Pyrazole pyrimidine derivatives and using them as pde10 inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula (I), which possesses phosphodiesterase 10 inhibitory activity. In formula (I), R1 represents hydrogen, halogen or lower alkyl; the ring A represents optionally substituted 6-10-merous monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms as heteroatoms, or a group containing a cycloaliphatic 6-merous ring condensed with the above heteroaryl, which is specified in 6-merous cycloalkane and aliphatic 6-merous heterocyclic ring containing an oxygen atom; the ring B represents optionally substituted 4-6-merous monocyclic nitrogen-containing group, which can additionally contain an oxygen atom or a 3-6-merous monocyclic hydrocarbonic group, which can be optionally saturated; R3 represents hydrogen; lower alkyl optionally substituted by a substitute specified in lower alkoxy; or lower cycloalky. The R2,Y radicals, as well as substitutes of the rings A and B are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compound, to a method of treating or preventing schizophrenia, anxiety disorders, drug addiction, disorders with a symptom of cognition deficiency, affective disorder or mood episode, each of which is mediated by phosphodiesterase 10 activity.

20 cl, 3 tbl

 

The technical field to which the invention relates.

The present invention relates to new derivatives of pyrazolopyrimidine with excellent inhibiting phosphodiesterase 10 (PDE10) activity and applicable as pharmaceuticals, and to methods of producing such compounds and their use.

The level of technology

Phosphodiesterase of cyclic nucleotides (hereinafter called phosphodiesterase or PDE) is an enzyme that hydrolyzes fosfodiesterazu communication in cyclic nucleotides such as camp (cyclic 3',5'-adenosine monophosphate or cGMP (cyclic 3',5'-guanosine monophosphate), and so on, as a substrate, forming nucleotides such as 5'-AMP (5'-monophosphate adenosine or 5'-GMP (5'-monophosphate guanosine), and so on

Cyclic nucleotides such as camp and cGMP, participate in the regulation of many functions in the living organism as second messengers in the transmission of intracellular signals. Intracellular levels of camp and cGMP, which change in response to extracellular signals, are regulated by the balance between the enzymes involved in the synthesis of camp and cGMP (cyclase and guanilatziklazy), and PDE involved in the hydrolysis of such enzymes.

As for the PDE mammals have so far been isolated and identified many types of PDE in melicope the surrounding, they were classified into many collections according to the amino acid sequence homology, biochemical properties, characterization of inhibitors, etc. (Francis et al., Prog. Nucleic Acid Res., vol. 65, pp. 1-52, 2001).

Among these different PDE families mammalian phosphodiesterase 10 (PDE10) [more specifically phosphodiesterase 10A (PDE10A)] recognizes as camp and cGMP as substrate. Described that PDE10 has a higher affinity for camp. In addition, isolated and identified cDNA PDE10A human, mouse and rat. Moreover, it was confirmed the existence of proteins PDE10. ((Fujishige et al., J. Biol. Chem., vol. 274, pp. 18438-18445, 1999;.Kotera et al., Biochem. Biophys. Res. Commun., vol. 261, pp. 551-557, 1999; Soderling et al., Proc. Natl. Sci. USA, vol. 96, pp. 7071-7076, 1999;.and Loughley et al., Gene, vol. 234, pp. 109-117, 1999).

As for inhibiting PDE10 compounds (PDE10 inhibitors, i.e. compounds with inhibitory effect on the enzymatic activity of PDE10, described the following connections.

For example, in EP 1250923 (Pfizer) and WO 2005/082883 (Pfizer) as PDE10 inhibitors described papaverine and aromatic heterocyclic compounds such as compounds hintline and isothiazoline.

In these publications also described that PDE10 inhibitors are applicable for the treatment or prevention of diseases or conditions, such as

psychotic illness:

for example, schizophrenia, schizophreniform ill the tion, delusion disorder, schizoaffective disorder, caused by substance psychotic disorder, paranoid or schizoid personality disorder, etc.;

anxiety disorder:

for example, panic disorder, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, etc.;

violation of movements:

for example, Huntington's disease, dyskinesia associated with therapy with dopamine agonist for Parkinson's disease, tired leg syndrome, etc.;

addiction to the excessive use of drugs:

for example, chronic alcoholism, addiction to amphetamine, cocaine, or opiate, etc.;

violations, with deficits in cognitive ability as a symptom:

for example, dementia (including Alzheimer's disease, dementia due to multiple heart attacks, and so on), delirium, impaired, causing memory loss, post-traumatic stress disturbance, mental retardation, learning disorder, attention deficit disorder and hyperactivity disorder (ADHD), age-related decline in cognitive abilities, etc.;

affective disorder:

for example, depressive episode, severe, destinies the disorder, minor depressive disorder, bipolar depressive disorder (including bipolar depressive disorder I and bipolar depressive disorder II), cyclothymic disorder, and so on, or

episode mood:

for example, major depressive episode, manic or mixed episode, and hypomanic episode and so on

In addition, they also described that PDE10 inhibitors are applicable for the treatment or prevention of neurodegenerative disorders, such as Parkinson's disease and Huntington's disease, and so on

In the publication Menniti et al. [Menniti et al., Curr. Opin. Investig. Drugs., 2007, 8(1): 54-59) described that PDE10 inhibitors have potential as an antipsychotic agents with the potential to improve cognitive symptoms in schizophrenia.

In WO 2003/000693 (Bayer) describes the connection imidazothiazole as PDE10 inhibitors. In this application also described that PDE10 inhibitors applicable for the treatment or prevention of neurodegenerative disorders, especially Parkinson's disease.

In WO 2003/014117 (Bayer) describes the various connections pyrroloquinoline as PDE10 inhibitors. It is also described that these compounds with inhibitory activity against PDE10 activity, exhibit antiproliferative activity and are applicable for the treatment of cancer. In addition, it describes h what about these compounds applicable for treating conditions of pain and/or to reduce body temperature in febrile condition.

In WO 2005/12485 (Bayer) described that PDE10 inhibitors used for stimulating insulin secretion from pancreatic cells. In addition, it is described that PDE10 inhibitors are applicable for the treatment or prevention of diabetes and related diseases such as type 1 diabetes or type 2 insulinorezistentne diabetes youth (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), a reduced content of fasting blood glucose (IGF) caused by pregnancy, diabetes, metabolic syndrome X, and so on

See also WO 2005/120514 (Pfizer), which describes the PDE10 inhibitors, which, reportedly, are applicable to reduce body weight and/or obesity in the treatment of obese patients. In addition, it is described that these PDE10 inhibitors are applicable for the treatment of insulinorezistentne mellitus (NIDDM), metabolic syndrome and glucose intolerance, and so on

With regard to compounds of pyrazolopyrimidine, currently known connections.

In WO 2007/076055 (Entremed Inc.) the described connections of pyrazolopyrimidine having activity as an antagonist of the activated receptor proteases. However, they clearly differ from the compounds of the present invention on the basis of their pharmacological action and structure.

About isana inventions

The present invention provides novel compounds having excellent PDE10 inhibitory activity, methods of making such compounds, the use of the compounds and pharmaceutical compositions containing such compounds, and the like.

The authors of the present invention have been found new connections pyrazolopyrimidine with excellent PDE10 inhibitory activity, thus leading to completion of the invention.

That is, the present invention relates to a compound represented by the formula [I]

in which

R1represents hydrogen, halogen, lower alkyl or cyano;

ring a represents an optionally substituted heterocyclic group;

the ring is an optionally substituted 3-6-membered monocyclic group; and

Y represents optionally substituted by an amino group,

optionally substituted cyclic amino group,

optionally substituted aliphatic 3-6-membered, monocyclic,

optionally substituted lower alkyl or

optionally substituted lower alkyl-O-,

or its pharmaceutically acceptable salt.

In addition, the present invention relates to a method of treating or preventing diseases, containing the introduction to the patient in need is this, effective quantities of the compounds of formula [I] or its pharmaceutically acceptable salt.

In addition, the present invention relates to pharmaceutical compositions containing a compound of the formula [I] or its pharmaceutically acceptable salt as an active ingredient, as well as to the use of the compounds for the manufacture of a medicinal product.

Moreover, the present invention relates to a method for obtaining compounds of formula [I] or its pharmaceutically acceptable salt.

The effect of the invention

The compounds of formula [I] or their pharmaceutically acceptable salts according to the present invention have excellent inhibiting PDE10 activity (i.e. inhibitory activity against the enzymatic activity of phosphodiesterase 10).

Industrial applicability

Compounds of the present invention and the pharmaceutical composition containing them as active ingredient, are applicable for the treatment or prevention of a disease or condition symptoms which can be alleviated by inhibition of PDE10 activity (i.e. inhibition of the enzymatic activity of phosphodiesterase 10) [for example, schizophrenia, anxiety disorders, addiction to the excessive use of drugs, diseases, having as a symptom of the lack of poznavatel the Noah ability, and episode mood, and so on].

The best way of carrying out the invention

In the present invention, the following terms have the following meanings, unless otherwise indicated.

Lower alkyl, including lower alkyl group in the (lower alkyl)amino or di(lower alkyl)amino and the like, includes an unbranched or branched group having 1-6 carbon atoms (C1-6), preferably 1-4 carbon atoms (C1-4). Lower alkyl specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, and the like.

Lowest cycloalkyl includes cyclic group having 3-8 carbon atoms (C3-8), preferably 3-6 carbon atoms (C3-6). Also included are cycloalkyl with 1-2 lower alkyl substituent their cyclic residue. Lowest cycloalkyl specifically includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

Lower cycloalkanes include a ring having from 3 to 8 atoms of carbon (C3-8), preferably from 3 to 6 carbon atoms (C3-6). Also included cycloalkanes having 1-2 lower alkyl substituent their cyclic residue. Lowest cycloalkane specifically includes cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane itomo similar.

The lower alkoxy include alkoxy having from 1 to 6 atoms of carbon (C1-6), preferably, from 1 to 4 carbon atoms (C1-4). In addition, included in any group, lower alkyl or lower cycloalkyl-O-. Lower alkoxy specifically includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy and the like.

Lowest alkanoyl includes unbranched or branched group having from 2 to 7 carbon atoms (C2-7), preferably, from 2 to 5 carbon atoms (C2-5). In addition, the lower alkanoyl includes any group of the groups lower alkyl-CO - or lower cycloalkyl-CO-. Lowest alkanoyl specifically includes formyl, acetyl, propanol, butanol, Isobutanol, pivaloyl and the like.

Lowest alkylen includes unbranched or branched group having 1-6 carbon atoms (C1-6), preferably 1-4 carbon atoms (C1-4).

Lower alkenyl and lower alkanine include groups having 2-7 carbon atoms (C2-7), preferably 2-5 carbon atoms (C2-5and at least one double bond.

Lower cycloalkenyl includes a cyclic group having from 3 to 8 carbon atoms (C3-8), preferably from 3 to 6 atoms of carbon (C3-6). Lower cycloalkenyl also includes issue cycloalkenyl, with 1-2 lower alkyl substituent their cyclic residue.

The halogen includes fluorine, chlorine, bromine or iodine.

Halogen(lower alkyl includes lower alkyl substituted by halogen atoms (usually from 1 to 5, preferably 1 to 3 halogen atoms). Halogen(lower alkyl) specifically includes foralkyl, littoralis, triptorelin, perfluoroalkyl, and the like. More specifically it includes vermeil, deformity, trifluoromethyl and the like.

Halogen(lower alkoxy) includes lower alkoxy substituted by halogen atoms (usually from 1 to 5, preferably 1 to 3 halogen atoms). Halogen(lower alkoxy) specifically includes feralcode, diflorasone, triptoreline, performace and the like. More specifically, halogen(lower alkoxy) includes deformedarse, triptoreline and the like.

Aryl includes6-14-monocyclic, is a bicyclic or tricyclic aromatic hydrocarbon group, preferably, C6-10is a monocyclic or bicyclic arily. Arily specifically include phenyl, naphthyl, tenantry, antril and the like.

Substituted amino includes mono - or disubstituted acyclic amino.

Cyclic amino includes 1-pyrrolidinyl, 1-piperidyl, 1-piperazinil, morpholine-4-yl and the like.

Wtorek the Oh hydroxy is hydroxy, which connects to a carbon atom United with one atom of hydrogen and two atoms of carbon.

Tertiary hydroxy is hydroxy, which is connected with the carbon atom connecting to three carbon atoms.

In the compound of the formula [I] of the present invention R1includes hydrogen, halogen, lower alkyl or cyano, preferred is a hydrogen atom.

Heterocyclic residue "optionally substituted heterocyclic group" represented by ring And, preferably, includes monocyclic or bicyclic heteroaryl containing from 1 to 3 nitrogen atoms as heteroatoms, or a group having condensed with him aliphatic 5-6-membered ring. "Aliphatic 5-6-membered ring, which is condensed, includes a 5-6-membered cycloalkane and aliphatic 5-6-membered heterocyclic ring (preferably, a 5-6-membered heterocyclic ring has a heteroatom selected from oxygen atom, nitrogen atom and sulfur atom, particularly oxygen atom), such as, in particular, cyclohexane, tetrahydropyran and the like.

Specific examples of the heterocyclic residue include pyridyl, pyrazinyl, hinely, honokalani, 5,6,7,8-tetrahydroquinoxaline, 7,8-dihydro-6N-pyrano[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrazolo[1,5-a]PI is imaginal and the like. Among them, preferred are pyrazinyl, hinely, honokalani, 5,6,7,8-tetrahydroquinoxaline, 7,8-dihydro-6N-pyrano[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl and pyrazolo[1,5-a]pyrimidinyl and especially preferred are pyrazinyl and honokalani. In addition, a heterocyclic residue preferably has a structure represented by the formula [II]:

in which

Xarepresents N or CH and

ring Xbrepresents a benzene ring, a pyridine ring or aliphatic 5-6-membered ring or is missing.

Specific examples of the heterocyclic residue include pyridine-2-yl, pyrazin-2-yl, quinoline-2-yl, cinoxacin-2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl, 7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl, pyrido[3,4-b]pyrazin-2-yl, pyrido[3,4-b]pyrazin-3-yl and the like. Among them, preferred are pyrazin-2-yl, quinoline-2-yl, cinoxacin-2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl, 7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl, pyrido[3,4-b]pyrazin-2-yl and pyrido[3,4-b]pyrazin-3-yl, and the like, and particularly preferred are pyrazin-2-yl and cinoxacin-2-yl.

"Optionally substituted heterocyclic group" represented by ring And may be unsubstituted or may have 1 or more (for example,from 1 to 6, preferably from 1 to 3) substituents, which are the same or different. Examples of such substituent include

lower alkyl;

lowest cycloalkyl;

halogen;

halogen(lower alkyl);

hydroxy,

lower alkoxy;

halogen(lower alkoxy);

optionally substituted amino (for example, he may have 1-2 substituent, which are the same or different and are selected from lower alkyl, halogen, and so on); and optionally substituted cyclic amino (for example, it may have 1-3 substituent, which are the same or different and are selected from lower alkyl, halogen and the like). Among them, preferred are lower alkyl, cycloalkyl, halogen, halo(lower alkyl), optionally substituted amino, and optionally substituted cyclic amino. Especially preferred are the lower alkyl and halogen.

Preferred ring And includes a group of the formula [VI] or [VII]:

in which Xwithrepresents a benzene ring, a pyridine ring or aliphatic 5-6-membered ring, each of which optionally is substituted by 1-2 substituents selected from lower alkyl; cycloalkyl; halogen; halo(lower alkyl); amino, optionally substituted by 1-2 substituents which are the same or different and wybraniec lower alkyl and halogen; and cyclic amino, optionally substituted by 1-3 substituents, which are identical or different and are selected from lower alkyl and halogen;

R4arepresents hydrogen or lower alkyl, in particular methyl;

R4brepresents hydrogen or lower alkyl, in particular methyl;

R4cand R4dindependently selected from lower alkyl; cycloalkyl; halogen; halo(lower alkyl); amino, optionally substituted by 1-2 substituents which are the same or different and are selected from lower alkyl and halogen; and cyclic amino, optionally substituted by 1-3 substituents, which are identical or different and are selected from lower alkyl and halogen.

"Aliphatic 5-6-membered ring" in the Xbor Xcincludes 5-6-membered cycloalkane and aliphatic 5-6-membered heterocyclic ring (preferably, aliphatic 5-6-membered heterocyclic ring has a heteroatom selected from oxygen atom, nitrogen atom and sulfur atom, particularly oxygen atom).

A specific example of a ring And includes

3-methylpyridin-2-yl;

3,6-dimethylpyrazine-2-yl;

3,5,6-trimethylpyrazine-2-yl;

3-methylpyridin-2-yl;

3,6-dimethylpyridin-2-yl;

3-methylphenoxy-2-yl;

3-utilisation-2-yl;

4-utilisation-2-yl;

3-cryptometrics-2-yl;

6-dimethylquinoxaline-2-yl;

3,7-dimethylquinoxaline-2-yl;

3,8-dimethylquinoxaline-2-yl;

7-fluoro-3-methylphenoxy-2-yl;

3-methyl-7-triptorelin-2-yl;

3,6,7-trimethylhexane-2-yl;

5-fluoro-3,7-dimethylquinoxaline-2-yl;

3-methylinosine-2-yl;

4-methylinosine-2-yl;

3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl;

3-methyl-5-propylpyrazine-2-yl;

2-methyl-5-propylpyridine-3-yl;

2,6-dimethyl-5-propylpyridine-3-yl;

5-isobutyl-2-methylpyridin-3-yl;

2,6-dimethyl-5-isobutylpyrazine-3-yl;

2,6-dimethyl-5-cyclopropylmethyl-3-yl;

2 methylpyridin[3,4-b]pyrazin-3-yl;

3 methylpyridin[3,4-b]pyrazin-2-yl;

2-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl;

3-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl; and

6-methylpyrazolo[1,5-a]pyrimidine-5-yl;

in particular, 3-methylphenoxy-2-yl and 7-fluoro-3-methylphenoxy-2-yl.

Monocyclic the remainder of the "optionally substituted 3-6-membered monocyclic group" represented by ring B includes "4-6-membered monocyclic nitrogen-containing heterocyclic group" and "3-6-membered monocyclic hydrocarbon group. Among them, preferred are 4-to 5-membered monocyclic nitrogen-containing aliphatic heterocyclic ring" and "3-5-membered monocyclic aliphatic hydrocarbon group". More preferred is 4-to 5-membered monocyclic nitrogen-containing aliphatic who heterocyclics group, with the bond of the nitrogen atom of the cyclic group".

Specific examples 4-6-membered monocyclic nitrogen-containing heterocyclic group" include pyrrolidinyl, azetidine, imidazolidine, pyrazolidine, piperidine, piperazinil, morpholinyl, thiomorpholine and corresponding unsaturated monocyclic group which is partially or fully unsaturated. Among them, preferred are pyrrolidinyl, azetidine, pyrazolidine and the corresponding unsaturated monocyclic group which is partially or fully unsaturated. Among them, more preferred are 1-pyrrolidinyl, 1-azetidine, 1-pyrazolidine and the corresponding unsaturated monocyclic group which is partially or completely unsaturated (e.g.,, 1-pyrazole, and the like), 1-pyrrolidinyl and 1-azetidinol are even more preferred, and 1-pyrrolidinyl is especially preferred.

Examples 3-6-membered monocyclic hydrocarbon group" include a C3-6cycloalkyl, which optionally is partially unsaturated. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl and the like. Among them predpochtite lname are cyclopentyl, cyclopentenyl (1-cyclopentenyl and the like) and the like.

Examples 3-6-membered monocyclic groups include 1-pyrrolidinyl, 1-azetidine, 1-pyrazolyl, cyclopropyl, cyclopentyl, cyclopenten-1-yl and the like.

“Optionally substituted 3-6-membered monocyclic group” represented by ring B may be unsubstituted or may have 1 or more (for example, from 1 to 3) substituents, which are the same or different. Examples of such substituents include

halogen;

oxo;

hydroxy;

optionally substituted lower alkyl (e.g., it may have 1-2 substituent, which are the same or different and selected from hydroxy, lower alkoxy, and the like);

lower alkoxy;

(lower alkyl)sulfonyloxy;

optionally substituted amino (for example, he may have 1-2 substituent, which are the same or different and are selected from lower alkyl and the like) and the like. Among them, preferred are halogen; hydroxy; optionally substituted lower alkyl (e.g., it may have 1-2 substituent, which are the same or different and selected from hydroxy, lower alkoxy, and the like) and the like, and particularly preferable is halogen, in particular fluorine.

Preferred examples of Y include a group is expressed by the following formula [III]:

-Z-R2[III],

in which

Z represents-N(R3)-, -O -, or C1-2alkylen;

R3represents hydrogen; lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy; or lower cycloalkyl; and

R2represents a

(1) lower alkyl, optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of hydroxy, halogen, cyano, lower alkoxy, lower cycloalkyl, replacement of the lower cycloalkyl, halogen(lower alkyl) and mono - or di(lower alkyl)amino, or

(2) optionally substituted aliphatic 3-6-membered monocyclic group.

Z preferably represents-N(R3)- or-O-, more preferably-N(R3)-.

R3preferably represents hydrogen or lower alkyl (e.g. methyl), more preferably, hydrogen.

"Lower alkyl, optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of hydroxy, halogen, cyano, lower alkoxy, lower cycloalkyl, replacement of the lower cycloalkyl, halogen(lower alkyl) and mono - or di(lower alkyl)amino, represents the radical R2, preferably, is with the combat replacement lower alkyl, optionally substituted by halogen(lower alkyl). Hydroxy "replacement lower alkyl" R2preferably represents a secondary or tertiary hydroxy, in particular, tertiary hydroxy.

A specific example of "lower alkyl, optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of hydroxy, halogen, cyano, lower alkoxy, lower cycloalkyl, replacement of the lower cycloalkyl, halogen(lower alkyl) and mono - or di(lower alkyl)amino” includes

2-hydroxypropan-1-yl,

2-hydroxy-2-methylpropan-1-yl,

1,1,1-Cryptor-2-hydroxypropan-3-yl and

3-hydroxy-3-methylbutane-1-yl.

Monocyclic the remainder of the "optionally substituted aliphatic 3-6-membered monocyclic group” represented by R2preferably, includes a 4-6-membered (preferably, 5 to 6-membered) aliphatic monocyclic heterocyclic group containing 1-2 heteroatom selected from oxygen atom, nitrogen atom and sulfur atom; C3-6(preferably, C5-6)cycloalkyl, and the like.

Specific examples of monocyclic residue include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, titanyl, piperidyl, C3-6cycloalkyl (cyclohexyl, cyclopentyl cyclobutyl and cyclopropyl) and the like. Among them tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, C3-6cycloalkyl and the like are preferred. Among them tetrahydropyrane, cyclohexyl and the like are particularly preferred.

In addition, more specific examples of monocyclic residue include 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-titanyl, 4-piperidyl, C3-6cycloalkyl and the like. Among them, 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3-tetrahydrofuryl, 4-piperidyl, C3-6cycloalkyl and the like are preferred. Among them, 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, cyclohexyl and the like are more preferred.

"Optionally substituted aliphatic 3-6-membered monocyclic group” represented by R2may be unsubstituted or may have 1 or more (e.g., 1-3) substituents, which are the same or different. Examples of such substituents include halogen, oxo, hydroxy, lower alkanoyl, lower alkoxy, and optionally substituted lower alkyl and the like (for example, he may have 1-2 substituent, which are the same or different and selected from hydroxy, lower alkoxy, and so on). Halogen, oxo, hydroxyl, lower and conoil, lower alkoxy, lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy, are even more preferred.

"Optionally substituted aliphatic 3-6-membered monocyclic group” represented by R2preferably represents a group represented by the following formula [IV]:

in which

X3represents-O-, -S-, -C(R2c)(R2d)- or-SO2-;

s and t are equal, each independently, 1, 2, 3 or 4;

s+t is 1, 2, 3, 4 or 5, and

R2a, R2b, R2c, R2dare the same or different and each independently represents hydrogen, halogen, oxo, hydroxy, lower alkanoyl, lower alkoxy or lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy.

X3represents preferably-O - or-C(R2c)(R2d)-.

s and t, preferably equal to 1 or 2, more preferably 2.

s+t, preferably equal to 2, 3 or 4, more preferably 3 or 4.

"Optionally substituted aliphatic 3-6-membered monocyclic group” represented by R2more preferably represents a group represented by the following formula [V]:/p>

in which the symbols have the same meanings as above.

Examples of "optionally substituted amino" represented by Y include unsubstituted amino and substituted amino. Among them, substituted amino is preferred.

Examples of "substituted amino” represented by Y include substituted amino, with 1-2 substituent, which are the same or different. Examples of such substituents of the "substituted amino" include substituents, which are similar to the above-mentioned groups represented by R3and R2in the formula [III].

"Substituted amino" represented by Y preferably is a monosubstituted amino. The substituent in this case, preferably, is a Deputy, which is similar to the above-mentioned groups represented by R2in the formula [III], and more preferably, the Deputy, which is similar to the "optionally substituted aliphatic 3-6-membered monocyclic group" or "optionally substituted lower alkyl" represented by R2.

Specific examples of the "substituted amino" represented by Y in the formula [I] include

4 tetrahydropyrimidine;

N-methyl-N-tetrahydropyran-4-ylamino;

(2-hydroxy-2-methylpropan-1-yl)amino;

(4-hydroxy-4-methylcyclohexyl)amino;

3-about what setonline;

(1-hydroxymethylpropane-1-yl)amino;

cyclopropylamino;

2-hydroxypropan-1 ylamino;

2-methoxyethane-1 ylamino;

4 hydroxycyclohexanone;

4 methoxycyclohexanone;

4 toxicologically;

2,2-dimethyltetrahydrofuran-4-ylamino;

2,6-dimethyltetrahydrofuran-4-ylamino;

1,1,1,-Cryptor-2-hydroxypropan-3-ylamino;

3 tetrahydropyrimidine;

2-lanoitan-1 ylamino;

(1-hydroxy-2-methylpropan-2-yl)amino;

1,1-deflorated-2-ylamino;

1-hydroxycyclopent-1 ylmethylamino;

3 tetrahydrofurfurylamine;

1 methylpiperidin-4-ylamino;

di-(1-methoxyethane-2-yl)amino;

N-cyclopropyl-N-tetrahydropyran-4-ylamino;

N-ethyl-N-tetrahydropyran-4-ylamino;

2-hydroxypropan-1 ylamino;

3-hydroxy-3-methylbutane-1-ylamino;

2-hydroxycyclohexane-1 ylamino;

1-hydroxy-2,2-dimethylpropyl-3-ylamino;

1,1-dioxotetrahydrofuran-3-ylamino;

1-acetylpiperidine-4-ylamino;

1-propylpiperidine-4-ylamino;

1-ethylpiperidine-4-ylamino;

1-(N,N-dimethylamino)ethane-2-ylamino; and

4,4-diverticulectomy,

in particular, 4-tetrahydropyranyl, (2-hydroxy-2-methylpropan-1-yl)amino, (4-hydroxy-4-methylcyclohexyl)amino, 2-hydroxypropan-1 ylamino, 1,1,1-Cryptor-2-hydroxypropan-3-ylamine and 3-hydroxy-3-methylbutane-1-ylamino.

Examples of the "cyclic amino" represented by Y, before occhialino, includes 1-pyrrolidinyl, morpholine-4-yl, 1-piperidyl, 1-piperazinil and the like. Among them, 1-pyrrolidinyl, morpholine-4-yl and the like are preferred.

Examples of the "optionally substituted aliphatic 3-6-membered monocyclic" balance "optionally substituted aliphatic 3-6-membered, monocyclic” represented by Y include residues that are similar to the above "optionally substituted aliphatic 3-6-membered monocyclic group” represented by R2in the formula [III].

"Optionally substituted lower alkyl" represented by Y may be unsubstituted alkyl or may be alkyl having 1 or more (for example, from 1 to 3) substituents, which are the same or different. Examples of such substituents include optionally substituted aliphatic 3-6-membered monocyclic group, hydroxy, halogen, cyano, lower alkoxy, mono - or di(lower alkyl)amino, cycloalkyl and the like. Examples of such optionally substituted aliphatic 3-6-membered monocyclic groups include groups that are similar to the above "optionally substituted aliphatic 3-6-membered monocyclic group" represented by R2in the formula [III].

"Optionally substituted lower alkyl-O -" represented by Y may be nezametili can have 1 or more (for example, 1 to 3) substituents, which are the same or different. Examples of such substituents include halogen, hydroxy, lower alkoxy, and the like.

One aspect of the present invention includes such a compound of the formula [I] in which R1represents hydrogen.

Another aspect of the invention includes the above compound in which ring a represents an optionally substituted monocyclic or bicyclic heteroaryl containing from 1 to 3 nitrogen atoms as heteroatoms, or a group having aliphatic 5-6-membered ring condensed with him.

In one of these aspects of the ring And represents a group of the formula [II], which is optionally substituted.

In one of these aspects, the ring a is a pyridyl, pyrazinyl, hinely, honokalani, 5,6,7,8-tetrahydroquinoxaline, 7,8-dihydro-6N-pyrano[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, each of which is optionally substituted.

In one of these aspects, the ring a is a pyridyl, pyrazinyl, hinely, honokalani, 5,6,7,8-tetrahydroquinoxaline, 7,8-dihydro-6N-pyrano[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl and pyrazolo[1,5-a]pyrimidinyl, each of which is optionally substituted.

In one of these aspects of the ring And not only is em pyrazinyl, chenail, honokalani, 5,6,7,8-tetrahydroquinoxaline, 7,8-dihydro-6N-pyrano[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl and pyrazolo[1,5-a]pyrimidinyl.

In one of these aspects of the ring And is pyrazinyl and honokalani, each of which is optionally substituted.

In one of these aspects of the ring And is pyrazin-2-yl, quinoline-2-yl, cinoxacin-2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl, 7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl, pyrido[3,4-b]pyrazin-2-yl and pyrido[3,4-b]pyrazin-3-yl, each of which is optionally substituted.

In one of these aspects of the ring And is pyrazin-2-yl and cinoxacin-2-yl, each of which is optionally substituted.

Other aspects of the invention include the above compound, which ring may have 1 or more (for example, from 1 to 6, preferably from 1 to 3) substituents, which are the same or different substituents selected from lower alkyl; lower cycloalkyl; halogen; halo(lower alkyl); hydroxy; lower alkoxy; halo(lower alkoxy); optionally substituted amino (for example, he may have 1-2 substituent, which are the same or different and are selected from lower alkyl, halogen and the like); and optionally substituted cyclic amino (EmOC is emer, he may have from 1 to 3 substituents, which are identical or different and are selected from lower alkyl, halogen and the like).

In one of these aspects of the substituents in "optionally substituted heterocyclic group" represented by ring A, are 1 to 6 substituents, which are the same or different and selected from the group consisting of lower alkyl; halogen; halo(lower alkyl); hydroxy; lower alkoxy; halo(lower alkoxy), amino, optionally substituted by 1-2 substituents which are the same or different and are selected from lower alkyl and halogen; and cyclic amino, optionally substituted by 1-3 substituents, which are identical or different and are selected from lower alkyl and halogen.

In one of these aspects of the substituents in "optionally substituted heterocyclic group" represented by ring A, are 1-3 substituent, which are the same or different and selected from the group consisting of lower alkyl; halogen; halo(lower alkyl); amino, optionally substituted by 1-2 substituents which are the same or different and are selected from lower alkyl and halogen; and cyclic amino, optionally substituted by 1-3 substituents, which are identical or different and are selected from lower alkyl and halogen.

In one the m of these aspects of the substituents in "optionally substituted heterocyclic group", represented by ring A, are 1-3 substituent, which are the same or different and selected from the group consisting of lower alkyl and halogen.

Another aspect of the invention includes compounds of formula [I] in which ring a represents a group of the formula [VI] or [VII].

In one of these aspects of the ring And represents a group of the formula [VI].

In one of these aspects of the ring And represents a group of the formula [VII].

Another aspect of the invention includes the above compound, which monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring B is a 4-6-membered monocyclic nitrogen-containing heterocyclic group.

In one of these aspects monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring B is a 4-6-membered monocyclic nitrogen-containing heterocyclic group or a 3-6-membered monocyclic hydrocarbon group.

In one of these aspects monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring B selected from the group consisting of pyrrolidinyl, azetidine, imidazolidine, pyrazolidine, piperidine, piperazinil, morpholinyl, thiomorpholine and C3-6qi is lalqila or corresponding unsaturated monocyclic group.

In one of these aspects monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring B selected from the group consisting of pyrrolidinyl, azetidine, imidazolidine, pyrazolidine, piperidine, piperazinil, morpholinyl, thiomorpholine and the corresponding unsaturated monocyclic group which is partially or fully unsaturated.

In one of these aspects monocyclic balance in the "optionally substituted 3-6-membered monocyclic group” represented by ring B is pyrrolidinyl, azetidinol, pyrazolidine and the corresponding unsaturated monocyclic group, which, preferably, is fully or partially unsaturated.

In one of these aspects monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring B is 1-pyrrolidinyl, 1-azetidinone, 1-pyrazolidinone and the corresponding unsaturated monocyclic group which is partially or fully unsaturated.

In one of these aspects monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring B is 1-pyrrolidinyl, 1-azetidinone, 1-pyrazolyl, cyclopropyl, cyclopentyl or cyclopentene-1 and the om.

In one of these aspects monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring B is 1-pyrrolidinium.

Another aspect of the invention includes the above compound, which "optionally substituted 3-6-membered monocyclic group" represented by ring B is a 3-6-membered monocyclic group, optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of halogen; oxo; hydroxy; lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy; lower alkoxy; lower alkylsulfonate; and amino, optionally substituted by 1-2 substituents which are the same or different and are selected from lower alkyl.

In one of these aspects of the "optionally substituted 3-6-membered monocyclic group" represented by ring B is a 3-6-membered monocyclic group, optionally substituted by 1-3 substituents, which are the same or different and selected from halogen; hydroxy; lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy.

Another aspect of the invention includes indicated the data above connection, in which Y is represented by formula [III].

In one of these aspects of Y represented by the formula [III] in which Z represents-N(R3)- or-O-.

In one of these aspects of Y represented by the formula [III] in which Z represents-N(R3) -.

Another aspect of the invention includes the above compound in which Y is represented by formula [III] in which R3is hydrogen.

Another aspect of the invention includes the above compound in which Y is represented by formula [III], in which the "optionally substituted aliphatic 3-6-membered monocyclic group” represented by R2is aliphatic 3-6-membered monocyclic group, optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of halogen; oxo; hydroxy; lower alkanoyl; lower alkoxy and lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy.

In one of these aspects monocyclic balance in the "optionally substituted aliphatic 3-6-membered monocyclic group represented by the formula [IV].

In one of these aspects monocyclic balance in the "optionally substituted aliphatic 3-6-membered monocyclic group" represented by formulas is th [V].

In one of these aspects monocyclic balance in the "optionally substituted aliphatic 3-6-membered monocyclic group" represented by R2selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, tetrahydropyranyl, tetrahydrofuryl, tatania, piperidyl, cyclohexyl, cyclopentyl and cyclobutyl.

In one of these aspects monocyclic balance in the “optionally substituted aliphatic 3-6-membered monocyclic group" represented by R2selected from the group consisting of 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuryl, 3-tatania, 4-piperidyl and C3-6cycloalkyl.

In one of these aspects of Y represented by the formula [III] in which R2represents lower alkyl, optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of hydroxy, halogen, cyano, lower alkoxy, lower cycloalkyl, replacement of the lower cycloalkyl, halogen(lower alkyl) and mono - or di(lower alkyl)amino.

In one of these aspects of Y represented by the formula [III] in which R2represents an optionally substituted aliphatic 3-6-membered monocyclic group.

In one of these aspects Y presents the form of the Oh [III], in which R2represents a

(1) lower alkyl, optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of hydroxy, halogen, cyano, lower alkoxy, replacement of the lower cycloalkyl, halogen(lower alkyl) and mono - or di(lower alkyl)amino; or

(2) 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3-tetrahydrofuryl, 4-piperidyl, cyclohexyl or C3-6cycloalkyl, each of which is optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of halogen; oxo; hydroxy; lower alkanoyl; lower alkoxy; lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy.

In one of these aspects of Y represented by the formula [III] in which R2selected from the group consisting of 4-tetrahydropyranyl; 4-hydroxy-4-methylcyclohexyl; 2-hydroxypropan-1-yl; 2-hydroxy-2-methylpropan-1-yl; 1,1,1-Cryptor-2-hydroxypropan-3-yl and 3-hydroxy-3-methylbutane-1-yl.

Another aspect of the invention includes the above compound in which Y is optionally substituted by an amino group.

Another aspect of the invention includes the above connection, where Y p is ecstasy an optionally substituted cyclic amino group.

Another aspect of the invention includes the above compound in which Y represents an optionally substituted aliphatic 3-6-membered monocyclohexyl.

Another aspect of the invention includes the above compound in which Y is optionally substituted lower alkyl.

Another aspect of the invention includes the above compound in which Y is optionally substituted lower alkyl-O-.

Preferably, examples of the compounds of formula [I] include a free form of each of the compounds described in the examples (examples 1.001-1.200, 2.001, 3.001, 4.001-4.005, 5.001 and 5.002), or its pharmaceutically acceptable salt.

Particularly preferred examples of the compounds include compounds selected from the group consisting of

2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.001);

N-methyl-2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.002);

5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.003);

1-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]Piri is one-7-yl}amino)-2-methylpropan-2-ol (the free form of the compound of example 1.006);

5-(2,5-dihydro-1H-pyrrol-1-yl)-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (example 1.009);

2-methyl-3-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-yloxy)pyrazolo[1,5-a]pyrimidine-2-yl]finokalia (the free form of the compound of example 1.010);

5-cyclopent-1-EN-1-yl-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (example 1.011);

TRANS-4-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol (the free form of the compound of example 1.013);

2-(5,7-dipyrrole-1-alprazola[1,5-a]pyrimidine-2-yl)-3-methylinosine (the free form of the compound of example 1.019);

(2S)-1,1,1-Cryptor-3-{[2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}propan-2-ol (the free form of the compound of example 1.027);

3-{[2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}propanenitrile (the free form of the compound of example 1.031);

N-(TRANS-4-methoxycyclohexyl)-2-[3-methyl-7-(trifluoromethyl)cinoxacin-2-yl]-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.047);

2-(3,7-dimethylquinoxaline-2-yl)-N,N-bis-(2-methoxyethyl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.050);

5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)-N-oxetan-3-alprazola,5-a]pyrimidine-7-amine (the compound of example 1.058);

1-{[5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-2-methylpropan-2-ol (the free form of the compound of example 1.059);

N-cyclopropyl-5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.062);

2-(3-utilisation-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]-N-(TRANS-4-methoxycyclohexyl)pyrazolo[1,5-a] pyrimidine-7-amine (free form of the compound of example 1.081);

TRANS-4-({5-[(3R)-3-ftorpirimidinu-1-yl]-2-[3-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol (the free form of the compound of example 1.085);

(1S,2S)-2-{[2-(7-fluoro-3-methylphenoxy-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol (the free form of the compound of example 1.097);

2-(3,5-dimethylquinoxaline-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.109);

2-(3,6-dimethylquinoxaline-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.111);

2-(3,7-dimethylquinoxaline-2-yl)-N-[(3R)-1,1-dissidocerida-3-thienyl]-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.112);

N-(1-acetylpiperidine-4-yl)-2-(3,7-dimethylquinoxaline-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine (svobodnaia connection example 1.114);

2-(3,7-dimethylquinoxaline-2-yl)-N-(1-propylpiperidine-4-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.123);

N'-[2-(3,7-dimethylquinoxaline-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]-N,N-dimethylated-1,2-diamine (free form of the compound of example 1.126);

N-(4,4-diverticulosis)-2-(3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine (example 1.133);

N-methyl-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-(3,5,6-trimethylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-7-amine (example 1.158);

((2S)-1-{2-(3-methylphenoxy-2-yl)-7-[(3R)-tetrahydro-2H-Piran-3-ylamino]pyrazolo[1,5-a]pyrimidine-5-yl}pyrrolidin-2-yl)methanol (the free form of the compound of example 1.147);

{(2S)-1-[7-[cyclopropyl(tetrahydro-2H-Piran-4-yl)amino]-2-(3,7-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5-yl]pyrrolidin-2-yl}methanol (the free form of the compound of example 1.152);

1-[2-(3,7-dimethylquinoxaline-2-yl)-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-5-yl]azetidin-3-ol (the free form of the compound of example 1.154);

2-methyl-3-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylmethyl)pyrazolo[1,5-a]pyrimidine-2-yl]finokalia (example 2.001);

TRANS-1-methyl-4-{[2-(3-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol (the free form of the compound of example 1.173);

CIS-4-({2-(7-for-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol (the free form of the compound of example 1.175);

N-methyl-2-(3-methyl-6-propylpyrazine-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.181);

2-methyl-1-[(6'-methyl-5-pyrrolidin-1-yl-2,5'-dipyrazolo[1,5-a]pyrimidine-7-yl)amino]propan-2-ol (the free form of the compound of example 1.184);

1-{[2-(6-isobutyl-3,5-dimethylpyridin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}-2-methylpropan-2-ol (example 1.187);

1-{[2-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}-2-methylpropan-2-ol (the free form of the compound of example 1.189);

2-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.190);

2-(3-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.197);

2-methyl-1-{[2-(3-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}propan-2-ol (the free form of the compound of example 1.198);

N-(TRANS-4-methoxycyclohexyl)-2-(3-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine (free form of the compound of example 1.199);

2-(2-methylpyridin[3,4-b]pyrazin-3-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (example is 5.001) and

2-(3-methylpyridin[3,4-b]pyrazin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine

(example 5.002);

or their pharmaceutically acceptable salts.

The compounds of formula [I] of the present invention may be in free form (free base or free acid or in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts of inorganic acids, such as cleaners containing hydrochloride, sulfate, nitrate, phosphate or hydrobromide salts, and organic acid salts such as acetate, fumaric, oxalate, citrate, methanesulfonate, benzosulfimide, p-toluensulfonate or maleate salt, and the like. In addition, when the compounds of the present invention contain a substituent(s) such as carboxyl group, a pharmaceutically acceptable salt include salts with bases (e.g. alkali metal salts such as sodium salt, potassium salt and the like, or salts of alkaline earth metals such as calcium salt).

The compounds of formula [I] or their salts of the present invention include any of their intramolecular salts, adducts, solvate or hydrate.

The compounds of formula [I] of the present invention can be obtained in accordance with the following methods, but the methods for their preparation shall not limit Atsa these methods.

The method of obtaining 1

The compounds of formula [I] in which R1represents hydrogen and Y represents optionally substituted amino, optionally substituted cyclic amino, optionally substituted aliphatic 3-6-membered monocyclohexyl or optionally substituted lower alkoxy, that is, compounds represented

the formula [Ia1] [in which B1represents an optionally substituted nitrogen-containing heterocyclic group, Yarepresents optionally substituted amino, optionally substituted cyclic amino, optionally substituted aliphatic (3-6-membered monocyclic)hydroxy or optionally substituted lower alkoxy and the other symbols have the meanings specified above];

the formula [Ia2] [in which B2represents an optionally substituted 3-6-membered monocyclic group, in which the monocyclic the rest is unsaturated, and other symbols have the meanings specified above]; and

the formula [Ia3] [in which B3represents an optionally substituted 3-6-membered monocyclic group, in which the monocyclic residue is saturated, and the other symbols have the meanings specified above];

can be obtained as follows receipt.

Link the formulas [1] [in which each symbol has the value above] is subjected to interaction with acetonitrile, thus obtaining the compound of the formula [2] [in which each symbol has the values listed above].

The compound of the formula [2] is subjected to interaction with hydrazine, thus obtaining the compound of the formula [3] [in which each symbol has the values listed above].

The compound of the formula [3] is subjected to interaction with ethylmaleimide followed by the addition of nucleophilic agent, thus obtaining the compound of the formula [4] [in which each symbol has the values listed above]. Alternatively, the compound of the formula [3] is subjected to interaction with ethylhydroxylamine, thus obtaining the compound of the formula [4].

The compound of the formula [4] is subjected to cyclization with obtaining the compounds of formula [5] [in which each symbol has the values listed above].

The compound of the formula [5] are galogenirovannyie, thus obtaining the compound of the formula [6] [in which each symbol has the values listed above].

The compound of the formula [6] is subjected to interaction with the compound of the formula [8] [in which each symbol has the values listed above], thus obtaining the compound of the formula [7] [in which each symbol has the values listed above].

The compound of the formula [7] is subjected to interaction with the compound of the formula [9] [in which each symbol has a value, indicated the data above], thus obtaining the compound of the formula [Ia1], which is not necessarily transform in pharmaceutically acceptable salt.

The compound of the formula [7] is subjected to interaction with the compound of the formula [10] [in which L represents-B(OR)2, -B(OH)2or SnR3R represents lower alkyl and the other symbols have the meanings specified above], thus obtaining the compound of the formula [Ia2], which is not necessarily transform in pharmaceutically acceptable salt.

The compound of the formula [Ia2] restore, thus obtaining the compound of the formula [Ia3], which is not necessarily transform in pharmaceutically acceptable salt.

The interaction of the compounds of formula [1] and acetonitrile conduct appropriate in the presence of a base. As such a base can appropriately be applied, for example, alkoxides of alkali metals, such as tert-piperonyl potassium hydrides of alkali metals, such as sodium hydride, hydroxides of alkali metals such as sodium hydroxide. The reaction can be carried out in a suitable solvent. As such a solvent can suitably be used any solvent which does not adversely influence the reaction, for example, toluene and the like. The reaction is carried out suitably at a temperature from -78°C to 100°C, particularly when rate is the atur from 0°C to room temperature.

The interaction of the compounds of formula [2] and hydrazine appropriately carried out in the presence of acid. As such acid can suitably be used, for example, organic acids such as acetic acid, and inorganic acids such as hydrochloric acid. The reaction can be carried out in a suitable solvent. As such a solvent can suitably be used any solvent which does not adversely influence the reaction, for example, alcohol solvents such as methanol and ethanol, organic solvents, such as acetic acid, or a combination of both. The reaction is suitably carried out at a temperature from 0°C to 150°C, in particular at temperatures from 80°C to 120°C.

With regard to the interaction of the compounds of formula [3] and ethylmaleimide, preferred examples of the nucleophilic agent include alcohols, such as ethanol. The reaction is appropriately carried out in the presence of a base. As such a base in a suitable manner can be used, for example, organic bases such as triethylamine and pyridine. The reaction can be carried out in a suitable solvent. As such a solvent can suitably be used any solvent which does not adversely influence the reaction, for example, methylthio the ID, chloroform, pyridine and the like or a combination thereof. The reaction is suitably carried out at a temperature from -78°C to 100°C, in particular at a temperature from 0°C to room temperature.

With regard to the interaction of the compounds of formula [3] and ethylhydroxylamine, the reaction is appropriately carried out in the presence of a condensing agent. As the condensing agent can appropriately be applied, for example, hydrochloride, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide and diisopropylcarbodiimide. The reaction can be carried out in a suitable solvent. As such a solvent can suitably be used any solvent which does not adversely influence the reaction such as methylene chloride, chloroform, pyridine, dimethylformamide and N-organic, and the like or their combination. The reaction is suitably carried out at a temperature from -20°C to 60°C, in particular at temperatures from 0°C to room temperature.

The cyclization reaction of the compounds of formula [4] suitably carried out in the presence of a base. As such a base in a suitable manner can be used, for example, organic bases such as dimethylaminopyridine and diisopropylethylamine, base metals, such as sodium hydride, or an aqueous solution of ammonia. The reaction can be about the contain in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the reaction, for example, alcohol solvents such as methanol and ethanol, water, dimethylformamide, dimethylacetamide or N-organic and the like or their combination. The reaction is suitably carried out at a temperature from -78°C to 100°C, in particular at temperatures from 0°C to room temperature.

The reaction of halogenation of the compounds of formula [5] can be performed by providing a compound capable of interacting with the halogenation agent. Examples of such halogenation agent include phosphorus oxychloride, and the like. The reaction can be carried out in a suitable solvent or without solvent. As such a solvent can be used any solvent which does not adversely influence the reaction, for example, preferably, can be applied toluene, xylene and the like. The reaction is suitably carried out at a temperature from 0°C to 150°C, in particular at temperatures from 80°C to 120°C.

The interaction of the compounds of formula [6] with the compound of the formula [8] suitably carried out in the presence of a base. When the compound of the formula [8] is a compound having an amino group, can appropriately be used as such a base, for example, the R, organic bases, such as dimethylaminopyridine and diisopropylethylamine, base metals, such as sodium bicarbonate and potassium carbonate, and the like. When the compound of the formula [8] is a compound having an alcoholic hydroxyl group, as such a base can be applied, for example, base metals, such as sodium hydride, and the like. When the compound of the formula [8] is a compound having a phenolic hydroxyl group, as such base can appropriately be applied, for example, base metals, such as sodium hydride and cesium carbonate, and the like. The reaction can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the reaction, for example, dimethylformamide, dimethylacetamide, N-organic, and the like, or a combination of both. The reaction is suitably carried out at a temperature from -78°C to 100°C, in particular at temperatures from 0°C to room temperature.

The interaction of the compounds of formula [7] with the compound of the formula [9] suitably carried out in the presence of a base. As such a base in a suitable manner can be used, for example, organic bases such as dimethylaminopyridine and diisopropylethylamine is, base metals, such as sodium bicarbonate and potassium carbonate, and the like. The reaction can be carried out in a suitable solvent. As such a solvent can suitably be used any solvent which does not adversely influence the reaction, for example, dimethylformamide, dimethylacetamide, N-the organic and the like or their combination. The reaction is suitably carried out at a temperature from -78°C to 100°C, in particular at temperatures from 0°C to 100°C.

The interaction of the compounds of formula [7] with the compound of the formula [10] suitably carried out in the presence of palladium catalyst. As a palladium catalyst in a suitable manner it is possible to apply a palladium catalyst with a valence of 0 or valence 2, such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, palladium(II) acetate. When L represents-B(OR)2or-B(OH)2the reaction is appropriately carried out in the presence of a base. As such a base in a suitable manner can be used, for example, base metals, such as carbonates of alkali metals, hydroxides of alkaline metals, phosphates of alkali metals and alkali metal fluorides, organic bases such as triethylamine, and the like. The reaction can be conducted in the walking solvent or without solvent. As such a solvent can suitably be used any solvent which does not adversely influence the reaction, for example, dimethoxyethane, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform, water or a combination of both. The reaction is suitably carried out at a temperature from 60°C to 150°C, in particular at temperatures from 80°C to 120°C.

The recovery of the compounds of formula [Ia2] well carry out the reaction of catalytic hydrogenation, which is carried out in the presence of a catalyst, such as palladium, in an atmosphere of hydrogen. The reaction can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the reaction, for example, it is possible to use solvents of the type of ester, such as ethyl acetate, alcohol solvents such as ethanol, solvents such as ether, such as tetrahydrofuran containing halogen solvents such as methylene chloride, or a combination of both. The reaction is carried out in an appropriate manner in such a solvent in a hydrogen atmosphere at a pressure of from 1 to 3 atmospheres and at a temperature from 0°C to room temperature.

The method of obtaining 2

The compounds of formula [I] in which R1represents hydrogen and Y represents an optionally substituted and the keel, that is, the compounds represented by the following formula:

the formula [Ia4] [in which Ybrepresents optionally substituted alkyl and the other symbols have the same meanings as described above],

the formula [Ia5] [in which each symbol has the same meanings as above]

the formula [Ia6] [in which each symbol has the same meanings as above]

can be obtained as follows receipt.

The compound of the formula [3] is subjected to interaction with the compound of the formula [11] [in which each symbol has the meanings as above], followed by addition of a nucleophilic agent, thus obtaining the compound of formula [12] [in which each symbol has the values listed above].

The compound of the formula {12] is subjected to cyclization, thus obtaining the compound of formula [13] [in which each symbol has the values listed above].

The compound of the formula [13] are galogenirovannyie, thus obtaining the compound of the formula [14] [in which each symbol has the values listed above].

The compound of the formula [14] [in which each symbol has the values listed above] are subjected to interaction with the compound of the formula [9], thus obtaining the compound of the formula [Ia4], which is not necessarily transform in pharmaceutically acceptable with the l.

The compound of the formula [14] is subjected to interaction with the compound of the formula [10], thus obtaining the compound of the formula [Ia5], which is not necessarily transform in pharmaceutically acceptable salt.

The compound of the formula [Ia5] restore, thus obtaining the compound of the formula [Ia6], which is not necessarily transform in pharmaceutically acceptable salt.

The interaction of the compounds of formula [11] with the compound of the formula [3] can be carried out by interaction of the compounds of formula [11] with a halogenation agent such as oxaliplatin, while receiving the acid chloride of the acid, with subsequent interaction of the product, similar to the interaction of the compounds of formula [3] with ethylmaleimide, as described in the method of obtaining 1. The compound of the formula [11] can be obtained conventional synthetic method for obtaining the complex of β-keeeper.

The cyclization of the compounds of formula [12] suitably carried out in the presence of a base. As such a base can appropriately be applied, for example, organic bases such as dimethylaminopyridine and diisopropylethylamine, base metals, such as sodium hydride, or an aqueous solution of ammonia. The reaction can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the Oia reaction, for example, you can appropriately apply alcohol solvents such as methanol and ethanol, water, dimethylformamide, dimethylacetamide, N-the organic and the like or a combination thereof. The reaction is suitably carried out at a temperature from -78°C to 100°C, in particular at a temperature from 0°C to room temperature.

Halogenoalkane compound of the formula [13] can be performed in the same manner as the reaction of halogenation of the compounds of formula [5], described in the method of obtaining 1.

The interaction of the compounds of formula [14] with the compound of the formula [9] can be similar to the interaction of the compounds of formula [7] with the compound of the formula [9], described in the method of obtaining 1.

The interaction of the compounds of formula [14] with the compound of the formula [10] can be similar to the interaction of the compounds of formula [7] with the compound of the formula [10], described in the method of obtaining 1.

The recovery of the compounds of formula [Ia5] can be similar to the recovery of the compounds of formula [Ia2] described the method of obtaining 1.

The method of obtaining 3

The compounds of formula [Ia3] can also be obtained by the following method.

The compound of the formula [3] is subjected to interaction with the compound of the formula [15] [in which R represents lower alkyl and the other symbols have the meanings at Azania above], thus obtaining the compound of the formula [16] [in which each symbol has the values listed above].

The compound of the formula [16] are galogenirovannyie to obtain the compounds of formula [17] [in which each symbol has the values listed above].

The compound of the formula [17] is subjected to interaction with the compound of the formula [8], thus obtaining the compound of the formula [Ia3], which is not necessarily transform in pharmaceutically acceptable salt.

The interaction of the compounds of formula [3] with the compound of the formula [15] suitably carried out in the presence of a base. As such a base can appropriately be applied, for example, sodium alkoxide, and the like. The reaction can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely affect the reaction, and suitably can be applied, for example, alcohol solvents such as methanol, ethanol and methoxyethanol or a combination thereof. The reaction is suitably carried out at a temperature from 60°C to 160°C, in particular at temperatures from 80°C to 130°C.

Halogenoalkane the compounds of formula [16] can be performed in the same manner as the reaction of halogenation of the compounds of formula [5], described in the method of obtaining 1.

The interaction of the compounds of formula [17] with the connection Faure the uly [8] can be performed in the same way, as the interaction of the compounds of formula [6] with the compound of the formula [8], described in the method of obtaining 1.

The method of obtaining 4

The compounds of formula [I] in which R1is not hydrogen, i.e. compounds represented

the formula [Ib1] [in which R1arepresents halogen and the other symbols have the meanings specified above]

the formula [Ib2] [in which R1brepresents a lower alkyl or cyano and the other symbols have the meanings specified above]

can be obtained as follows receipt.

The compound of the formula [Ia] is subjected to interaction with a halogenation agent, thus obtaining the compound of the formula [Ib1], which is not necessarily transform in pharmaceutically acceptable salt.

The compound of the formula [Ib1] is subjected to interaction with an alkylating agent or tianyoude agent, thus obtaining the compound of the formula [Ib2], which is not necessarily transform in pharmaceutically acceptable salt.

Examples of the halogenation agent used in the above method for obtaining the compounds of formula [Ib1] include, for example, N-halogenating. This reaction can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not exert negative is considerable influence on the reaction, can appropriately be applied, for example, galogensoderjashimi solvents, such as chloroform and methylene chloride. The reaction is suitably carried out at a temperature from 0°C to room temperature.

The above-described method of obtaining the compounds of formula [Ib2] suitably carried out in the presence of palladium catalyst. As the palladium catalyst can suitably be applied palladium catalyst with a valence of 0 or valence 2, such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, diphenylphosphino(dppf)palladium(II) chloride, palladium(II) acetate and the like. As such alkylating agent used in this method can appropriately be applied boron-containing agents, such as trimethylboroxine, and zinc-containing agents, such as dialkylzinc and alkylcyclohexane. As such tianyoude agent used in the method can appropriately be applied cyanide zinc and the like. When the boron-containing agent is used as the alkylating agent, the reaction is appropriately carried out in the presence of a base. As such a base in a suitable manner can be used, for example, base metals, such as carbonates, alkali metal hydroxides, alkali metal phosphate is an alkali metal and the alkali metal fluorides, organic bases such as triethylamine and the like. This method can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the reaction can suitably be used, for example, dimethoxyethane, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform, water or a combination of both. The reaction is suitably carried out at a temperature from 60°C to 150°C, in particular at a temperature from 80°C to 120°C.

The method of obtaining 5

The compounds of formula [Ia7] [in which each symbol has the values listed above] can be obtained also by the following method.

The compound of the formula [19] [in which each symbol has the values listed above] can be obtained in the same manner as the above methods of obtaining 1-4, the compounds of formula [18] [in which each symbol has the values listed above], an alternative to the compound of formula [3].

The compound of the formula [19] is subjected to hydrolysis, thus obtaining the compound of the formula [20] [in which each symbol has the values listed above].

The compound of the formula [20] is subjected to interaction with the hydrochloride with N,O-dimethylhydroxylamine, thus obtaining the compound of the formula [21] [in which each symbol has the value of the order the items above].

The compound of the formula [21] is subjected to interaction with the compound of the formula [23] [where Hal is a halogen and each character has the values listed above], thus obtaining the compound of the formula [22] [in which each symbol has the values listed above].

The compound of the formula [22] is subjected to oxidation, thus obtaining the compound of the formula [24] [in which each symbol has the values listed above].

The compound of the formula [24] is subjected to interaction with the compound of the formula [25] [wheremeans single bond or double bond, and each symbol has the same meanings which are listed above], thus obtaining the compound of the formula [Ia7] [in which each symbol has the same meanings which are listed above].

The hydrolysis of compounds of formula [19] suitably carried out in the presence of a base. As such a base is used, the alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like. The hydrolysis can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the reaction, for example, appropriately you can use water; alcohol such as methanol, ethanol and the like; ether such as tetrahydrofuran, dioxane and the like, or their mixture. Reacts the Yu suitably carried out at a temperature from 0°C to room temperature.

The interaction of the compounds of formula [20] with the hydrochloride of N,O-dimethylhydroxylamine appropriately carried out in the presence of a condensing agent such as carbodiimide reagent (such as carbodiimide reagent used dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the like), phosphate reagent (such as phosphorous reagent used diethylthiophosphate and the like) or the reagent type gelegenheid acid (such as reagent type gelegenheid acid used alkylchlorosilanes and the like). The reaction can be carried out in the presence of a base such as triethylamine. The reaction can be carried out in a suitable solvent. As such a solvent can suitably be used any solvent which does not adversely influence the reaction, for example, can appropriately be applied halogenated solvents such as chloroform and methylene chloride. The reaction is carried out suitably at a temperature from 0°C to room temperature.

The interaction of the compounds of formula [21] with the compound of the formula [23] appropriately carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the reaction, for example, K is included, you can apply ether, such as tetrahydrofuran, dioxane and the like. The reaction is suitably carried out at a temperature from -78°C to room temperature. The reaction can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the reaction, for example, appropriately you can apply tetrahydrofuran, dioxane and the like. The reaction is suitably carried out at a temperature from 0°C to room temperature.

Oxidation of compounds of formula [22] suitably carried out in the presence of oxidizing reagent. As such oxidizing reagent can appropriately apply sodium nitrite. The reaction can be performed in the presence of acid, such as conc. hydrochloric acid. The reaction can be carried out in a suitable solvent. As such a solvent can be used any solvent which does not adversely influence the reaction, for example, can appropriately be applied tetrahydrofuran, dioxane and the like. The reaction is suitably carried out at a temperature from 0°C to room temperature.

The interaction of the compounds of formula [24] with the compound of the formula [25] appropriately carried out in a suitable solvent. As such a solvent can be applied to any dissolve the spruce, which does not adversely influence the reaction, for example, appropriately you can use water, alcohol such as methanol, ethanol and the like, or their mixture. The reaction is suitably carried out at a temperature from 0°C to room temperature. When in the formula [25] symbolmeans a single bond, the compound of the formula [Ia7] can be obtained by the oxidation reaction is an accepted way after the above interaction of the compounds of formula [24] with the compound of the formula [25].

Starting compound in the above schemes (methods of obtaining 1-4) can be obtained by methods known in this field and/or as specified in the reference examples described below.

In addition, the compounds of formula [I] obtained by the above schemes (methods of obtaining 1-4), you can provide opportunities for structural transformation into other compounds of formula [I] by the methods indicated in examples described below, and/or known in the field, or a combination thereof.

When the compound of the present invention, synthetic intermediate or starting compound have a functional group (hydroxyl group, amino, carboxy), the reaction can be conducted by protecting the functional group protecting group commonly used in organic this is eskay chemistry, such as the groups described in Greene's Protecting Group in Organic Synthesis, and then the protective group can be removed to obtain the desired connection.

Compounds of the present invention or their original connection, you can select and clear in the form of the free form (free base or free acid or in the form of their salts. Salt can be obtained commonly used treatments for the formation of salts. For example, processing for obtaining the salts can be carried out by adding acid or base, or their solution to the solution or suspension of the compounds of the present invention. The preferred acid to obtain pharmaceutically acceptable salts include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrobromic acid, acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonate, benzosulfimide, p-toluensulfonate and maleic acid. The preferred basis for obtaining pharmaceutically acceptable salts include salts of alkali metals such as sodium and potassium salts, and salts of alkaline earth metals such as calcium salts. Solvent to obtain a solution or suspension of the compounds of the present invention can be any solvent which does not adversely influence the reaction of the salt.Examples include water; alcohol, such as methanol, ethanol and propanol; esters such as ethyl acetate; an ether such as diethyl ether, dioxane and tetrahydrofuran; dichloromethane and chloroform, or a mixture.

Isolation and purification can be carried out by ordinary chemical procedures such as extraction, concentration, crystallization, filtration, recrystallization and various types of chromatography.

The compounds of formula [I] or their pharmaceutically acceptable salts according to the present invention have excellent inhibiting PDE10 activity, i.e. inhibitory activity against the enzymatic activity of phosphodiesterase 10 (PDE10, in particular PDE10A), in mammals. The compounds of formula [I] or their pharmaceutically acceptable salts according to the present invention are also very selective in respect of PDE10.

In addition, the compounds of formula [I] or pharmaceutically acceptable salts of the present invention exhibit various pharmacological efficiency due to their inhibiting PDE10 activity. Accordingly, the pharmaceutical composition comprising the compounds of formula [I] or its pharmaceutically acceptable salt as an active ingredient, can be used for inhibiting PDE10 activity. In addition, the mentioned pharmaceutical composition can be used for treatment or prevention C the illnesses or conditions, the symptoms which can be alleviated by inhibition of PDE10 activity.

As the disease or condition, the symptoms of which may be alleviated by inhibition of PDE10 activity, you can specify, for example,

psychotic illness, such as schizophrenia:

for example, schizophrenia, schizophreniform disease, delusion disorder, schizoaffective disorder, caused by substance psychotic disorder, paranoid or schizoid personality disorder, etc.;

anxiety disorder:

for example, panic disorder, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, etc.;

addiction to the excessive use of drugs:

for example, chronic alcoholism, an addiction to amphetamine, cocaine, or opiate, etc.;

violations of containing the deficit in cognitive ability as a symptom:

for example, dementia (including Alzheimer's disease, dementia due to multiple heart attacks, and so on), delirium, impaired, causing memory loss, posttraumatic stress disturbance, mental retardation, learning disorder, attention deficit disorder and hyperactivity disorder (ADHD) associated with age of mythology the reduced cognitive abilities, and so on; and

affective disorder:

for example, depressive episode, severe, delimitable disorder, minor depressive disorder, bipolar depressive disorder (includes polar depressive disorder I and bipolar depressive disorder II), cyclothymic disorder, and so on, or

episode mood:

for example, major depressive episode, manic or mixed episode, and hypomanic episode and so on

Of these diseases and conditions may be desirable to focus on the treatment of the following diseases through the use of compounds of the invention:

schizophrenia;

anxiety disorders:

for example, panic disorder, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder;

addiction to the excessive use of the medication;

violations of containing the deficit in cognitive ability as a symptom:

for example, dementia (including Alzheimer's disease, and so on), learning disorders, attention deficit disorder and hyperactivity disorder (ADHD) and associated with age, the decline in cognitive abilities; and

affective disorder,

for example, major depressive episode, severe, disti the systematic disorder, minor depressive disorder, bipolar disorder.

Of these diseases and conditions may be desirable to more specifically focus on the treatment of the following diseases through the use of compounds of the invention:

schizophrenia;

anxiety disorders:

for example, panic disorder, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and

affective disorder,

for example, major depressive episode, severe, distimicescie disorder, minor depressive disorder, bipolar disorder.

It may be desirable to focus more specifically on the treatment of schizophrenia through the use of compounds of the invention.

In addition, the compounds of the invention can be used to treat the disease or condition, the symptoms of which may be alleviated by inhibition of PDE10 activity, including, for example,

of movement disorder or neurodegenerative disorders,

including dyskinesia associated with therapy with dopamine agonist;

Huntington's disease;

Parkinson's disease, and

tired leg syndrome.

In addition, the compounds of the invention can be used to treat the disease or condition symptoms, which is about may be alleviated by inhibition of PDE10 activity, including, for example, cancer.

In addition, the compounds of the invention can be used to treat the disease or condition, the symptoms of which may be alleviated by inhibition of PDE10 activity, which includes, for example,

diabetes type 1 or type 2 or non-insulin dependent diabetes (NIDDM),

impaired glucose tolerance (IGT),

the low content of fasting blood glucose (IGF),

metabolic syndrome and

associated with metabolic disorders, including obesity or excess fat in the body from suffering from obesity of the patient.

In the scope of the present invention, there is also a method of treating or preventing a disease or condition by administration to the patient (or subject) in need, an effective amount of the compounds of formula [I] or its pharmaceutically acceptable salt.

In addition, the scope of the present invention also includes the use of compounds of formula [I] or its pharmaceutically acceptable salt for the manufacture of a medicinal product.

Inhibitory effect on PDE10 and pharmacological actions of the compounds of the present invention can be confirmed by known methods and equivalent methods.

For example, measurements PDE10 inhibitory activity can be carried out by a method described below in the experimental example 1, or by the methods described in writer is the atur. See, for example, Fujishige et al., Eur. J. Biochem., vol. 266, pp. 1118-1127, 1999, and Mukai et al., Br. J. Pharmacol., vol. 111, pp.389-390, 1994.

In addition, the selectivity of the compounds described in the context in respect of PDE10, can be estimated using the methods described in the literature. See, for example, Kotera et al., Biochem. Pharmacol., vol. 60, pp. 1333-1341, 2000;. Sasaki et al., Biochem. Biophys. Res. Commun., vol. 271, pp. 575-583, 2000; Yuasa et al., Journal of Biological Chemistry, vol. 275, pp. 31469-31479, 2000; Gamanuma et al., Cellular Signaling, vol. 15, pp. 565-574, 2003.

Pharmacological effect on the symptoms of schizophrenia can be detected through testing systems in vivo in mice or rats.

- MK-801-induced locomotor activity:

[O'neil and Shaw, Psychopharmacology, 1999, 145:237-250].

- Apomorphine-induced locomotor activity:

[Geyer et al., Pharmacol. Biochem. Behav., 1987, 28:393-399; Ellenbroek, Pharmacol. Ther., 1993, 57:1-78].

- Avoidance conditioned reflex:

[Moor et al., J. Pharmacol. Exp. Ther., 1992, 262:545-551].

Pharmacological actions to improve symptomatic of a lack of cognitive ability in schizophrenia, etc. can be determined by the following test systems in vivo in mice or rats.

- MK-801-induced failure of inhibition of the preceding pulse (PPI) for the content in isolation:

[Mansbach and Geyer, Neuropsychopharmacology., 1989, 2:299-308; Bakshi et al., J. Pharmacol. Exp. Ther, 1994, 271:787-794;. Bubenikova et al., Pharmacol. Biochem. Behav., 2005, 80:591-596].

- Lack of inhibition of the previous the total impulse (PPI), caused by content in isolation:

[Cilia et al., Psychopharmacology, 2001, 156:327-337].

- MK-801-induced failure when setting the unknown object recognition (NOR):

[Karasawa et al., Behav. Brain. Res., 2008, 186:78-83].

The compounds of formula [I] or their pharmaceutically acceptable salts can be used for introduction in conventional pharmaceutical preparations such as tablets, granules, capsules, powder, solution, suspension, emulsion, inhalation means, injecting means, drops and so on, by mixing the compound(s) with inert pharmaceutically acceptable carrier that is suitable for each route of administration.

Examples of such carriers include any conventional pharmaceutically acceptable substances such as connecting means (Arabian gum, gelatin, sorbitol, polyvinylpyrrolidone, and so on), excipients (lactose, sucrose, corn starch, sorbitol and so on), lubricants (magnesium stearate, talc, polyethylene glycol and so on), dezintegriruetsja substances (potato starch and so on), and the like.

In the case of the injection of funds and drops compounds of the present invention can be mixed with distilled water for injection, physiological saline, aqueous glucose solution and the like liquid.

Route of administration of compounds of the formula [I] or their pharmaceutically acceptable salts is not only limited specific way. They can be administered orally or parenterally (for example, by intravenous, intramuscular, subcutaneous, transdermal, transnasal, enteral route or through the mucous membrane).

In addition, in the case of treatment of diseases of the Central nervous system (CNS) drug, directly or indirectly, to enter into the brain, overcoming the blood-brain barrier (BBB). Examples of such methods include intracerebroventricular (i.c.v.) introduction and method of administration, followed by an intravenous infusion of a hypertonic solution, which enables the temporal opening of the BBB (osmotic opening).

When the compound of the formula [I] or its pharmaceutically acceptable salt is used for medical uses, the dosage of compounds can be determined in accordance with the performance or properties of the compounds to establish the dose range that is sufficiently effective to achieve the desired pharmacological effectiveness. The dosage may vary depending on the method of administration, age, weight and condition of the patient. The usual dose range may be, for example, range from 0.001 to 300 mg/kg / day, preferably 0.001 to 30 mg/kg / day.

The method of treatment or prevention using the compounds to which the present invention is used for the treatment or prevention of human disease. However, it can also be applied to a mammal other than the human.

Below the present invention is illustrated in more detail by the following examples. Examples are given to illustrate the invention, but should not be construed as limiting the invention. Reference is made to the claims to determine that was not presented by the authors of the invention.

EXAMPLES

Experimental example 1: measurement of PDE10 inhibitory activity

(1) Bullish PDE10A (bPDE10A) were isolated and obtained from bovine striatum, according to the methods described in the link Fujishige et al., Eur. J. Biochem., vol. 266, pp. 1118-1127, 1999. PDE10A person (hPDE10A) was isolated from COS-7 cells, transfected with plasmids encoding PDE10A2, according to the methods described in the link Kotera et al., Biochem. Biophys. Res. Commun., vol. 261, pp. 551-557, 1999. The obtained solutions of the enzymes used for the analysis of PDE.

The PDE analysis was performed according to the modified method specified in the publication Kotera et al. (Kotera et al., Biochem. Pharmacol., vol. 60, pp. 1333-1341, 2000), method radiometric nucleotides.

In particular, measurement of inhibitory activity was performed by the following method.

Way

Compound was dissolved in dimethyl sulfoxide (DMSO). 2 μl of a solution of compounds were added in a 96-well plate, and in this 96-well plate was added to the reaction mixture (20 μl of a solution of the enzyme PDE 50 is M Tris-HCl, pH 8.0, 40 μl of buffer for analysis (50 mm Tris-HCl, pH 8.0, 2 mm MgCl2, of 0.07% 2-mercaptoethanol and 0,825 mg/ml bovine serum albumin) and 20 ál of 1 mg/ml snake venom in 50 mm Tris-HCl, pH 8.0). The enzymatic reaction was started by adding and mixing with 20 µl of substrate solution containing approximately 35 nm3N-camp in 50 mm Tris-HCl, pH 8.0. The final concentration of camp in the reaction mixtures was 7 nm. The reaction mixture was incubated at room temperature for 90 min After incubation the reaction was stopped by adding 100 μl of methanol, and the resulting solutions were applied to filter the tablet containing Dowex (1×8 200-400) and centrifuged. 50 μl of the eluate with eluate washing with an additional 100 μl of methanol was collected in another tablet, and measured the radioactivity.

(2) Compounds of the examples below, were tested for inhibition of PDE using the method described above.

They had the value of the IC5030 nm or less. The value of the IC50some preferred compounds are given in the following tables I and II.

Table I
# exampleIC50(nm)# exampleIC50(nm)№ PR is a measure IC50(nm)
1.001 (HCl)0,111.0470,0451.1120,0085
1.002 (3/2 HCl)0,00451.0500,0191.1140,044
1.003 (HCl)0,831.0580,651.1230,15
1.0060,0901.0590,321.1260,17
1.0090,201.0620,871.1330,23
1.010 (HCl)0,381.0810,391.144 (free)0,48
1.0110,221.0850,18 1.1470,39
1.0130,0901.0970,0351.1520,0068
1.0190,571.1090,781.1541,08
1.0270,131.1110,462.0010,36
1.0310,052
* These results were obtained with the use of a bullish PDE10A.

0,60
Table II
# exampleIC50(nm)# exampleIC50(nm)# exampleIC50(nm)
1.1730,271.1871.1980,82
1.1750,121.1890,181.1990,89
1.1810,641.1900,695.0010,15
1.1842,51.1972,55.0020,28
* These results were obtained with the use of PDE10A person.

Example 1.001

(a)

Method a: obtaining carried out in a manner analogous to the method described in Helv. Chim. Acta. 2001, 84, 2379).

Method B: a suspension of 3-chlorination-2-carboxylate (86,0 g, 363 mmol), trimethylboroxine (of 22.8 g of 0.182 mmol) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.90 g, 11.0 mmol) and potassium carbonate (100 g, 727 mmol) in 1,4-dioxane (726 ml) was heated at 115°C for 4 hours. Then again added trimethylboroxine (of 22.8 g of 0.182 mmol) and the mixture was heated at the same temperature for 2 hours. After cooling to ambient temperature the reaction mixture was diluted with ethyl acetate (70 ml) and filtered through celite using ethyl acetate (1000 ml). The filtrates were combined and concentrated in vacuum. The residue was purified column chromatography on silica gel (900 g silica gel, hexane:ethyl acetate=9:1-17:3) followed by recrystallization from cold hexane, thus obtaining the ethyl-3-methylphenoxy-2-carboxylate.

MC (APCI): m/z 217 (M+H).

(b)

To a suspension of tert-butoxide potassium (72,7 g, 647 mmol) in toluene (810 ml) was added a solution of ethyl-3-methylphenoxy-2-carboxylate (70,0 g, 324 mmol) and acetonitrile (38,3 ml, 809 mmol) in toluene (270 ml) dropwise over 50 min at 5°C. After stirring for 5 min at 0°C was added water (585 ml). The organic layer was extracted with water (100 ml), and aqueous layers were combined and acidified to pH 3-4 with 10% aqueous hydrochloric acid. The precipitate was collected and dissolved in tetrahydrofuran. Then the organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The crude solid was purified column chromatography on silica gel (2.2 kg of silica gel, elution with the use of chloroform to the mixture of chloroform:ethyl acetate=19:1), thus obtaining 3-(3-methylphenoxy-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 212 (M+H).

(c)

A suspension of 3-(3-methylphenoxy-2-yl)-3-oxopropanenitrile (45,8 g, 217 mmol) and hydrazine monohydrate (15,8 ml, 325 mmol) in acetic acid (109 ml) and ethanol (1083 ml) was boiled under reflux during the 17 hours. After cooling to ambient temperature, the reaction mixture was diluted with water (360 ml) and podslushivaet to pH 8 with sodium bicarbonate. The precipitate was collected and washed with diisopropyl ether. The crude product was diluted with methanol (1077 ml) was added potassium carbonate (29,9 g), and then the mixture was heated at 60°C for 2 hours. The precipitate was collected and washed with diisopropyl ether, thus obtaining 3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 226 (M+H).

(d)

Method a: to a solution of 3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-amine (5,00 g of 22.2 mmol) in N,N-dimethylacetamide (111 ml) was added ethylmalonate (of 5.68 ml, 44.4 mmol) and pyridine (37,2 ml, at 45.9 mmol) at 0°C. After stirring for 3 h, the reaction mixture was diluted with ethanol (118 ml) and stirred at room temperature for 18 hours. After adding water (260 ml) the precipitate was collected and washed with water, thus obtaining the ethyl-3-{[3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 340 (M+H).

Method B: to a suspension of 3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-amine (5,00 g of 22.2 mmol) and ethylhydroxylamine (2,88 ml, 24.4 mmol) in pyridine (89 ml) were added hydrochloride, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (6,38 g, 33.3 mmol) at 0°C, and the mixture was stirred for 30 minutes, the Reaction mixture was stirred for 1 hour at room temperature and the eat was concentrated in vacuum. The residue was diluted with water (100 ml) and the precipitate was collected and washed with water followed by washing with diethyl ether, thus obtaining the ethyl-3-{[3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 340 (M+H).

(e)

Method A (free form): a suspension of ethyl-3-{[3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (20,0 g, of 58.9 mmol) of 28% aqueous ammonia (295 ml) and methanol (1176 ml) was stirred over night at room temperature and then concentrated in vacuum. The residue was diluted with water (1500 ml) and ethyl acetate (1000 ml). The aqueous layer was concentrated in vacuo and added water (40 ml). The mixture was acidified to pH 5-6 with 10% aqueous hydrochloric acid and then added ethanol (360 ml). The precipitate was collected and washed with 95% aqueous ethanol and ethanol, thus obtaining 2-(3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 292 (M-H).

Method B (g DMAP): a suspension of ethyl-3-{[3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (1,00 g, 2,95 mmol) and 4-dimethylaminopyridine (DMAP) (1.08 g, 8,84 mmol) in water (7 ml), tetrahydrofuran (7 ml) and methanol (7 ml) was heated at 65°C for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with water and ethyl acetate. The aqueous layer was collected and concentrated in vacuum. The residue is triturated with ethyl acetate, the of learn at the same time, DMAP salt 2-(3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 294 (M+H).

(f)

A suspension of 2-(3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (2,98 g, 6.95 mmol) in phosphorus oxychloride (10,7 ml) was heated at 100°C for 1 hour. After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The residue was poured into aqueous potassium carbonate solution and then precipitate was collected and washed with water, thus obtaining 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-methylpenicillin.

MC (APCI): m/z 330/332 (M+H).

(g)

A suspension of 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-methylinosine (991 mg, 3.00 mmol), 4-aminotetrahydrofuran (364 mg, of 3.60 mmol) and triethylamine (1.25 ml, of 9.00 mmol) in N,N-dimethylformamide (30 ml) was stirred for 2 hours at room temperature. After cooling to 0°C the reaction mixture was diluted with water. The precipitate was collected and purified column chromatography on silica gel (200 g of silica gel, elution with the use of chloroform to the mixture of chloroform:ethyl acetate=1:1), while receiving 5-chloro-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APC1): m/z 395/397 (M+H).

(h)

A suspension of 5-chloro-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (620 mg, 1.57 mmol) in pyrrolidine (12 ml) was heated at 80°C for 3 hours. Then the reaction mixture was poured into cold water. The sediment when Bireli and washed with water, thus obtaining 2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APCI): m/z 430 (M+H).

(i)

To a suspension of 2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (655 mg, of 1.52 mmol) in ethanol (15 ml) was added 2 N. aqueous solution of hydrochloric acid (0,915 ml). The mixture was heated at 80°C for 3 h and then added water (3.1 ml) and ethanol (5.0 ml). The mixture was a clear solution and then cooled to ambient temperature to give the hydrochloride of 2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 1.001 specified in the table of examples below).

1H-NMR (500 MHz, DMSO-d6): δ 1,86 is 1.91 (4H, m), 2,04 e 2.06 (4H, m), is 3.08 (3H, s), 3.46 in-of 3.53 (2H, m), 3,63 (4H, m), of 3.94 (2H, m), 4.09 to (1H, m), 5,62 (1H, s), 6.87 in (1H, s), 7,83-of 7.90 (2H, m), 8,08 (1H, DD, J=8,2, 1,4 Hz) to 8.14 (1H, DD, J=8,0, 1.3 Hz), to 8.20 (1H, Shir.).

Getting dihydrochloride salt was also conducted in a similar way with the use of an excess quantity of an aqueous solution of hydrochloric acid.

Example 1.002

(a)

Obtaining carried out in the same manner as in example 1.001 (g) of 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-methylinosine (200 mg, 0,606 mmol) and N-methyl-4-aminotetrahydrofuran (84 mg, advanced 0.729 mmol), while receiving 5-chloro-N-methyl-2-(3-metalink the Alin-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APCI): m/z 409/411 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (h), 5-chloro-N-methyl-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (100 mg, 0,245 mmol), thus obtaining N-methyl-2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APCI): m/z 444 (M+H).

(C)

The receipt was produced in the same manner as in example 1.001 (i), of N-methyl-2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (692 mg, 1.53 mmol) to give the hydrochloride of N-methyl-2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 1.002 specified in the table of examples below).

1H-NMR (500 MHz, DMSO-d6): δ 1,78-of 1.81 (2H, m), 1,98-2,07 (6H, m), 3,10 (3H, s), of 3.13 (3H, s), 3,63 (4H, W), 3,39-3,44 (2H, m) to 3.99 (2H, DD, J=11,2, 4.5 Hz), 5,24 (1H, m), 5,46 (1H, s), 7,02 (1H, s), a 7.85-7,89 (2H, m), 8,05-8,07 (1H, m), 8,13-of 8.15 (1H, m).

Obtaining 3/2-cleaners containing hydrochloride salt was also conducted in a similar way with the use of an excess quantity of an aqueous solution of hydrochloric acid.

Example 1.003

(a)

To a suspension of 5-chloro-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (example 1.001 (g)) (4.26 deaths / g to 10.8 mmol), hydrochloride (R)-3-terpinolene (13,7 g, 108 mmol) and Diisopropylamine the ina (20.7 g, 160 mmol) in N-methyl-2-pyrrolidinone (108 ml) was heated at 80ºC for 3 days. After cooling to ambient temperature, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (800 g silica gel, elution with application from a mixture of hexane:ethyl acetate=1:1 to ethyl acetate) to give 5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APCI): m/z 448 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (i), from 5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (4.15 g, 9,27 mmol) to give the hydrochloride 5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 1.003 specified in the table of examples below).

1H-NMR (500 MHz, DMSO-d6): δ 1,83-of 1.94 (4H, m), 2.21 are of 2.45 (2H, m), is 3.08 (3H, s), 3,47-to 3.52 (1H, m), 3,66-and 3.72 (1H, m), 3,80-to 4.14 (4H, m), to 5.58 (1H, m), to 5.66 (1H, s), to 6.88 (1H, s), 7,83-of 7.90 (2H, m), 8,07 (1H, m), 8,14 (1H, m), 8,19 (1H, Shir.).

Getting dihydrochloride salt also conducted in a similar way with the use of excess water races is the thief of hydrochloric acid.

Example 1.004

(a)

Obtaining carried out in the same manner as in example 1.001 (a). To a solution of tert-butyl(E)-[(1E)-1-ethyl-3-methoxy-3-oxoprop-1-EN-1-yl]disincorporate (see Synlett. 2003, 8, 1183; 1.50 g, to 6.19 mmol) in tetrahydrofuran (30 ml) was added 1,2-phenylenediamine (683 mg, to 6.19 mmol) at room temperature. After stirring for 22 h, the reaction mixture was poured into water and was extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (elution with the use of hexane to a mixture of hexane:ethyl acetate=6:1), thus obtaining the ethyl-3-utilisation-2-carboxylate.

MC (APCI): m/z 217 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3-utilisation-2-carboxylate (2.37 g, or 10.3 mmol), thus obtaining 3-(3-utilisation-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 226 (M+H).

(C)

Obtaining carried out in the same manner as in example 1.001 (C), from 3-(3-utilisation-2-yl)-3-oxopropanenitrile (1,00 g, 9,01 mmol), thus obtaining 3-(3-utilisation-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 240 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3-utilisation-2-yl)-1H-pyrazole-5-amine (1,41 g of 5.89 mmol), thus obtaining the ethyl-3-{[3-(3-utilisation-2-yl)-1-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 354 (M+H).

(e)

Obtaining carried out in the same manner as the method And example 1.001, (e) of ethyl-3-{[3-(3-utilisation-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (1.70 g, to 4.81 mmol), thus obtaining 2-(3-utilisation-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 306 (M-H).

(f)

Obtaining carried out in the same manner as the method of example 1.001 (f) from 2-(3-utilisation-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (1,03 g, is 2.41 mmol), thus obtaining 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-utilisation.

MC (APCI): m/z 344/346 (M+H).

(g)

Obtaining carried out in the same manner as the method of example 1.001 (g), 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-acylhomoserine (734 mg, 2,13 mmol), while receiving 5-chloro-2-(3-utilisation-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APCI): m/z 409/411 (M+H).

(h)

Obtaining carried out in the same manner as the method of example 1.001 (h), 5-chloro-2-(3-utilisation-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (204 mg, 0,500 mmol), thus obtaining 2-(3-utilisation-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APCI): m/z 444 (M+H).

(i)

To a solution of 2-(3-utilisation-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (132 mg, 2.00 mmol) in chloroform (2.0 ml) was added a 4 n solution of hydrogen chloride in 1,4-dioxane (0.5 ml). Obrazovash is the action scene precipitate was collected and washed with diethyl ether, while receiving the dihydrochloride of 2-(3-utilisation-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 1.004 specified in the table of examples below).

1H-NMR (400 MHz, DMSO-d6): δ is 1.31 (3H, t, J=7.4 Hz), 1.85 to 1.91 a (4H, m), 2,04 e 2.06 (4H, m), of 3.45 (2H, square, J=7,4 Hz), the 3.65 (4H, m), of 3.94 (2H, m), of 4.12 (1H, m), 5,64 (1H, s) 6,86 (1H, s), 7,84-a 7.92 (2H, m), 8,10-of 8.15 (2H, m), a 8.34 (1H, Shir.d, J=8,8 Hz).

Example 1.005

(a)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3-triftormetilfosfinov (10.4 g, a 38.5 mmol), thus obtaining 3-(3-cryptometrics-2-yl)-3-oxopropanenitrile.

MC (ESI): m/z 264 (M-H).

(b)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3-cryptometrics-2-yl)-3-oxopropanenitrile (8,33 g of 31.4 mmol), thus obtaining 3-(3-cryptometrics-2-yl)-1H-pyrazole-5-amine.

MC (ESI): m/z 280 (M+H).

(C)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3-cryptometrics-2-yl)-1H-pyrazole-5-amine (6,34 g, 22.7 mmol), thus obtaining the ethyl-3-{[3-(3-cryptometrics-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (ESI): m/z 394 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-{[3-(3-cryptometrics-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (6,87 g, 17.5 mmol), thus obtaining 2-(3-cryptometrics-2-yl)pyrazolo[1,5-a]Piri is one-5,7-diol.

MC (ESI): m/z 346 (M-H).

(e)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3-cryptometrics-2-yl)pyrazolo[1,5-a] pyrimidine-5,7-diol (4.94 g, of 14.2 mmol), thus obtaining 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-cryptometrics.

MC (APCI): m/z 384/386 (M+H).

(f)

Obtaining carried out in the same manner as in example 1.001 (g), 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-triftormetilfosfinov (300 mg, 0,781 mmol), while receiving 5-chloro-N-(tetrahydro-2H-Piran-4-yl)-2-(3-cryptometrics-2-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APCI): m/z 449/451 (M+H).

(g)

Obtaining carried out in the same manner as in example 1.001 (h), 5-chloro-N-(tetrahydro-2H-Piran-4-yl)-2-(3-cryptometrics-2-yl)pyrazolo[1,5-a]pyrimidine-7-amine (172 mg, 0.384 mmol), while receiving 5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-[3-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-amine.

MC (APCI): m/z 484 (M+H).

(h)

Obtaining carried out in the same manner as in example 1.001 (i), from 5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-[3-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-amine (177 mg, 0,367 mmol) to give the hydrochloride of 5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-[3-(trifluoromethyl) cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 1.005 specified in the table of examples below).

1H-NMR (400 MHz, DMSO-d6 ): δ 1,78 is 1.86 (4H, m), 2,03-2,07 (4H, m), 3,,45-3,51(2H, m), 3,63 (4H, m), 3,91 (2H, m), 4.09 to (1H, m), the 5.65 (1H, s), 6,69 (1H, s), 8,11-8,19 (2H, m), 8,31-8,39 (2H, m).

Example 1.006

(a)

To a suspension of sodium hydride (60% dispersion in mineral oil, 12.0 g, 300 mmol) in toluene (450 ml) was added a solution of ethyl-7-fluoro-3-methylphenoxy 2-carboxylate (35.1 g, 150 mmol) and acetonitrile (19.6 ml, 375 mmol) in toluene (40 ml) dropwise over 35 min at 85°C. After stirring for 5 min at the same temperature, the reaction mixture was cooled to 0°C, and then added water (175 ml). The aqueous layer was separated and the organic layer was extracted with 1 N. aqueous sodium hydroxide solution (200 ml). The combined aqueous layer was acidified to pH 2 conc. hydrochloric acid (45,0 ml) at 0°C, and the precipitate was collected and washed with water (150 ml). The solid was dissolved in chloroform (1000 ml) and water (500 ml). The aqueous layer was extracted with chloroform (300 ml). The combined organic layer was washed with saturated salt solution, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuum. The residue is triturated with ethanol, thus obtaining 3-(7-fluoro-3-methylphenoxy-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 230 (M+H).

(b)

To a suspension of 3-(7-fluoro-3-methylphenoxy-2-yl)-3-oxopropanenitrile (48.6 g, 212 mmol) in ethanol (530 ml) and acetic acid (53 ml) was added hydrazinehydrate (79% and 19.6 ml, 318 mmol). The reaction is th mixture was boiled under reflux for 5 hours and then concentrated in vacuum. The residue was sequentially washed with water and diisopropyl ether, thus obtaining 3-(7-fluoro-3-methylphenoxy-2-yl)-1H-Pirat-5-amine.

MC (APCI): m/z 244 (M+H).

(c)

To a suspension of 3-(7-fluoro-3-methylphenoxy-2-yl)-1H-pyrazole-5-amine (of 45.7 g, 188 mmol) in pyridine (750 ml) was added acylhydrolase (5,35 ml, 62.5 mmol) and the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (54,0 g, 282 mmol) at 0°C. the Reaction mixture was stirred at ambient temperature for 3 h and then concentrated in vacuum. The residue was washed successively with water, ethanol and acetone, thus obtaining the ethyl-3-{[3-(7-fluoro-3-methylphenoxy-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 358 (M+H).

(d)

To a suspension of ethyl-3-{[3-(7-fluoro-3-methylphenoxy-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (30.0 g, 84,0 mmol) in methanol (210 ml), tetrahydrofuran (210 ml) and water (210 ml) was added 4-dimethylaminopyridine (51,3 g, 420 mmol) at ambient temperature. After stirring at 85°C for 5 hours, the reaction mixture was diluted with ethyl acetate (750 ml) and water (750 ml) at ambient temperature. The insoluble substance was separated by filtration. The filtrate was washed with water (450 ml). The combined aqueous layer was washed with ethyl acetate (500 ml ×2) and acidified to pH 2 conc. hydrochloric acid (17,0 ml) at ambient temperature and then stirred n is for night. The precipitate was collected and washed with water, thus obtaining 2-(7-fluoro-3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 312 (M+H).

(e)

A suspension of 2-(7-fluoro-3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (8,30 g, to 26.7 mmol) in phosphorus oxychloride (81,1 g, 534 mmol) was heated at 100°C for 3 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The residue was poured into 10% aqueous potassium carbonate solution (700 ml) at 0°C. the precipitate was collected and washed with water, thus obtaining 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-6-fluoro-2-methylphenoxy.

MC (APCI): m/z 348/350 (M+H).

(f)

A suspension of 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-6-fluoro-2-methylinosine (157 mg, 0,451 mmol) in N,N-dimethylformamide (4.0 ml), 1-amino-2-methylpropan-2-ol (48 mg, 0,541 mmol) and potassium carbonate (187 mg, 1.35 mmol) was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and the precipitate was collected and washed with water, thus obtaining 1-{[5-chloro-2-(7-fluoro-3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-2-methylpropan-2-ol.

MC (APCI): m/z 401/403 (M+H).

(g)

A suspension of 1-{[5-chloro-2-(7-fluoro-3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-2-methylpropan-2-ol (170 mg, 0,424 mmol), hydrochloride (s)-3-terpinolene (268 mg, 2,12 mmol) and 1,8-databits the CLO[5,4,0]undec-7-ene (387 mg, 2.54 mmol) in N-methylpyrrolidinone (5.0 ml) was heated at 70°C over night. After cooling to ambient temperature the reaction mixture was diluted with ice water. The precipitate was collected and washed with water, thus obtaining 1-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-2-methylpropan-2-ol.

MC (APCI): m/z 454 (M+H).

(h)

To a suspension of 1-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-2-methylpropan-2-ol (213 mg, 0,470 mmol) in ethanol (3.0 ml) was added 2 N. aqueous hydrochloric acid (0,282 ml), and the mixture was heated at 80°C, and then added ethanol (2.0 ml) and water (0.2 ml). The mixture was slowly cooled to ambient temperature and then was added ethanol (2.0 ml). The precipitate was collected and washed with diethyl ether to give the hydrochloride of 1-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-2-methylpropan-2-ol (the compound of example 1.006 specified in the table of examples below).

1H-NMR (400 MHz, DMSO-d6): δ 1,24 (6H, s), 2,25 is 2.43 (2H, m), 3,10 (3H, s), 3,62-3,70 (2H, m), 3,80-4,01 (4H, m), 5,52-5,63 (1H, m), 5,71 (1H, s) 6,94 (1H, s), 7,81 (1H, DDD, J=9,1, of 8.8, 2.7 Hz), 7,95 (1H, DD, J=9,6, 2,9 Hz), to 7.99 (1H, W), to 8.14 (1H, DD, J=9,1, 5,9 Hz).

Example 1.007

A suspension of 5-chloro-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)feast of the olo[1,5-a]pyrimidine-7-amine (example 1.001 (g)) (398 mg, 1.01 mmol) and (S)-3-hydroxypyrrolidine (351 mg, a 4.03 mmol) in N-methyl-2-pyrrolidinone (5.0 ml) was heated at 80°C for 6 hours. Then the reaction mixture was poured into cold water. The precipitate was collected and purified column chromatography on silica gel (elution with use of ethyl acetate is added to a mixture of ethyl acetate:methanol=7:3) to give 1-[2-(3-methylphenoxy-2-yl)-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-5-yl]pyrrolidin-3-ol (the compound of example 1.007 specified in the table of examples below).

1H-NMR (500 MHz, CDCl3): δ 1,74-of 1.81 (2H, m), 2,12-2,22 (4H, m), 3,03 (3H, s) to 3.58 (2H, dt, J=2,3, with 11.9 Hz), 3,65 is 3.76 (5H, m), 4,08 (2H, dt, J=11,6, a 3.2 Hz), with 4.64-of 4.67 (1H, m), 5,16 (1H, s), 6,16 (1H, d, J=8.0 Hz), of 6.66 (1H, s), 7,70-7,76 (2H, m), 8,03-with 8.05 (1H, m), 8.17-a 8,19 (1H, m).

Example 1.008

To a solution of 1-[2-(3-methylphenoxy-2-yl)-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-5-yl]pyrrolidin-3-ol (200 mg, 0,449 mmol) and methanesulfonamide (77 mg, 0,673 mmol) in dichloromethane (5.0 ml) was added triethylamine (0,125 ml, 0,898 mmol) at 0°C. After stirring for 2 h the reaction mixture was poured into water. The mixture was extracted with chloroform, and the organic layer was washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (elution with the use of chloroform to the mixture chlorof the RM:methanol=97:3), while receiving (3S)-1-[2-(3-methylphenoxy-2-yl)-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-5-yl]pyrrolidin-3-elmersolver (compound of example 1.008 specified in the table of examples below).

1H-NMR (400 MHz, CDCl3): δ 1,73 of-1.83 (2H, m), 2,12-of 2.15 (2H, m), 2,30-2,39 (1H, m), 2,47-2,52 (1H, m), 3.04 from (3H, s), is 3.08 (3H, s), 3,56-3,63 (2H, m), 3,68-to 3.89 (4H, m), 3,99-was 4.02 (1H, m), 4,07-4,10 (2H, m), 5,19 (1H, s), 5,44-5,46 (1H, m), of 6.20 (1H, d, J=8,2 Hz), to 6.67 (1H, s), 7,70-to 7.77 (2H, m), 8,03-of 8.06 (1H, m), 8,16-8,19 (1H, m).

Example 1.009

A solution of (3S)-1-[2-(3-methylphenoxy-2-yl)-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-5-yl]pyrrolidin-3-ylmethanone (50 mg, 0,0955 mmol), 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (108 mg, 0,286 mmol) and potassium fluoride (17 mg, 0,286 mmol) in acetonitrile (2.0 ml) boiled under reflux for 15 minutes After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The crude product was purified column chromatography on silica gel (elution with the use of chloroform to the mixture of chloroform:methanol=97:3), while receiving 5-(2,5-dihydro-1H-pyrrol-1-yl)-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 1.009 specified in the table of examples below).

1H-NMR (400 MHz, CDCl3): δ 1,73-to 1.82 (2H, m), 2,13-of 2.16 (2H, m), 3.04 from (3H, s) and 3.59 (2H, dt, J=11.8 in, and 2.1 Hz ), 3,68-of 3.78 (1H, m), 4.09 to (2H, dt, J=11.8 in, and 3.6 Hz), to 4.38 (4H, W), of 5.17 (1H,s), 5,98 (2H, s), 6,17 (1H, d, J=7.9 Hz), to 6.67 (1H, s), 7,69-to 7.77 (2H, m), 8,03-of 8.06 (1H, m), 8.17-a 8,19 (1H, m).

Example 1.010

(a)

To a suspension of sodium hydride (60% dispersion in mineral oil, 12 mg, 0,303 mmol) in 1,4-dioxane (3.0 ml) was added 4-hydroxymitragynine (31 mg, 0,303 mmol) at 0°C. After stirring at room temperature for 10 min, was added 5-chloro-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (example 1.001 (g)) (100 mg, 0,303 mmol). The reaction mixture was stirred at the same temperature overnight and then poured into water, and the mixture was extracted with chloroform. The organic layer was washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=9:1-1:1), thus obtaining 2-[5-chloro-7-(tetrahydro-2H-Piran-4-yloxy)pyrazolo[1,5-a]pyrimidine-2-yl]-3-methylpenicillin.

MC (APCI): m/z 396/398 (M+H).

(b)

A mixture of 2-[5-chloro-7-(tetrahydro-2H-Piran-4-yloxy)pyrazolo[1,5-a]pyrimidine-2-yl]-3-methylinosine (90 mg, 0,227 mmol), pyrrolidine (49 mg, 0,682 mmol), tert-butoxide sodium (33 mg, 0,341 mmol), palladium(II) acetate (52 mg, 0,227 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)diphenyl (179 mg, 0,454 mmol) in 1,4-dioxane (4.0 ml) was heated at 100°C for 40 minutes After cooling to ambient temperature the reaction mixtures is ü poured into water and the mixture was extracted with chloroform. The organic layer was washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=1:1-1:9), thus obtaining 2-methyl-3-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-yloxy)pyrazolo[1,5-a]pyrimidine-2-yl]cinoxacin.

MC (APCI): m/z 431 (M+H).

(c)

Obtaining carried out in the same manner as in example 1.001 (i) to give the hydrochloride of 2-methyl-3-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-yloxy)pyrazolo[1,5-a]pyrimidine-2-yl]finokalia (compound of example 1.010 specified in the table of examples below).

1H-NMR (400 MHz, DMSO-d6): δ 1,82-1,90 (2H, m), 2,04-2,07 (4H, m), 2,14-to 2.18 (2H, m) to 3.09 (3H, s), 3,62-3,68 (6H, m), 3,90-of 3.95 (2H, m), 5,35-5,41 (1H, m), 6,12 (1H, s), of 6.99 (1H, s), 7,82-7,89 (2H, m), 8,03-8,08 (1H, m), 8,13-of 8.15 (1H, m).

Getting dihydrochloride salt also conducted in a similar way with the use of an excess quantity of an aqueous solution of hydrochloric acid.

Example 1.011

A suspension of 5-chloro-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (example 1.001 (g)) (97 mg, 0,246 mmol), cyclopenten-1-Voronovo acid (55 mg, 0,491 mmol), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0,0493 mmol) and cesium fluoride (112 mg, 0,737 mmol) in 1,2-dimethoxyethane (2.0 ml) was heated at 80°C for 3 hours. After cooling to ambient temperature with the food, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=9:1-2:3), while receiving 5-cyclopent-1-EN-1-yl-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 1.011 specified in the table of examples below).

1H-NMR (400 MHz, CDCl3): δ 1,73 is 1.86 (2H, m), 2,03-of 2.21 (4H, m), 2,60-of 2.66 (2H, m), 2,86-of 2.93 (2H, m), 3,05 (3H, s), 3,61 (2H, DDD, J=11.8 in, 11,8, 2.4 Hz), of 3.77-a 3.87 (1H, m), 4,10 (2H, DDD, J=11.8 in, 3,3, 3,3 Hz), to 6.19 (1H, s), 6,33 (1H, d, J=8,2 Hz), of 6.68 (1H, s), was 7.08 (1H, s), 7,72-7,79 (2H, m), 8,04-8,08 (1H, m), 8.17-a 8,21 (1H, m).

Example 1.012

A suspension of 5-cyclopent-1-EN-1-yl-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (30 mg, 0,0703 mmol) and palladium on coal (5%, 30 mg) in dichloromethane (2.0 ml) and methanol (2.0 ml) was stirred for 3 hours in hydrogen atmosphere. Then the reaction mixture was filtered with the use of chloroform and the filtrate was concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=19:1-1:1), while receiving 5-cyclopentyl-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 1.012 specified in the table of examples below).

1H-NMR (400 MHz, CDCl3): δ 1,67-of 1.95 (8H, m), 2,08-2,20 (H, m), 3,05 (3H, s), 3,11-of 3.23 (1H, m), of 3.60 (2H, DDD, J=11.8 in, 11,8, 2.4 Hz), 3,74-of 3.85 (1H, m), 4,10 (2H, DDD, J=11,5, 3,3, 3,3 Hz) 5,94 (1H, s), 6,32 (1H , d, J=7.9 Hz), 7,02 (1H, s), 7,71-7,79 (2H, m), 8,04-8,08 (1H, m), 8,16-to 8.20 (1H, m).

Example 1.013

(a)

Obtaining carried out in the same manner as in example 1.006 (f), 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-6-fluoro-2-methylinosine (1.90 g, 5.46 mmol) and TRANS-4-amino-1-methylcyclohexanol (846 mg, 6,55 mmol), get TRANS-4-{[5-chloro-2-(7-fluoro-3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-1-methylcyclohexanol.

MC (APCI): m/z 441/443 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.006 (g) of TRANS-4-{[5-chloro-2-(7-fluoro-3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-1-methylcyclohexanol (1,32 g, 3.00 mmol), get TRANS-4-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol).

MC (APCI): m/z 494 (M+H).

(c)

Obtaining carried out in the same manner as in example 1.006 (h), from TRANS-4-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol (1.18 g, 2,39 mmol) to give the hydrochloride TRANS-4-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol (compound of example 1.013 specified in the table of examples below).

1H-NMR (500 MHz, DMSO-d 6): δ 1,22 (3H, s), 1,55-1,65 (4H, m), 1.70 to is 1.81 (2H, m), 1,83-of 1.92 (2H, m), 2,19 is 2.44 (2H, m), 3,06 (3H, s), 3,63-4,01 (5H, m), of 5.55 (1H, m), 5,61 (1H, s), PC 6.82 (1H, s), 7,79-7,83 (1H, m), to $ 7.91-7,94 (2H, m), 8,14-8,17 (1H, m).

Examples 1.014-1.171

Connection examples 1.014-1.171 listed in the table of examples below was obtained in the same manner as described above in example 1.001.

Example 1.172

(a)

Salt (S)-2-(tert-butoxycarbonylamino-5-benzyloxyethanol acid and dicyclohexylamine (10.0 g, to 19.8 mmol) was purified column chromatography on silica gel (elution with use of ethyl acetate is added to a mixture of ethyl acetate:methanol=19:1) to remove dicyclohexylamine. The resulting oil, ethyl-2-amino-3-oxobutanoate (of 3.60 g of 19.8 mmol), hydrochloride ethyl-3-(3-dimethylaminopropyl)carbodiimide (5,69 g, 29.7 mmol), 1-hydroxybenzotriazole (4,01 g, 29.7 mmol), triethylamine (6,87 ml of 49.5 mmol) in chloroform (40 ml) was stirred for 6 hours at room temperature, and then the reaction mixture was poured into water. The organic layer was separated, washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=9:1-3:2), thus obtaining the ethyl-2-{[5-(benzyloxy)-N-(tert-butoxycarbonyl)-1-norvell]amino}-3-oxobutanoate.

MC (APCI): m/z 468 (M+NH4).

(b)

To a solution of ethyl-2-{[5-(benzyloxy)-N-(t is et-butoxycarbonyl)-L-Norwell]amino}-3-oxobutanoate (5.31g, to 11.8 mmol) in ethanol (20 ml) was added 4 N. hydrochloric acid in 1,4-dioxane (20 ml) at room temperature. After stirring for 16 h at the same temperature, the reaction mixture was concentrated in vacuum. A solution of the residue in pyridine (40 ml) was heated at 60°C for 23 hours. After cooling to ambient temperature the mixture was concentrated in vacuum. The residue was poured into water and the mixture was extracted with chloroform. The organic layer was washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. To a solution of the residue in dichloromethane (20 ml) was added manganese dioxide (1,03 g) at room temperature. After stirring for 1.5 h at the same temperature, the reaction mixture was filtered through celite using chloroform. The filtrates were combined and concentrated in vacuum. The crude product was purified column chromatography on silica gel (elution with the use of chloroform to the mixture of chloroform:methanol=19:1), thus obtaining the ethyl-5-[3-(benzyloxy)propyl]-6-hydroxy-3-methylpyrazine-2-carboxylate.

MC (APCI): m/z 331 (M+H).

(C)

A suspension of ethyl-5-[3-(benzyloxy)propyl]-6-hydroxy-3-methylpyrazine-2-carboxylate (2.91 in g 8,80 mmol) and palladium hydroxide (1.06 g) in ethanol (60 ml) was boiled under reflux for 7 hours. After cooling to tempera is URS environmental reaction mixture was filtered through celite with the use of ethanol. The filtrates were combined and concentrated in vacuum. The crude product was purified column chromatography on silica gel (elution with the use of chloroform to the mixture of chloroform:methanol=19:1), thus obtaining the ethyl-6-hydroxy-5-(3-hydroxypropyl)-3-methylpyrazine-2-carboxylate.

MC (APCI): m/z 241 (M+H).

(d)

To a solution of ethyl-6-hydroxy-5-(3-hydroxypropyl)-3-methylpyrazine-2-carboxylate (1,03 g, the 4.29 mmol) and triphenylphosphine (1,69 g, to 6.43 mmol) in tetrahydrofuran (86 ml) was added a solution of diethylazodicarboxylate (40 wt.% solution in toluene, of 2.92 ml, to 6.43 mmol) at room temperature. After stirring for 50 min, the reaction mixture was concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=9:1-7:3), rubbing with diisopropyl ether and column chromatography on silica gel (elution with the use of chloroform to the mixture of chloroform:methanol=19:1), thus obtaining the ethyl-2-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-carboxylate.

MC (APCI): m/z 223 (M+H).

(e)

Obtaining carried out in the same manner as the method in example 1.006 (a) of ethyl-2-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-carboxylate (725 mg, 3,26 mmol), thus obtaining 3-(2-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl)-3-oxopropanenitrile.

MC (APCI): m/z 218 (M+H).

(f)

Obtaining carried out in the same manner as in example 1.001 (C), from 3-(2-what ethyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl)-3-oxopropanenitrile (505 mg, 2.32 mmol), thus obtaining 3-(2-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 232 (M+H).

(g)

Obtaining carried out in the same manner as the method In example 1.006 (C), from 3-(2-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl)-1H-pyrazole-5-amine (550 mg, of 2.38 mmol), thus obtaining the ethyl-3-{[3-(2-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 346 (M+H).

(h)

A suspension of ethyl-3-{[3-(2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (535 mg, 1.55 mmol) and N,N-dimethylaminopyridine (946 mg, of 7.75 mmol) in methanol (15 ml), tetrahydrofuran (15 ml) and water (15 ml) was boiled under reflux for 25 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The residue was acidified to pH 2 6 N. aqueous hydrochloric acid at 0°C, and then concentrated in vacuum. The residue is triturated with ethyl acetate.

The crude product is and phosphorus oxychloride (11.9 g, 77.5 mmol) was treated in the same manner as in example 1.001 (f), thus obtaining 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin.

MC (APCI): m/z 336/338 (M+H).

(i)

Obtaining carried out in the same manner as in example 1.001 (g), 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazine (150 mg, 0,466 mmol), get TRANS-4-{[5-CHL is R-2-(2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-1-methylcyclohexanol.

MC (APCI): m/z 429/431 (M+H).

(j)

Obtaining carried out in the same manner as in example 1.001 (f) of TRANS-4-{[5-chloro-2-(2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-1-methylcyclohexanol (183 mg, 0,427 mmol), get TRANS-1-methyl-4-{[2-(2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol.

MC (APCI): m/z 464 (M+H).

(k)

Obtaining carried out in the same manner as in example 1.004 (i) of TRANS-1-methyl-4-{[2-(2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol (140 mg, 0,302 mmol) to give the hydrochloride of TRANS-1-methyl-4-{[2-(2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol (compound of example 1.172 specified in the table of examples below).

MC (APCI): m/z 464 (M+H).

1H NMR (500 MHz, DMSO-d6) δ: was 12.75 (1H, W), a 7.92 (1H, Shir.d) to 6.67 (1H, s), of 5.55 (1H, s), 4,36 (2H, t, J=4,8 Hz), 3,88 (1H, W), 3,62 (4H, W), 2,96 (2H, t, J=6.4 Hz), 2,80 (3H, s), 2,04-2,11 (6H, m), 1,82 is 1.86 (2H, m), 1,72 and 1.80 (2H, m), 1,58 is 1.60 (4H, m), 1,22 (3H, s).

Example 1.173

(a)

To a solution of 2-methoxy-6,7-dihydro-8H-pyrano[2,3-b]pyrazine (J. Chem. Soc. Perkin Trans. I 1988, 2585-2593; and 3.16 g, 19.0 mmol) in N,N-dimethylformamide (95 ml) was added N-bromosuccinimide (5,08 g, 28.5 mmol) at room temperature and then was heated at 60°C for 5 hours. After cooled the I to the ambient temperature, the reaction mixture was diluted with ethyl acetate, washed with 2% aqueous solution of sodium sulfite, water and saturated salt solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=9:1-7:3), thus obtaining 3-bromo-2-methoxy-7,8-dihydro-6H-pyrano[2,3-b]pyrazin.

MC (APCI): m/z 247 (M+H).

(b)

Obtaining carried out in the same manner as the method In example 1.001 (a), from 3-bromo-2-methoxy-7,8-dihydro-6H-pyrano[2,3-b]pyrazine (2,50 mg, 10.2 mmol), thus obtaining 2-methoxy-3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin.

MC (APCI): m/z 181 (M+H).

(c)

To a suspension of 2-methoxy-3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazine (1,95 g to 10.8 mmol) in sulfolane (25 ml) was added attributively (15.0 g, 75,0 mmol) at 30°C. the Reaction mixture was heated at 40-45°C for 8 h and then was cooled to ambient temperature and was stirred for 2 days. The reaction mixture was diluted with ethyl acetate and washed with 2% aqueous sodium sulfite. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (elution with use of ethyl acetate is added to a mixture of ethyl acetate:methanol=93:7), thus obtaining 3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-ol and dedicated ex is the initial connection.

MC (APCI): m/z 177 (M+H).

(d)

To a suspension of 3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-ol (735 mg, 6,33 mmol) and N,N-diisopropylethylamine (2,45 g, 19.0 mmol) in dichloromethane (37 ml) was added dropwise over 5 min at 0°C triftormetilfullerenov anhydride (2.14 g, to 7.59 mmol). After stirring for 30 min at the same temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, and the organic layer was washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=9:1-7:3), thus obtaining 3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-intraformational.

MC (APCI): m/z 299 (M+H).

(e)

A solution of 3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-intraformational (298 mg, 1.00 mmol), palladium(II) acetate (11 mg, 0,0490 mmol), bis(diphenylphosphino)ferrocene (55 mg, 0,0992 mmol) and triethylamine (202 mg, 2.00 mmol) in N,N-dimethylacetamide (3.0 ml) was heated at 80°C for 24 hours in an atmosphere of carbon monoxide. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on Sealy is agile (elution with application from a mixture of hexane:ethyl acetate=3:1 to ethyl acetate), while receiving ethyl-3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-carboxylate.

MC (APCI): m/z 223 (M+H).

(f)

Obtaining carried out in the same manner as the method In example 1.006 (a) of ethyl-3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-carboxylate (337 mg, of 1.52 mmol), thus obtaining 3-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 218 (M+H).

(g)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-3-oxopropanenitrile (236 mg, of 1.09 mmol), thus obtaining 3-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-1H-pyrazole-5-amine.

MC(APCI): m/z 232 (M+H).

(h)

Obtaining carried out in the same manner as the method And example to 1006 (c), from 3-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-1H-pyrazole-5-amine (253 mg, of 1.09 mmol), thus obtaining the ethyl-3-{[3-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 346 (M+H).

(i)

A suspension of ethyl-3-{[3-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (293 mg, 0,848 mmol) and N,N-dimethylaminopyridine (518 mg, 4,24 mmol) in methanol (3 ml), tetrahydrofuran (3 ml) and water (3 ml) was heated for 8 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuum. The residue is triturated with ethyl acetate, thus obtaining 2-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)Piras the lo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 300 (M+H).

(j)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (376 mg, 0,843 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin.

MC (APCI): m/z 336/338 (M+H).

(k)

Obtaining carried out in the same manner as in example 1.001 (g), 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazine (98 mg, 0,241 mmol), get TRANS-4-{[5-chloro-2-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-1-methylcyclohexanol.

MC (APCI): m/z 429/431 (M+H).

(l)

Obtaining carried out in the same manner as in example 1.001 (f) of TRANS-4-{[5-chloro-2-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-1-methylcyclohexanol (46 mg, 0,107 mmol), get TRANS-1-methyl-4-{[2-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol.

MC (APCI): m/z 464 (M+H).

(m)

Obtaining carried out in the same manner as in example 1.004 (i) of TRANS-1-methyl-4-{[2-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol (44 mg, 0,0949 mmol) to give the hydrochloride of TRANS-1-methyl-4-{[2-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-and the]amino}cyclohexanol (compound of example 1.173, specified in the table of examples below).

MC (APCI): m/z 464 (M+H).

1H-NMR (500 MHz, DMSO-d6): δ of 7.95 (1H, d, J=8.7 Hz), of 6.65 (1H, s) 5,52 (1H, s), 4,39 (2H, t, J=5,1 Hz), 3,80-of 3.94 (1H, m), 3,57-to 3.67 (4H, m), 2,96 (2H, DD, J=6,4, 6,1 Hz), is 2.74 (3H, s), is 2.09 (2H, DDT, J=6,4, 6,1, 5,1 Hz), 2,00-2,07 (4H, m), 1.70 to to 1.87 (4H, m), 1,55-to 1.63 (4H, m) to 1.21 (3H, s).

Examples 1.174-1.200

Connection examples 1.174-1.200 listed in the table of examples below was obtained in the same manner as described above in example 1.001.

Example 2.001

(a)

Obtaining carried out in the same manner as described in Chem. Pharm. Bu11. 1980, 28, 2494, from ethylhydroxylamine (2.65 g, and 19.3 mmol) and (tetrahydro-2H-Piran-4-yl)acetylchloride (1.50 g, 8,76 mmol), thus obtaining the ethyl-3-oxo-4-(tetrahydro-2H-Piran-4-yl)butanoate.

MC (APCI): m/z 215 (M+H).

(b)

A suspension of ethyl-3-oxo-4-(tetrahydro-2H-Piran-4-yl)butanoate (960 mg, 4,48 mmol) and 1 N. aqueous sodium hydroxide solution (9,00 ml of 9.00 mmol) was stirred at room temperature for 48 hours. The reaction mixture was washed with diethyl ether and then acidified to pH 3 with 0.5 N. sulfuric acid. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered and concentrated under vacuum, thus obtaining 3-oxo-4-(tetrahydro-2H-Piran-4-yl)butane acid.

MC (ESI): m/z 185 (M-H).

(c)

To a solution of 3-oxo-4-(tetrahydro-2H-Piran-4-yl)butane acid (186 mg, 1.00 mmol) in toluene (2.5 ml) and tetrahydro the wound (2.5 ml) was added oxaliplatin (190 mg, 1.50 mmol) at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under vacuum, thus obtaining the crude acid chloride acid (3-oxo-4-(tetrahydro-2H-Piran-4-yl)butanolide).

To a solution of 3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-amine (example 1.001 (c)) (68 mg, 0,300 mmol) and diisopropylethylamine (194 mg, 1.50 mmol) in dichloromethane (2.0 ml) was added a solution of crude acid chloride of acid in dichloromethane (1.0 ml) at 0°C. After stirring at room temperature for 3 hours, the reaction mixture was concentrated in vacuum. The residue was diluted with ethanol (6.0 ml) and heated at 60°C for 3 hours. After cooling to ambient temperature, the mixture was concentrated in vacuum. The residue was purified column chromatography on silica gel (elution with the use of chloroform to the mixture of chloroform:methanol=9:1), thus obtaining N-[3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-yl]-3-oxo-4-(tetrahydro-2H-Piran-4-yl)butanamide.

MC (APCI): m/z 394 (M+H).

(d)

Obtaining carried out in the same manner as the method in example 1.001 (e), from N-[3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-yl]-3-oxo-4-(tetrahydro-2H-Piran-4-yl)butanamide (41 mg, 0.104 g mmol), thus obtaining 2-(3-methylphenoxy-2-yl)-7-(tetrahydro-2H-Piran-4-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-ol.

MC (ESI): m/z 374 (M-H).

(e)

Obtaining carried out in the same manner as in example 1.001 (f, from 2-(3-methylphenoxy-2-yl)-7-(tetrahydro-2H-Piran-4-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-ol (18 mg, 0,047 mmol), thus obtaining 2-[5-chloro-7-(tetrahydro-2H-Piran-4-ylmethyl)pyrazolo[1,5-a]pyrimidine-2-yl]-3-methylpenicillin.

MC (APCI): m/z 394/396 (M+H).

(f)

Obtaining carried out in the same manner as in example 1.001 (h) from 2-[5-chloro-7-(tetrahydro-2H-Piran-4-ylmethyl)pyrazolo[1,5-a]pyrimidine-2-yl]-3-methylinosine (16 mg, 0,041 mmol), thus obtaining 2-methyl-3-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylmethyl)pyrazolo[1,5-a]pyrimidine-2-yl]cinoxacin (compound of example 2.001 specified in the table of examples below).

1H-NMR (400 MHz, CDCl3): δ 1,43-of 1.53 (2H, m), 1,67-1,71 (2H, m), 2,01-of 2.08 (5H, m), a 2.36-to 2.41 (1H, m), 3,03 (2H, d, J=7,0 Hz), of 3.12 (3H, s), 3,28 is 3.40 (3H, m), of 3.97 (2H, DD, J=11,3, a 3.2 Hz), 6,00 (1H, s) 6,86 (1H, s), 7,68 to 7.75 (2H, m), 8,01-of 8.06 (1H, m), 8,12-8,16 (1H, m).

Example 3.001

(a)

A mixture of 3-(3-methylphenoxy-2-yl)-1H-pyrazole-5-amine (example 1.001 (c)) (200 mg, 0,888 mmol), ethyl-3-cyclopropyl-3-oxopropionate (416 mg, of 2.66 mmol) and sodium methoxide (28% solution in methanol, of 1.03 g of 5.34 mmol) in 2-methoxyethanol (2.0 ml) was boiled under reflux for 10 hours. After cooling to ambient temperature the reaction mixture was acidified to pH 3-4 with acetic acid. The mixture was diluted with water, and the precipitate was collected and washed with diisopropyl ether, thus obtaining 5-cyclopropyl-2-(3-methylphenoxy-2-yl)pyrazole,5-a]pyrimidine-7-ol.

MC (APCI): m/z 318 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (f), from 5-cyclopropyl-2-(3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-ol (153 mg, 0,481 mmol), thus obtaining 2-(7-chloro-5-cyclopropylethanol[1,5-a]pyrimidine-2-yl)-3-methylphenoxy.

MC (APCI): m/z 336/338 (M+H).

(c)

Obtaining carried out in the same manner as in example 1.001 (g), 2-(7-chloro-5-cyclopropylethanol[1,5-a]pyrimidine-2-yl)-3-methylinosine (140 mg, 0,418 mmol), while receiving 5-cyclopropyl-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 3.001, specified in the table of examples below).

1H-NMR (400 MHz, DMSO-d6): δ of 1.31-1.42 (4H, m), 1,80-2,02 (4H, m), 2.26 and-is 2.37 (1H, m), is 3.08 (3H, s), 3,49 (2H, DDD, J=11.8 in, 11,8, 1.8 Hz), of 3.96 (2H, DD, J=10,6, and 3.3 Hz), 4,18-4,37 (1H, m), 6,50 (1H, s), to 7.09 (1H, s), 7,83-7,94 (2H, m), of 8.09 (1H, DD, J=7,9, 1.8 Hz), 8,17 (1H, DD, J=7,9, 1.8 Hz), 9,18-9,36 (1H, m).

Example 4.001

5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-[3-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-amine (50 mg, 0,0962 mmol) was neutralized with saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. Raw substance and N-bromosuccinimide (17 mg, 0,0962 mmol) in chloroform (1.0 ml) was stirred at 0°C for 50 minutes and Then the reaction mixture was poured into a saturated solution of bicarbonate on the RIA and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=3:1-1:1), thus obtaining 3-bromo-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-[3-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 4.001 specified in the table of examples below).

1H-NMR (500 MHz, DMSO-d6): δ 1,67 is 1.75 (2H, m), 1,86-1,89 (2H, m) of 1.97 (4H, W), 3,44-of 3.48 (2H, m), 3,53 (4H, W), a 3.87-to 3.89 (3H, m) to 5.56 (1H, s), 7,13 (1H, d, J=8.7 Hz), 8,14-to 8.20 (2H, m), 8,33-8,35 (1H, m), 8,39-to 8.41 (1H, m).

Example 4.002

Obtaining carried out in the same manner as the method in example 1.001 (a), from 3-bromo-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-[3-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-amine (30 mg, 0,0533 mmol), while receiving 3-methyl-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-[3-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 4.002 specified in the table of examples below).

1H-NMR (400 MHz, DMSO-d6): δ 1,62-1,72 (2H, m), 1,89-of 1.93 (2H, m), 1,94-of 1.97 (4H, m), is 2.05 (3H, s), 3.45 points-of 3.53 (6H, m), 3,86-to 3.89 (3H, m), 5,49 (1H, s) 6,70 (1H, d, J=8,8 Hz), 8.07-a of 8.15 (2H, m), 8,28-8,30 (1H, m), 8.34 per-at 8.36 (1H, m).

Examples 4.003-4.005

Connection examples 4.003-4.005 listed in the table of examples below was obtained in the same manner as described in the above-described example 4.001.

Examples 5.001 and 5.002

(a)

MC (APCI): m/z 270 (M+H).

(b)

To a suspension of ethyl-5-[(3-ethoxy-3-oxopropanoic)amino]-1H-pyrazole-3-carboxylate (2,60 g to 9.66 mmol) in ethanol (50 ml) and water (50 ml) was added N,N-dimethylaminopyridine (3,54 g, 29,0 mmol) at room temperature. After stirring for 22 h, the reaction mixture was concentrated in vacuum. The residue is triturated with a mixture of ethyl acetate/ethanol, thus obtaining the ethyl-5,7-dihydrotetrazolo[1,5-a]pyrimidine-2-carboxylate.

MC (APCI): m/z 224 (M+H), 123 (M+H DMAP).

(c)

A suspension of ethyl-5,7-dihydrotetrazolo[1,5-a]pyrimidine-2-carboxylate (9,59 g, 43,0 mmol) and phosphorus oxychloride (20,0 ml, 215 mmol) was boiled under reflux for 1 hour. After cooling to ambient temperature reaction the second mixture was poured into saturated sodium bicarbonate solution and chloroform. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and concentrated under vacuum, thus obtaining the ethyl-5,7-dichloropyrazine[1,5-a]pyrimidine-2-carboxylate.

MC (APCI): m/z 260/262 (M+H).

(d)

To a solution of ethyl-5,7-dichloropyrazine[1,5-a]pyrimidine-2-carboxylate (of 7.82 g, to 30.1 mmol) in N,N-dimethylformamide (100 ml) was added 4-aminotetrahydrofuran (3,65 g, 36,1 mmol) and triethylamine (9,12 g, 90,2 mmol) at 0°C. the Reaction mixture was stirred for 70 min at room temperature and then poured into water. The precipitate was collected, thus obtaining the ethyl-5-chloro-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate.

MC (APCI): m/z 325 (M+H).

(e)

To a solution of ethyl-5-chloro-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate (5,88 g of 18.1 mmol) in N,N-dimethylacetamide (50 ml) was added triethylamine (5.50 g, to 54.3 mmol) and pyrrolidine (1,59 ml, 19.0 mmol) at 0°C. the Mixture was heated at 60°C for 20 hours. Then add pyrrolidine (1,59 ml, 19.0 mmol) and the mixture was heated at 60°C for 24 hours. After cooling to ambient temperature the reaction mixture was poured into water. The precipitate was collected, thus obtaining the ethyl-5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate.

MC (APCI): m/z 360 (M+H).

(f)

To a solution of ethyl-5-pyrrolidin-1-yl-7-(tetrahydro-2H-PI is an-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate (1.89 g, of 5.26 mmol) in ethanol (25 ml) and tetrahydrofuran (25 ml) was added 1 N. aqueous solution of sodium hydroxide (10.5 ml, 10.5 mmol) at room temperature. After stirring for 23 h at the same temperature was added 6 N. aqueous hydrochloric acid (1.75 ml, 3.50 mmol), and then the reaction mixture was concentrated in vacuum. The residue is triturated with diisopropyl ether, thus obtaining 5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid.

MC (APCI): m/z 330 (M-H).

(g)

To a suspension of 5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (2.15 g, 5,26 mmol) in dichloromethane (60 ml) was added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.27 g, 13,0 mmol), hydrochloride of N,O-dimethylhydroxylamine (2,49 g, 13,0 mmol) and triethylamine (2.30 g, 22.7 mmol) at 0ºC. After stirring for 17 hours at room temperature the reaction mixture was poured into saturated sodium bicarbonate solution. The mixture was extracted with chloroform. The organic layer was washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (elution with the use of chloroform to the mixture of chloroform:methanol=19:1), thus obtaining N-methoxy-N-methyl-5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-yl) - Rev. Mino)pyrazolo[1,5-a]pyrimidine-2-carboxamide.

MC (APCI): m/z 375 (M+H).

(h)

To a suspension of N-methoxy-N-methyl-5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxamide (4,34 g, 11.6 mmol), di-tert-BUTYLCARBAMATE (15.2 g, to 69.6 mmol) and N,N-dimethylaminopyridine (1,49 g, 12.1 mmol) in tetrahydrofuran (100 ml) was stirred at room temperature for 3 days and then was heated at 50ºC for 10 hours. After cooling to ambient temperature the reaction mixture was poured into water. The mixture was extracted with chloroform. The organic layer was washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (elution with application from a mixture of chloroform:ethyl acetate=13:7 to ethyl acetate and then a mixture of ethyl acetate:methanol=4:1), while receiving tert-butyl(2-{[methoxy(methyl)amino]carbonyl}-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl)tetrahydro-2H-Piran-4-ylcarbamate.

MC (APCI): m/z 475 (M+H).

(i)

To a solution of tert-butyl(2-{[methoxy(methyl)amino]carbonyl}-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl)tetrahydro-2H-Piran-4-ylcarbamate (2,22 g, and 4.68 mmol) in tetrahydrofuran (50 ml) was added a solution of ethylmagnesium (1 M in tetrahydrofuran, of 14.0 ml, 14.0 mmol) at 0°C. After stirring for 20 min at the same temperature, the reaction mixture was poured into saturated rest the R of ammonium chloride. The mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (elution with the use of chloroform to the mixture of chloroform:ethyl acetate=3:2), while receiving tert-butyl-(2-propionyl 5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl)tetrahydro-2H-Piran-4-ylcarbamate.

MC (APCI): m/z 444 (M+H).

(j)

To a suspension of tert-butyl(2-propionyl 5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl)tetrahydro-2H-Piran-4-ylcarbamate (500 mg, 1.13 mmol) and sodium nitrite (233 mg, to 3.38 mmol) in tetrahydrofuran (10 ml) was added conc. a solution of hydrochloric acid (36%, 5.0 ml) at 0°C. After stirring for 20 h at room temperature, the reaction mixture was poured into saturated sodium bicarbonate solution. The mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (chloroform:ethyl acetate=1:1-1:9), thus obtaining 1-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-yl]propane-1,2-dione.

MC (APCI): m/z 358 (M+H).

(k)

To a solution of 1-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-yl]propane-1,2-dione (87 mg, 0,243 mmol) in methanol (3 ml) and water (0.3 ml) was added 3,4-diamine the one (29 mg, 0,268 mmol) at room temperature. After stirring for 24 h at the same temperature, the reaction mixture was concentrated in vacuum. The crude product was purified column chromatography on silica gel (chloroform:methanol=99:1 to 19:1) and HPLC (chirapaq IC, 20 FT×250 mm, hexane:ethanol:diethylamine=30:70:0.1, flow rate of 5.0 ml/min), thus obtaining 2-(3-methylpyridin[3,4-b]pyrazin-3-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 5,001 specified in the table of examples below) as a more polar compounds and 2-(2-methylpyridin[3,4-b]pyrazin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (the compound of example 5,002 specified in the table of examples below) as a less polar compounds. The absolute configuration was determined by x-ray diffraction analysis of 2-(2-methylpyridin[3,4-b]pyrazin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

The more polar compound, MS (APCI): m/z 358 (M+H).

1H-NMR (400 MHz, CDCl3): δ 9,58(1H, s), 8,79 (1H, d, J=5.7 Hz), 7,87 (1H, d, J=5.7 Hz), 6,70 (1H, s), 6,07 (1H, d, J=8,2 Hz), to 5.21 (1H, s) 4,08 (2H, dt, J=11,9, and 3.4 Hz), 3,68 of 3.75 (1H, m), 3,57-3,62 (6H, m), 3,10 (3H, s), 2,13-of 2.16 (2H, m), 2,03-2,07 (4H, m), 1,72-to 1.82 (2H, m).

The less polar compound, MC (APCI): m/z 358 (M+H).

1H-NMR (400MHz, CDCl3): δ 9,48(1H, s), 8,78 (1H, d, J=5.7 Hz), to 7.99 (1H, d, J=5.7 Hz), was 6.73 (1H, s), 6,07 (1H, d, J=8,2 Hz), 5,1 (1H, C) 4,08 (2H, dt, J=11,9, 3.6 Hz), 3,68 of 3.75 (1H, m), 3,57-3,62 (6H, m), 3,11 (3H, s), 2,13-of 2.16 (2H, m), 2,03-2,07 (4H, m), 1,72-to 1.82 (2H, m).

Reference example 1.01

(a)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3,5-dimethylquinoxaline-2-carboxylate (1,03 g, 4,47 mmol), thus obtaining 3-(3,5-dimethylquinoxaline-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 226 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3,5-dimethylquinoxaline-2-yl)-3-oxopropanenitrile (797 mg, 3.54 mmol), thus obtaining 3-(3,5-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 240 (M+H).

(c)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3,5-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine (783 mg, of 3.27 mmol), thus obtaining the ethyl-3-{[3-(3,5-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 354 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-{[3-(3,5-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (1,17 g of 3.31 mmol), thus obtaining 2-(3,5-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 306 (M-H).

(e)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3,5-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (997 mg, 3,24 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-3,5-dimethylquinoxaline (compound of reference example 1.01 specified in Alice reference examples below).

Reference example 1.02

(a)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3,6-dimethylquinoxaline-2-carboxylate (555 mg, 2,41 mmol), thus obtaining 3-(3,6-dimethylquinoxaline-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 226 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3,6-dimethylquinoxaline-2-yl)-3-oxopropanenitrile (385 mg, 1,71 mmol), thus obtaining 3-(3,6-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 240 (M+H).

(c)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3,6-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine (347 mg, 1,45 mmol), thus obtaining the ethyl-3-{[3-(3,6-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 354 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-{[3-(3,6-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (452 mg, 1.28 mmol), thus obtaining 2-(3,6-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 306 (M-H).

(e)

Obtaining carried out in the same manner as in example 1.001 (f), 2-(3,6-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (383 mg, 1.25 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-3,6-dimethylquinoxaline (compound of reference example 1.02 specified in the table of reference examples below).

MC (APCI): m/z 344/34 (M+H).

Reference example 1.03

(a)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3,7-dimethylquinoxaline-2-carboxylate (10.0 g, a 43.4 mmol), thus obtaining 3-(3,7-dimethylquinoxaline-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 226 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3,7-dimethylquinoxaline-2-yl)-3-oxopropanenitrile (8,11 g, 36,0 mmol), thus obtaining 3-(3,7-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 240 (M+H).

(c)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3,7-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine (300 mg, 1.25 mmol), thus obtaining the ethyl-3-{[3-(3,7-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 354 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-{[3-(3,7-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (700 mg, to 1.98 mmol), thus obtaining 2-(3,7-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 306 (M-N).

(e)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3,7-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (1.39 g, to 4.52 mmol), thus obtaining 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2,6-dimethylquinoxaline (compound of reference example 1.03 specified in the table of reference examples below).

Reference example 1.04

(a)

P is receiving carried out in the same way, as in the example 1.001 (b) of ethyl-3,8-dimethylquinoxaline-2-carboxylate (1.50 g, 6,51 mmol), thus obtaining 3-(3,8-dimethylquinoxaline-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 226 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3,8-dimethylquinoxaline-2-yl)-3-oxopropanenitrile (400 mg, 1.78 mmol), thus obtaining 3-(3,8-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 240 (M+H).

(c)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3,8-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine (250 mg, 1.04 mmol), thus obtaining the ethyl-3-{[3-(3,8-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 354 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-{[3-(3,8-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (158 mg, 0,447 mmol), thus obtaining 2-(3,8-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 308 (M+H).

(e)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3,8-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (316 mg, 1.01 mmol), thus obtaining 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2,5-dimethylquinoxaline (compound of reference example 1.04 specified in the table of reference examples below).

Reference example 1.05

(a)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3-methyl--cryptometrics-2-carboxylate (15.0 g, of 52.8 mmol), while receiving methyl-3-methyl-7-(trifluoromethyl)cinoxacin-2-carboxylate.

MC (APCI): m/z 280 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (c) from methyl 3-methyl-7-(trifluoromethyl)cinoxacin-2-carboxylate (2,11 g, 7.56 mmol), thus obtaining 3-[3-methyl-7-(trifluoromethyl)cinoxacin-2-yl]-1H-pyrazole-5-amine.

MC (APCI): m/z 294 (M+H).

(C)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-[3-methyl-7-(trifluoromethyl)cinoxacin-2-yl]-1H-pyrazole-5-amine (2,13 g of 7.25 mmol), thus obtaining the ethyl-3-({3-[3-methyl-7-(trifluoromethyl)cinoxacin-2-yl]-1H-pyrazole-5-yl}amino)-3-oxopropanoic.

MC (APCI): m/z 408 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-({3-[3-methyl-7-(trifluoromethyl)cinoxacin-2-yl]-1H-pyrazole-5-yl}amino)-3-oxopropanoic (to 2.29 g, 5,63 mmol), thus obtaining 2-[3-methyl-7-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 360 (M-H).

(e)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-[3-methyl-7-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-5,7-diol (2.00 g, 5,54 mmol), thus obtaining 3-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-2-methyl-6-(trifluoromethyl)cinoxacin (compound of reference example 1.05 specified in the table of reference examples below).

Reference example 1.06

(a)

Obtaining carried out in the same manner as in the example 1.001 (b), of ethyl-5-fluoro-3,7-dimethylquinoxaline-2-carboxylate (970 mg, 3,91 mmol), thus obtaining 3-(5-fluoro-3,7-dimethylquinoxaline-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 244 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(5-fluoro-3,7-dimethylquinoxaline-2-yl)-3-oxopropanenitrile (250 mg, of 1.03 mmol), thus obtaining 3-(5-fluoro-3,7-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 258 (M+H).

(c)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(5-fluoro-3,7-dimethylquinoxaline-2-yl)-1H-pyrazole-5-amine (262 mg, of 1.02 mmol), thus obtaining the ethyl-3-{[3-(5-fluoro-3,7-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 372 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-{[3-(5-fluoro-3,7-dimethylquinoxaline-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (224 mg, 0,605 mmol), thus obtaining 2-(5-fluoro-3,7-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 324 (M-N).

(e)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(5-fluoro-3,7-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (198 mg, 0,605 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-5-fluoro-3,7-dimethylquinoxaline (compound of reference example 1.06 specified in the table of reference examples below).

Reference example 1.07

(a)

To a solution of the hydrochloride of D-Alans is Yes (18,5 g 149 mmol) in methanol (230 ml) and water (23 ml), was added 50% aqueous solution of sodium hydroxide (13.5 g, 338 mmol) at -10°C. and then was added 1,2-cyclohexandione (15,1 g, 135 mmol) at the same temperature. After stirring over night the reaction mixture was neutralized 2 N. aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The precipitate was collected and washed with water and diisopropyl ether, thus obtaining 2-hydroxy-3-methyl-4,5,6,7-tetrahydroquinoxalin.

MS APCI): m/z 165 (M+H).

(b)

A mixture of 2-hydroxy-3-methyl-4,5,6,7-tetrahydroquinoxaline (1,61 g, 9,78 mmol) and phosphorus oxychloride(V) (7.50 g, for 48.9 mmol) was boiled under reflux for 6 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The residue was poured into saturated sodium bicarbonate solution at 0°C, and the mixture was extracted with chloroform. The organic layer was washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (elution with the use of hexane to a mixture of hexane:ethyl acetate=17:3), thus obtaining 2-chloro-3-methyl-4,5,6,7-tetrahydroquinoxalin.

MS APCI): m/z 183/185 (M+H).

(C)

A mixture of 2-hydroxy-3-methyl-4,5,6,7-tetrahydroquinoxaline (1,16 g, 6,36 mmol), molibden is kakabona (2.35 g, a 9.35 mmol), palladium(II) acetate (142 mg, 0,636 mmol), 2,2'-bis(diphenylphosphino)-1,1'-genatalia (396 mg, 0,636 mmol), cesium carbonate (2,07 g, 6,36 mmol) and ethanol (0,482 ml, compared to 8.26 mmol) in toluene (19 ml) and acetonitrile (12 ml) was heated at 80°C over night. After cooling to ambient temperature the reaction mixture was filtered with the use of chloroform. The filtrates were combined and washed with water and saturated salt solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=97:3-3:2), thus obtaining the ethyl-3-methyl-4,5,6,7-tetrahydroquinoxalin.

MS APCI): m/z 221 (M+H).

(d)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3-methyl-4,5,6,7-tetrahydroquinoxaline, (2,39 g, 10.9 mmol), thus obtaining 3-(3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl)-3-oxopropanenitrile.

MS (APCI): m/z 216 (M+H).

(e)

Obtaining carried out in the same manner as in example 1.001 (C), from 3-(3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl)-3-oxopropanenitrile (1,82 g, 8,46 mmol), thus obtaining 3-(3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl)-1H-pyrazole-5-amine.

MS (APCI): m/z 230 (M+H).

(f)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl)-1H-pyrazole-5-amine (2,08 g, 8,46 mmol) and compound of example 1.001 (e), obtaining p and 2-(3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 296 (M-H).

(g)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (2.16 g, 6,93 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-3-methyl-5,6,7,8-tetrahydroquinoxaline (compound of reference example 1,07 specified in the table of reference examples below).

Reference example 1.08

(a)

Suspension 3,5,6-trimethylpyrazine-2-yl)methanol (see Bioorg. Med. Chem. 2007, 15, 3315; 14.8 g, 97,2 mmol) and manganese oxide(IV) (30.0 g) in dichloromethane was stirred at room temperature for 3 days. The reaction mixture was filtered through celite using dichloromethane. The filtrates were combined and concentrated under vacuum, thus obtaining 3,5,6-trimethylpyrazine-2-carbaldehyde.

MC (APCI): m/z 151 (M+H).

(b)

To a solution of 3,5,6-trimethylpyrazine-2-carbaldehyde (4,51 g, 30.0 mmol), 2-methyl-2-butene (12,8 ml, 120 mmol) and the dihydrate of sodium dihydrophosphate (4.68 g, 30.0 mmol) in tert-butanol (90 ml) and water (30 ml) was added by portions at 0°C 80% solution of sodium chlorite (10.2 g, 90,0 mmol). After stirring at room temperature for 50 min, the reaction mixture was poured into 2 N. aqueous hydrochloric acid. The mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuum, obtaining the ri this 3,5,6-trimethylpyrazine-2-carboxylate.

MC (ESI): m/z 165 (M-H).

(c)

To a solution of 3,5,6-trimethylpyrazine-2-carboxylate (5,38 g, 30.0 mmol) in methanol (90 ml) at 0°C was added thionyl chloride (3,70 ml of 51.0 mmol). After stirring at room temperature overnight the reaction mixture was poured into saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated under vacuum, thus obtaining methyl-3,5,6-trimethylpyrazine-2-carboxylate.

MC (APCI): m/z 181 (M+H).

(d)

Obtaining carried out in the same manner as in example 1.001 (b) from methyl-3,5,6-trimethylpyrazine-2-carboxylate (2.91 in g, 16,1 mmol), thus obtaining 3-oxo-3-(3,5,6-trimethylpyrazine-2-yl)propanenitrile.

MC (APCI): m/z 190 (M+H).

(e)

Obtaining carried out in the same manner as in example 1.001 (c), 3-oxo-3-(3,5,6-trimethylpyrazine-2-yl)propanenitrile (2.58 g, to 13.6 mmol), thus obtaining 3-(3,5,6-trimethylpyrazine-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 204 (M+H).

(f)

Obtaining carried out in the same manner as the method In example 1.001 (d), 3-(3,5,6-trimethylpyrazine-2-yl)-1H-pyrazole-5-amine (1,00 g, to 4.92 mmol), thus obtaining the ethyl-3-oxo-3-{[3-(3,5,6-trimethylpyrazine-2-yl)-1H-pyrazole-5-yl]amino}propanoate.

MC (APCI): m/z 318 (M+H).

(g)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-oxo-3-{[3-(3,5,6-three is ethylpyrazine-2-yl)-1H-pyrazole-5-yl]amino}of propanoate (1.25 g, of 3.94 mmol), thus obtaining 2-(3,5,6-trimethylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 272 (M+H).

(h)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3,5,6-trimethylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (1,16 g, 4,28 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-3-methyl-5,6,7,8-tetrahydroquinoxaline (compound of reference example 1.08 specified in the table of reference examples below).

Reference example 1.09

(a)

A mixture of 2-nitrobenzaldehyde (10.0 g, 66,2 mmol) and iron sulfate heptahydrate(II) (129 g, 464 mmol) in ethanol (150 ml) and water (150 ml) was heated at 100°C for 5 min, and then carefully added dropwise at the same temperature was added 28% aqueous ammonia (173 ml). The reaction mixture was filtered through celite using diethyl ether. The organic layer was washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated under vacuum, thus obtaining the crude 2-aminobenzaldehyde.

A solution of 2-aminobenzaldehyde, 2-oxomalonate acid (13.5 g, 132 mmol) and ethoxide sodium (13.5 g, 198 mmol) in ethanol (331 ml) was boiled under reflux for 20 hours. After cooling to 0°C, was added 96% sulfuric acid a (10.6 ml, is 97.9 mmol). The reaction mixture is boiled under reflux for 20 hours. After cooling to 0°C. the reaction mixture under elatively to pH 8-9 with saturated solution of sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=19:1-2:1), thus obtaining the ethyl-3-methylinosine-2-carboxylate.

MC (APCI): m/z 218 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3-methylinosine-2-carboxylate (500 mg, 2.32 mmol), thus obtaining 3-(3-methylinosine-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 211 (M+H).

(c)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3-methylinosine-2-yl)-3-oxopropanenitrile (243 mg, of 1.16 mmol), thus obtaining 3-(3-methylinosine-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 225 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3-methylinosine-2-yl)-1H-pyrazole-5-amine (250 mg, 1.11 mmol), thus obtaining the ethyl-3-{[3-(3-methylinosine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 339 (M+H).

(e)

Obtaining carried out in the same manner as the method in example 1.001 (e) of ethyl-3-{[3-(3-methylinosine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (369 mg, of 1.09 mmol), thus obtaining 2-(3-methylinosine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 293 (M-H).

(f)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3-methylinosine-2-yl)piraso what about[1,5-a]pyrimidine-5,7-diol (295 mg, 1.01 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-3-methylinosine (compound of reference example 1.09 specified in the table of reference examples below).

Reference example 1.10

(a)

Obtaining carried out in the same manner as in example 1.001 (b) from methyl-4-methylinosine-2-carboxylate (see Chem. Pharm. Bu11. 1981, 29, 2485; 1,00 g, equal to 4.97 mmol), thus obtaining 3-(4-methylinosine-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 211 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(4-methylinosine-2-yl)-3-oxopropanenitrile (674 mg, 3.35 mmol), thus obtaining 3-(4-methylinosine-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 225 (M+H).

(c)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(4-methylinosine-2-yl)-1H-pyrazole-5-amine (985 mg, 3.35 mmol), thus obtaining the ethyl-3-{[3-(4-methylinosine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 339 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-{[3-(4-methylinosine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (1,32 g, 3.35 mmol), thus obtaining 2-(4-methylinosine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 291 (M-N).

(e)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(4-methylinosine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (1.08 g, of 3.32 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-4-methyl shall inulin (compound of reference example 1.10, specified in the table of reference examples below).

Reference example 1.11

(a)

To a solution of 3,6-dimethyl-2-iodopyrazine (see J. Org. Chem. 1961, 26, 1907; 1,00 g, 4,27 mmol) in diethyl ether (13 ml) was added dropwise n-utility (2,6 M solution in hexane, of 1.64 ml, 4,27 mmol) at-35ºC. After stirring at the same temperature for 10 min, the reaction mixture was poured into dry ice. The mixture was extracted with 4 N. aqueous sodium hydroxide solution, and then the aqueous layer was acidified using conc. hydrochloric acid. The mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product is triturated with diethyl ether, thus obtaining 3,6-dimethylpyrazine-2-carboxylate.

MC (ESI): m/z 151 (M-H).

(b)

Obtaining carried out in the same manner as in reference example 1.08 (c) of 3,6-dimethylpyrazine-2-carboxylate (161 mg, 1.06 mmol), while receiving methyl-3,5,6-trimethylpyrazine-2-carboxylate.

MC (APCI): m/z 181 (M+H).

(c)

Obtaining carried out in the same manner as in example 1.001 (b), methyl-3,6-dimethylpyrazine-2-carboxylate (2.38 g, and 14.3 mmol), thus obtaining 3-(3,6-dimethylpyrazine-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 176 (M+H).

(d)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3,6-dimethylpyrazine-2-yl)-3-oxopropanenitrile (2,47 g, 14.1 mmol), sex is friends with 3-(3,6-dimethylpyrazine-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 190 (M+H).

(e)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3,6-dimethylpyrazine-2-yl)-1H-pyrazole-5-amine (1,81 g of 9.56 mmol), thus obtaining the ethyl-3-{[3-(3,6-dimethylpyrazine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 304 (M+H).

(f)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-{[3-(3,6-dimethylpyrazine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (1.78 g, by 5.87 mmol), thus obtaining 2-(3,6-dimethylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 258 (M+H).

(g)

Obtaining carried out in the same manner as in example 1.001 (f), 2-(3,6-dimethylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (750 mg, of 2.92 mmol), while receiving 5,7-dichloro-2-(3,6-dimethylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine (compound of reference example 1.11 specified in the table of reference examples below).

Reference example 1.12

(a)

Obtaining carried out in the same way as described in the publication Helv. Chim. Acta. 2001, 84, 2379, from 3,4-dimethyl-1,2-phenylenediamine (12.0 g, for 52.6 mmol), thus obtaining the ethyl-3,6,7-trimethylhexane-2-carboxylate.

MC (APCI): m/z 231 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.001 (b) of ethyl-3,6,7-trimethylhexane-2-carboxylate (of 7.90 g, to 34.3 mmol), thus obtaining 3-oxo-3-(3,6,7-trimethylhexane-2-yl)propanenitrile.

MC (APCI): m/z 240 (M+H).

(c)

Obtaining spent the mayor the same way, as in the example 1.001 (c), 3-oxo-3-(3,6,7-trimethylhexane-2-yl)propanenitrile (5,18 g, 21.6 mmol), thus obtaining 3-(3,6,7-trimethylhexane-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 254 (M+H).

(d)

Obtaining carried out in the same manner as the method And example 1.001 (d), 3-(3,6,7-trimethylhexane-2-yl)-1H-pyrazole-5-amine (3,90 g of 15.4 mmol), thus obtaining the ethyl-3-oxo-3-{[3-(3,6,7-trimethylhexane-2-yl)-1H-pyrazole-5-yl]amino]propanoate.

MC (APCI): m/z 368 (M+H).

(e)

Obtaining carried out in the same manner as the method And example 1.001 (e) of ethyl-3-oxo-3-{[3-(3,6,7-trimethylhexane-2-yl)-1H-pyrazole-5-yl]amino}of propanoate (1.06 g, 2.89 mmol), thus obtaining 2-(3,6,7-trimethylhexane-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (ESI): m/z 320 (M-H).

(f)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3,6,7-trimethylhexane-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (1.44 g, 2.89 mmol), thus obtaining 2-(5,7-dichloropyrazine[1,5-a]pyrimidine-2-yl)-3,6,7-trimethylhexane (compound of reference example 1.12 specified in the table of reference examples below).

Reference example 1.13

(a)

N-(tert-butoxycarbonyl)glycine (22,4 g, 128 mmol), ethyl-2-amino-3-oxobutanoate (21.1 g, 116 mmol), hydrochloride ethyl-3-(3-dimethylaminopropyl)carbodiimide (28,9 g, 151 mmol), 1-hydroxybenzotriazole (23.1 g, 151 mmol), triethylamine (16.2 ml, 116 mmol) in chloroform (350 ml) was stirred for 13 h p is at room temperature and then was added triethylamine (20,0 ml, 143 mmol). After stirring for 4 h at the same temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel (hexane:ethyl acetate=2:1-1:1), thus obtaining the ethyl-2-{[N-(tert-butoxycarbonyl)glycyl]amino}-3-oxobutanoate.

MC (APCI): m/z 320 (M+NH4), 303 (M+H).

(b)

Obtaining carried out in the same manner as in example 1.172 (b) of ethyl-2-{[N-tert-butoxycarbonyl)glycyl]amino}-3-oxobutanoate (22.1 g, 73,1 mmol), thus obtaining the ethyl-6-hydroxy-3-methylpyrazine-2-carboxylate.

MC (APCI): m/z 183 (M+H).

(c)

Obtaining carried out in the same manner as in reference example 1.07 (b) of ethyl-6-hydroxy-3-methylpyrazine-2-carboxylate (of 6.73 g, 36,9 mmol), thus obtaining the ethyl-6-chloro-3-methylpyrazine-2-carboxylate.

MC (APCI): m/z 201/203 (M+H).

(d)

A suspension of ethyl-6-chloro-3-methylpyrazine-2-carboxylate (1,94 g, 9,67 mmol), isobutylamino acid (1.97 g, and 19.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (212 mg, 0,290 mmol) and potassium carbonate (2.67 g, and 19.3 mmol) in 1,4-dioxane (30 ml) was heated at 100ºC for 4.5 hours. After cooling to the fact the temperature of the environment, the reaction mixture was diluted with ethyl acetate and filtered through celite using ethyl acetate. The filtrates were combined and concentrated in vacuum. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution, dried over sodium bicarbonate, filtered and concentrated in vacuum. The residue was dissolved in dichloromethane and the insoluble matter was separated by filtration. The filtrate was concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=9:1-3:1), thus obtaining the ethyl-6-isobutyl-3-methylpyrazine-2-carboxylate.

MC (APCI): m/z 223 (M+H).

(e)

Obtaining carried out in the same manner as the method And example to 1006 (a) of ethyl-6-isobutyl-3-methylpyrazine-2-carboxylate (1,76 g, a 7.92 mmol), thus obtaining 3-(6-isobutyl-3-methylpyrazine-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 218 (M+H).

(f)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(6-isobutyl-3-methylpyrazine-2-yl)-3-oxopropanenitrile (1,61 g, 7.41 mmol), thus obtaining 3-(6-isobutyl-3-methylpyrazine-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 232 (M+H).

(g)

Obtaining carried out in the same manner as the method And example to 1006 (c), from 3-(6-isobutyl-3-methylpyrazine-2-yl)-1H-pyrazole-5-amine (1.25 g, 5.40 mmol), thus obtaining the ethyl-3-{[3-(6-isobutyl-3-methylpyrazine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 346 (M+H).

(h)

A suspension of ethyl-3-{[3-(6-isobutyl-3-methylpyrazine-2-yl)-1H-pyrazole-5-yl]AMI is on}-3-oxopropanoic (1.13 g, 3,29 mmol) and triethylamine (1.38 in ml 9,88 mmol) in methanol (9 ml), tetrahydrofuran (9 ml) and water (9 ml) was boiled under reflux for 2 hours. After cooling to ambient temperature the reaction mixture was acidified to pH 2 2 N. aqueous hydrochloric acid and concentrated in vacuum. The residue is triturated with water, thus obtaining 2-(6-isobutyl-3-methylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 300 (M+H).

(i)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(6-isobutyl-3-methylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (663 mg, 2.22 mmol), while receiving 5,7-dichloro-2-(6-isobutyl-3-methylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine (compound of reference example 1.13 specified in the table of reference examples below).

Reference example 1.14

(a)

Obtaining carried out in the same manner as the method In example 1.001 (d), from N-(tert-butoxycarbonyl)-L-alanine (5,62 g, 29.7 mmol) and the hydrochloride of the ethyl ester of L-threonine (4,58 g of 27.0 mmol), while receiving methyl-N-(tert-butoxycarbonyl)-L-alanyl-L-Traviata.

MC(APCI): m/z 305 (M+H).

(b)

To a solution of methyl-N-(tert-butoxycarbonyl)-L-alanyl-L-Traviata (9.00 g, 29.6 mmol) in dichloromethane (90 ml) was added periodinane dess-Martin (15,1 g, 35.5 mmol) at room temperature. After stirring for 70 min, was added a saturated aqueous solution of thiosulfate is sodium, then the reaction mixture was stirred for 15 min. the Mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1-1:1), while receiving methyl-(2S)-2-{[N-(tert-butoxycarbonyl)-L-alanyl]amino}-3-oxobutanoate.

MC (APCI): m/z 303 (M+H).

(c)

A solution of methyl-(2S)-2-{[N-(tert-butoxycarbonyl)-L-alanyl]amino}-3-oxobutanoate (3,05 g, 10.1 mmol), and 4 N. hydrochloric acid in 1,4-dioxane (10 ml) was stirred at room temperature. After stirring for 1 hour at the same temperature, the reaction mixture was concentrated in vacuum. A solution of the residue in pyridine (50 ml) was heated at 60°C for 4 hours. After cooling to ambient temperature the mixture was concentrated in vacuum. The residue was poured into water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated salt solution, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is triturated with a mixture of hexane-ethyl acetate (1:1), while receiving methyl-6-hydroxy-3,5-dimethylpyrazine-2-carboxylate.

MC (APCI): m/z 183 (M+H).

(d)

Obtaining carried out in the same manner as in the reference p is the iMER 1.07 (b), from methyl-6-hydroxy-3,5-dimethylpyrazine-2-carboxylate (4,55 g, 25,0 mmol), while receiving methyl-6-chloro-3,5-dimethylpyrazine-2-carboxylate.

MC (APCI): m/z 201/203 (M+H).

(e)

Obtaining carried out in the same manner as in reference example 1.13 (d) of methyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate (960 mg, 4,78 mmol), while receiving methyl-6-isobutyl-3,5-dimethylpyrazine-2-carboxylate.

MC(APCI): m/z 223 (M+H).

(f)

Obtaining carried out in the same manner as the method And example to 1006 (a), from methyl-6-isobutyl-3,5-dimethylpyrazine-2-carboxylate (945 mg, of 4.25 mmol), thus obtaining 3-(6-isobutyl-3,5-dimethylpyridin-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 232 (M+H).

(g)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(6-isobutyl-3,5-dimethylpyridin-2-yl)-3-oxopropanenitrile (972 mg, 4.20 mmol), thus obtaining 3-(6-isobutyl-3,5-dimethylpyridin-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 246 (M+H).

(h)

Obtaining carried out in the same manner as the method And example to 1006 (c), from 3-(6-isobutyl-3,5-dimethylpyridin-2-yl)-1H-pyrazole-5-amine (950 mg, a 3.87 mmol), thus obtaining the ethyl-3-{[3-(6-isobutyl-3,5-dimethylpyridin-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 360 (M+H).

(i)

Obtaining carried out in the same manner as in example 1.006 (d) of ethyl-3-{[3-(6-isobutyl-3,5-dimethylpyridin-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (1.12 g, of 3.12 mmol), thus obtaining 2-(6-isobutyl-3,5-dimethyl shall irisin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 314 (M+H).

(j)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(6-isobutyl-3,5-dimethylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (845 mg, 2,70 mmol), while receiving 5,7-dichloro-2-(6-isobutyl-3,5-dimethylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine (compound of reference example 1.14 specified in the table of reference examples below).

Reference example 1.15

(a)

Obtaining carried out in the same manner as in reference example 1.13 (d) of ethyl-6-chloro-3-methylpyrazine-2-carboxylate (reference example 1.13 (c)) (1.50 g, of 7.48 mmol) and n is propylboronic acid (1,32 g, 15.0 mmol), thus obtaining the ethyl-3-methyl-6-propylpyrazine-2-carboxylate.

MC (APCI): m/z 209 (M+H).

(b)

Obtaining carried out in the same manner as the method And example to 1006 (a) of ethyl-3-methyl-6-propylpyrazine-2-carboxylate (1,09 g, 5,23 mmol), thus obtaining 3-(3-methyl-6-propylpyrazine-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 204 (M+H).

(c)

Obtaining carried out in the same manner as in example 1.001 (c), from 3-(3-methyl-6-propylpyrazine-2-yl)-3-oxopropanenitrile (1.07 g, 5,23 mmol), thus obtaining 3-(3-methyl-6-propylpyrazine-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 218 (M+H).

(d)

Obtaining carried out in the same manner as the method And example to 1006 (c), from 3-(3-methyl-6-propylpyrazine-2-yl)-1H-pyrazole-5-amine (1,15 g of 5.29 mmol), thus obtaining the ethyl-3-{[3-(3-methyl-6-propylpyrazine-2-yl)-1H-p is razol-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 332 (M+H).

(e)

Obtaining carried out in the same manner as in reference example 1.13 (h) of ethyl-3-{[3-(3-methyl-6-propylpyrazine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (1.07 g, 3,23 mmol), thus obtaining 2-(3-methyl-6-propylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 286 (M+H).

(f)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(3-methyl-6-propylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (803 mg, of 2.81 mmol), while receiving 5,7-dichloro-2-(3-methyl-6-propylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine (compound of reference example 1.15 specified in the table of reference examples below).

Reference example 1.16

(a)

Obtaining carried out in the same manner as in reference example 1.13 (d) of methyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate (described in reference example 1.14 (d)) (2.30 g, is 10.7 mmol) and cyclopropylboronic acid (1.84 g, with 21.4 mmol), thus obtaining the ethyl-6-cyclopropyl-3,5-dimethylpyrazine-2-carboxylate.

MC (APCI): m/z 221 (M+H).

(b)

Obtaining carried out in the same manner as the method And example to 1006 (a) of ethyl-6-cyclopropyl-3,5-dimethylpyrazine-2-carboxylate (2.30 g, 10.4 mmol), thus obtaining 3-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 216 (M+H).

(c)

First receipt was performed in the same manner as in example 1.001 (c), from 3-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)-3-oxoprop is onitrile (872 mg, of 4.05 mmol), thus obtaining the crude compound (839 mg, 90%). Then getting carried out in the same manner as the method And example to 1006 (c) of the crude compound (839 mg), thus obtaining the ethyl-3-{[3-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 344 (M+H).

(d)

Obtaining carried out in the same manner as in reference example 1.13 (h) of ethyl-3-{[3-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (990 mg, is 2.88 mmol), thus obtaining 2-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 298 (M+H).

(e)

Obtaining carried out in the same manner as in example 1.001 (f) from 2-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol (772 mg, 2,60 mmol), while receiving 5,7-dichloro-2-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine (compound of reference example 1.16 specified in the table of reference examples below).

Reference example 1.17

(a)

Obtaining carried out in the same manner as the method In example 1.001 (d), from N-(tert-butoxycarbonyl)-L-Norvaline (13,0 g, to 59.8 mmol) and the hydrochloride of the ethyl ester of L-threonine (9,23 g of 54.4 mmol), while receiving methyl-N-(tert-butoxycarbonyl)-L-Norwell-L-threonine.

MC (APCI): m/z 333 (M+H).

(b)

Obtaining carried out in the same manner as reference example 1.14 (b), from methyl-N-(tert-b is oxycarbonyl)-L-Norwell-L-Traviata (15,8 g, as a result, 47.5 mmol), while receiving methyl-(2S)-2-{[N-(tert-butoxycarbonyl)-L-Norwell]amino}-3-oxobutanoate.

MC (APCI): m/z 348 (M+H).

(c)

Obtaining carried out in the same manner as in example 1.172 (b), from methyl(2S)-2-{[N-(tert-butoxycarbonyl)-L-Norwell]amino}-3-oxobutanoate (10.3 g, and 31.2 mmol), while receiving methyl-6-hydroxy-3-methyl-5-propylpyrazine-2-carboxylate.

MC (APCI): m/z 211 (M+H).

(d)

Obtaining carried out in the same manner as in reference example 1.07 (b), from methyl-6-hydroxy-3-methyl-5-propylpyrazine-2-carboxylate (3,49 g of 16.6 mmol), while receiving methyl-6-chloro-3-methyl-5-propylpyrazine-2-carboxylate.

MC (APCI): m/z 229/231 (M+H).

(e)

To a solution of methyl 6-chloro-3-methyl-5-propylpyrazine-2-carboxylate (3.00 g, 13,1 mmol) and triethylamine (1,83 ml of 13.1 mmol) in tetrahydrofuran (40 ml) was added palladium on coal (5%, M, wet, 300 mg) at 0°C in an argon atmosphere. The reaction mixture was stirred for 8 hours in a hydrogen atmosphere, and then filtered through celite with the use of tetrahydrofuran. To the filtrate was added manganese dioxide (1.0 g) at room temperature. After stirring over night the reaction mixture was filtered through celite using tetrahydrofuran. The filtrate was concentrated in vacuo, and the residue was poured into saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed nassen the m salt solution, was dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=4:1-13:7), while receiving methyl-3-methyl-5-propylpyrazine-2-carboxylate.

MC (APCI): m/z 195 (M+H).

(f)

Obtaining carried out in the same manner as the method And example to 1006 (a), from methyl 3-methyl-5-propylpyrazine-2-carboxylate (1.77 g, 9,11 mmol), thus obtaining 3-(3-methyl-5-propylpyrazine-2-yl)-3-oxopropanenitrile.

MC (APCI): m/z 204 (M+H).

(g)

First receipt was performed in the same manner as in example 1.001 (c), from 3-(3-methyl-5-propylpyrazine-2-yl)-3-oxopropanenitrile (2,00 mg, 9,84 mmol), thus obtaining 3-(3-methyl-5-propylpyrazine-2-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 218 (M+H).

(h)

The first receipt was performed in the same manner as the method And example to 1006 (C), from 3-(3-methyl-5-propylpyrazine-2-yl)-1H-pyrazole-5-amine (1,37 g of 6.31 mmol), thus obtaining the crude compound (2,19 g).

MC (APCI): m/z 344 (M+H).

The second receipt was performed in the same manner as in reference example 1.13 (h) of ethyl-3-{[3-(3-methyl-5-propylpyrazine-2-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (2,19 g), thus obtaining the crude compound (1.04 g).

MS (APCI): m/z 286 (M+H).

Third obtaining carried out in the same manner as in example 1.001 (f) of the crude compound (1.04 g), while receiving 5,7-dichloro-2-(3-methyl-5-propylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine (compound silo the aqueous example 1.17, specified in the table of reference examples below).

Reference example 1.18

(a)

A solution of 3-aminopyrazole (5,00 g, a 60.2 mmol) and antilocapridae (24.3 g, 120 mmol) in ethanol (602 ml) was boiled under reflux for 24 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The residue is triturated with chloroform and diisopropyl ether, thus obtaining the crude compound (10.4 g, 78%).

A solution of the crude compound (7,38 g, 33.4 mmol) and phosphorus oxychloride (62.3 g, 668 mmol) in toluene (67 ml) was boiled under reflux for 3 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The residue was dissolved in chloroform, and the solution was poured into 10% aqueous potassium carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=9:1-7:3), thus obtaining the crude compound (7,07 g, 88%).

A suspension of crude compound (4,49 g, to 18.7 mmol), palladium on coal (5%, M, wet, 2.25 g) and triethylamine (2,61 ml, to 18.7 mmol) in tetrahydrofuran (190 ml) was stirred at room Tempe is the atur for 40 min in an atmosphere of hydrogen. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=4:1-2:3), thus obtaining the ethyl-6-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate.

MC (APCI): m/z 206 (M+H).

(b)

Obtaining carried out in the same manner as the method And example to 1006 (a) of ethyl-6-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate (3.42 g, and 16.7 mmol), thus obtaining 3-(6-methylpyrazolo[1,5-a]pyrimidine-5-yl)-3-oxopropionate.

MC (APCI): m/z 201 (M+H).

(c)

First receipt was performed in the same manner as in example 1.001 (c), from 3-(6-methylpyrazolo[1,5-a]pyrimidine-5-yl)-3-oxopropanenitrile (2,45 g, 12.2 mmol), thus obtaining 3-(6-methylpyrazolo[1,5-a]pyrimidine-5-yl)-1H-pyrazole-5-amine.

MC (APCI): m/z 215 (M+H).

(d)

Obtaining carried out in the same manner as the method And example to 1006 (c), from 3-(6-methylpyrazolo[1,5-a]pyrimidine-5-yl)-1H-pyrazole-5-amine (2.30 g, is 10.7 mmol), thus obtaining the ethyl-3-{[3-(6-methylpyrazolo[1,5-a]pyrimidine-5-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic.

MC (APCI): m/z 329 (M+H).

(e)

Obtaining carried out in the same manner as in example 1.006 (d) of ethyl-3-{[3-(6-methylpyrazolo[1,5-a]pyrimidine-5-yl)-1H-pyrazole-5-yl]amino}-3-oxopropanoic (3,20 g of 9.75 mmol), while receiving 6'-methyl-2,5'-dipyrazolo[1,5-a]pyrimidine-5,7-diol.

MC (APCI): m/z 283 (M+H).

(f)

Obtaining carried out in the same manner as in example 1.001 (f) from 6'-methyl-2,5'-dipilato what about[1,5-a]pyrimidine-5,7-diol (2.86 g, of 9.75 mmol), while receiving 5,7-dichloro-6'-methyl-2,5'-dipyrazolo[1,5-a]pyrimidine (compound of reference example 1.18 specified in the table of reference examples below).

The description used the following abbreviations:

"MC (APCI)" means of mass spectrometry (mass spectrometry with chemical ionization at atmospheric pressure);

"MC (ESI)" means of mass spectrometry (mass spectrometry with ionization by elektrorazpredelenie);

"Me" means methyl group;

"Et" means ethyl group;

"Pr" means through the group;

"Bu" means boutelou group and

"Boc" means tert-butoxycarbonyl group.

The structural formula and physical properties, etc. of the compounds of the examples and reference examples are shown in the following tables of examples and tables reference examples.

444 (M+H)
Table examples
ExampleStructureSolMS (APCI)
1.001HCl
2 HCl
430 (M+H)
1.002HCl
3/2 HCl
1.003HCl
2 HCl
448 (M+H)
1.0042 HCl444 (M+H)
1.005HCl484 (M+H)
1.006HCl454 (M+H)

1.007Free form446 (M+H)
1.008Free form524 (M+H)
1.009Free form428 (M+H)
1.010HCl
2 HCl
431 (M+H)
1.011Free form427 (M+H)
1.012Free form429 (M+H)
1.013HCl494 (M+H)
1.014Free form402 (M+H)

1.015HCl416 (M+H)
1.016HCl386 (M+H)
1.017HCl
3/2 HCl
458(M+H)
1.018HCl 404 (M+H)
1.0192 HCl400 (M+H)
1.0202 HCl404 (M+H)
1.021HCl
2 HCl
444 (M+H)
1.022HCl
3/2 HCl
458 (M+H)
1.023HCl
3/2 HCl
472 (M+H)

1.0243/2 HCl458 (M+H)
1.0253/2 HCl476 (M+H)
1.026Free form346 (M+)
1.027HCl458 (M+H)
1.028HCl
2 HCl
458 (M+H)
1.0293/2 HCl430 (M+H)
1.030HCl418 (M+H)
1.031HCl399 (M+H)
1.032HCl418 (M+H)

td align="center">
1.033HCl410 (M+H)
1.034HCl416 (M+H)
1.035HCl458 (M+H)
1.036HCl416 (M+H)
1.0372 HCl458 (M+H)
1.038HCl
2 HCl
444 (M+H)
1.0392 HCl430 (M+H)
1.0403/2 HCl430 (M+H)
1.041HCl458 (M+H)

1.042HCl416 (M+H)
1.043 5/2 HCl443 (M+H)
1.044Free form487 (M+H)
1.0455/2 HCl444 (M+H)
1.046HCl498 (M+H)
1.0475/4 HCl526 (M+H)
1.0482 HCl462 (M+H)
1.049HCl462 (M+H)
1.0502 HCl476 (M+H)

1.0512 HCl1.0522 HCl472 (M+H)
1.053HCl448 (M+H)
1.054HCl462 (M+H)
1.055HCl436 (M+H)
1.056Free form427 (M+H)
1.057HCl434 (M+H)
1.058Free form420 (M+H)

1.060
1.059HCl436 (M+H)
3/2 HCl476 (M+H)
1.0613/2 HCl476 (M+H)
1.062HCl404 (M+H)
blade 1.063HCl428 (M+H)
1.064HCl476 (M+H)
1.065HCl476 (M+H)
1.0662 HCl476 (M+H)

1.067HCl448 (M+H)
1.068 HCl422 (M+H)
1.069HCl462 (M+H)
1.070HCl434 (M+H)
1.0713/2 HCl476 (M+H)
1.072HCl436 (M+H)
1.073HCl476 (M+H)
1.074HCl434 (M+H)
1.075HCl
3/2 HCl
476 (M+H)

1.076Free the I form 434 (M+H)
1.077HCl
3/2 HCl
462 (M+H)
1.0783/2 HCl516 (M+H)
1.079HCl544 (M+H)
1.0802 HCl462 (M+H)
1.0812 HCl490 (M+H)
1.0823/2 HCl462 (M+H)
1.083HCl530 (M+H)

1.084HCl502 (M+H)
1.085HCl530 (M+H)
1.086HCl468 (M+H)
1.087HCl494 (M+H)
1.0889/10 HCl440 (M+H)
1.089HCl494 (M+H)
1.090HCl466 (M+H)
1.091HCl490 (M+H)

1.092HCl
4/5 HCl
490 (M+H)
1.093 2 HCl472 (M+H)
1.0943/2 HCl444 (M+H)
1.095 has3/4 HCl512 (M+H)
1.096HCl512 (M+H)
1.097HCl462 (M+H)
1.098HCl462 (M+H)
1.099HCl476 (M+H)
1.100HCl448 (M+H)

1.101 HCl454 (M+H)
1.102HCl476 (M+H)
1.103HCl462 (M+H)
1.104HCl436 (M+H)
1.105HCl422 (M+H)
1.106HCl450 (M+H)
1.107HCl450 (M+H)
1.108HCl476 (M+H)
1.1092 HCl444 (M+H)

1.110
Free form462 (M+H)
1.1112 HCl444 (M+H)
1.1122 HCl478 (M+H)
1.113HCl458 (M+H)
1.1145/2 HCl485 (M+H)
1.115HCl
2 HCl
472 (M+H)
1.1163/2 HCl444 (M+H)
1.1172 HCl430 (M+H)
1.118 HCl458 (M+H)

1.119HCl472 (M+H)
1.120HCl
2 HCl
472 (M+H)
1.1212 HCl418 (M+H)
1.122HCl472 (M+H)
1.1233 HCl485 (M+H)
1.1243 HCl471 (M+H)
1.1252 HCl472 (M+H)
1.1263 HCl431 (M+H
1.127HCl
2 HCl
444 (M+H)

1.135
1.128HCl462 (M+H)
1.129HCl448 (M+H)
1.130Free form434 (M+H)
1.1313/5 HCl408 (M+H)
1.132HCl422 (M+H)
1.133Free form468 (M+H)
1.134HCl462 (M+H)
HCl440 (M+H)
1.1363/4 HCl452 (M+H)

1.137HCl480 (M+H)
1.138Free form408 (M+H)
1.139Free form436 (M+H)
1.1406/5 HCl410 (M+H)
1.141HCl436 (M+H)
1.142Free form396 (M+H)
1.143HCl422 (M+H)
1.144HCl Free form422 (M+H)
1.145HCl460 (M+H)

number 1,1463/2 HCl446 (M+H)
1.1473/2 HCl460 (M+H)
1.148HCl446 (M+H)
1.1493/2 HCl460 (M+H)
1.1503/2 HCl502 (M+H)
1.151 HCl474 (M+H)
1.1523/2 HCl514 (M+H)
1.153HCl449 (M+H)
1.1542 HCl446 (M+H)

1.1552 HCl458 (M+H)
1.156Free form523 (M+H)
1.157Free form419 (M+H)
1.158Free form408 (M+H)
1.159 Free form394 (M+H)
1.160Free form414 (M+H)
1.1612 HCl447 (M+H)
1,162 notices2 HCl447 (M+H)

1.1632 HCl446 (M+H)
1.1642 HCl488 (M+H)
1.1652 HCl429 (M+H)
1.1662 HCl429 (M+H)
1.167 2 HCl474 (M+H)
1.168Free form454 (M+H)
1.1693/2 HCl476 (M+H)
1.170HCl417 (M+H)

1.171HCl448 (M+H)
1.1723/2 HCl464 (M+H)
1.1733/2 HCl464 (M+H)
1.174HCl494 (M+H)
1.175 HCl494 (M+H)
1.176Free form436 (M+H)
1.177Free form450 (M+H)
1.178Free form450 (M+H)

1.179Free form424 (M+H)
1.180Free form464 (M+H)
1.181HCl436 (M+H)
1.182HCl410 (M+H)
1.183 HCl450 (M+H)
1.184HCl407 (M+H)
1.185Free form450 (M+H)
1.186Free form436 (M+H)
1.187Free form438 (M+H)

1.188Free form456 (M+H)
1.189HCl422 (M+H)
1.190HCl434 (M+H)
1.191 HCl452 (M+H)
1.1922 HCl440 (M+H)
1.1933/2 HCl436 (M+H)
1.194Free form470 (M+H)
1.195Free form470 (M+H)

1.1963/2 HCl424 (M+H)
1.1975/2 HCl436 (M+H)
1.1983/2 HCl424 (M+H)
1.199 3/2*HCl464 (M+H)
1.2003/2*HCl482 (M+H)
2.001Free form429 (M+H)
3.001Free form401 (M+H)
4.001Free form562/564 (M+H)

4.002Free form498 (M+H)
4.003Free form532/534 (M+H)
4.004Free form526/528 (M+H)
4.005 Free form522/524 (M+H)
5.001Free form431 (M+H)
5.002Free form431 (M+H)

The table of reference examples
Reference examplesStructureSolMS (APCI)
1.01Free form344/346 (M+H)
1.02Free form344/346 (M+H)
1.03Free form344/346 (M+H)
1.04With the rim form 344/346 (M+H)
1.05Free form398/400 (M+H)
1.06Free form362/364 (M+H)
1.07Free form334/336 (M+H)
1.08Free form308/310 (M+H)

1.09Free form329/331 (M+H)
1.10Free form329/331 (M+H)
1.11Free form294/296 (M+H)
1.12 Free form358/360 (M+H)
1.13Free form336/338 (M+H)
1.14Free form350/352 (M+H)
1.15Free form322/324 (M+H)
1.16Free form334/336 (M+H)
1.17Free form322/324 (M+H)

1.18Free form319/321 (M+H)

1. The compound represented by the formula [I]

in which
R1represents hydrogen, halogen is whether lower alkyl;
ring a represents an optionally substituted heterocyclic group, where
heterocyclic residue "optionally substituted heterocyclic group" represented by ring a, is a 6-10-membered monocyclic or bicyclic heteroaryl containing from 1 to 3 nitrogen atoms as heteroatoms, or a group containing cycloaliphatic 6-membered ring condensed with the specified heteroaryl, which is selected from 6-membered cycloalkane and aliphatic 6-membered heterocyclic ring containing an oxygen atom, and where the "optionally substituted heterocyclic group" represented by ring A, optionally substituted from 1 to 3 substituents that are the same or different and selected from the group includes lower alkyl, lower cycloalkyl, lower alkoxy, halogen, halogen - lower alkyl and 5-membered cyclic amino group, optionally substituted with halogen;
the ring is an optionally substituted 3-6-membered monocyclic group, where
monocyclic the remainder of the "optionally substituted 3-6-membered monocyclic group" represented by ring B, is a 4-6-membered monocyclic nitrogen-containing heterocyclic group, which may optionally contain an oxygen atom or a 3-6-membered monocyclic carbohydrate is native group, which is optionally partially saturated, and where
"optionally substituted 3-6-membered monocyclic group" represented by ring, optionally substituted from 1 to 2 substituents which are the same or different and selected from the group comprising halogen, hydroxy, lower alkylsulfonate and lower alkyl, optionally substituted from 1 to 2 substituents which are the same or different and selected from the group consisting of hydroxy and lower alkyl; and
Υ represents an amino group,
5-6-membered cyclic amino group which may optionally contain an oxygen atom,
lower alkyl, substituted tetrahydropyran-4-yl, or
a group of the formula [III]
,
where
Ζ represents-N(R3)-, -O - or1-2alkylen;
R3represents hydrogen; lower alkyl, optionally substituted Deputy selected from lower alkoxy; or lower cycloalkyl; and
R2represents a
(1) lower alkyl, optionally substituted from 1 to 2 substituents which are the same or different and selected from the group consisting of hydroxy, halogen, cyano, lower alkyl, lower alkoxy, lower cycloalkyl, replacement of the lower cycloalkyl, halogen-lower alkyl and mono - or di-lower alkylamino; or
(2) 4-6-membered aliphatic monocyclic heterocycle is ical group, containing 1 to 2 heteroatoms selected from oxygen, nitrogen or sulfur, or With3-6-cycloalkyl group, each of which is optionally substituted from 1 to 2 substituents which are the same or different and selected from the group consisting of halogen, oxo, hydroxyl, lower alkanoyl, lower alkoxy and lower alkyl,
or its pharmaceutically acceptable salt.

2. Connection on p. 1 or its pharmaceutically acceptable salt, where
heterocyclic residue optionally substituted heterocyclic group" represented by ring And selected from the group consisting of pyridyl, pyrazinyl, chinoline, khinoksalinona, 5,6,7,8-tetrahydroquinoxaline, 7,8-dihydro-6N-pyrano[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl and pyrazolo[1,5-a]pyrimidinyl,
monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring selected from the group consisting of pyrrolidinyl, azetidine, imidazolidine, pyrazoline, piperidine, piperazinil, morpholinyl and C3-6cycloalkyl, or the corresponding unsaturated monocyclic group; and
heterocyclic residue 4-6-membered aliphatic monocyclic heterocyclic group" represented by R2selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, tetrahydrate is Iranica, tetrahydrothieno, tatania and piperidyl.

3. Connection on p. 2 or its pharmaceutically acceptable salt, where
the heterocyclic residue in the "optionally substituted heterocyclic group" represented by ring And selected from the group consisting of pyridine-2-yl, pyrazin-2-yl, quinoline-2-yl, cinoxacin-2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl, 7,8-dihydro-6N-pyrano[2,3-b]pyrazin-3-yl, pyrido[3,4-b]pyrazin-2-yl and pyrido[3,4-b]pyrazin-3-Il,
monocyclic balance in the "optionally substituted 3-6-membered monocyclic group" represented by ring selected from the group consisting of 1-pyrrolidinyl, 1-azetidine, 1-pyrazolidine, cyclopentyl and cyclopentenyl; and
the heterocyclic residue in 4-6-membered aliphatic monocyclic heterocyclic group" represented by R2selected from the group consisting of 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuryl, 3-tatania and 4-piperidyl.

4. Connection on p. 2 or its pharmaceutically acceptable salt, where
ring a represents pyrazinyl, hinely, honokalani, 5,6,7,8-tetrahydroquinoxaline, 7,8-dihydro-6N-pyrano[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl and pyrazolo[1,5-a]pyrimidinyl, each of which is optionally substituted by 1-3 substituents, which is what raised the same or different and selected from the group consisting of lower alkyl; lower cycloalkyl; halogen; halo(lower alkyl), and 5-membered cyclic amino group, optionally substituted by a Deputy selected from halogen;
the ring is 1-pyrrolidinyl, 1-azetidine, 1-pyrazolyl, cyclopropyl, cyclopentyl or cyclopentene-1-yl, each of which is optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of halogen; hydroxy; lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy,
R2represents a
(1) lower alkyl, optionally substituted by 1-2 substituents which are the same or different and selected from the group consisting of hydroxy, halogen, cyano, lower alkyl, lower alkoxy, replacement of the lower cycloalkyl, halogen(lower alkyl) and mono - or di(lower alkyl)amino; or
(2) 3 - or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3-tetrahydrofuryl, 4-piperidyl or3-6cycloalkyl, each of which optionally is substituted by 1-2 substituents which are the same or different and selected from the group consisting of halogen; oxo; hydroxy; lower alkanoyl; lower alkoxy; lower alkyl; and
R3represents bodoro is.

5. Connection on p. 4 or its pharmaceutically acceptable salt, where
ring a represents pyrazin-2-yl or cinoxacin-2-yl, each of which is optionally substituted by 1-3 substituents, which are the same or different and selected from the group consisting of lower alkyl and halogen; and
the ring is 1-pyrrolidinyl, which is optionally substituted by 1-2 substituents which are the same or different and selected from the group consisting of halogen; hydroxy; lower alkyl, optionally substituted by 1-2 substituents which are the same or different and is selected from hydroxy and lower alkoxy.

6. Connection on p. 1 or its pharmaceutically acceptable salt, where R1represents hydrogen.

7. Connection on p. 1 or its pharmaceutically acceptable salt, where R1represents hydrogen and Z represents-N(R3)-.

8. Connection on p. 1, or its pharmaceutically acceptable salt selected from the group consisting of
2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
N-methyl-2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
1-({2-(7-fluoro-3-methylphenoxy the Jn-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-2-methylpropan-2-ol;
5-(2,5-dihydro-1H-pyrrol-1-yl)-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
2-methyl-3-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-yloxy)pyrazolo[1,5-a]pyrimidine-2-yl]cinoxacin;
5-cyclopent-1-EN-1-yl-2-(3-methylphenoxy-2-yl)-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
TRANS-4-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol;
2-(5,7-dipyrrole-1-alprazola[1,5-a]pyrimidine-2-yl)-3-methylinosine;
(2S)-1,1,1-Cryptor-3-{[2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}propan-2-ol;
3-{[2-(3-methylphenoxy-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}propanenitrile;
N-(TRANS-4-methoxycyclohexyl)-2-[3-methyl-7-(trifluoromethyl)cinoxacin-2-yl]-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine;
2-(3,7-dimethylquinoxaline-2-yl)-Ν,Ν-bis(2-methoxyethyl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine;
5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)-N-oxetan-3-alprazola[1,5-a]pyrimidine-7-amine;
1-{[5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl]amino}-2-methylpropan-2-ol;
N-cyclopropyl-5-[(3R)-3-ftorpirimidinu-1-yl]-2-(3-methylphenoxy-2-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
2-(3-utilisation-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]-N-(TRANS-4-methoxycyclohexyl)pyrazolo[1,5-is]pyrimidine-7-amine;
TRANS-4-({5-[(3R)-3-ftorpirimidinu-1-yl]-2-[3-(trifluoromethyl)cinoxacin-2-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol;
(1S,2S)-2-{[2-(7-fluoro-3-methylphenoxy-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol;
2-(3,5-dimethylquinoxaline-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
2-(3,6-dimethylquinoxaline-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
2-(3,7-dimethylquinoxaline-2-yl)-N-[(3R)-1,1-dissidocerida-3-thienyl]-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine;
N-(1-acetylpiperidine-4-yl)-2-(3,7-dimethylquinoxaline-2-yl)-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine;
2-(3,7-dimethylquinoxaline-2-yl)-N-(1-propylpiperidine-4-yl)-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine;
Ν'-[2-(3,7-dimethylquinoxaline-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]-Ν,Ν-dimethylated-1,2-diamine;
Ν-(4,4-diverticulosis)-2-(3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-amine;
N-methyl-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)-2-(3,5,6-trimethylpyrazine-2-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
((2S)-1-{2-(3-methylphenoxy-2-yl)-7-[(3R)-tetrahydro-2H-Piran-3-ylamino]pyrazolo[1,5-a]pyrimidine-5-yl}pyrrolidin-2-yl)methanol;
{(2S)-1-[7-[cyclopropyl(tetrahydro-2H-Piran-4-yl)amino]-2-(3,7-dimethylquinoxaline-2-yl)pyrazolo[1,5-a]pyrimidine-5-yl]pyrrolidin-yl}methanol;
1-[2-(3,7-dimethylquinoxaline-2-yl)-7-(tetrahydro-2H-Piran-4-ylamino)pyrazolo[1,5-a]pyrimidine-5-yl]azetidin-3-ol;
2-methyl-3-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-Piran-4-ylmethyl)pyrazolo[1,5-a]pyrimidine-2-yl]cinoxacin;
TRANS-1-methyl-4-{[2-(3-methyl-7,8-dihydro-bn-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}cyclohexanol;
CIS-4-({2-(7-fluoro-3-methylphenoxy-2-yl)-5-[(3R)-3-ftorpirimidinu-1-yl]pyrazolo[1,5-a]pyrimidine-7-yl}amino)-1-methylcyclohexanol;
N-methyl-2-(3-methyl-6-propylpyrazine-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
2-methyl-1-[(6'-methyl-5-pyrrolidin-1-yl-2,5'-dipyrazolo[1,5-a]pyrimidine-7-yl)amino]propan-2-ol;
1-{[2-(6-isobutyl-3,5-dimethylpyridin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}-2-methylpropan-2-ol;
1-{[2-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}-2-methylpropan-2-ol;
2-(6-cyclopropyl-3,5-dimethylpyridin-2-yl)-5-pyrrolidin-1-yl-
Ν-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
2-(3-methyl-7,8-dihydro-bn-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine;
2-methyl-1-{[2-(3-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl)-5-pyrrolidin-1-alprazola[1,5-a]pyrimidine-7-yl]amino}propan-2-ol;
Ν-(TRANS-4-methoxycyclohexyl)-2-(3-methyl-7,8-dihydro-6N-pyrano[2,3-b]pyrazin-2-yl)-5-Pyrrhus is lidin-1-alprazola[1,5-a]pyrimidine-7-amine;
2-(2-methylpyridin[3,4-b]pyrazin-3-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine; and
2-(3-methylpyridin[3,4-b]pyrazin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine.

9. A method of inhibiting the activity of phosphodiesterase 10, comprising introducing an effective amount of a compound according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt.

10. A method of treating or preventing a disease or condition, the symptoms of which may be alleviated by inhibition of the activity of phosphodiesterase 10, by inhibiting the activity of phosphodiesterase 10 in a patient, comprising the administration to a patient an effective amount of a compound according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt.

11. A method of treating or preventing schizophrenia, anxiety disorders, addiction to the excessive use of drugs, diseases, having as a symptom of the lack of cognitive abilities, affective disorder or mood episode, each of which is mediated by the activity of phosphodiesterase 10, comprising introducing an effective amount of a compound according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt.

12. The compound according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt for use in the inhibition of the activity of the phosphodiesterase 10.

13. Connection on p. 12 or its pharmaceutically acceptable salt for use in the treatment or prevention of a disease or condition, the symptoms of which may be alleviated by inhibition of the activity of phosphodiesterase 10, by inhibiting the activity of phosphodiesterase 10 patients.

14. Connection on p. 12 or its pharmaceutically acceptable salt for use in the treatment or prevention of schizophrenia, anxiety disorders, addiction to the excessive use of drugs, diseases, having as a symptom of the lack of cognitive abilities, affective disorder or mood episode, each of which is mediated by the activity of phosphodiesterase 10.

15. The use of compounds according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt for the manufacture of a medicine for inhibiting the activity of phosphodiesterase 10.

16. The use of compounds according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of a disease or condition symptoms which can be alleviated by inhibition of the activity of phosphodiesterase 10, by inhibiting the activity of phosphodiesterase 10 patients.

17. The use of compounds according to any one of paragraphs.1-8 or its pharmaceutically acceptable salts of the otopleniya drugs for treatment or prevention of schizophrenia, anxiety disorders, addiction to the excessive use of drugs, diseases, having as a symptom of the lack of cognitive abilities, affective disorder or mood episode, each of which is mediated by the activity of phosphodiesterase 10.

18. Pharmaceutical composition for inhibiting the activity of phosphodiesterase 10 containing the compound according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt as an active ingredient.

19. Pharmaceutical composition for treating or preventing disease or condition, the symptoms of which may be alleviated by inhibition of the activity of phosphodiesterase 10, by inhibiting the activity of phosphodiesterase 10 from the patient containing the compound according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt as an active ingredient.

20. Pharmaceutical composition for treatment or prevention of schizophrenia, anxiety disorders, addiction to the excessive use of drugs, diseases, having as a symptom of the lack of cognitive abilities, affective disorder or mood episode, each of which is mediated by the activity of phosphodiesterase 10 containing the compound according to any one of paragraphs.1-8 or its pharmaceutically acceptable salt as an act of the main ingredient.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formula , fragment A is specified in a group consisting of , or , R1, R3, R4 and R5 mean hydrogen or alkyl; each of R4a and R5a represents hydrogen; G1 represents aryl or heteroaryl, which can by unsubstituted or substituted by 1, 2, 3, 4 or 5 substitutes specified in a group consisting of alkyl, halogen, cyano, -OR1b, -S(O)R2b, -C(O)R1b, -C(O)OR1b, -OC(O)N(Rb)(R3b), -(CR4bR5b)m-OR1b, -C(OH)[(CR4bR5b)m-R4b]2, and halogenalkyl; G2 means cycloalkyl, cycloalkenyl or heterocycle unsubstituted or substituted by 1, 2, 3, 4 or 5 substitutes specified in a group consisting of alkyl; Rb represents hydrogen or alkyl; R1b and R3b represents hydrogen, alkyl or halogenalkyl; R2b represents alkyl; R4b and R5b represents hydrogen, halogen, alkyl or halogenalkyl; m represents 1, 2, 3, 4 or 5; R2 is specified in a group consisting of hydrogen, alkyl, -(CR4aR5a)m-G1 and -S(O)2R6, R6 represents G1, X1 means N or CR9; X2 means N or CR10; X3 means CR11; X4 means N or CR12; provided one fragment of X1, X2 or X4 can represent N; each of R9, R10, R11, R12, R13 and R14 independently represents hydrogen, alkyl, alkenyl, halogen, -G1, -G2, -OR1a, -C(O)G3, -C(O)OR1a, -C(O)N(Rb)(R3a), -N(Rb)(R3a), -(CR4aR5a)m-G1, -CR4a=CR5a-G1, -(CR4aR5a)m-G2, -CR6a=C(R7a)2, halogenalkyl and fragment ; R1a and R3a represents hydrogen, alkyl, haloalkyl, G1, -(CR4aR5a)m-G1, G2 or -(CR4aR5a)m-G2; R6a is alkyl or halogenalkyl; R7a represents hydrogen, alkyl or helogenalkyl; G3 represents heterocycle attached to an adjoining carbonyl fragment through a nitrogen atom being a part of heterocycle; or R10 and R11 or R13 and R14 together with carbon atoms which they are attached to, form unsubstituted phenyl or cycloalkyl; Y1 means NR17, CR18R19, C(O), S(O)n or O; Y2 means NR20, CR18R19 or C(O); Y3 means NR17, CR18R19 or C(O); or Y1 and Y2 together represent CR18=CR19, n means 2; R17 represents hydrogen; R18 and R19 represents hydrogen; and R20 is specified in a group consisting of hydrogen, alkyl and -S(O)n-G1.

EFFECT: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts possessing the properties of a 5-HT2C and/or 5-HT6 receptor modulator, to a based pharmaceutical composition and to methods for preparing them.

33 cl, 7 tbl, 20 dwg, 278 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclic indolysincarboxamides and azaindolysincarboxamides of formulas Ia and Ib:

presented below, wherein the values of R, Ra, R10, R20, R30, R40, Y, n, p and q are specified in cl. 1 of formula. What is described is a method for preparing them.

EFFECT: compounds exhibit rennin-inhibitory activity that enables using them in the pharmaceutical composition and for treating hypertension.

11 cl, 4 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula Ia, their stereoisomers or pharmaceutically acceptable salts, inhibiting JAK kinase activity. Compounds can be applied in treatment of inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis, in treatment of autoimmune diseases, such as lupus, multiple sclerosis, neurodegenerative diseases, such as Alzheimer's disease, etc. In formula Ia R1 represents H; R2 represents -OR4, -NR3R4- or -NR3S(O)2R4; R3 represents H or C1-C6alkyl, where said alkyl is optionally substituted with ORa; R4 represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atoms as heteroatoms, or -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R8 and said aryl, cycloalkyl and heteroaryl are optionally substituted with group R9; or R3 and R4, taken together with nitrogen atom, which they are bound to, form C3heterocyclyl, containing 1 nitrogen atom as heteroatom, optionally substituted with group R13; Z represents -NR5R6; R5 represents H; R6 represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains oxygen atom as heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected fromoxygen, nitrogen and sulphur, as heteroatoms, -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R10, and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with group R11; R7 represents H; R8 and R10 each independently represents halogen or ORa; R9 independently represents -CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted with F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted with group oxo or F, -(C0-C5alkyl)C3-C6heterocyclyl, where heterocyclyl contains 1-2 heteroatoms, selected from atoms of oxygen and nitrogen, and where heterocyclyl is optionally substituted with halogen or C1-C3alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogen, or -(C0-C5alkyl)C4-C5heteroaryl, where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected from atom of oxygen, nitrogen and sulphur as heteroatoms, and where heteroaryl is optionally substituted with or C1-C3alkyl; R10 independently represents halogen or ORa. Other values of radicals are given in the invention formula.

EFFECT: obtaining pharmaceutically acceptable salts, inhibiting JAK kinase activity.

15 cl, 4 tbl, 452 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

Jak inhibitors // 2538204

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I wherein R means C1-6alkyl, C1-6halogenalkyl, hydroxy-C1-6alkyl, hydroxygroup or halogen; m, n is equal to 0 or 1; Z1 means CH or NH; Z2 means CH or N; Z3 means CR1, N or NR2; R1 means H, C1-6alkyl, C3-7cycloalkyl, cyanogroup, cyano-C1-6alkyl or halogen; R2 means H or C1-6alkyl; X means CH, CR' or N; X' means CH, CR' or N; r is equal to 1; Y means CH or CR'; R' means R'a or R'b; R'a means a halogen or cyanogroup; R'b means C1-6alkyl, heterocycloalkyl specified in piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, OR", SR", S(=O)2R" or NR"R", optionally substituted by one or more R'c; R'c means a hydroxygroup, oxogroup, cyanogroup, C1-6alkyl, pyridinyl, carboxy-C1-6alkyl, aminocarbonyl-C1-6alkylaminogroup, C1-6alkylaminogroup, C1-6dialkylaminogroup or C1-6alkoxygroup; R" means H, C1-6alkyl, hydroxy-C1-6alkyl, piperidinyl, C3-7cycloalkyl or pyridinyl; Q means S(=O)2Q1, C(=O)Q2, C(=O)OQ3 or Q4; Q1 means C1-6alkyl, C3-7cycloalkyl-C1-6alkyl, C1-6alkylaminogroup or C1-6dialkylaminogroup optionally substituted by one or more Q1'; each Q1' independently means C1-6alkyl or cyanogroup; Q2 means C1-6alkyl optionally substituted by one or more Q2'; each Q2' independently means a cyanogroup; Q3 means C1-6alkyl; Q4 means C1-6alkyl, oxetanyl optionally substituted by one or more Q4'; each Q4' independently means a halogen, cyanogroup, cyano-C1-6alkyl; p is equal to 0, 1 or 2; q is equal to 1 or 2; each means a single bond or a double bond; provided one of Z1 and Z2, and Z3 and Z3 bonds are double and single.

EFFECT: compounds of formula I as JAK inhibitors.

23 cl, 2 tbl, 121 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically 4-((2-hydroxyethoxy)methyl)-5-methyl-2-methylmercapto-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one of formula (I) . The invention also relates to a method of producing and using said compound to treat West Nile fever.

EFFECT: obtaining a novel compound with useful biological activity.

3 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: described is novel biologically active compound 2-methylsulphanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazinide L-argininium dehydrate of formula , which has antiviral action, method of its obtaining and application for prevention and treatment of West Nile fever.

EFFECT: increased efficiency of compound application.

3 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to compounds of N-phenyl(pyperazinyl or homopyperazinyl)benzenesulphonamide or benzenesulphonylphenyl(pyperazine or homopyperazine), or to their physiologically acceptable acid addition salts, described by general formulas (I) and (I'), where X is a chemical bond or a group N-R4; R1 is hydrogen or methyl; R2 is hydrogen or methyl; R3 is hydrogen, C1-C3alkyl, fluorine, C1-C2alkoxy or fluorinated C1-C2alkoxy; R4 is hydrogen, C1-C4alkyl or C3-C4cycloalkyl-CH2-; R5 is hydrogen, fluorine, chlorine, C1-C2alkyl, C1-C2alkoxy or fluorinated C1-C2alkoxy; R6 is hydrogen and n is 1 or 2. The invention also relates to a pharmaceutical composition based on the compound of formula

or

.

EFFECT: novel compounds, modulating activity of the 5HT6 receptor are obtained.

35 cl, 2 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, in particular to a composition, the application of the composition and a method of treating abuse with substances, causing painful addiction in a subject. The composition contains a carbamoyl compound, or its pharmaceutically acceptable salt, or an ester as an active ingredient and the method includes the introduction of a therapeutically effective quantity of the carbamoyl compound, or its pharmaceutically acceptable salt, or the ester.

EFFECT: composition is used for the treatment of abuse with substances, causing painful addiction in a subject, as well as to an improvement of behaviour associated with the abuse.

14 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to psychiatrics and addictology, and concerns treating psychoactive substance dependence, particularly alcohol and nicotine addiction. That is ensured by administering a therapeutic agent containing an activated potentiated form of antibodies against the brain-specific S-100 protein and an activated potentiated form of antibodies to a human cannabinoid receptor, more preferentially to the human cannabinoid receptor type I.

EFFECT: method provides suppressing both physical and mental alcohol and nicotine addiction.

11 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to immunology, and can be used for treating drug abuse, industrial and domestic poisonings, and in man-induced disasters, etc. The invention represents a synthetic immunogen for the protection against toxic action of narcotic and psychoactive substances. The immunogen is presented in the form of a conjugate of a macromolecular carrier specified in: natural or artificial protein, oligo- and polypeptide, carbohydrate, lipid or nucleotide, and haptene - a narcotic or psychotropic compound, and additionally contains poly(4-nitrophenyl)acrylate covalently bond to the conjugate within the range of ratios 2 to 7 moles of the conjugate per one mole of poly(4-nitrophenyl)acrylate with the ratio of haptene and the macromolecular carrier in the conjugate makes 2-17 moles of haptene per 1 mole of the carrier.

EFFECT: using this invention leads to eliciting a stable immune response for a long period of time and providing the body protection against toxic action of the narcotic and psychotropic substances by produced specific haptene antibodies.

3 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), having affinity to the µ-opioid receptor and the to the ORL1 receptor, a medicinal agent containing said compounds and use thereof to obtain a medicinal agent for treating pain and other diseases. In general formula (1), Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; R1 and R2 independently denote -CH3; R3 denotes R0, where R0 denotes C1-8-alkyl; aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; unsubstituted heteroaryl, selected from a 5-member heteroaryl with one S atom as a heteroatom; R4 denotes R0, where R0 denotes aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, mono-substituted with -S(O)2-phenyl; unsubstituted -dihydroisoindolyl or unsubstituted -indolyl; or R4 denotes -OR0 or -SR0, where R0 denotes a cycloaliphatic group selected from -C5-6-cycloalkyl; aryl, selected from unsubstituted phenyl; C1-2-alkylaryl, where aryl denotes phenyl, which is unsubstituted or mono-substituted with -OR0, where R0 denotes -C1-3-alkyl; and R5 denotes -H or -CH3.

EFFECT: obtaining a medicinal agent for treating pain and other diseases.

7 cl, 3 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented versions of pharmaceutical compositions able to resist the recovery of a pharmaceutical substance containing alkaloids if used for non-medical purposes and to prevent the recreational misuse. They contain at least one pharmaceutical substance (PS) of alkaloid with the properties of an anxiolytic, an anti-depressant, a hypnotic, or a psychotropic, or an anti-cold in the acid form; polyphenol able to bind to the acid form of the PS to form a complex resistant to the common recovery, and an ingredient able to bind selectively to polyphenol, and thereby release the PS from the complex. What is presented is an additive for preventing the commercial and recreational misuse of the pharmaceutical substance containing: polyphenol - the first ingredient able to bind to the acid form of the PS to form the complex resistant to the common recovery, and the second ingredient able to bind selectively to polyphenol thereby releasing the PS from the complex. There are presented the methods for preparing the above pharmaceutical compositions and the additive, and also the method for administering the PS.

EFFECT: provided resistant properties of the pharmaceutical compositions to the recreational misuses have been shown.

28 cl, 12 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely a method for individual's addictive behaviour correction. The method for individual's addictive behaviour correction involving the simultaneous introduction into the individual's body a combination of organic preparations: Hirnstamm D5, Placenta D5, Hypophysis D5, Thymus D5, according to the specific schedule in a combination with the course of psychotherapy.

EFFECT: developing the method for individual's addictive behaviour correction.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented methods of treating or preventing an addiction or recurrent addictive behaviour, including: alcohol, nicotine, marijuana, marijuana derivative, opioid receptor antagonist, benzodiazepine, barbiturate and psychostimulant by administering the peroxisome proliferator-activated receptor gamma (PPARγ) agonist thiazolidinedione, alone or in a combination with another therapeutic agent - an opioid receptor agonist, a mixed partial opioid receptor agonist/antagonist, an anti-depressant, an antiepileptic agent, an antiemetic agent, a corticotrophin releasing factor 1 (CRF-1) receptor antagonist, a selective serotonin 5-HT3 receptor antagonist, a 5-HT2A/2C antagonist or a cannabinoid 1 (CB1) receptor antagonist (versions), related pharmaceutical compositions with the above combinations (versions), a standard dosage form (versions) and kits (versions).

EFFECT: it is shown that the PPARγ agonist pioglitazone had no effect on amphetamine sensitisation, however it reduced opiate consumption and opiate addiction, also reduced nicotine self-administration in rats, and reduced alcohol consumption if synergistically combined with topiramate Pioglitazone reduced ethanol self-administration in rats.

33 cl, 23 dwg, 27 ex

FIELD: medicine.

SUBSTANCE: there are presented: using (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetra-hydronaphth-2-yl)-2,3-dihydro-2-tioxo-1H-imidazole, (R)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-hydronaphth-2-yl)-2,3-dihydro-2-tioxo-1H-imidazole and a mixture thereof, as well as a pharmaceutically acceptable salts thereof, such as a hydrochloride salt (compound A, nepicastat) in a method of treating a patient suffering or prone to any symptom(s) of addiction, cocaine addiction or withdrawal, and using the compound A in the method of treating at least one phase of cocaine addiction specified in acquisition, maintenance, inhibition and recurrence. What is shown is: nepicastat significantly increased dopamine and the dopamine/norepinephrine in rat's brain, decreased norepinephrine, inhibited dopamine-β-hydroxylase in spontaneously hypertensive rats, with no effect on locomotor activity.

EFFECT: nepicastat therapy of cocaine addiction has shown no significant deterioration of patient's mood, sleep and cognitive abilities.

15 cl, 11 dwg, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to neurology, and concerns treating vegetative-vascular dystonia, dizziness syndrome of various origins, and kinetosis. That is ensured by administering a therapeutic agent containing an activated-potentiated form of brain-specific protein S-100 antibody and using the activated-potentiated form of endothelial NO-synthase antibodies as an additional exalting agent.

EFFECT: invention provides the effective treatment of the above pathological conditions by the synergetic effect of the ingredients of the therapeutic agent.

9 cl, 16 tbl, 4 ex

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