more and when the external temperature from 35 to 45°C for 12 hours or more, obtaining the target compound (23,52 kg, 65,63 mol, yield: 86,8%) as a pale yellow crystal.

Range1H-NMR (CDCl3) δ (ppm): 4,07 (2H, s), lower than the 5.37 (2H, s), 5,42 (2H, users), and 6.25 (1H, s)of 6.71 (1H, DD, J=5,2, 7,6 Hz), to 6.80 (1H, d, J=8,4 Hz), 6.87 in-6,91 (1H, m), 7,30 (2H, d, J=7,6 Hz), 7,44 (2H, d, J=7,6 Hz), 7,56-to 7.61 (1H, m,), of 7.70 (1H, DD, J=2.0 a, 7,6 Hz), 8,14 (1H, DD, J=2.0 a, 4,8 Hz), 8,16-8,19 (1H, m).

The HPLC conditions: column: CAPCELL PAK C18 MGII (5 μm, 150×4.6 mm inner diameter, SHISEIDO), mobile phase: acetonitrile/water/triperoxonane acid = 180/820/1-900/100/1 (about./about./vol.).

Industrial applicability

According to the method of receiving according to the present invention the invention relates to an efficient method for producing a substituted heterocycle derivatives of pyridine, and industrial applicability is that substituted heterocycle derivatives of pyridine can be obtained on an industrial scale.

1. The method of obtaining the compounds represented by the following formula (I):

includes introduction to the reaction of the compound represented by the following formula (III):

and is soedineniya, represented by the following formula (II):

in a solvent and in the presence of a catalyst based on palladium and base,
and R1denotes a hydrogen atom;
R2denotes an amino group which may be protected by a protective group selected from acetyl, pivaloyl, t-butoxycarbonyl; one of X and Y represents a nitrogen atom and the other denotes an oxygen atom;
Q denotes a group to delete selected from halogen, p-toluensulfonate group, benzylmalonate group, a methane-sulfonyloxy group, tripterocalyx group, chloromethanesulfonyl group;
ring a represents a benzene ring;
Z represents-CH2O-;
R denotes a hydrogen atom or a C1-6alkyl, if both groups R denote With1-6alkyl, they together form a ring;
R3denotes pyridinyl; and
R4denotes a hydrogen atom.

2. The method of receiving according to claim 1, in which Q in the formula (III) denotes a halogen atom or substituted, sulfonyloxy group selected from p-toluensulfonate group, benzylmalonate group, methanesulfonate group, tripterocalyx group, chloromethanesulfonyl group.

3. The method of receiving according to claim 1 or 2, in which a partial structure represented by:

in the decree which authorized the formula (I) represents the following partial structure:

4. The method of receiving according to claim 1 or 2, where R2denotes an amino group which may be protected by a protective group selected from acetyl, pivaloyl, t-butoxycarbonyl, and the method further includes removing the protective group.

5. The method of receiving according to claim 1 or 2, wherein the compound represented by the following formula (III):

produced by the production method, including the introduction phase compounds represented by the following formula (VI):

in the reaction of cyclization;
implementation of reduction reaction; and
implementation of halogenation,
and R1, R2, R4X, Y and Q have the meanings given above,
R10represents C1-6alkyl, and
R13denotes a hydroxyl group.

6. The method of receiving according to claim 5, in which R2denotes an amino group having a protective group selected from acetyl, pivaloyl, t-butoxycarbonyl, and the method further includes removing the protective group after the reaction of recovery.

7. The method of receiving according to claim 5, in which R2denotes the amino group, the method further comprises protecting the amino group.

8. The compound represented by the following formula (VII)or its salt:

in which the Oh
R1denotes a hydrogen atom;
R2denotes an amino group which may be protected by a protective group selected from acetyl, pivaloyl, t-butoxycarbonyl; one of X and Y represents a nitrogen atom and the other denotes an oxygen atom;
R4denotes a hydrogen atom; and
R10stands With1-6alkyl.

9. The compound or its salt of claim 8, in which a partial structure represented by:

in this formula (VII) represents the following partial structure:

10. The compound represented by the following formula (X)or its salt:

in which
R1denotes a hydrogen atom;
R2denotes an amino group which may be protected by a protective group selected from acetyl, pivaloyl, t-butoxycarbonyl;
one of X and Y represents a nitrogen atom and the other denotes an oxygen atom;
W denotes a hydroxyl group, a halogen atom or substituted sulfonyloxy selected from p-toluensulfonate group, benzylmalonate group, methanesulfonate group, tripterocalyx group, chloromethanesulfonyl group; and
R4denotes a hydrogen atom.

11. The compound or its salt of claim 10, in which a partial structure represented by:

in the formula (X) represents the following partial structure:

12. The compound represented by the following formula (XI)or its salt:

in which
R1denotes a hydrogen atom;
R14denotes the amino group protected with a protective group selected from acetyl, pivaloyl, t-butoxycarbonyl;
one of X and Y represents a nitrogen atom and the other denotes an oxygen atom;
ring a represents a benzene ring;
Z represents-CH2O-;
R3denotes pyridinyl; and
R4denotes a hydrogen atom.

13. The compound or its salt according to item 12, in which a partial structure represented by:

in the formula (XI) is the following partial structure:

14. The compound represented by the following formula (XII)or its salt:

in which the ring represents a benzene ring;
U represents-CH2O-;
R denotes a hydrogen atom or a C1-6alkyl, and when both groups R denote With1-6alkyl, they may together form a ring; and
R15denotes a pyridine ring.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a mTOR kinase inhibitor. In formula (I): A represents a 6-8-member mono- or bicyclic heterocyclic ring containing 1 to 2 heteroatoms optionally specified in N and O as apexes of the ring and having 0-2 double bonds; and wherein the ring A is additionally substituted by 0 to 2 substitutes RA specified in a group consisting of -ORa, -Rc and -(CH2)1-4-ORa wherein Ra is optionally specified in hydrogen and C1-6alkyl; Rc represents C1-6alkyl; G is specified in a group consisting of -C(O)-, -OC(O)-, -NHC(O)- and -S(O)0-2-; B is specified in a group consisting of phenylene and 5-6-member heteroarylene consisting 1-2 nitrogen heteroatom as apexes of the ring, and substituted by 0 to 1 substitutes RB specified in F, Cl, Br, I and Rp; wherein Rp represents C1-6 alkyl; D is specified in a group consisting of -NR3C(O)NR4R5, -NR4R5, C(O)NR4R5, -NR3C(=N-CN)NR4R5, -NR3C(O)R4, -NR3C(O)OR4 and -NR3S(O)2R4, and wherein the group D and a substitute placed on an adjoining atom in the ring B, optionally combined to form a 5-6-member heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms specified in N, O and S, as apexes of the ring and substituted by the substitute 0-1 RD. The R1-R5 radical values are presented in the patent claim.

EFFECT: invention also refers to a pharmaceutical composition containing said compounds, and to the use of the compounds for preparing a drug for treating a malignant tumour mediated by mTOR kinase activity.

33 cl, 13 dwg, 4 tbl, 498 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is 7-methyl-5-(3-piperazin-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having potentiating activity on glutamate receptors, containing the compound described above; also described is use of the compound or a pharmaceutically acceptable salt in claim 1 in producing a medicinal agent for therapy of neurological and mental disorders associated with glutamate dysfunction.

EFFECT: novel compound which can be used in therapy of neurological and mental disorders is obtained and described.

5 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II , where Q is (CR4R5)n3; n1 equals 1 or 2; n2 equals 1 or 2; n3 equals 1; R2 is R2-1 or R2-2 , Ar is phenyl or a heteroaryl ring consisting of 8-10 carbon atoms and 1-2 heteroatoms selected from O or S; X denotes 1-2 substitutes located on Ar, each independently selected from a group consisting of OR8, NR8R9, SR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9 and CN; R3-R5 denote H; R8 is H, alkyl, cyclopropyl, phenyl or pyridinyl; optionally substituted with one or more halogens or heteroatom-containing substitutes selected from a group consisting of OR11, NR11R12, CO2R11, CONR11R12, NRnC(=O)Ri2; R9 is H or alkyl; R11-R12 independently denote H, alkyl, pyridinyl or morpholinyl.

EFFECT: compounds are inhibitors of rho-associated protein kinase which can be used in medicine to prevent or treat diseases or conditions associated with cytoskeleton readjustment, specifically treat high intraocular pressure such as primary open angle glaucoma.

10 cl, 3 tbl, 226 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is oxazolidinone of general formula , where values of radicals are given in invention formula, and pharmaceutical antibiotic composition, which includes as active ingredient novel oxazolidinone derivative, its hydrate, solvate, isomer or pharmaceutically acceptable salt.

EFFECT: compounds are characterised by wide antibacterial spectrum and high antibacterial activity against gram-positive and gram-negative resistant bacteria, low toxicity and can be applied as antibiotic.

7 cl, 3 tbl, 106 ex

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, specifically to 16-(1,2,4-oxadiazol-3-yl)-15,16-epoxilabdanoids of formula

wherein R=Me(Ia), Ph(1b), CH2Cl(lc) possessing an ability to inhibit human tumour cell growth. The compounds are produced of lambertianic acid contained in Siberian cedar gum and fir needles.

EFFECT: there are produced new compounds which possess considerable cytotoxic activity on human tumour cells.

1 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the use of compounds of formula (wherein R1, R2, X, Y and n have the values specified in the patent claim) or their pharmaceutically acceptable salts for treating the diseases related to the biological function of the trace amine associated receptors, namely depression, anxiety disorders, bipolar disorders, attention deficit/hyperactivity disorder, stress-induced disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, addictions, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy consumption and assimilation disorders, thermal homeostasis disorders and disturbances, sleeping and circadian rhythm disorders, and cardiovascular diseases. Besides, the invention refers to compounds of formulas I-A, I-B, I-C, I-D, l-E, l-F, I-G, I-H (structural formulas of which are presented in the patent claim) and to a pharmaceutical composition based on the compounds of formula (I) for treating the diseases related to the biological function of the trace amine associated receptors.

EFFECT: use of the compounds of formula 1 in preparing the drugs for treating the diseases related to the biological function of the trace amine associated receptors.

45 cl, 9 dwg, 1 tbl, 379 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

EFFECT: compounds may be used for treating disorders, such as schizophrenia, resistant schizophrenia, bipolar disorder, psychotic depression, resistant depression, depressive conditions related to schizophrenia, treating resistant OCD, autism, senile dementia, psychotic dementia, L-DOPA-induced psychotic disorder, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleeping disorders.

39 cl, 25 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: invention relates to condensed bicyclic compounds, having affinity with mineralocorticoid receptor (VR) of formula [I] and formula [ii], as well as to pharmaceutical compositions on their basis. In general formula [I[ and [ii] ring A represents benzene ring, which has substituent R1, condensed with adjacent 6-membered heterocyclic ring, and said benzene ring additionally optionally is substituted with one or two substituent(s), selected from halogen atom and C1-8-alkyl group, R1 represents C1-8-alkylsulfonyl amino group or C1-8-alkyl aminosulfonyl group, R2 and R3 (a) are similar or different and represent group, selected from hydrogen atom, C1-8-alkyl group, and from 6- to 10-membered monocyclic or bicyclic aryl group (said aryl group is optionally substituted with halogen atom), (b) are combined with each other with formation of oxogroup or (c) are combined with each other on their ends together with adjacent carbon atom with formation of C3-10-cycloalkyl group, X represents the following group =N-, =C(R4)- or -CH(R4)-, R4 represents hydrogen atom, cyanogroup, halogen atom, C1-6-alkyl group, C2-6-alkenyl group, C3-10-dicloalkyl group, C1-7-alkanoyl group, carbamoyl group or C3-8cycloalkenyl group, Ar represents from 6- to 10-membered monocyclic or bicyclic aryl group, optionally containing one or several heteroatom(s), selected from sulphur atom, oxygen atom and nitrogen atom (said aryl group is optionally substituted with similar or different, one or two substituent(s), selected from halogen atom, cyanogroup, C1-8-alkyl group, trihalogen- C1-8-alkyl group and C1-8alkoxygroup), and dotted line represents presence or absence of double bond, Xa represents the following group =N- or =C(CN)-, RZ represents hydrogen atom or halogen atom, R25 and R35 represent alkyl group, and Ar3 represents phenyl group, optionally substituted with one or two group(s), which is(are) selected from halogen atom and trihalogenalkyl group.

EFFECT: compounds can be applied as antihypertensive medication.

15 cl, 18 tbl, 8 dwg, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of dihydroquinone and dihydronaphthyridinone of formula (I) or to its pharmaceutically acceptable salts, in which X represents group CR11 or N; Y represents group -C(O)R3, oxazolyl or isoxazolyl; Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and is substituted with groups R1 and R2; R1 and R2 each independently represents H, halogen, CN group, C1-6alkyl or group -Y1-Y2-Y3-R8, or R1 and R2 together form group -O(CH2)nO-, where n represents 1 or 2; Y1 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O), -S-, -SO2- or bond; Y2 represents heterocycloalkylene, C1-6alkylene or bond, where heterocycloalkylene stands for cycloalkylene group, in which one, two carbon atoms are substituted with heteroatoms O or N, where heterocycloalkylene group also contains, at least, two carbon atoms and cycloalkylene represents ; Y3 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2- or bond; R8 represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, or group -NR9R10, where R8, different from H, is optionally substituted with C1-6alkyl, halogen, group -CF3 or group -OH; R9 and R10 each independently represents H or C1-6alkyl; R3 represents OH, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy; R4 represents C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1 -dioxide, and is optionally substituted with C1-6alkyl, hydroxyl group, C1-6alkoxy, halogen, nitro group, amino group, cyano group or halo-lower alkyl; R5 and R6 each independently represents H, halogen, C1-6alkyl, group -CF3, C1-6alkoxy; R7 represents H; R11 represents H. Invention also re4lates to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel dihydroquinone and dihydronaphthyridinone derivatives, useful for treatment of disease mediated by JNK kinase.

9 cl, 4 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I), its optical isomer or pharmaceutically acceptable salt, R is specified in cl.1 of the patent claim. The compounds may be presented both as an optical isomer, and as a racemic substance, and may be used for mental disorders, such as schizophrenia.

EFFECT: higher efficacy of using the compounds.

8 cl, 4 tbl, 3 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: described are novel trisubstituted 1,2,4-triazoles of general formula (I) (values of radicals are given in the claim) or pharmaceutically acceptable salts or hydrates or solvates thereof and a pharmaceutical composition containing said compounds. The novel compounds relate to potential positive allosteric modulators of nicotinic acetylcholine receptors, which can be used in medicine to treat psychotic disorders, intellectual impairment disorders, inflammatory diseases or conditions.

EFFECT: capacity to increase efficiency of agonists of nicotinic receptors.

9 cl, 7 tbl, 9 ex

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