Methods of obtaining and purification of heteroaryl compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of obtaining heteroaryl compounds, represented by structural formulae (I) or (II): where R1-R4 have values, given in subcl. 1,14 of the formula.

EFFECT: compounds can be used for treatment or prevention of cancer, inflammatory states, immunological states, etc.

29 cl, 20 ex

 

The present application claims priority on provisional application U.S. No. 61/254917, filed October 26, 2009, and provisional application U.S. No. 61/328480, filed on April 27, 2010, the full contents of each of which are incorporated herein by reference.

1. The technical field TO WHICH the INVENTION RELATES

In the application the proposed methods, which are mostly in the field of chemical synthesis and purification, and more specifically, to methods of synthesis and/or purification of certain heteroaryl compounds.

2. Prior art

The relationship between abnormal phosphorylation of proteins and the cause or consequence of diseases has been known for more than 20 years. Accordingly, protein kinases have become a very important group of the studied drugs. Cm. Cohen, Nature, 1:309-315 (2002). Various inhibitors of protein kinases have been used in clinics for treating a wide range of diseases such as cancer and chronic inflammatory diseases, including diabetes and stroke. Cm. Cohen, Eur. J. Biochem., 268:5001-5010 (2001).

The elucidation of the complexity of the cascade of reactions of protein kinases and complexity of relationships and interactions among and between the various protein kinases and cascades of kinase reactions highlights the importance of establishing pharmacological agents that can act as modulators, regulators and�and inhibitors of protein kinases which have positive activity against multiple kinases or multiple cascades of kinase reactions. Accordingly, there remains a need for new modulators of kinases.

A protein called mTOR (target of rapamycin in mammals), which is also called FRAP, RAFTI or RAPT1, is a 2549-amino acid Ser/Thr protein kinase, which has been shown, is one of the most important proteins in the pathway mTOR/PI3K/Akt, which regulates the growth and proliferation of cells. Georgakis and Younes Expert Rev. Anticancer Ther. 6(1): 131-140 (2006). mTOR exists in two complexes, mTORC1 and mTORC2. mTORC1 sensitive to rapamycin analogs (such as temsirolimus or everolimus) and mTORC2 largely resistant to rapamycin. Some mTOR inhibitors have been evaluated in clinical trials (or are in the process of testing) for the treatment of cancer. Temsirolimus was tested for use for patients with renal cell carcinoma in 2007, and everolimus was tested in 2009 for patients with renal cell carcinoma who have progressed in relation to anti-vascular endothelial receptors of growth factors. In addition, sirolimus was tested in 1999 for the prevention of rejection of kidney transplants. Interesting, but limited clinical success of these mTORC1 compounds demonstrates the usefulness and�of hibition mTOR in cancer treatment and rejection of organ transplants, and an increased potential for connections with both mTORC1 and mTORC2 inhibitor activity.

Citation or identification of any reference in section 2 of the description should not be interpreted as the assumption that the link is a prototype of this application.

3. Summary of the INVENTION

In the description of the proposed methods for obtaining compounds of the following formula (I):

and their pharmaceutically acceptable salts, tautomers and stereoisomers, where R1-R4have mentioned in the description.

Further, in the invention proposed methods of obtaining compounds of the following formula (II):

and their pharmaceutically acceptable salts, tautomers and stereoisomers, where R1, R2and R3have mentioned in the description.

Further, in the invention proposed chemical intermediate compounds that can be used in the description of the methods.

Compounds of formulas (I) and (II), or their pharmaceutically acceptable salts, tautomers and stereoisomers (each of which is in the description referred to as "heteroaryl compounds"), can be used for treating or preventing cancer, inflammatory conditions, immunological conditions, neurodegenerative, diabetes, diabetes, obesity, neurological disorders�rd, age-related diseases, and cardiovascular conditions, and conditions that can be treated or prevented by inhibiting the cascade of kinase reactions, for example, of pathway mTOR/PI3K/Akt.

The options presented can be understood more fully with reference to the detailed description and examples, which should represent examples limitiruesh options.

4. DETAILED DESCRIPTION of PREFERRED VARIANTS of the INVENTION

4.1 DEFINITIONS

The term "alkyl" group is a saturated or partially unsaturated acyclic hydrocarbons with unbranched or branched chain, containing from 1 to 10 carbon atoms, usually from 1 to 8 carbon atoms, or in some embodiments from 1 to 6, 1 to 4 or from 2 to 6 carbon atoms. Representative alkyl groups include-methyl, -ethyl, -n-propyl, n-butyl, n-pentyl and-n-hexyl; while saturated branched alkali include-isopropyl, -sec-butyl, -isobutyl, tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Examples of unsaturated alkyl groups, among others, include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, - C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3and CH 2C≡C(CH7CH3). If specified in the description of the alkyl groups referred to as "substituted," they may be substituted by any Deputy or alternate specified in the disclosed in the description of examples of connections and options, such as halogen (chlorine, iodine, bromine or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; Yiming; imide; amidine; guanidine; ionamin; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamino; arelaxing; N-oxide; hydrazine; hydrazide; hydrazon; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2or(alkyl)aminocarbonyl. The alkyl group can be substituted or unsubstituted.

The term "cycloalkyl" group is a saturated, partially saturated or unsaturated cyclic alkyl group containing 3 to 10 carbon atoms containing a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted from 1 to 3 alkyl groups. In some embodiments cycloalkyl group contains from 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms can be from 3 to 5, from 3 to 6 or 3 to 7. Facialgallery groups include, as examples, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentene, 2-methylcyclohexyl, etc., or polycondensation or bridged ring structures such as adamantyl, etc. Examples of unsaturated cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl. Cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, as an example, cyclohexanone, etc.

The term "aryl" group is an aromatic carbocyclic group containing from 6 to 14 carbon atoms containing one ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or antril). In some embodiments, aryl groups contain 6-14 carbons, and in other embodiments from 6 to 12, or even 6 to 10 carbon atoms in the ring portion of said groups. Specific arily include phenyl, biphenyl, naphthyl, etc., Aryl group can be substituted or unsubstituted. The phrase "aryl groups" includes groups containing fused rings, such as condensed aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphtyl�l, etc.).

The term "heteroaryl" group is an aryl ring system containing one to four heteroatoms as ring atoms in a heteroaromatic ring system, in which the remaining atoms are carbon atoms. In some embodiments, heteroaryl groups contain 5 to 6 ring atoms, and in other embodiments from 6 to 9, or even from 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In some embodiments, the heteroaryl ring system is monocyclic or bicyclic. Limitiruyuschie examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pirolli, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenes, furanyl, benzofuranyl (e.g. isobenzofuran-1,3-diamin), indole, azaindole (e.g. pyrrolopyridine or 1H - imidazo[2,3-b]pyridyl), indazole, benzimidazolyl (for example, 1H-benzo[d]imidazolyl), imidazopyridine (e.g. asianshemales, 3H-imidazo[4,5-b]pyridyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyrimidine, triazolopyrimidine, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, isoxazolidine, tianeptine, purinol, xantinol, adenine, guanine, chinoline, ethenolysis, tetrahydroquinolines,chinoxalin and chinazoline.

The term "heterocyclyl" is an aromatic (also referred to as as heteroaryl) or a non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced by heteroatoms selected from the group consisting of O, S and N. In some embodiments heterocyclyl groups include from 3 to 10 ring members, whereas other such groups contain from 3 to 5, 3 to 6 or 3 to 8 ring members. Heterocyclyl can also be associated with other groups on any of the ring atoms (i.e., any carbon atom or heteroatom of the heterocyclic ring). Geteroseksualnoe group can be substituted or unsubstituted. Heterocyclyl groups include unsaturated, partially saturated or saturated ring system, such as, for example, imidazolidine, imidazolidinone and imidazolidinethione group. The expression heterocyclyl includes types of condensed rings, including such types that contain condensed aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxines and benzo[1,3]dioxole. The said expression also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, Hinkley. Representative examples geterotsiklicheskikh groups include, but �e limited aziridinyl, azetidin, pyrrolidyl, imidazolidinyl ureido, pyrazolidine, thiazolidine, tetrahydrothiophene, tetrahydrofuranyl, dioxole, furanyl, thiophenyl, pyrrolyl, pyrrolidyl, imidazolyl, imidazolyl, pyrazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholine, tetrahydropyranyl (for example, tetrahydro-2H-pyranyl), tetrahydrothiopyran, Ossetian, dioxin, dithienyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridin, dehydrodidemnin, dehydratation, homopiperazine, Hinkley, indole, indoline, isoindole, azaindole (pyrrolopyridine), indazole, indolizine, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzothiazole, benzoxadiazole, benzoxazines, benzodithiol, benzoxanthene, benzothiazines, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzo[1,3]dioxole, pyrazolopyrimidine, imidazopyridine (asianshemales; for example, 1H-imidazo[4,5-b]pyridyl or 1H-imidazo[4,5-b]pyridine-2(3H)-o'neill), triazolopyridine, isoxazolidine, purinol, xantinol, adenine, guanine, chinoline, ethenolysis, hemolysins, chinoxalin, chinazoline, cinnoline, phthalazine, naphthyridine, pteridine, tianeptine, dihydrobenzofuranyl, dihydrobenzofuran�Neal, dihydroindole, dihydroergotoxine, tetrahydroindole, tetrahydroindazole, tetrahydroimidazo, tetrahydrobenzothieno, tetrahydropyrrole, tetrahydropapaverine, tetrahydroindazole, tetrahydrochloride and tetrahydroquinolines.

Representative substituted heterocyclyl groups may be mono-substituted or may be substituted more than once, such as, but not limited to, peredelnye or morpholinyl groups that have 2, 3, 4, 5 or 6 substituents, or may be tizamidine various substituents, such as listed below.

The term "cycloalkenyl" group is a radical of the formula: -alkyl-cycloalkyl, where the alkyl and cycloalkyl have the previously mentioned meanings. Substituted cycloalkenyl groups may be substituted by alkyl, cycloalkyl or and alkyl, and cycloalkyl the parts of the group. Representative cycloalkenyl groups include, but are not limited to, cyclopentylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl and cyclohexylprop. Representative substituted cycloalkenyl groups may be mono-substituted or may be substituted by more than one Deputy.

The term "kalkilya" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl youtubesandee earlier values. Substituted kalkilya groups may be substituted by alkyl, aryl, or and alkyl, and the aryl parts of the group. Representative kalkilya groups include, but are not limited to, benzyl and pentelow group and condensed (cycloalkenyl)alkyl groups, such as 4-acylinder.

The term "geterotsiklicheskikh" group is a radical of the formula: -alkyl-heterocyclyl, where the alkyl and heterocyclyl have the previously mentioned meanings. Substituted geterotsiklicheskikh groups may be substituted by alkyl, heterocyclyl, or and alkyl, and heterocyclyl the parts of the group. Representative geterotsiklicheskikh groups include, but are not limited to, 4-ethylmorpholine, 4-propylbiphenyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, (tetrahydro-2H-Piran-4-yl)methyl, (tetrahydro-2H-Piran-4-yl)ethyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-retil and indole-2-ylpropyl.

The term "halogen" represents fluorine, chlorine, bromine or iodine.

The term "hydroxyalkyl" group represents an alkyl group, as disclosed above, substituted by one or more hydroxy groups.

The term "alkoxygroup" represents-O-(alkyl), where alkyl has the previously mentioned values.

The term "alkoxyalkyl group" represents -(alkyl)-O-(alkyl), where alkyl is of UK�mentioned earlier.

The term "amino group" represents a radical of the formula: -NH2.

The term "alkylamino" represents a radical of the formula: -NH-alkyl or-N(alkyl)2where each alkyl independently has the specified value.

The term "carboxyl" group is a radical of the formula: -C(O)OH.

The term "aminocarbonyl" group is a radical of the formula: -C(O)N(RNo.)2, -C(O)NH(RNo.) or-C(O)NH2where each RNo.independently represents a substituted or unsubstituted alkyl, cycloalkyl, aryl, Uralkaliy, heterocyclyl or heterocyclyl group, as defined in the description.

The term "alluminare" represents a radical of the formula: -NHC(O)(RNo.) or-N(alkyl)C(O)(RNo.), where each alkyl, and RNo.independently have the specified values.

The term "alkylsulfonamides" represents a radical of the formula: -NHSO2(RNo.) or-N(alkyl)SO2(RNo.), where each alkyl, and RNo.have the specified values.

The term "urea" represents a radical of the formula: -N(alkyl)C(O)N(RNo.)2, -N(alkyl)C(O)NH(RNo.), -N(alkyl)C(O)NH2, -NHC(O)N(RNo.)2, -NHC(O)NH(RNo.), or-NH(CO)NHRNo.where each alkyl, and RNo.independently has the specified value.

If more open�x in the description of groups, except alkyl groups, say groups are substituted, they can be replaced by any suitable Deputy or deputies. Illustrative examples of substituents are substituents, which are presented in the disclosed in the description of the compounds of examples and variants, as well as Halogens (chlorine, iodine, bromine or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; Yiming; imide; amidine; guanidine; ionamin; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamino; arelaxing; N-oxide; hydrazine; hydrazide; hydrazon; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or condensed, or neskondensirovannyh polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclyl, which may be monocyclic or condensed, or neskondensirovannyh polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl or triazinyl); monocyclic or condensed, or neskondensirovannyh polycyclic aryl or heteroaryl (for example, phenyl, naphthyl, pyrrolyl, indole, furanyl, �iopener, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, chinoline, ethenolysis, acridines, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophene or benzofuranyl); aryloxy; aralkylated; heterocyclics; and geterotsiklicheskie.

In the same sense as used in the description, the term "pharmaceutically acceptable salt (salt)" refers to salts derived from pharmaceutically acceptable non-toxic acid or base including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable salts of accession of the grounds heteroaryl compounds include, but are not limited to, metal salts obtained with aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts derived from lysine, Ν,Ν'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-metilglyukaminom) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, Anthranilic, mixture of Benzenesulfonic, benzoic, camphorsulfonic, lemon, Tinsulanonda, formic, fumaric, frankenbaby, galacturonic, gluconic, glucuronic, glutamina, glycolic, Hydrobromic, chloris�vodorodnaya, setinova, lactic, maleic, malic, mandelic, methanesulfonic, murinova, nitrogen, amoeba, Pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, fullfamily, sulfuric, tartaric acid and p-toluensulfonate acid. Specific non-toxic acids include hydrochloric, Hydrobromic, phosphoric, sulfuric and methanesulfonic acids. Thus, examples of specific salts include hydrochloride and mesilate. Other salts well known in the art, see, e.g., Remington's Pharmaceutical Sciences, 18theds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19theds., Mack Publishing, Easton PA (1995).

In the same sense as used in the description, and unless otherwise specified, the term "stereoisomer" or "stereoisomers pure" means one stereoisomer heteroaryl compounds which is essentially free of other stereoisomers of the compound. For example, stereoisomers pure compound containing one chiral centre, practically does not contain the opposite enantiomer of the compound. Stereoisomers pure compound containing two chiral center, almost does not contain other diastereomers of the compound. Typical stereoisomers net connection is more than about 80% of the mass. of one stereoisomer of the compound and less than n� about 20% of the mass. other stereoisomers of the compound, more than about 90% of the mass. of one stereoisomer of the compound and less than about 10 wt%. other stereoisomers of the compound, more than about 95% of the mass. of one stereoisomer of the compound and less than about 5 wt%. other stereoisomers of the compound, or more than about 97% of the mass. of one stereoisomer of the compound and less than about 3 wt%. other stereoisomers of the compound. Heteroaryl compounds can have chiral centers and exist in the form of racemates, individual enantiomers or diastereomers and their mixtures. All such isomeric forms are included in disclosed in the description of options, including mixtures thereof. Use stereoisomers pure forms of such heteroaryl compounds as well as mixtures of these forms is included in disclosed in the description of the options. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular heteroaryl compounds can be used in disclosed in the description of the methods and compositions. These isomers can be obtained using asymmetric synthesis, or divide, using standard techniques such as chiral columns or chiral separating agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); E. L. Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen S. H., Tbles of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

It should also be noted that heteroaryl compounds can include E and Z isomers, or mixtures thereof, andCIS- andTRANSisomers or mixtures thereof. In some embodiments, the heteroaryl compound is isolated as aCIS- orTRANS-isomers. In other embodiments, the heteroaryl compounds are a mixture ofCIS- andTRANS-isomers.

The term "tautomers" refers to isomeric forms of compounds that are in equilibrium with each other. The concentration of the isomeric forms will depend on the environment where there is a connection, and can be different depending on, for example, whether the connection is in solid form, or the compound is in an organic or aqueous solution. For example, in an aqueous solution of the pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

As can easily be understood by the specialists, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of compounds of formula (I) and formula (II) is included in the scope of the present invention.

It should also be noted that heteroaryl compounds can contain parts of non-natural isotopes of atoms one or more atoms. For example, the compounds can be introduced� RFID tags with radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125I), sulfur-35 (35S) or carbon-14 (14C), or the compounds can be isotopically enriched, such as deuterium (2H), carbon-13 (13C) or nitrogen-15 (15N). In the sense used here, the term "isotopolog" indicates an isotopically enriched compound. The term "isotopically enriched" refers to the atom whose isotopic composition is different from the natural isotopic composition of the specified atom. The term "isotopically enriched" may also refer to a compound containing at least one atom whose isotopic composition is different from the natural isotopic composition of the specified atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiometrie and isotopically enriched compounds can be used as therapeutic agents, e.g., therapeutic agents in the treatment of cancer and inflammation, research reagents, e.g., reagents in binding assays, and diagnostic agents, e.g., agents for imaging in vivo. All isotopic variants heteroaryl compounds, as disclosed in the description, regardless of whether they are radioactive or not, should be included in the amount presented in the description of the options. Some�the options proposed isotopolog heteroaryl compounds, for example, isotopologues are enriched with deuterium, carbon-13 or nitrogen-15 heteroaryl compounds.

In the same sense as it is used here, the term "treatment" means an alleviation, in whole or in part, the disease or disorder, or symptoms associated with the specified disease or disorder, or slowing or stopping further development of or worsening of a disease or disorder, or symptoms associated with said disease or disorder.

In the same sense as it is used here, the term "prevention" means preventing the onset, recurrence or spread of the disease or disorder, or symptoms associated with a disease or disorder in a patient, at risk of developing a specified disease or condition.

The term "effective amount" in connection with heteroaryl compounds means, in one embodiment, an amount capable of facilitating, in whole or in part, symptoms associated with the disease or disorder, or slowing or stopping further development of or worsening of these symptoms, or in another embodiment, the amount capable of preventing or prevent this disease or disorder in a subject at risk of developing diseases or disorders as disclosed in the description�AI, such as cancer, inflammatory condition, an immunological condition, neurodegenerative disease, diabetes, obesity, neurological disorders, age-related diseases, or cardiovascular conditions, and conditions that can be treated or prevented by inhibiting the kinase pathways, for example, the mTOR/PI3K/Akt pathways. In one embodiment, the effective amount of the heteroaryl compound is an amount that inhibits a kinase in a cell, such as, for example, in vitro or in vivo. In one embodiment, this kinase is a mTOR, DNA-PK, PI3K, or a combination of both. In some embodiments, an effective amount heteroaryl compounds inhibit the kinase in the cell on 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, compared with the activity of the indicated kinase in untreated cells. An effective amount heteroaryl compounds, for example, in the pharmaceutical composition may be at a level that will provide the desired effect; for example, from about 0.005 mg/kg body weight of subject to about 100 mg/kg of body weight of the patient in a single dose for both oral and parenteral administration. As should be obvious to experts, it is expected that the effective amount of the disclosed here, the heteroaryl compounds can vary depending on subject to treatment indications, for example, effective amounts� heteroaryl compounds apparently, it will be different for the treatment of patients with inflammatory diseases, or at risk of inflammatory diseases, compared with an effective amount of a compound for treating patients with some other disease, or at risk of another disease, e.g., cancer or metabolic disorders.

The term "patient" includes animals, including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cat, dog, mice, rats, rabbits and Guinea pigs, in one embodiment a mammal, in another embodiment of the people.

The term "cancer" refers to any of various malignant neoplasms characterized by the proliferation of cells that can invade surrounding tissue and metastasize to new areas of the body. Both benign and malignant tumors are classified according to the type of tissue in which they are found. For example, fibromas are fibrous neoplasms of connective tissue, and melanoma represent an abnormal growth of pigment (melanin) cells. Malignant tumors arising from epithelial tissues, e.g., tissues of the skin, bronchi, and stomach, are called carcinomas. Malignancy of epithelial glandular tissues such as are found in the mammary glands, p�the mod and the colon known as adenocarcinoma. Malignant growth of connective tissues, such as muscles, cartilage, lymph tissue and bone are called sarcomas. Lymphoma and leukemia are malignant tumors that occur in leukocytes. In the process of metastasis, tumor cells migrate to other parts of the body with an established neoplasm, in areas located away from the site of initial appearance. Bone tissue is one of the most favorable sites of metastasis of malignant tumors and occur in approximately 30% of all cases of cancer. It is known that among other cancers lung cancers, breast, prostate, etc. very often metastasize in bone.

In the context of neoplasms, inhibition of cancer, tumor growth or tumor cell growth can be assessed, along with others, on the delayed appearance of primary or secondary tumors, slowing the development of primary or secondary tumors, to reduce the appearance of primary or secondary tumors, to slow or reduce the severity of secondary effects of disease, to halt tumor growth and tumor reduction. In extreme cases, complete inhibition is referred to in the description as prophylaxis or chemoprophylaxis. In this context, the term "prevention" includes either full� preventing the onset of clinically diagnosed neoplasia, or preventing the onset of diagnosed preclinical stage of neoplasia in at-risk individuals. This definition includes the prevention of malignant transformation in cells or stop or reverse the development prelocating cells into malignant cells. This includes prophylactic treatment of those who are at risk of developing neoplasia.

4.2 SYNTHESIS of HETEROARYL COMPOUNDS

In the proposed invention the methods of obtaining the compounds of the following formula (I):

and their pharmaceutically acceptable salts, tautomers and stereoisomers, where:

R1is a substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie;

R2represents H, substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl or a substituted or unsubstituted cycloalkenyl;

R3and R4each independently, represents H, substituted or unsubstituted C1-8alkyl , alkyl substituted or unsubstituted aryl, z�aligned or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkenyl, or R3and R4together with the atoms to which they are attached to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;

or R2and one of R3and R4together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl;

provided that the specified connection is not a connection, the following, namely:

6-(4-hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-(1H-1,2,4-triazole-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

or

(R)-6-(4-(1H-1,2,4-triazole-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he.

In the description of the proposed methods for obtaining compounds of formula (I)

where the specified method comprises the interaction of a compound of formula (III)

with R1-Y in a solvent in the presence of a palladium catalyst, where the said contacting occurs under conditions suitable� to obtain the compound of formula (I), where R1, R2, R3and R4have mentioned in the description of the value, and

X represents a halogen, B(OR+)2or Sn(R++)3;

Y represents halogen, triflic, B(OR+)2or Sn(R++)3; where

(a) if X represents a halogen (e.g., Br, Cl or I), then Y is B(OR+)2or Sn(R++)3; or

(b) if Y represents a halogen (e.g., Br, Cl, or I) or triflic, then X is a B(OR+)2or Sn(R++)3;

where each R+independently represents hydrogen or substituted or unsubstituted C1-3alkyl, or each R+together with the boron atom and the atoms to which they are attached, form a cyclic boronate; and R++represents C1-4alkyl.

Usually the solvent is a dimethyl formamide, isopropanol, dioxane, toluene, dimethylacetamide, tetrahydrofuran, acetonitrile, isopropylacetate, dimethylsulfoxide, acetone, methanol, methyl tert-butyl ether, or combinations thereof, in the presence or in the absence of water, and the palladium catalyst is dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloro methane), palladium(dba)2/three-o-tolylphosphino, dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium, dichlorobis(p-p dimethylaminophenyl-tert-butylphosphine)fell�ADI(II), tetrakis(triphenylphosphine)palladium(0) or palladium acetate(II)/4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. In some embodiments, if X or Y are halogen, specified halogen is Br. In some embodiments, if either X or Y represents B(OR+)2specified communication occurs in the presence of base, such as sodium carbonate, triethylamine, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate or sodium hydroxide. In some such embodiments, B(OR+)2represents B(OH)2or B(-OC(CH3)2C(CH3)2O-). In other embodiments, if X or Y is Sn(R++)3the implementation of the contacting optionally occurs in the presence of base, such as triethylamine, sodium carbonate, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate or sodium hydroxide. In some such embodiments, R++is methyl or n-butyl.

Also proposed methods for obtaining compounds of formula (III),

where method comprising contacting the compound of formula (IV)

with R2-NH2in a solvent such as acetonitrile or tetrahydrofuran, in the presence of base, such as three!�ylamine or diisopropylethylamine, where the said contacting occurs under conditions suitable to produce compound of formula (III), where R2is mentioned in the description of the values, R3and R4represents H, X represents halogen, such as Br, Hal represents halogen, such as Br, and Hal2represents Br or I.

Suggested methods for obtaining compounds of formula (III)

where the specified method comprises cyclization of a compound of formula (V)

in a solvent such as acetonitrile, in the presence of a palladium catalyst, such as palladium(II)acetate, a ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and bases, such as sodium bicarbonate, where the said cyclization occurs under conditions suitable to produce compound of formula (III), where R2has the above significance, R3and R4have mentioned in the description of values, X is a halogen, such as Br, and Hal represents halogen, such as Br.

In some embodiments, in the description presented, salts (including pharmaceutically acceptable salts), solvates and hydrates of compounds of formula (III), formula (IV) and formula (V).

In some embodiments of compounds of formula (I) R1is a substituted or unsubstituted aryl or substituted or �timesany heteroaryl. In one embodiment, R1represents phenyl, pyridyl, pyrimidyl, benzimidazolyl, indole, indazole, 1H-imidazo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl, 1H-imidazo[4,5-b]pyridine-2(3H)-o'neill, 3H-imidazo[4,5-b]pyridyl or pyrazolyl, each of which is optionally substituted. In some embodiments, R1represents phenyl substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8of alkyl (e.g., methyl), substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted triazolyl or pyrazolyl), halogen (e.g. fluorine), aminocarbonyl, cyano, hydroxyalkyl (e.g. hydroxypropyl) and hydroxy. In other embodiments, R1represents pyridyl substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8of alkyl, substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl, -OR and-NR2where each R independently represents H or substituted or unsubstituted C1-4alkyl. In still other embodiments, R1represents a 1H-imidazo[2,3-b]pyridyl or benzimidazolyl, each of which is optionally substituted by one or more of the substituents, �ezavisimo selected from the group consisting of substituted or unsubstituted C1-8alkyl, and-NR2where each R independently represents H or substituted or unsubstituted C1-4alkyl.

In some embodiments of compounds of formula (I) R1is a

where R in each case independently represents H or substituted or unsubstituted C1-4alkyl (e.g., methyl); R' represents independently in each case substituted or unsubstituted C1-4alkyl, halogen (e.g., fluorine), cyano, -or, or-NR2; m represents 0-3; and n is 0-3. Professionals should be clear that any of the substituents R' may be attached to any suitable atom of any of the rings in a condensed ring systems. Professionals should also be clear that the connecting link is R1(denoted by a wavy line crossing the line) can be attached to any atoms of any of the rings in a condensed ring systems.

In some embodiments of formula (I) R1is a

where R in each case independently represents H or substituted or unsubstituted C1-4alkyl; R' in each case independently represents a substituted or unsubstituted C 1-4alkyl, halogen, cyano, -or, or-NR2; m represents 0-3; and n is 0-3.

In some embodiments of compounds of formula (I) R2represents H, substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C1-4Alkylglucoside, substituted or unsubstituted C1-4alkylaryl or substituted or unsubstituted C1-4alkylsilanes. For example, R2represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (C1-4alkyl)-phenyl, (C1-4alkyl)-cyclopropyl, (C1-4alkyl)-cyclobutyl, (C1-4alkyl)-cyclopentyl, (C1-4alkyl)-cyclohexyl, (C1-4alkyl)-pyrrolidyl, (C1-4alkyl)-piperidyl, (C1-4alkyl)-piperazinyl, (C1-4alkyl)-morpholinyl, (C1-4alkyl)-tetrahydrofuranyl or (C1-4alkyl)-tetrahydropyranyl, each of which is optionally substituted.

In other embodiments, R2represents H, C1-4alkyl, (C1-4alkyl)(OR)

where R in each case independently represents H or substituted or unsubstituted C1-4alkyl (e.g., methyl); R' ineach case independently represents H, -OR, cyano, or substituted or unsubstituted C1-4alkyl (e.g., methyl); and p represents 0-3.

In some such embodiments, R2represents H, C1-4alkyl, (C1-4alkyl)(OR)

where R in each case independently represents H or substituted or unsubstituted C1-2alkyl; R' in each case independently represents H, -OR, cyano, or substituted or unsubstituted C1-2alkyl; and p is a 0-1.

In some other embodiments of compounds of formula (I) R2and one of R3and R4together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl. For example, in some embodiments, the compound of formula (I) is a

where R in each case independently represents H or substituted or unsubstituted C1-4alkyl; R" represents H, or substituted or unsubstituted C1-4alkyl; and R1takes defined in the description.

In some embodiments of compounds of formula (I) R3and R4both represent N. In other embodiments, one of R3and R4represents H and the other is different from N. In still other embodiments, one of R3and R4represents C1-4alkyl(e.g., methyl) and the other represents N. In still other embodiments, both of R3and R4represent With1-4alkyl (e.g., methyl).

In some such embodiments presented above, R1is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. For example, R1represents phenyl, pyridyl, pyrimidyl, benzimidazolyl, indole, indazole, 1H-imidazo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl, 1H-imidazo[4,5-b]pyridine-2(3H)-o'neill, 3H-imidazo[4,5-b]pyridyl or pyrazolyl, each of which is optionally substituted. In some embodiments, R1represents phenyl substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8of alkyl, substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl, cyano, hydroxyalkyl and hydroxy. In other embodiments, R1represents pyridyl substituted by one or more substituents, independently selected from the group consisting of cyano, substituted or unsubstituted C1-8of alkyl, substituted or unsubstituted heterocyclyl, hydroxyalkyl, halogen, aminocarbonyl, -OR and-NR2where each R independently represents H or substituted or unsubstituted C1-4alkyl. In other embodiments, R1represents a 1H-imidazo[2,3-b]�iridis or benzimidazolyl, optionally substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8alkyl and-NR2where R independently represents H or substituted or unsubstituted C1-4alkyl.

In some embodiments of a compound of formula (I) contains a group R1as presented in the description hereinafter, and the group R2as presented in the description below.

In some embodiments of compounds of formula (I) compound in a concentration of 10 μm inhibits mTOR, DNA-PK, or PI3K or a combination thereof by at least about 50%. It can be shown that compounds of formula (I) are inhibitors of the above kinases in any suitable analytical system, such as those disclosed in the description of the examples.

In some embodiments of compounds of formula (I) compound is:

6-(1H-imidazo[2,3-b]pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triaz�l-3-yl)pyridin-3-yl)-4-(( TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-((TRANS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((TRANS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((CIS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-((CIS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-�resol-3-yl)pyridin-3-yl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-ethyl-6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(2-methoxyethyl)-6-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-DIH�dropyridine[2,3-b]pyrazine-2(1H)-he;

6-(3-(1H-1,2,4-triazole-5-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

5-(8-(2-methoxyethyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;

3-(6-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzamide;

3-(6-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzonitrile;

5-(8-(TRANS-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;

6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(1H-indazol-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-((1R,3S)-3-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-((1S,3R)-3-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-((1R,3R)-3-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-((1S,3S)-3-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-ethyl-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(1H-imidazo[2,3-b]pyridin-5-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(1H-ind�l-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(1H-indol-5-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(((1R,3S)-3-methoxycyclohexyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(((1S,3R)-3-methoxycyclohexyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3,3-dimethyl-6-(4-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1R,3S)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3R)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1S,3S)-3-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3R)-3-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3S)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1R,3R)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-�hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3S)-3-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1S,3R)-3-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'-((tetrahydro-2H-Piran-4-yl)methyl)-1 N-Spiro[cyclopentane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-it;

7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'-((tetrahydro-2H-Piran-4-yl)methyl)-1 N-Spiro[CYCLOBUTANE-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-it;

4-(cyclopropylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'H-Spiro[cyclopentane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-it;

7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'H-Spiro[CYCLOBUTANE-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-it;

7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'H-Spiro[cyclopropane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-it;

(R)-6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(S)-6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(1H-indazol-5-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(6-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzamide;

4-(2-methoxyethyl)-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-ethyl-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(R)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)-4-methylpyridine-3-yl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)-4-methylpyridine-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-yl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(S)-6-(6-(1-hydro�Sitel)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(CIS-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(TRANS-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(2-methoxyethyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

9-(6-(4H-1,2,4-triazole-3-yl)-3-pyridyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;

6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

5-(8-(CIS-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-6-methilpiralidone;

6-(6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

9-(4-(4H1,2,4-triazole-3-yl)-2-methylphenyl)-3-(2-methoxyacetyl)-6,11,4 a-trihydroxybenzene[1,2-e]pyrazino[2,3-b]pyrazine-5-it;

9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-6,11,4 a-trihydroxybenzene[1,2-e]pyrazino[2,3-b]pyrazine-5-it;

9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-3-(2-methoxyethyl)-6,11,4 a-trihydroxybenzene[1,2-e]pyrazino[2,3-b]pyrazine-5-it;

4-(cyclopentylmethyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

9-(6-(4H-1,2,4-triazole-3-yl)-2-methyl-3-pyridyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;

4-(TRANS-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(CIS-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(cyclopentylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-neopentyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-isobutyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3-methyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(piperidine-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-3-yl)ethyl)-3,4-dihydropyrido[2,3-b]PIR�Zin-2(1H)-he;

8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)(3aS,2R)-2-methoxy-5,10,3 a-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;

8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)(2R,3aR)-2-methoxy-5,10,3 a-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;

8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)(2S,3aR)-2-methoxy-5,10,3 a-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;

8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)(2S,3aS)-2-methoxy-5,10,3 a-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-methoxypropyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-3-methyl-6,11,4 a-trihydroxybenzene[1,2-e]pyrazino[2,3-b]pyrazine-5-it;

9-(4-(4H-1,2,4-triazole-3-yl)phenyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;

9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-6,11,4 a-trihydrobromide[1,2-e]pyrazino[2,3-b]pyrazine-5-it;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(CIS-4-methoxycyclohexyl)3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

9-[6-(1-hydroxyisopropyl)-3-pyridyl]-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b-2(1H)-he;

6-(2-amino-7-methyl-1H-benzo[d]imidazol-5-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;

6-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-5,10,3 a-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;

6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-methyl-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he, or

6-(4-(1H-1,2,4-triazole-5-and�)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he.

Further, in the invention proposed methods of obtaining compounds of the following formula (II):

and their pharmaceutically acceptable salts, tautomers and stereoisomers, where:

R1is a substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie;

R2represents H, substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl or a substituted or unsubstituted cycloalkenyl;

R3represents H or substituted or unsubstituted C1-8alkyl;

provided that the compound of formula (II) is not a 7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he is depicted next:

Also proposed methods for obtaining compounds of formula (II)

where the specified method comprising contacting the compound of formula (VI)

with R1-Y in a solvent in the presence of a palladium catalyst, g�e the said contacting occurs under conditions that suitable to produce compound of formula (I), where R1, R2and R3have mentioned in the description of the value, and

(a) if X represents a halogen (e.g., Br, Cl or I), then Y is B(OR+)2or Sn(R++)3; or

(b) if Y represents a halogen (e.g., Br, Cl or I) or triflic, then X is a B(OR+)2or Sn(R++)3;

where each R+independently represents hydrogen or substituted or unsubstituted C1-3alkyl, or each R+together with the boron atom and the atoms to which they are attached, form a cyclic boronate; and each R++represents C1-3alkyl.

A typical solvent is a dimethyl formamide, isopropanol, dioxane, toluene, dimethylacetamide, tetrahydrofuran, acetonitrile, isopropylacetate, dimethylsulfoxide, acetone, methanol, methyl tert-butyl ether, or combinations thereof, in the presence or in the absence of water, and the palladium catalyst is a dichloro[1,1'bis(diphenylphosphino)ferrocene]palladium(II)dichloro methane), palladium(dba)2/three-o-tolylphosphino, dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium, dichlorobis(p-p dimethylaminophenyl-tert-butylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), dichloro(2-)palladium, and�and palladium acetate(II)/4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. In some embodiments, if X or Y are halogen, specified halogen is Br. In some embodiments, if either X or Y represents B(OR+)2,the said contacting occurs in the presence of base, such as sodium carbonate, triethylamine, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate or sodium hydroxide. In some such embodiments, B(OR+)2represents B(OH)2or B(-OC(CH3)2C(CH3)2O-). In other embodiments, if X or Y are Sn(R++)3the contacting optionally occurs in the presence of base, such as triethylamine, sodium carbonate, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate or sodium hydroxide. In some such embodiments, R++is methyl or n-butyl.

Also proposed methods for obtaining compounds of formula (VI)

Where the specified method comprises cyclization of a compound of formula (VII)

in the presence of base, such as potassium butoxide, or acids, such as acetic acid, TFA, HCl, or phosphoric acid, where the said cyclization occurs under conditions suitable to produce compound of formula (VI), where R2and R3ima�t mentioned in the description of the values Hal represents halogen, such as Br, and R represents H or C1-4alkyl, or a salt of an alkali metal carboxylate, for example, sodium salt. Usually specified cyclization is carried out in a solvent such as, for example, methanol or water.

Also proposed methods for obtaining compounds of formula (VII)

where the specified method comprising contacting the compound of formula (VIII)

with R2-NH2in a solvent such as dimethyl sulfoxide or N-methylpyrrolidinone, optionally in the presence of base, such as triethylamine or diisopropylethylamine where the contacting occurs under conditions suitable to produce compound of formula (VII), where R2and R3are specified in the description of the meaning, and Hal represents halogen, such as Br.

In some embodiments, the proposed salts (including pharmaceutically acceptable salts), solvates and hydrates of compounds of formula (VI), formula (VII) and formula (VIII).

In some embodiments of compounds of formula (II) R1is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. For example, R1represents phenyl, pyridyl, pyrimidyl, benzimidazolyl, 1H-imidazo[2,3-b]pyridyl, indazole, indole, 1H-imidazo[4,5-b]pyridi�, 1H-imidazo[4,5-b]pyridine-2(3H)-o'neill, 3H-imidazo[4,5-b]pyridyl or pyrazolyl, each of which is optionally substituted. In some embodiments, R1represents phenyl substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8of alkyl (e.g., methyl), substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted triazolyl or pyrazolyl), aminocarbonyl, halogen (e.g., fluorine), cyano, hydroxyalkyl and hydroxy. In other embodiments, R1represents pyridyl substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8of alkyl (e.g., methyl), substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl (e.g. hydroxypropyl), -OR and-NR2where each R independently represents H or substituted or unsubstituted C1-4alkyl. In some embodiments, R1represents a 1H-imidazo[2,3-b]pyridyl or benzimidazolyl, optionally substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8alkyl and-NR2where R independently represents H or�ewenny or unsubstituted C 1-4alkyl.

In some embodiments, R1is a

where R in each case independently represents H or substituted or unsubstituted C1-4alkyl (e.g., methyl); R' in each case independently represents a substituted or unsubstituted C1-4alkyl (e.g., methyl), halogen (e.g., fluorine), cyano, -or, or-NR2; m represents 0-3; and n is 0-3. Professionals should be clear that any of the substituents R' may be attached to any suitable atom of any ring of the condensed ring systems.

In some embodiments of compounds of formula (II) R1is a

where R in each case independently represents H or substituted or unsubstituted C1-4alkyl; R' in each case independently represents a substituted or unsubstituted C1-4alkyl, halogen, cyano, -or, or-NR2; m represents 0-3; and n is 0-3.

In some embodiments of compounds of formula (II) R2represents H, substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C1-4Alkylglucoside, substituted�th or unsubstituted C 1-4alkylaryl or substituted or unsubstituted C1-4alkylsilanes. For example, R2represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (C1-4alkyl)-phenyl, (C1-4alkyl)-cyclopropyl, (C1-4alkyl)-cyclobutyl, (C1-4alkyl)-cyclopentyl, (C1-4alkyl)-cyclohexyl, (C1-4alkyl)-pyrrolidyl, (C1-4alkyl)-piperidyl, (C1-4alkyl)-piperazinyl, (C1-4alkyl)-morpholinyl, (C1-4alkyl)-tetrahydrofuranyl or (C1-4alkyl)-tetrahydropyranyl, each of which is optionally substituted.

In other embodiments, R2represents H, C1-4alkyl, (C1-4alkyl)(OR)

where R in each case independently represents H, or substituted or unsubstituted C1-4alkyl (e.g., methyl); R' in each case independently represents H, -OR, cyano, or substituted or unsubstituted C1-4alkyl (e.g., methyl); and p represents 0-3.

In other embodiments of compounds of formula (II) R2represents H, C1-4alkyl, (C1-4alkyl)(OR)

where R in each case independently represents H or substituted or nez�aligned With 1-2alkyl; R' in each case independently represents H, -OR, cyano, or substituted or unsubstituted C1-2alkyl; and p is a 0-1.

In other embodiments of compounds of formula (II) R3represents H.

In some such disclosed in the description of embodiments, R1is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. For example, R1represents phenyl, pyridyl, pyrimidyl, benzimidazolyl, 1H-imidazo[2,3-b]pyridyl, indazole, indole, 1H-imidazo[4,5-b]pyridine, pyridyl, 1H-imidazo[4,5-b]pyridine-2(3H)-o'neill, 3H-imidazo[4,5-b]pyridyl or pyrazolyl, each of which is optionally substituted. In some embodiments, R1represents phenyl substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8of alkyl, substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen, cyano, hydroxyalkyl and hydroxy. In other embodiments, R1represents pyridyl substituted by one or more substituents, independently selected from the group consisting of C1-8of alkyl, substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl, cyano, hydroxyalkyl, -OR and-NR2where each R independently represents H or substituted or unsubstituted C alkyl. In still other embodiments, R1represents a 1H-imidazo[2,3-b]pyridyl or benzimidazolyl, optionally substituted by one or more substituents, independently selected from the group consisting of substituted or unsubstituted C1-8alkyl and-NR2where R independently represents H or substituted or unsubstituted C1-4alkyl.

In some embodiments of a compound of formula (II) contain presented here further group, R1here is a further group R2.

In some embodiments of compounds of formula (II) compound in a concentration of 10 μm inhibits mTOR, DNA-PK, PI3K, or a combination of at least about 50%. It can be shown that compounds of the formula (II) are inhibitors of the above kinases in any suitable analytical system, such as those disclosed in the description of the examples section.

In some embodiments of compounds of formula (II) compound is a

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-imidazo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((CIS-4-Metacritic�hexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-ethyl-7-(1H-imidazo[3,2-b]pyridin-5-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-imidazo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((TRANS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((CIS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(tetrahydro-2H-Piran-4-yl)-3,4-dihydro�erazine[2,3-b]pyrazine-2(1H)-he;

7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((TRANS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((CIS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-hydroxypyridine-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrazine,3-b]pyrazine-2(1H)-he;

5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;

7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-aminopyrimidine-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-hydroxypyridine-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(pyrimidine-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-methoxypyridine-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(2-methoxyethyl)-7-(1H-imidazo[2,3-b]pyridin-5-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-ethyl-7-(1H-imidazo[2,3-b]pyridin-5-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(pyridin-4-yl)-1-(2-(tetras�hydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-methyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

2-(2-hydroxypropan-2-yl)-5-(8-(TRANS-4-methoxycyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)pyridine 1-oxide;

4-methyl-5-(7-oxo-8-((tetrahydro-2H-Piran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)picolinate;

5-(8-((CIS-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;

7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(TRANS-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3-((7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)methyl)benzonitrile;

1-((TRANS-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

3-(7-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzamide;

5-(8-((TRANS-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;

3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)methyl)benzonitrile;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl-1-((1R,3R)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(TRANS-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(CIS-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-((CIS-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(TRANS-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(CIS-4-hydroxycyclohexyl)-7-(6-(2-hydroc�propan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

4-(7-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzamide;

7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-imidazo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-((1S,3R)-3-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-((1R,3R)-3-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-((1R,3S)-3-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-((1S,3S)-3-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-((Tran� -4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(TRANS-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihidro�razine[2,3-b]pyrazine-2(1H)-he;

7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Pyra�-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

(S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;

7-(4-(1H-1,2,4-triazole-5-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyri�eno[2,3-b]pyrazine-2(1H)-he;

1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he; or

1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he.

4.3 METHODS of OBTAINING HETEROARYL COMPOUNDS

Heteroaryl compounds are prepared as depicted in figures 1-9 further, as in the examples presented in section 5.1. It should be noted that specialists in this field can modify presents further illustrative schemes and examples of procedures to obtain the desired product.

Scheme 1

The synthesis of compounds of formula (I) represented in scheme 1. Based on 5-bromopyrazine-2-amine A, the group R1you can enter using the appropriate Bronevoy acid or borate complex ether (R+represents H, or together with the boron atom and the atoms to which they are attached, form a cyclic boronate), palladium catalyst (such as, for example, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloro methane), solvent (such as dimethylformamide) and a base (such as sodium carbonate), using the reaction combinations Suzuki, or alternatively, using the appropriate stannane (R++represents C1-4alkyl), palladium catalyst (such as dichloro[1,1'-bis(diphen�phosphino)ferrocene]palladium(II)dichloro methane or palladium(dba) 2/three-o-tolylphosphino) and the solvent (such as dimethylformamide with or without added base, such as triethylamine), using the reaction of a combination of Steele. Typical conditions of reactions and reagents for Suzuki reactions and can still be found here (see also Rossi et al, Synthesis 15:2419-2440 (2004), Buchwald et al. Accounts of Chemical Research, 41: 1461-1473 (2008), Fu. Accounts of Chemical Research, 41: 1555-1564 (2008), and Echavarren et al. Angew. Chem. Int. Ed., 43: 4704-4734 (2004) and cited in these references). Received R1aminopyrazine B can be bronirovanie using NBS or other standard conditions of bromination, receiving brominated intermediate compound C, which is then subjected to the interaction with the anhydride of 2-bromoxynil acid, yielding acetylated intermediate compound D. Deputy R2administered by attaching to D amine and subsequent closure of the ring in the presence of an amine base (such as triethylamine) and by heating in a suitable solvent (such as acetonitrile), receiving the right products.

Scheme 2

Alternatively, as shown in figure 2, 3.5-dibromopyrazine-2-amine E, is treated with the anhydride of 2-bromoxynil acid, as indicated above, receiving the intermediate connection F. As was disclosed above, the substituent R2administered by attaching amine to F and the subsequent semiconical, receiving the intermediate connection of G. Then it is possible to introduce a group R1using disclosed above, namely, interacting with the corresponding Bronevoy acid or borate complex ether, in the presence of palladium catalyst and base via a reaction combinations Suzuki, or alternatively, using the appropriate stannane, in the presence of a palladium catalyst, using the method of reaction of a combination of Steele, as disclosed above, getting the right products.

Scheme 3

Using another approach (scheme 3), 3,5-dibromopyrazine-2-amine E, is treated with the anhydride of 2-Chloroacetic acid, then sodium iodide, getting iodotoluene intermediate compound F2. Intermediate compound F2 is converted into the desired products in accordance with the method presented in scheme 2 for F.

Scheme 4

To obtain analogues with alpha-substitution at the carbonyl (scheme 4), appropriately substituted amino-protected amino acid H (PNis aminosidine group, such as Boc) is subjected to interaction with a 3.5-dibromopyrazine-2-amine in the presence of a binding agent, such as, for example, 1,1'-carbonyldiimidazole. The conditions of removal of the protective groups (for example, if P is a Boc protective group is removed�, for example, processing TFA or HC1), followed by the closure ring, with a palladium catalyst (using, for example, sodium bicarbonate, palladium acetate(II) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), receiving the intermediate compound I. As before, the group R1you can enter using the appropriate Bronevoy acid or a complex borate ester, palladium catalyst, solvent and base through a reaction combinations Suzuki, or alternatively, using the appropriate stannane, palladium catalyst and solvent using the method of reaction of a combination of Steele (disclosed above), getting the right products. The method can also be used for obtaining analogs in which R2represents hydrogen. In addition, this method can be used to obtain compounds in which R3and R4together with the atom to which they are both attached, form a Spiro-cyclic ring, by using the appropriate source of amino acids.

Scheme 5

Analogs in which R2and R3together with the atoms to which they are attached, form a ring (see scheme 5) can be obtained in reactions similar to those shown in scheme 4, starting from the corresponding cyclic amino acids J.

�Hema 6

While getting the right products reactivity matching partners can be changed to the opposite. For example, as shown in the scheme 6, the intermediate compound I can be converted into the corresponding stannane K by reaction with, for example, hexamethyldisilane (R++is methyl) in the presence of a palladium catalyst (such as tetrakis(triphenylphosphine)palladium), and group R1you can enter using an appropriate leaving group, for example, halogen (such as bromide) or triflic, and solvent using the method of reaction of a combination of Steele, as disclosed above, getting the right products. Alternatively, the intermediate compound I can be converted into the corresponding complex borodaty ether K2, by reaction with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in the presence of a palladium catalyst such as 1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloro methane) and base (such as potassium acetate) in a solvent such as dioxane. Group, R1you can enter using an appropriate leaving group, for example, halogen (such as bromide) or triflic, palladium catalyst and solvent using the method of reaction of a combination of Suzuki, as disclosed above, getting the right products.

Scheme 7

Connected�I of the formula (II) can be obtained as shown in scheme 7. Reductive amination of 3,5-dibromopyrazine-2-amine (E ethyl 2-oxoacetate (in the presence of, for example, sodium borohydride as a reducing agent) results in the intermediate L. Alternatively, 3,5-dibromopyrazine-2-Amin E can be converted to the intermediate compound L, interacting with ethyl 2-CHLOROACETATE in the basic conditions (using, for example, Cs2CO3). Deputy R2administered by attaching amine to L, in the presence of an amine base, such as diisopropylethylamine, and when heated in an appropriate solvent (such as DMSO), and the subsequent closure of the ring with acid catalyst (using, for example, acetic acid), receiving the intermediate connection M. the Closure ring product accession amine L may also occur in basic conditions with a catalyst, such as the treatment of tert-butoxide potassium in the solvent. Alternatively, a fragment of the ethyl ester can hydrolyze (e.g., processing base) before the reaction with R2-NH2in the water, with the subsequent closure of the ring, kataliziruemykh acid. As before, the group R1you can enter using the appropriate Bronevoy acid or borate ester, palladium catalyst, solvent and about�the identification, through the reaction of a combination of Suzuki, or alternatively, using the appropriate stannane, palladium catalyst and solvent using the method of reaction of a combination of Steele (disclosed above), getting the right products.

Scheme 8

An alternative approach (scheme 8) begins with the reaction of 2,6-dichloropyrazine N with an appropriate amine ester (R^ represents C1-3alkyl), with subsequent recovery dehalogenating using hydrogen and a palladium catalyst such as palladium hydroxide, a base such as potassium carbonate, in a solvent such as ethanol, and subsequent bromination of, interacting with brainwashin agent such as NBS, receiving the intermediate connection O. As mentioned above, the substituent R2administered by attaching amine to O and the subsequent closure of the ring, catalyzed by acid, receiving the intermediate connection Group P. R1you can enter using the appropriate Bronevoy acid or borate ester, palladium catalyst, solvent and base through a reaction combinations Suzuki, or alternatively, using the appropriate stannane, palladium catalyst and solvent using the method of reaction of a combination of still, getting the right products (disclosed in�above). This method also permits to synthesize analogues with R3the substituent in the alpha-position to the carbonyl group.

Scheme 9

As before, to obtain the desired products reactivity matching partners can be reversed (scheme 9). For example, the intermediate compound P can be converted into the corresponding stannane Q and group R1you can enter using an appropriate leaving group, for example, halogen (such as bromide) or triflic, palladium catalyst and solvent using the method of reaction of a combination of Steele, as disclosed above, getting the right products. Alternatively, the intermediate compound P can be converted into the corresponding complex borodaty ester Q2, and the group R1you can enter using an appropriate leaving group, for example halogen (such as bromide) or triflic, palladium catalyst and solvent using the method of reaction of a combination of Suzuki, as disclosed above, getting the right products.

Pharmaceutically acceptable salt of the heteroaryl compounds can be conventional and known methods, such as the implementation of the interaction heteroaryl compound with an appropriate acid, as disclosed above. Such salts are generally prepared with high yields at moderate pace�off-highway vehicles used, and often get, simply highlighting the connection from the corresponding acid washing at the final stage of the synthesis. Forming the acid salt can be dissolved in an appropriate organic solvent, in water or an organic solvent, such as alkanol, a ketone or an ester. On the other hand, if you want to get a heteroaryl compound in free base form, it is possible to allocate on flush end-main stage by known methods. For example, a typical way of obtaining hydrochloride salt is to dissolve the free base in a suitable solvent and thorough drying of the resulting solution, for example, over molecular sieves, before bubbling through his gaseous hydrogen chloride.

Proposed chemical intermediate compounds that can be used in the methods of the invention include:

(i) compounds of the formula (III):

or their salts, tautomers or stereoisomers, where:

X represents a halogen, B(OR+)2or Sn(R++)3;

each R+independently represents hydrogen or substituted or unsubstituted C1-3alkyl, or each R+together with the boron atom and the atoms to which they are attached, form a cyclic boronate;

each R++discover ameri� With a 1-4alkyl;

R2represents H, substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl or a substituted or unsubstituted cycloalkenyl; and

R3and R4each independently, represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkenyl, or R3and R4together with the atom to which they are attached to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;

or R2and one of R3and R4together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl;

(ii) compounds of the formula (IV):

or their salts, tautomers or stereoisomers, where:

each Hal independently represents a halogen;

and

Hal2represents Br or I;

(iii) compounds of the formula (V):

or their salts, tautomers or stereoisomers, where:

R2represents H, substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl or a substituted or unsubstituted cycloalkenyl;

R3and R4each independently, represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkenyl, or R3and R4together with the atom to which they are attached to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;

or R2and one of R3and R4together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl; and

each Hal independently represents a halogen;

(iv) compounds of the formula (VI):

or their salts, tautomers or stereoisomers, where:

X represents a halogen, B(OR+)2or Sn(R++)3;

each R+independently represents hydrogen or substituted or unsubstituted C1-3+together with the boron atom and the atoms to which they are attached, form a cyclic boronate;

each R++independently represents C1-3alkyl;

R2represents H, substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl or a substituted or unsubstituted cycloalkenyl; and

R3represents H, or substituted or unsubstituted C1-8alkyl;

(v) compounds of the formula (VII):

or their salts, tautomers or stereoisomers, where:

Hal represents halogen;

R represents H or C1-4alkyl, or the alkali metal salt of the carboxylate;

R2represents H, substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl or a substituted or unsubstituted cycloalkenyl; and

R3represents H or substituted or unsubstituted C1-8alkyl; and

(vi) compounds of the formula (VIII):

or their salts, tautomers or stereoisomers, where:

every� Hal independently represents a halogen;

R represents H or C1-4alkyl, or a salt of an alkali metal carboxylate; and

R3represents H or substituted or unsubstituted C1-8alkyl.

4.4 METHODS of USE

Disclosed in the description heteroaryl compounds are used as pharmaceuticals for the treatment or prevention of diseases in animals and humans. In addition, disclosed in the description heteroaryl compounds are active against kinases (e.g., protein kinases), including those which are involved in diseases such as cancer, inflammatory condition, an immunological condition, neurodegenerative disease, diabetes, obesity, neurological disorders, age-related diseases and cardiovascular conditions. Without limitation by theory, believe that heteroaryl compounds are useful for treatment and prophylaxis of these diseases and conditions through their ability to modulate (e.g., inhibit) kinases, which are involved in the etiology of these diseases and conditions. Accordingly, in the invention proposed a number of use cases heteroaryl compounds, including the treatment or prevention of the following diseases. Proposed in the invention methods include the introduction of an effective amount of one or more of the heteroaryl �of soedinenii the needy in this patient. In some embodiments, these methods further comprise introducing a second active agent, as disclosed in the description.

Representative immunological status, for the treatment or prevention of which can use a heteroaryl compounds include, but are not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiple sclerosis, lupus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, graves ' disease, encephalomyelitis, type II diabetes, dermatomyositis, and graft rejection (e.g., in the treatment of transplant recipients, for example, heart, lung, combined heart-lung, liver, kidney transplants, pancreas transplants, skin or cornea; or to treat disease graft versus host, such as after bone marrow transplantation).

Representative inflammatory conditions, for the treatment or prevention of which can use a heteroaryl compounds include, but are not limited to, psoriasis, asthma and allergic rhinitis, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis and obesity.

Representative �Ardeche disease, for the treatment or prevention of which can use a heteroaryl compounds include, but are not limited to, restenosis, syndrome Wolff-Parkinson-white, blow, myocardial infarction or ischemic damage to the heart, lungs, stomach, kidneys, liver, pancreas, spleen or brain.

Representative neurodegenerative diseases, for the treatment or prevention of which can use a heteroaryl compounds include, but are not limited to, Huntington's disease, Alzheimer's disease, Parkinson's Disease, dementia caused by Tau mutations, spinal-cerebellar ataxia type 3, als caused by SOD1 mutations, neuronal waxy lipofuscinosis/batten disease (pediatric neurodegeneration diet) and is associated with HIV encephalitis.

Representative age-related diseases, for the treatment or prevention of which can use a heteroaryl compounds include, but are not limited to, cancer, obesity, diabetes type II, autoimmune diseases, cardiovascular diseases and degeneration of neurons.

In another embodiment proposed in the invention methods for the treatment or prevention of fibrotic diseases and disorders. In a specific embodiment proposed in the invention methods for the treatment or prophylaxis of scleroderma, idiopathic�ski pulmonary fibrosis, renal fibrosis, cystic fibrosis, myelofibrosis, hepatic fibrosis, sealifebase and steatohepatitis.

Representative cancers, for the treatment or prevention of which can use a heteroaryl compounds include, but are not limited to, cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, mammary glands, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or Central nervous system. Heteroaryl compounds can also be used for treatment or prevention of solid tumors and associated with blood tumors.

Specific cancers in the amount proposed in the invention methods include those that are associated with cascades of reactions mTOR, PI3K, or Akt kinases and mutants or isoforms. Other cancers in the amount proposed in the invention methods include those that are associated with cascades of reactions of the following kinases: ΡI3Κα, ΡI3Κβ, ΡI3Κδ, KDR, GSK3α, GSK3ß, ATM, ATX, ATR, cFMC and/or DNA-PK kinases and mutants or isoforms. In some embodiments, cancers that are associated with cascades of reactions mTOR/PI3K/Akt include solid tumors or associated � blood tumor, for example, multiple myeloma, lymphoma from mantle cell, diffuse large b-cell lymphoma, acute myeloid lymphoma, follicular lymphoma, chronic lymphocytic leukemia; cancer of the breast, lung, endometrial, ovarian, stomach, cervix and prostate cancer; glioblastoma; renal carcinoma; hepatocellular carcinoma; carcinoma of the colon; neuroendocrine tumors; head and neck tumor; and sarcomas.

In a specific embodiment proposed in the invention methods for the treatment or prevention of diseases or disorders associated with activation of mTOR signaling pathways, including, but not limited to, symptoms of tumors, arising directly or indirectly from genetic defects in PTEN (phosphatase deletions and homologue Tenzin on chromosome 10), TSC1 (tuberous sclerosis 1), TSC2 (tuberous sclerosis 2), NF1 (1 neurofibromas), AMPK (AMP-dependent protein kinase STK11, serine/trionychidae 11), LKB1, VHL disease (von Hippel-Lindau) and PKD1 (polycystin-1). Not limited to any theory, believe that genetic defects associated with these proteins, leading to hyperactivation of the pathway of mTOR/PI3K/Akt. Some specific diseases that can be treated or prevented by inhibition of pathway mTOR/PI3K/Akt include, but are not limited to, Cowden disease, Cowden syndrome, a syndrome that is similar to� Cowden syndrome, syndrome Bannayan-the time zone syndrome Bannayan-Riley-Ruvalcaba, disease, Lhermitte-Duclos, endometrial carcinoma, tuberous sclerosis complex, Lam, neurofibromatosis 1, the syndrome Peutz-Jeghers, renal cell carcinoma, disease von Hippel-Lindau syndrome, Proteus and polycystic kidney disease.

In a specific embodiment proposed in the invention methods of treating or preventing diseases or disorders associated with a signaling system mTOR, PI3K, Akt and/or DNA-PK. Specific diseases that can be treated or prevention by inhibiting mTOR, PI3K, Akt and/or DNA-PK signaling system include, but are not limited to, rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; erythematous; atherosclerosis; restenosis after angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic heart disease, lung, stomach, kidney, liver, pancreas, spleen and brain; acute or chronic rejection of a transplanted organ; to�the collegiate organ for transplantation; organ failure or loss of limb (e.g., including, but not limited to, as a result of ischemic-reperfusion injury, trauma, extensive body damage, car accidents, fragmentation or transplant rejection); the disease is graft versus host; endotoxin shock; multiple organ damage; psoriasis; burns when exposed to flame, chemical or radiation burns; eczema; dermatitis; skin graft; ischemia; ischemic conditions associated with surgery or trauma (e.g., traffic incidents, gunshot wounds or broken limbs); epilepsy; Alzheimer's disease; Parkinson's disease; immunological response to bacterial or viral infection; cachexia; angiogenic or proliferative diseases (including pigmentary dystrophy of the retina), solid tumors, and cancers of various tissues such as the colon, the rectum, prostrate, liver, lungs, bronchi, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovaries or uterus.

In the invention proposed methods of inhibiting kinase in a cell expressing the indicated kinase, comprising the implementation of contacting the specified cell with an effective amount heteroaryl� connection as disclosed in the description. In one embodiment, the kinase is a mTOR, DNA-PK, or PI3K or a combination thereof. In some embodiments, the cell is inside the patient's body.

In the invention proposed methods of treatment or prevention of conditions which can be treated or prevention by inhibiting the cascade of kinase reactions, for example, of pathway mTOR/PI3K/Akt and/or DNA-PK, comprising administering to the needy in this patient an effective amount of the heteroaryl compounds, as disclosed in the description. In some embodiments, the condition that can be treated or prevention by inhibition of pathway mTOR/PI3K/Akt include associated with solid and blood tumors such as multiple myeloma, lymphoma from mantle cell, diffuse large b-cell lymphoma, acute myeloid lymphoma, follicular lymphoma, chronic lymphocytic leukemia; cancer of the breast, lung, endometrial, ovarian, stomach, cervix and prostrate; glioblastoma; renal carcinoma; hepatocellular carcinoma; carcinoma of the colon; neuroendocrine tumors; head and neck tumor; sarcoma; tumor syndromes arising directly or indirectly from genetic defects in PTEN (phosphatase deletions and homologue Tenzin on chromosome 10), TSC1 (tuberous SC�Eros 1), TSC2 (tuberous sclerosis 2), NF1 (1 neurofibromas), AMPK (AMP-dependent protein kinase STK11, serine/trionychidae 11), and LKB1, VHL disease (von Hippel-Lindau) and PKD1 (polycystin-1); disease Cowden syndrome Cowden syndrome-like syndrome Cowden syndrome Bannayan-the time zone syndrome Bannayan-Riley-Ruvalcaba, the disease Lhermitte-Duclos, endometrial carcinoma, tuberous sclerosis complex, Lam, neurofibromatosis 1, the syndrome Patsa-Jeghers, carcinoma cells of the kidneys, the disease von Hippel-Lindau, the Proteus syndrome, and polycystic kidney disease; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; erythematous; atherosclerosis; restenosis after angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic damage to the heart, lungs, stomach, kidneys, liver, pancreas, spleen and brain; acute or chronic rejection of a transplanted organ; preservation of the organ for transplantation; organ damage or loss of limb (e.g., including, but not limited to, those �the matured result of ischemia-reperfusion injury, trauma, extensive body damage, car accidents, injuries at breaking up or transplant rejection); the disease is graft versus host; endotoxin shock; multiple organ damage; psoriasis; burns when exposed to flame, chemical or radiation burns; eczema; dermatitis; skin graft; ischemia; ischemic conditions associated with surgery or trauma (e.g., traffic incidents, gunshot wounds or broken limbs); epilepsy; Alzheimer's disease; Parkinson's disease; immunological response to bacterial or viral infection; cachexia; angiogenic or proliferative diseases, including pigmentary dystrophy of the retina, solid tumors, and cancers of various tissues such as colon, rectum, prostate, liver, lungs, bronchi, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovaries or uterus.

4.5 PHARMACEUTICAL COMPOSITIONS AND routes of ADMINISTRATION

Heteroaryl compounds obtained are presented in the invention methods can be used to obtain pharmaceutical compositions comprising an effective amount heteroaryl compounds and a pharmaceutically acceptable carrier or means sufficient�Ki. In some embodiments disclosed in the description of pharmaceutical compositions can be used for oral, parenteral, via mucosal, transdermal or local administration.

5. EXAMPLES

To create names for chemical structures using software Chem-4D Draw (ChemInnovation Software, Inc., San Diego, CA) or ChemDraw Ultra (Cambridgesoft, Cambridge, MA).

In the description and in the examples use the following abbreviations:

AmPhos: p-dimethylaminophenyl-tert-butylphosphine

Boc: tert-butoxycarbonyl

dba: dibenzylidene acetone

DIPEA: N,N-diisopropylethylamine

DMSO: dimethyl Sulfoxide

ESI: electrospray Ionization

HPLC: high performance liquid chromatography

mp: melting point

MS: Mass spectrometry

NBS: N-bromosuccinimide

NMR: Nuclear magnetic resonance

NMP: N-methylpyrrolidinone

TFA: Trifluoroacetic acid;

TLC: Thin layer chromatography

MTBE: Methyl tert-butyl ether

The following examples are provided to illustrate, but not limit.

5.1 SYNTHETIC EXAMPLES

Example 1: 7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. Ethyl 2-(6-chloropyrazine-2-ylamino)acetate

To 2,6-dichloropyrazine (50 g, 336 mmol) and ethyl 2-aminoacetate (34,6 g, 336 mmol) was added �ritilin (140 ml, 1007 mmol) and acetonitrile (350 ml). The reaction mixture was heated at 80°C for 3 days. The precipitated salt of triethylamine was removed by filtration and washed with ethyl acetate and hexane (1:1) several times. The obtained filtrate and the washing solvent are combined and concentrated. The resulting precipitate is white-yellow filtered and washed with 20% ethyl acetate in hexane, obtaining a solid substance not quite white. The filtrate obtained is subjected to the same process, getting an additional portion of solid substances not quite white. The portions were pooled, receiving specified in the title compound (35.5 g, 164 mmol, 49% yield). MS (ESI) m/z 216,1 [M+1]+.

B. Ethyl 2-(pyrazine-2-ylamino)acetate

Ethyl 2-(6-chloropyrazine-2-ylamino)acetate (23,6 g, 109 mmol) was dissolved in denatured ethanol (250 ml) and add potassium carbonate (15,13 g, 109 mmol). The reaction mixture was placed in a nitrogen atmosphere, and added palladium hydroxide (3,84 g, were 5.47 mmol). The reaction mixture was stirred in hydrogen atmosphere for 18 hours. Add additional palladium hydroxide (3,84 g, were 5.47 mmol), and added to the reaction mixture optionally hydrogen, and left with stirring over night. The reaction mixture was filtered through celite, and the solvent removed under reduced pressure, obtaining specified in the header connection (15,13 g, 84 mmol, 76% in�course). MS (ESI) m/z 182,3 [M+1]+.

C. Ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate

Ethyl 2-(pyrazine-2-ylamino)acetate (7.6 g, a 41.9 mmol) was dissolved in dimethylsulfoxide (80 ml) and water (4,00 ml) and cooled to 0°C. N-bromosuccinimide (18,66 g, 105 mmol) was slowly added over 15 minutes and the reaction mixture is allowed to warm to room temperature and stirred for 48 hours. Add an additional 1.5 equiv. N-bromosuccinimide and left with stirring over night. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (150 ml). The aqueous layer is slowly neutralized with sodium carbonate until pH~7 and extracted with ethyl acetate (3×150 ml). The organic layers were pooled, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is triturated with 25-33% ethyl acetate in hexane, and the resulting residue was filtered, getting a solid yellow color. The resulting brown residue is purified using chromatography on silica gel biotage AB (0-60% ethyl acetate in hexane), receiving another portion of solid substances not quite white. Two portions were combined, yielding 24 g specified in the title compound (24 g, 71 mmol, 75% yield). MS (ESI) m/z 338,1 [M]+, 340,1 [M+2]+, 342,1 [M+4]+.

D. Ethyl 2-(5-bromo-3-((tetrahydro-2H-Piran-4-yl)methylamino)pyrazine-2-silts�about)acetate

Ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (2.00 g, 5,90 mmol), (tetrahydro-2H-Piran-4-yl)methanamine (of 0.713 g, 6,19 mmol), N,N-diisopropylethylamine (is 3.08 ml, 17,70 mmol) and dimethylsulfoxide (4 ml) are combined in a microwave vial with a magnetic stirrer and heated in a microwave reactor biotage AB Emrys Optimizer at 150°C for 1 hour. The obtained mixture was transferred into a round bottom flask with methanol. Methanol and Ν,Ν-diisopropylethylamine removed under reduced pressure, and the residue purified using flash chromatography biotage AB (5-100% ethyl acetate in hexane). Fractions containing the desired product, combined in a separatory funnel and washed twice with water and once with saline. The organic portion was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dried in high vacuum at 50°C, obtaining the crude target product (1,578 g) as an amber waxy solid which is used in next step without further purification. MS (ESI) m/z 373,4 [M]+, 375,4 [M+2]+.

E. 7-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A stirred solution of ethyl 2-(5-bromo-3-((tetrahydro-2H-Piran-4-yl)methylamino)pyrazine-2-ylamino)acetate (1,474 g 3,95 mmol) in acetic acid (13 ml) in a sealed reactor was heated at 120°C in an oil bath for 2 hours. Acetic cyclotourist under reduced pressure. The residue is divided between ethyl acetate and saturated aqueous sodium bicarbonate solution, shaken and the layers were separated. The aqueous layer twice extracted with ethyl acetate. The combined organic portion was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is placed in dichloromethane and hexane, and the obtained solid substance is harvested using vacuum filtration. The solid part was washed with hexane and dried under vacuum to give the desired product (0,879 g, 2,688 mmol, 68% yield) as a solid purple color. MS (ESI) m/z 327,1 [M]+, 329,0 [M+2]+.

F. 2-methyl-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

4-bromo-2-methyl-6-nitroaniline (5 g, 21,64 mmol), bis(pinacolato)dibor (5,50 g, 21,64 mmol), potassium acetate (6,37 g, with 64.9 mmol) and N,N-dimethylformamide (100 ml) were pooled, and Tegaserod in a vacuum. Add palladium acetate (0,243 g, 1,082 mmol), and the system again Tegaserod. The reaction mixture was heated to 90°C for 2 hours. The reaction mixture was extracted with water and dichloromethane. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified using column chromatography on silica gel (0-30% ethyl acetate in hexano), getting a solid yellow solid (5.3 g, 19,0 mmol, 88% yield). MS (ESI) m/z 279,0 [M+1]+.

G. 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane�olan-2-yl)benzene-1,2-diamine

A solution of 2-methyl-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.3 g, 19,06 mmol) in methanol (50 ml) was purged with nitrogen gas. Add palladium-on-charcoal (10% by weight, 50 mg) and the reaction mixture was stirred in an atmosphere of hydrogen supplied from the cylinder, for 16 hours. The reaction mixture was filtered through celite, and the filter cake washed with methanol. The obtained filtrate was concentrated, and the resulting material is purified using column chromatography on silica gel (0-100% ethyl acetate in hexano), obtaining a dark oil. The resulting oil was triturated with 10% ether in hexano, getting a solid yellow-brown color (4.2 g, to 16.9 mmol, 89% yield). MS (ESI) m/z 248,9 [M+1]+.

H. 7-(3,4-diamino-5-methylphenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (0,523 g, 2,109 mmol), 7-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0,600 g, is 1.834 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0,150 g, 0,183 mmol), sodium carbonate (1 M in water, of 5.50 mmol), 1,4-dioxane (4,1 ml) and isopropanol (1.4 ml) are combined in a pressurized reactor with a magnetic stirrer. The system was purged with nitrogen. The resulting mixture was sealed, intensively stirred and heated at 100°C in the�Linux 3.5 hours. The resulting mixture was diluted with 20% methanol in dichloromethane and all volatiles removed under reduced pressure. The residue is placed in 20% methanol in dichloromethane and concentrated under reduced pressure with silica gel. The residue is purified using flash chromatography (1-10% methanol in dichloromethane), obtaining the target product (0,669 g, 1,818 mmol, 99% yield) in the form of a solid brown color. MS (ESI) m/z 369,1 [M+1]+.

I. 7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

Methyl cyanide (0,059 g, 0,556 mmol) in N,N-dimethylformamide (0.5 ml) was added to a stirred solution of 7-(3,4-diamino-5-methylphenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she (0,195 g, 0,529 mmol) in N,N-dimethylformamide (3 ml) at 0°C. the resulting mixture was dark brown sealed and stirred at room temperature for 16 hours. The resulting mixture was diluted with MeOH, filtered and purified using preparative HPLC with reversed phase (5-50% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Fractions containing the product were pooled and most of the solvent was removed under reduced pressure. The residue is introduced into ion-exchange column (Strata X-C from Phenomenex. The column is sequentially washed with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. Product� eluted with 5% ammonium hydroxide in methanol as eluent, concentrated under reduced pressure and dried in high vacuum at 50°C, obtaining the target product (0,130 g, 0,331 mmol, 62% yield) in the form of a solid orange color.1H NMR (400 MHz, D2O and DMSO-d6) δ (M. D.) 8,13 (s, 1H), 7,56 (s, 1H), of 7.36 (s, 1H), 4,18 (s, 2H), 4,03 (d, J=6,64 Hz, 2H), 3,84-3,90 (m, 2H), 3,24 (t, J=made 11.32 Hz, 2H), is 2.40 (s, 3H), 2,04-2,19 (m, 1H), 1,59 (d, J=12,10 Hz, 2H), 1,25-of 1.41 (m, 2H); MS (ESI) m/z 394,2 [M+1]+.

Example 2: 3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 3-(4-bromo-3-methylphenyl)-4H-1,2,4-triazole

4-bromo-3-methylbenzonitrile (10.0 g, 51,0 mmol) was dissolved in ethanol (200 ml) with stirring and cooled to 0°C in an atmosphere of nitrogen. Gaseous hydrogen chloride was bubbled through the reaction mixture for 20 minutes. The obtained reaction mixture was sealed and slowly stirred, warming to room temperature for 5.5 hours. The solvent was removed under reduced pressure, and the residue was dried under vacuum to give 13,86 g of solid substances not quite white. A solid substance not quite white, formic acid hydrazide (4.48 g, 74,6 mmol), triethylamine (28,0 ml, 199 mmol) and ethanol (90 ml) was combined in a sealed tube and heated with stirring at 90°C for 6.5 hours. All the solvent was removed under reduced pressure, and the obtained OST�OK is divided between ethyl acetate and water. The layers were separated and the organic portion washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in hot ethyl acetate (13 ml), cover and leave to stand at room temperature over night. The solvent was decanted from the solids remaining on the bottom of the flask. The solid part was washed with ethyl acetate and diethyl ether and dried in vacuo at 45°C, yielding the desired product (7,47 g, of 31.4 mmol, 63% yield) in the form of solid light yellow color. MS (ESI) m/z 238,2 [M]+, 240,3 [M+2]+.

B. 3-(4-bromo-3-methylphenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole

3-(4-bromo-3-methylphenyl)-4H-1,2,4-triazole (2.00 g, 8,40 mmol) was dissolved in tetrahydrofuran (10 ml) at room temperature under stirring in a nitrogen atmosphere. 3,4-dihydro-2H-Piran (3,80 ml, 42.0 mmol) and methanesulfonic acid (0,027 ml of 0.42 mmol) was added, and the mixture was heated at 50°C at reflux in a nitrogen atmosphere for 20 hours. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The organic portion was dried over magnesium sulfate, filtered and concentrated under reduced pressure. As a result of processing using flash chromatography (10-30-50% ethyl acetate in g�the Xan) get the target product (2,64 g, 8,22 mmol, 98% yield) as a yellow oil. MS (ESI) m/z 322 [M]+, 324 [M+2]+.

C. 3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole

3-(4-bromo-3-methylphenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole (2,294 g, 7.12 mmol), bis(pinacolato)dibor (1,898 g, of 7.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (291 mg, 0,36 mmol), potassium acetate (2,096 g, 21.4 mmol) and dimethyl sulfoxide (15 ml) combine in a round bottom flask and stirred. The air in the flask is removed, creating a vacuum, and fill three times with nitrogen. The resulting mixture was heated at 90°C in a nitrogen atmosphere for 4 hours. The resulting mixture was diluted with ethyl acetate and filtered through celite. The filter cake washed thoroughly with ethyl acetate. The resulting filtrate is washed twice with water, once with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. As a result of processing using flash chromatography (30-50% ethyl acetate in hexano) receive a waxy semi-solid substance, which is triturated with hexane at 45°C. the Remaining solid was dried under vacuum to give the desired product (2.10 g, 5,69 mmol, 80% yield) in the form of powder pink. MS (ESI) m/z 370 [M+1]+.

D. Tert-butyl 1-(3,5-dibromopyrazine-2-ylamino)-2-methyl-1-oxoprop�-2-ylcarbamate

1,1'-carbonyldiimidazole (2,63 g, 16,24 mmol) was added to a stirred solution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (3,00 g, of 14.76 mmol) in N,N-dimethylformamide (4 ml) and dichloromethane (8 ml) at room temperature. The resulting clear colorless mixture was stirred at room temperature in a nitrogen atmosphere for 3 hours. Add N,N-diisopropylethylamine (3,86 ml 22,14 mmol), then added 3.5-dibromopyrazine-2-amine (5,60 g, 22,14 mmol). The resulting mixture was heated at 50°C at reflux in a nitrogen atmosphere for 71 hours. Dichloromethane removed under reduced pressure. The residue is diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is triturated with 30% ethyl acetate in hexane and the solid part was collected using vacuum filtration. The filtrate obtained is concentrated under reduced pressure and purified using flash chromatography (5-50% ethyl acetate in hexane). Fractions containing the desired product, combined with the solid part obtained by filtration, and concentrated under reduced pressure. The obtained residue was dried in high vacuum to give the desired product (2,38 g, 5.43 mmol, 37% yield) in �IDA solid substances not quite white. MS (ESI) m/z 439,3 [M+1]+, 461,1 [M+Na]+.

E. N-(3,5-dibromopyrazine-2-yl)-2-methyl-2-(2-(tetrahydro-2H-Piran-4-yl)ethylamino)propanamide triptorelin

TFA (3,66 ml of 47.5 mmol) was added to a stirred mixture of tert-butyl 1-(3,5-dibromopyrazine-2-ylamino)-2-methyl-1-oxoprop-2-ylcarbamate (1.04 g, 2,374 mmol) in dichloromethane (20 ml). The resulting clear yellow solution was stirred at room temperature for 3 hours. All volatiles are removed under reduced pressure, and the residue was dried in high vacuum to give a semi-solid yellow solid. MS (ESI) m/z 339,1 [M+1]+. Add sodium sulfate (1,686 g, 11,87 mmol), then added 2-(tetrahydro-2H-Piran-4-yl)acetaldehyde (0,396 g 3,09 mmol) and 1,2-dichloroethane (20 ml). The resulting mixture was intensively stirred and heated at 80°C at reflux in a nitrogen atmosphere for 2.5 hours. Add 2-(tetrahydro-2H-Piran-4-yl)acetaldehyde (0,100 g, 0,780 mmol) and sodium sulfate (1.00 g, to 7.04 mmol) and heating at 80°C was continued for another 2 hours. The resulting yellow solution is removed by pipette from the solid sodium sulfate in a dry 250 ml round bottom flask equipped with a magnetic stirrer. The resulting mixture was intensively stirred and cooled to 0°C in an atmosphere of nitrogen. Slowly add triacetoxyborohydride sodium (0,553 g, 2,61 mmol). The resulting mixture was intensively stirred� at 0°C in a nitrogen atmosphere for 30 minutes. A cooling bath is removed, and the resulting mixture was stirred at room temperature in a nitrogen atmosphere for 2 hours. The mixture is cooled to 0°C and add triacetoxyborohydride sodium (0,250 g, 1,180 mmol). A cooling bath is removed, and the resulting mixture was stirred at room temperature in a nitrogen atmosphere for 1.5 hours. Add more triacetoxyborohydride sodium (0.055 g, is 0.260 mmol). The resulting mixture was intensively stirred at room temperature in a nitrogen atmosphere for 1 hour and then stirred overnight at 0°C. the resulting mixture was diluted with methanol and the volatiles removed under reduced pressure. The residue is placed in methanol, filtered and purified using preparative HPLC with reversed phase (10-40% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Fractions containing the product were pooled, and the solvent removed under reduced pressure. The obtained residue was dried under vacuum to give the desired product (0,890 g, 1,978 mmol, 67% yield) as slightly yellow foamy solid. MS (ESI) m/z 451,3 [M+1]+.

F. 6-bromo-3,3-dimethyl-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

N-(3,5-dibromopyrazine-2-yl)-2-methyl-2-(2-(tetrahydro-2H-Piran-4-yl)ethylamino)propanamide triptorelin (0,856 g, 1,517 mmol), N,N-diisopropylethylamine (1,321 ml members, 7.59 mmol) and 1,4-dioxane (25 ml) are combined in z�palaemon reactor with a magnetic stirrer. The system was purged with nitrogen, and the resulting mixture was sealed, intensively stirred and heated at 110°C for 2.5 hours. The reaction mixture was concentrated under reduced pressure and purified using flash chromatography (5-50% ethyl acetate in hexane), obtaining the target product (0,394 g, 1,068 mmol, 70% yield) in the form of white solids. MS (ESI) m/z by 369.4 [M]+, 371,3 [M+2]+.

G. 3,3-dimethyl-6-(2-methyl-4-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole (1 equiv.), 6-bromo-3,3-dimethyl-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.1 equiv.), 1 M sodium carbonate in water (3 equiv.), 1,4-dioxane and isopropanol were combined, and the system was purged with nitrogen. The resulting mixture was intensively stirred and heated at 100°C for 1.5 hours. The resulting mixture was cooled to room temperature, diluted with methanol and the volatiles removed under reduced pressure. The remainder is divided between dichloromethane and water, shaken and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic portion was dried over magnesium sulfate, filtered and conc�t under reduced pressure. The residue is purified using flash chromatography (20-100% ethyl acetate in hexane and then 0-10% methanol in dichloromethane), obtaining the target product with a yield of 97%. MS (ESI) m/z 532,7 [M+1]+.

N. 3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

6 N. aqueous solution of hydrochloric acid is added to a stirred mixture of 3,3-dimethyl-6-(2-methyl-4-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)is she in ethanol at 80°C. the resulting mixture was intensively stirred and heated at 80°C at reflux in a nitrogen atmosphere for 70 minutes. The resulting mixture was filtered and purified using preparative HPLC with reversed phase (10-65% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Fractions containing the product were combined, neutralized with saturated aqueous sodium bicarbonate solution and acetonitrile was removed under reduced pressure. The solid part was collected using vacuum filtration, thoroughly washed with water and diethyl ether and dried in a high vacuum at 50°C, obtaining the target product with a yield of 48%.1H NMR (400 MHz, DMSO-d6) δ (M. D.) made 11.32 (user.s, 1H), 8,44 (user.s, 1H), 7,96 (s, 1H), 7,90 (d, J=8,59 Hz, 1H), of 7.70 (s, 1H), 7,56 (d, J=7,81 Hz, 1H), 3,78 (DD, J=2,93, 11,13 Hz, 2H), 3,52-to 3.64 (m, 2H), 3,23 (t, J=10,93 Hz, 2H), 2,48 (�, 3H), 1,51-of 1.66 (m, 5H), 1,49 (s, 6H), 1,11-of 1.26 (m, 2H); MS (ESI) m/z 448,3 [M+1]+.

Example 3: 7-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she hydrochloride

A. Ethyl 2-(5-bromo-3-(2,4-dimethoxyaniline)pyrazine-2-ylamino)acetate

Ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (see example I. C) (1,06 g, 3,13 mmol), (2,4-dimethoxyphenyl)methanamine (0,601 g, of 3.60 mmol), N,N-diisopropylethylamine (1,63 ml, at 9.38 mmol) and dimethyl sulfoxide (1.6 ml) combined in a microwave vial with a magnetic stirrer and heated in a microwave reactor at 150°C for 2 hours. The resulting mixture was purified using flash chromatography (5-60% ethyl acetate in hexane). Fractions containing the product were pooled and concentrated almost to dryness under reduced pressure. Add ethyl acetate (2 ml) and hexane (18 ml). The remaining solid substance is harvested using vacuum filtration, washed with hexane and dried in high vacuum to give the desired product (0,636 g, 1,495 mmol, 48% yield) in the form of a solid light pink color.1H NMR (300 MHz, DMSO-d6) δ (M. D.) of 7.24 (s, 1H), of 7.19 (d, J=8,52 Hz, 1H), 7,11 (t, J=5,63 Hz, 1H), at 6.84 (t, J=4,81 Hz, 1H), 6,59 (d, J= 2,47 Hz, 1H), 6,50 (DD, J=2,20, 8,24 Hz, 1H), 4,37 (d, J=4,67 Hz, 2H), 3,96-4,15 (m, 4H), 3,81 (s, 3H), of 3.75 (s, 3H), of 1.17 (t, 3H); MS (ESI) m/z 425,3 [M]+, 426,9 [M+2]+.

B. 7-bromo-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he triptorelin

Ethyl 2-(5-b�ω-3-(2,4-dimethoxyaniline)pyrazine-2-ylamino)acetate (0,484 g, 1,138 mmol), methanol (0,461 ml, 11,38 mmol) and TFA (7 ml) was combined in a sealed reactor with a magnetic stirrer. The system was purged with nitrogen. The resulting mixture was sealed, intensively stirred and heated at 75°C on an oil bath for 25 minutes. The resulting mixture was diluted with water (14 ml) and stirred at room temperature for 5 minutes. The solid part was collected using vacuum filtration, washed with water and diethyl ether and dried in high vacuum to give the desired product (0.375 g, 1,093 mmol, 96% yield) as a solid pink color. MS (ESI) m/z 229,0 [M]+, 231.3 of which the [M+2]+.

C. 7-(2-methyl-4-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole (see example 2.C) (of 0.465 g, 1,259 mmol), 7-bromo-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she's triptorelin (0,432 g, 1,259 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0,103 g, 0,126 mmol), sodium carbonate (1 M in water, a 3.78 ml, of 3.78 mmol), 1,4-dioxane (2.5 ml) and isopropanol (1 ml) combined in a sealed reactor with a magnetic stirrer. The system was purged with nitrogen. The resulting mixture was sealed, intensively stirred and heated at 100°C for 70 minutes. The resulting mixture was diluted with water and dichloromethane and filtered through� funnel from sintered glass. The hard part is washed with 20% methanol in dichloromethane. The filtrate and washing were combined, and the solvent removed under reduced pressure. The residue is triturated with acetonitrile. Add water. The solid part was collected using vacuum filtration, and thoroughly washed with water and diethyl ether. The hard part was washed using 20% methanol in dichloromethane. The filtrate and washing were combined, and the solvent removed under reduced pressure. The residue is placed in hot DMSO and MeOH, filtered and purified using preparative HPLC with reversed phase (20-65% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Fractions containing the product were combined, neutralized with saturated aqueous sodium bicarbonate solution and concentrated almost to dryness under reduced pressure. The solid part was collected using vacuum filtration, washed with water and dried in high vacuum to give the desired product (0,072 g, 0,184 mmol, 15% yield) in the form of solid substances not quite white. MS (ESI) m/z 392,1 [M+1]+.

D. 7-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she hydrochloride

Hydrochloric acid (6 n in water 0,149 ml 0,894 mmol) was added to a stirred mixture of 7-(2-methyl-4-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she (0,070 g, 0,179 mmol), which contains chamazulene�e (3 ml) at 80°C. The system was purged with nitrogen. The resulting mixture was sealed and heated at 80°C. the resulting mixture was heated at 80°C for 25 min and then cooled to room temperature. The solid part was collected by filtration, washed with methanol and dried in a high vacuum at 40°C, obtaining the target product (0,058 g, 0,169 mmol, 94% yield) in the form of a solid substance of white color.1H NMR (300 MHz, DMSO-d6) δ (M. D.) made 11.32 (s, 1H), 8.66 roubles (s, 1H), 7,97 (s, 1H), 7,92 (DD, J=1,37, compared to 7.97 Hz, 1H), 7,74 (s, 1H), 7,50 (d, J=compared to 7.97 Hz, 1H), 4,14 (s, 2H), 2,44 (s, 3H); MS (ESI) m/z 308,3 [M+1]+.

Example 4: 6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 2-bromo-N-(3,5-dibromopyrazine-2-yl)acetamide

A solution of 2-amino-3,5-dibromopyrazine (6,17 g, 23,7 mmol) and bromohydrin acetic acid (3.0 g, to 11.9 mmol) in acetonitrile (40 ml) was stirred at 70°C. After complete consumption of the initial substance (according to TLC), the resulting solution is condensed and separated between water and ethyl acetate (3×). The organic layers were combined, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting material is purified using column chromatography biotage AB (5-80% ethyl acetate in hexano), receiving specified in the header connection (of 3.78 g, 10.1 mmol, 85% yield). MS (ESI) m/z 372,1 [M-2]+, 374,0 [M]+, 376,1 [M+2]+378,3 [M+4] +.

B. 6-bromo-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

2-bromo-N-(3,5-dibromopyrazine-2-yl)acetamide (3,30 g, 8,83 mmol) and 2-(tetrahydro-2H-Piran-4-yl)canamingadapter (1,46, 8,83 mmol) and diisopropylethylamine (6,67 ml, 35,3 mmol) are combined and heated at 85°C. After complete consumption of the initial substance (according to TLC), the reaction solution was condensed and purified using chromatography biotage AB (0-100% ethyl acetate in hexano), receiving specified in the title compound (1.53 g, 4,48 mmol, 50% output). MS (ESI) m/z 341,4 [M]+, 343,1 [M+2]+.

C. 2-(4-bromophenyl)propan-2-ol

1-(4-bromophenyl)alanon (9,25 g, a 46.5 mmol) was dissolved in tetrahydrofuran (200 ml). The resulting solution was cooled in a bath at -50°C. Methylmagnesium (3M in ether, and 46.5 ml, 139 mmol) is added over a 15 minute period of time. The reaction mixture is allowed to warm to room temperature and then stirred for 20 hours. The reaction was quenched using a saturated solution of ammonium chloride, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated, obtaining oil. The oil is purified using a column with silica gel (0-20% ethyl acetate in hexano), receiving the product as a colorless oil (9.1 g, or 46.2 mmol, 91% yield). MS (ESI) m/z 197,1 [M]+, 199,1 [M+2]+.

D. 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa�Rolan-2-yl)phenyl)propan-2-ol

2-(4-bromophenyl)propan-2-ol (4.7 g, 21,85 mmol), bis(pinacolato)dibor (6,66 g, 26,2 mmol), potassium acetate (6,43 g, 65,6 mmol) and dimethyl sulfoxide (50 ml) was stirred and Tegaserod in vacuum for 10 minutes. Added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0,892 g, 1,093 mmol) and the reaction mixture Tegaserod for another 5 minutes. Then the reaction mixture was heated to 80°C in a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and then extracted with a mixture of 1:1 ether:ethyl acetate and water. The resulting black emulsion was filtered through a layer of cellite, and the resulting filtrate is combined with the extraction layers. The organic layer was dried over magnesium sulfate, filtered and then purified using a column with silica gel (0-25% ethyl acetate in hexano). Containing the product fractions concentrated and then triturated with hexane, getting a white solid (4.0 g, of 15.3 mmol, 70% yield). MS (ESI) m/z 263,3 [M+1]+.

E. 6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

6-bromo-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0,250 g, mmol 0,733), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (0,192 g, 0,733 mmol) and dichloromethane dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.030 g, 0,037 mmol)are combined in dimethylformamide (1.0 ml). Add sodium carbonate (0,311 g of 2.93 mmol) in water (0.2 ml), and the reaction solution is then heated in a microwave reactor biotage AB Emrys Optimizer at 120°C for 15 minutes. The cooled reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate and ethylacetate washing were combined, and the solvent removed under reduced pressure. The resulting material is purified using column chromatography biotage AB (0-5% methanol in ethyl acetate), then triturated with dimethylformamide and water to give specified in the header connection (to 0.074 g, 0,19 mmol, 25%).1H NMR (400 MHz, DMSO-d6) δ (M. D.) to 12.24 (s, 1H), 7,98 (s, 1H), to 7.89 (d, J=of 8.39 Hz, 2H), 7,53 (l, J=of 8.39 Hz, 1H), 5,04 (s, 1H), 4,16 (s, 1H), 3,82 (DD, J=11,1, 2,39 Hz, 2H), 3,61 (t, J=RUB 7.59 Hz, 2H), 3,25 (t, J=9,59 Hz, 3H), of 1.70 (s, 1H), of 1.66 (s, 1H), 1,58 (m, 3H), of 1.44 (s, 6H), 1,25 (m, 2H); MS (ESI) m/z 397,2 [M+1]+; T a MP 210-212°C.

Example 5: 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 2-chloro-N-(3,5-dibromopyrazine-2-yl)acetamide

A solution of 2-amino-3,5-dibromopyrazine (3.0 g, to 11.9 mmol) and Chloroacetic anhydride (4.2 g, 8,7 mmol) is subjected to interaction in acetonitrile (10 ml) at 70°C for 16 hours. The solution was condensed and diluted with ethyl acetate. The organic portion was washed using a 1:1 solution of sodium bicarbonate (saturated) and potassium carbonate (1,75 M in water) (4×). The organic parts were combined, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. Received the solid is triturated with 10% ethyl acetate in hexano, receiving specified in the title compound (3.12 g, 9.3 mmol, 72% yield). MS (ESI) m/z 328,3 [M-1]+, 330,4 [M+1]+, 332,3 [M+3]+.

B. N-(3,5-dibromopyrazine-2-yl)-2-iodoacetamide

To a solution of 2-chloro-N-(3,5-dibromopyrazine-2-yl)acetamide (3.0 g, of 9.11 mmol) in acetone (40 ml) was added sodium iodide (13,65 g, 91 mmol) dissolved in acetone (20 ml). The solution is kept under stirring at room temperature for 16 hours. The solution was condensed under reduced pressure and diluted with ethyl acetate (500 ml) and washed successively with water (5×) to remove the blue color. The organic part was dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, obtaining the crude product. The hard part is diluted with 10% ethyl acetate in hexano (40 ml) and treated with ultrasound, scraping at this time, the walls of the flask. The solution was then heated using a heat gun for 5 minutes, then cooled, processing ultrasound at ambient temperature. The obtained solid was filtered and washed with additional amount of hexanol and dried in vacuum, obtaining specified in the title compound (3.0 g, 7,13 mmol, 78% o�d). MS (ESI) m/z 420,3 [M-1]+, 422,0 [M+1]+, 424,0 [M+3]+.

C. 6-bromo-4-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

N-(3,5-dibromopyrazine-2-yl)-2-iodoacetamide (0.5 g, 1,188 mmol), diisopropylethylamine (0,415 ml 2,376 mmol) and 2-morpholinoethyl (0,162 g, 1,248 mmol) are combined in acetonitrile (5 ml). The solution was heated to 45°C for 1 hour. The solution was condensed and diluted with 75% ethyl acetate in hexano. The resulting solid substance was filtered, and the filtrate obtained is collected and condensed, and then purified using chromatography biotage AB (0-75% ethyl acetate in hexano, then 0-10% methanol in ethyl acetate), obtaining specified in the header connection (0,228 g, 0.67 mmol, 56% yield). MS (ESI) m/z 342,4 [M]+, To 344.4 [M+2]+.

D. 2-(5-bromopyridin-2-yl)propan-2-ol

2,5-dibromopyridine (1.04 g, 4,39 mmol) was dissolved in toluene (22 ml) in a 100-ml round-bottom flask. The resulting mixture was cooled to -78°C. was added, dropwise, n-butyllithium (3,02 ml of 4.83 mmol). The resulting mixture was stirred 30 minutes, then added acetone (2 ml). The resulting mixture was stirred for 40 min and then allowed to warm to room temperature. The mixture was washed with ammonium chloride (5% water., 50 ml), water (50 ml) and then brine (50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified using biotage AB (16% ethyl acetate in hexano). As a result the end�of tiravanija the desired fractions to give the product (0,82 g, A 3.78 mmol, 86% yield). MS (ESI) m/z 216,0 [M]+, 218,1 [M+2]+.

E. 2-(5-(tributylstannyl)pyridin-2-yl)propan-2-ol

2-(5-bromopyridin-2-yl)propan-2-ol (0,34 g, 1,574 mmol), 1,1,1,2,2,2-hexamethyldisilane (0,361 ml 1,652 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,182 g 0,157 mmol) are combined in toluene (5 ml) in 50-ml re-sealed flask. The reaction mixture was stirred at 115°C for 1.5 hours. Then the resulting mixture was concentrated to a volume of approximately 2 ml., the Residue was purified using biotage AB (16% ethyl acetate in hexano). As a result of concentrating the desired fractions receive specified in the title compound (0.33 g, 1.10 mmol, 70% yield). MS (ESI) m/z 302,1 [M+1]+.

F. 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

6-bromo-4-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0,228 g, 0,666 mmol) and 2-(5-(tributylstannyl)pyridin-2-yl)propan-2-ol (0,220 g, 0,733 mmol) are combined in dimethylformamide (3 ml). The solution was purged with nitrogen gas, then added dichloromethane dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0,109 g of 0.133 mmol). The solution was heated to 100°C for 2 hours. The solution was condensed under reduced pressure and the resulting oil was purified using preparative HPLC with reversed phase (5-60% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min), and the desired fraction is introduced into the ion exchange�th column (Strata-XC. The column is washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with 5% ammonium hydroxide in methanol and concentrated under reduced pressure and dried, obtaining specified in the header connection (0,070 g, 0.18 mmol, 26% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,33 (user.s, 1H), 9,05 (d, J=1,56 Hz, 1H), 8,27 (DD, J=8,59, 2,34 Hz, 1H), 8,06 (s, 1H), 7,72 (d, J=8,59 Hz, 1H), 5,27 (s, 1H), 4,29 (s, 2H), 3,71 (t, J=6,44 Hz, 2H), 3,54 (t, J=4,49 Hz, 4H), 2,62 (t, J=6,44 Hz, 2H), 2,40-2,48 (m, 4H), of 1.46 (s, 6H); MS (ESI) m/z 399,2 [M+1]+; T a MP 239-241°C.

Example 6: 1-(((TRANS)-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 5-bromo-4-methilpiralidone

2,5-dibrom-4-methylpyridine (5.0 g to 19.9 mmol), copper cyanide (1.43 g, 15,9 mmol), sodium cyanide (0,801 g, 16.3 mmol) and dimethylformamide (30 ml) are combined in a sealed reactor and heated at 158°C for 3 hours. The reaction mixture was purified using column chromatography on silica gel (0-80% ethyl acetate in hexano). The resulting material is treated in the second column of silica gel (0-20% methanol in dichloromethane). Pure fractions were pooled and concentrated, obtaining specified in the title compound in the form of white solids (2.30 g, 11.6 mmol, 58% yield). MS (ESI) m/z 198,0 [M+1]+.

B. Ethyl 2-(3,5-Dobromir�Zin-2-ylamino)acetate

In a 2000-ml three-neck round bottom flask is loaded 2-amino-3,5-dibromopyrazine (172 g, 680 mmol) in dimethylformamide (860 ml) and cooled to 0-5°C. One portion is added cesium carbonate (288 g, 884 mmol), and then portions add ethylchloride (87 ml, 816 mmol). The resulting solution was allowed to warm to 20-25°C, then heated to 55°C (exothermic reaction is observed, the maximum observed temperature 76°C). After the internal temperature of the reaction is reduced to 65°C, the reaction mixture was heated at 65°C for ~4 hours. The reaction mixture was cooled to 20-25°C and filtered through filter paper to remove inorganic salts, and a solid portion was washed with dimethylformamide (3 total). The resulting filtrate is added dropwise to 16 volumes of a mixture of ice-water (8 volumes of ice/8 volumes of water) and obtained a suspension is left under stirring for 12-24 hours. The obtained solid brown color highlight, then filtered and washed with water (10 volumes) and air-dried. The crude product was dissolved in methyl tert-butyl ether (3,46 l, 15 volumes). Add charcoal (C-906 of Ecosorb, 20 wt.%, 46,1 g) and the mixture was heated at reflux for 1 hour. After cooling to room temperature, the charcoal was removed on a layer of celite, and the resulting filtrate concentrated to dryness. Cheese�th product is dissolved in ethyl acetate (576 ml, 2.5 volume) and concentrated to a thick slurry. Add 2% solution of ethyl acetate in heptane (1.15 l, 5 volumes) and the resulting mixture was stirred at room temperature for 30-60 minutes. The resulting product is collected by filtration, washed with heptane (2-3 volumes) and dried in high vacuum at 35-40°C for 16 hours, yielding the desired compound in the form of solid substances not quite white (109 g, 47% yield). The second portion is isolated from the mother liquor as follows: the filtrate obtained was concentrated, obtaining the crude oil. Add ethyl acetate (1 volume). The resulting solution was seeded with previously isolated product and cooled at 0-5°C for 1 hour. The obtained solid product is collected by filtration and washed with cold mixture of ethyl acetate:heptane (1:1 mixture, <1 volume). The obtained solid substance was dried, as disclosed previously, and combine with the first portion, receiving specified in the title compound (132 g, 57% yield). MS (ESI) m/z 337,8 [M-1]+, 339,8 [M+1]+, 341,8 [M+3]+.

C. 7-bromo-1-(((TRANS)-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A solution of ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (500 mg, about 1.47 mmol), ((TRANS)-4-methoxycyclohexyl)methanamine (317 mg, or 2.21 mmol) and diisopropylethylamine (of 0.77 ml, 4,42 mmol) in anhydrous dimethylsulfoxide (8.0 ml) was placed in a microwave vial (20 ml). Re�clonney the mixture was heated to 150°C for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate (2×100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dissolved in acetic acid (30 ml) and placed in a sealed ampoule. The reaction mixture was heated to 120°C over night. The resulting solution was cooled, concentrated under reduced pressure, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×100 ml), dried over sodium sulfate, filtered, and adsorb on the silica gel. Treatment as a result of processing using flash chromatography (50% ethyl acetate in hexano) yields a solid light orange color (400 mg, 1.12 mmol, 76% yield). MS (ESI) m/z of 355.2 [M+]+, 357,2 [M+2]+.

D. 1-(((TRANS)-4-methoxycyclohexyl)methyl)-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

7-bromo-1-(((TRANS)-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (2.71 g, 7,63 mmol), 1,1,1,2,2,2-hexamethyldisilane (3,00 g, 9,15 mmole) and tetrakis(triphenylphosphine)palladium(0) (882 mg, 0,76 mmol) combined in a sealed tube containing anhydrous dioxane (40 ml), and purged with nitrogen gas. The reaction mixture was heated to 100°C for 4 hours. The reaction mixture is diluted with ethyl acetate, filtered through celite, celite washed with ethyl acetate, and the obtained �intrat concentrated under reduced pressure. The crude substance is purified by treating with using flash chromatography (0-50% ethyl acetate in hexane) and the desired fractions pooled and concentrated, obtaining a solid of light yellow color (2.32 g, 5,28 mmol, 69% yield). MS (ESI) m/z 441,1 [M+1]+.

E. 5-(8-(((TRANS)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methilpiralidone

1-(((TRANS)-4-methoxycyclohexyl)methyl)-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0,721 g of 1.64 mmol), 5-bromo-4-methilpiralidone (0,323 g of 1.64 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,150 g, 0,164 mmol), triethylamine (0,687 ml, is 4.93 mmol), tri-ortho-tolylphosphino (0,100 g, 0,328 mmol) and dimethylformamide (8 ml) combine in a pressurized reactor. Nitrogen was bubbled through the reaction mixture for 5 min, and the reaction mixture was heated at 100°C for 3 hours. The reaction mixture was filtered, concentrated and purified using column chromatography on silica gel (0-80% ethyl acetate in hexano). Fractions were pooled and concentrated, obtaining the crude specified in the title compound, which was used directly in the next stage (0,607 g, a 1.55 mmol, 94% yield). MS (ESI) m/z 393,5 [M+1]+.

F. 5-(8-(((TRANS)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine

5-(8-(((TRANS)-4-methoxycyclohexyl�l)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methilpiralidone (0,607 g, 1,55 mmol), trifluoroacetic acid (2.0 ml, for 26.0 mmol) and sulfuric acid (0.5 ml, at 9.38 mmol) were pooled and heated at 65°C for 1 hour. the pH of reaction mixture was adjusted to 10 using sodium carbonate, and the resulting solution was extracted with ethyl acetate (3×15 ml). The organic layers are collected, dried over magnesium sulfate, concentrated and purified using preparative HPLC with reversed phase (10-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions combined and condensed under reduced pressure and dried in high vacuum, obtaining specified in the title compound in a solid yellow color (0,425 g, 1.04 mmol, 67% yield). MS (ESI) m/z 411,5 [M+1]+.

G. (Z)-N-((dimethylamino)methylene)-5-(8-(((TRANS)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine

5-(8-(((TRANS)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine (0,412 g, 1.00 mmol), dimethylformamide dineopentyl (1.5 ml) and tetrahydrofuran (10 ml) are combined and heated at 85°C for 3 hours. The reaction mixture was concentrated under a stream of nitrogen and placed in a reactor. The crude product was used directly in the next stage (0,467 g, 1.00 mmol, 100%) yield). MS (ESI) m/z 466,6 [M+1]+

N. 1-(((TRANS)-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)PI�idin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

(Z)-N-((dimethylamino)methylene)-5-(8-(((TRANS)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine (0,467 g, 1.00 mmol) was added to acetic acid (6 ml). The reaction mixture was cooled to 0°C and added dropwise hydrazine (1,00 ml, 32 mmol). The reaction mixture is left under stirring and heated to 25°C for 10 minutes. The reaction mixture was concentrated under a stream of nitrogen in the reactor. Add water (5 ml) and the product collected by filtration and purified using semi-preparative HPLC with reversed phase (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions combined and condensed under reduced pressure and dried in high vacuum, obtaining specified in the title compound in a solid yellow color (0,046 g, 0,106 mmol, 11% yield).1H NMR (400 MHz, METHANOL-d4) δ (MD), 8,72 (s, 1H), 8,62 (s, 1H), 8,37 (s, 1H), 7,93 (s, 1H), 4,30 (s, 2H), (d, J=of 7.03 Hz, 2H), 3,32 (s, 3H), is 3.08-3,17 (m, 1H), 2,71 is 2.76 (m, 3H), of 2.06 (user.s, 2H), 1,80-1,89 (m, 1H), 1,74 (user.s, 2H), of 1.09 (d, J=made 11.32 Hz, 4H); MS (ESI) m/z 435,5 [M+1]+.

Example 7: 7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. Ethyl 2-(5-bromo-3-(isopropylamino)pyrazine-2-ylamino)acetate

A mixture of ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (see example 6.(B) (1.5 g, 4,43 mmol), Isopropylamine (0.17 g, 4,87 mmol), NN-diisopropylethylamine (1.14 g, Is 8.84 mmol) and dimethylsulfoxide (10 ml) to the reaction vial was heated in an oil bath at 150°C for 16 hours. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure and purified using a chromatographic column with silica gel (10-20% ethyl acetate in petroleum ether) to obtain specified in the title compound (780 mg, 55.7 per cent of output). MS (ESI) m/z 316,9 [M+1]+.

B. 7-bromo-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A mixture of ethyl 2-(5-bromo-3-(isopropylamino)pyrazine-2-ylamino)acetate (780 mg, and 2.26 mmol), methanol (5 ml) and TFA (10 ml) in a sealed reactor was purged with nitrogen, sealed, intensively stirred and heated at 90°C in oil bath for 16 hours. The resulting mixture was diluted with methanol, and the solvent removed under reduced pressure. Add methanol (10 ml) and the solvent was again removed under reduced pressure. Add methanol (10 ml) and sodium bicarbonate. The resulting mixture was stirred at room temperature until pH=6 (in water), the solvent was removed under reduced pressure. Add water (20 ml). The resulting mixture was extracted with methylene chloride (20 ml × 3). The organic layer is dried over anhydrous sodium sulfate, concentrated, obtaining the crude product�t, and purified using a chromatographic column with silica gel (10-20% ethyl acetate in petroleum ether) to obtain specified in the title compound (360 mg, 39.4% of the output).

C. 1-isopropyl-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

7-bromo-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0.5 g, 1,844 mmol), hexamethyldisilane (0,725 g, 2,213 mmol), tetrakis(triphenylphosphine)palladium(0) (0,213 g, 0,184 mmol) and 1,4-dioxane (3 ml) was combined in a sealed reactor with a magnetic stirrer. Gaseous nitrogen was bubbled through the solution. The vessel is sealed, intensively stirred and heated at 100°C for 2 hours. The obtained turbid black mixture was diluted with ethyl acetate, filtered, and the filter cake washed thoroughly with ethyl acetate. The filtrate obtained is concentrated under reduced pressure and purified using column flash chromatography on silica gel (20-80% ethyl acetate in hexano), obtaining the target product (0.49 g, 1.38 mmol, 75% yield) in the form of solids, white and yellow. MS (ESI) m/z 357,4 [M+2]+.

D. 4-bromo-2-fluoro-5-methylbenzamide

A solution of 4-bromo-2-fluoro-5-methylbenzonitrile (40 g, 190 mmol) in a mixture of sulfuric acid (98%) and TFA (about./about. = 4:1, 480 ml) was stirred at 80°C for 16 hours. After the resulting mixture was cooled to room temperature, the mixture was poured into ice water. The remaining residue is collected �altropane, washed with water and dried under reduced pressure, obtaining specified in the title compound (41 g, 95% yield) in the form of white solids. MS (ESI) m/z 232,0 [M+1]+.

E. 4-bromo-N-((dimethylamino)methylene)-2-fluoro-5-methylbenzamide

A solution of 4-bromo-2-fluoro-5-methylbenzamide (20 g, 86 mmol) in N,N-dimethylformamide dimethylacetal (200 ml) was stirred at 100°C in a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated and dried, obtaining the target product (24.6 g, 95% yield) as a yellow oil, which was used for next step without further purification. MS (ESI) m/z 287,0 [M+1]+.

F. 3-(4-bromo-2-fluoro-5-methylphenyl)-1H-1,2,4-triazole

To a solution of 4-bromo-N-((dimethylamino)methylene)-2-fluoro-5-methylbenzamide (24.6 g, of 86.2 mmol) in acetic acid (200 ml) was added dropwise hydrazine hydrate (25 ml, of 0.70 mol) at 0°C. the Reaction mixture was stirred at room temperature over night. The resulting mixture was filtered, washed with water (500 ml × 3) and dried under reduced pressure, obtaining specified in the title compound (15 g, 68% yield) in the form of white solids. MS (ESI) m/z 256,0 [M+1]+.

G. 3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole

A solution of 3-(4-bromo-2-fluoro-5-methylphenyl)-1H-1,2,4-triazole (15 g, 60 mmol), toluene-4-sulfonic acid (2.0 g, 12 mmol) and 3,4-dihydro-2H-PYRAN (20 g, 240 mmol) in tetrahydrofuran� (200 ml) was stirred at 80°C in a nitrogen atmosphere for 15 hours. The resulting mixture was concentrated and purified using a column with silica gel (1-25% ethyl acetate in petroleum ether) to give the protected triazole product (15 g, 75% yield) in the form of a solid substance of white color.1H NMR (DMSO-d6, 400 MHz): δ (M. D.) 8,83 (s, 1H), 7,96 (d, J=7,6 Hz, 1H), 7,66 (d, J=10.0 Hz, 1H), 5,61 (DD, J1=2.4 Hz, J2=9,6 Hz, 1H), 3,96 (d, J=1.6 Hz, 1H), 3,69 (m, 1H), a 2.36 (s, 3H), 2,00 (m, 2H), 1,70 (m, 2H), of 1.57 (m, 2H); MS (ESI) m/z 340,0 [M+1]+.

N. 7-(5-fluoro-2-methyl-4-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

1-isopropyl-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (300 mg, 0,84 mmol), 3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (428 mg, of 1.26 mmol) and bis(triphenylphosphine)palladium(II)dichloride (56 mg, 0.08 mmol) are combined in N,N-dimethylformamide (5 ml). The resulting mixture Tegaserod and heated at 140°C in a nitrogen atmosphere for 3 hours. After cooling to room temperature the reaction mixture was filtered, and the filtrate obtained is separated between ethyl acetate (15 ml) and water (15 ml). The organic layer is isolated, and the aqueous layer was extracted with ethyl acetate (10 ml × 2). The combined organic layers dried over sodium sulfate, filtered, concentrated under reduced pressure and purified using preparative TLC (15% methanol in dichloromethane), obtaining specified in the header connection� (200 mg, yield 52%) as a solid.

I. 7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A solution of 7-(5-fluoro-2-methyl-4-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she (200 mg, 0.44 mmol) in methanolic hydrochloride solution (20 ml, 2 M) was stirred for 5 hours at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (25 ml) and aqueous mixture was extracted with ethyl acetate (25 ml × 2). The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure and purified using a column with silica gel (50-100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure, obtaining specified in the title compound (75 mg, 46% yield).1H NMR (DMSO-d6, 400 MHz): δ (M. D.) 14,25 (user.s, 1H), 8,20 (user.s, 1H), 7,90 (m, 2H), 7,58 (s, 1H), 7,35 (s, 1H), 5,24 (m, 1H), 4,10 (s, 2H), 2,43 (s, 3H), of 1.44 (d, J=7,2, 6H); MS (ESI) m/z 368,2 [M+1]+.

Example 8: 7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'H-Spiro[cyclopropane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-he

A. Tert-butyl 1-(3,5-dibromopyrazine-2-ylcarbonyl)cyclopropylboronic

1,1'-carbonyldiimidazole (4,37 g, of 27.0 mmol) was added to a stirred solution of 1-(tert-butoxycarbonylamino)cyclopropanecarbonyl�howling acid (4,93 g, You € 24.50 mmol) in N,N-dimethylformamide (6 ml) and dichloromethane (12 ml) at room temperature. The resulting clear yellow mixture was stirred at room temperature in a nitrogen atmosphere for 4 hours. Add N,N-diisopropylethylamine (8,54 ml of 49.0 mmol), then added 3.5-dibromopyrazine-2-amine (9,29 g, to 36.8 mmol). The resulting mixture was heated at 50°C at reflux in a nitrogen atmosphere for 60 hours. The resulting mixture was diluted with ethyl acetate and washed with water. The layers were separated, and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is placed in dichloromethane and purified using flash chromatography (biotage AB) (5-60% ethyl acetate in hexane). Fractions containing the desired product were pooled and concentrated under reduced pressure. The residue is triturated with 15% ethyl acetate in hexane and dried in high vacuum to give the desired product (5,349 g, 12,27 mmol, 50% yield) in the form of solid substances not quite white.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,92 (user.s, 1H), 8,76 (s, 1H), 7,70 (user.s, 1H), 1,41 (s, 9H), 1,34-of 1.40 (m, 2H), 1,02-of 1.09 (m, 2H); MS (ESI) m/z 437,3 [M+1]+, 459,1 [M+Na]+.

B. 1-amino-N-(3,5-dibromopyrazine-2-yl)cyclopropanecarboxamide bistrutturate

TFA (6,02 ml, 78 mmol) was added to a stirred mixture of tert-butyl 1-(3,5-dibromopyrazine-2-ilkar�email)cyclopropylamine (3,410 g, Of 7.82 mmol) in dichloromethane (20 ml). The resulting clear yellow solution was stirred at room temperature for 4 hours. All volatiles are removed under reduced pressure, and the residue was dried in high vacuum at 40°C, obtaining the target product (4.42 g, 7.85 mmol, 100% yield) as a waxy solid yellow color. MS (ESI) m/z 337,1 [M+1]+.

C. 7'-bromo-1'H-Spiro[cyclopropane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-he

1-amino-N-(3,5-dibromopyrazine-2-yl)cyclopropanecarboxamide bistrutturate (0,394 g, 0,700 mmol), N,N-diisopropylethylamine (0,610 ml, 3.50 mmol) and 1,4-dioxane (6 ml) was combined in a sealed reactor with a magnetic stirrer. The system was purged with nitrogen. The resulting mixture was sealed, intensively stirred and heated at 110°C for 2 hours. Volatiles are removed under reduced pressure. The residue was dissolved in DMSO and methanol, filtered and purified using preparative HPLC with reversed phase (10-65% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Fractions containing the product were combined, neutralized with saturated aqueous sodium bicarbonate solution and most of the solvent was removed under reduced pressure. The solid part was collected using vacuum filtration, thoroughly washed with water and dried in high vacuum to give the desired product (0,141 g, 0,553 mmol, 79% yield) as a solid visistadvaita yellow. 1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,27 (s, 1H), 8,04 (s, 1H), of 7.46 (s, 1H), 1,29-1,38 (m, 2H), of 0.91 for 1.01 (m, 2H); MS (ESI) m/z to 255.1 [M]+, RUB 257.0 [M+2]+.

D. Triptorelin 7'-(2-methyl-4-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)phenyl)-1 N-Spiro[cyclopropane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-it

3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole (see example 2.(C) (0,201 g, 0,545 mmol), 7'-bromo-1'H-Spiro[cyclopropane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-he (0,139 g, 0,545 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.045 g, 0,054 mmol), sodium carbonate (1 M in water, 1,635 ml 1,635 mmol), 1,4-dioxane (1.2 ml) and isopropanol (0.4 ml) are combined in a pressurized reactor with a magnetic stirrer. The system was purged with nitrogen. The resulting mixture was sealed, intensively stirred and heated at 100°C for 1 hour. The resulting mixture was diluted with water and extracted three times with dichloromethane. The combined organic fractions concentrated under reduced pressure. The residue is placed in DMSO and MeOH, filtered and purified using preparative HPLC with reversed phase (20-70% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Fractions containing the product were pooled, and the solvent removed under reduced pressure. The obtained residue was dried in high vacuum to give the desired product (0,109 g, 0,205 mmol, 38% of output) in the form of a solid orange color. MS (ESI) m/z 418,4 [M+1]+.

E. 7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1 N-Spiro[cyclopropane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-he

6 n hydrochloric acid in water (0,171 ml of 1.025 mmol) was added to a stirred mixture of triptoreline 7'-(2-methyl-4-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)phenyl)-1 N-Spiro[cyclopropane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4 N)-she (0,109 g, 0,205 mmol) in ethanol (4 ml) at 80°C. the resulting mixture was intensively stirred and heated at 80°C at reflux in a nitrogen atmosphere for 30 minutes. The resulting mixture was filtered and purified using preparative HPLC with reversed phase (10-60% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Fractions containing the product were combined, neutralized with saturated aqueous sodium bicarbonate solution and most of the solvent was removed under reduced pressure. The solid part was collected using vacuum filtration, thoroughly washed with water and dried in a high vacuum at 45°C, yielding the desired product (0,027 g, 0,079 mmol, 39% yield) as a solid yellow color.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,22 (user.s, 1H), 8,63 (user.s, 1H), 7,93 (s, 1H), to 7.89 (d, J=7,81 Hz, 1H), 7.62 mm (s, 1H), 7,58 (s, 1H), 7,47 (user.s, 1H), 2,43 (s, 3H), of 1.29-1,38 (m, 2H), 0,95-1,04 (m, 2H); MS (ESI) m/z 334,2 [M+1]+.

Example 9: 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((TRANS)-4-methoxycyclohexyl)-3,4-dihydr�pyrazino[2,3-b]pyrazine-2(1H)-he

A. Ethyl 2-(5-bromo-3-(TRANS-4-methoxycyclohexanone)pyrazine-2-ylamino)acetate

Ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (see example 6.(B) (30,0 g, 88 mmol),TRANS-4-methoxycyclohexanone (17,15 g, 133 mmol), N,N-diisopropylethylamine (30,8 ml, 177 mmol) and dimethyl sulfoxide (70,8 ml) are combined in the reaction vial with a magnetic stirrer and heated on an oil bath at 150°C for 16 hours with stirring. The resulting mixture was diluted with ethyl acetate, and volatiles removed under reduced pressure. The residue is purified using chromatography treatment on silica gel biotage AB SP1 (12% ethyl acetate in hexano). Fractions containing the product were pooled and the organic volatiles removed under reduced pressure. The residue was triturated with 5% ethyl acetate in hexane. The solid part was collected using vacuum filtration, washed with hexane and dried in vacuum, obtaining specified in the header connection (to 15.37 g, 39.7 mmol, 44.8% of output) in the form of solid substances not quite white. MS (ESI) m/z 387,0 [M]+, 389,0 [M+2]+.

B. 7-bromo-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

The following reaction is carried out by distributing the reaction mixture in three separate sealed vials, and treated separately. The substance is then combined with subsequent purification. Ethyl 2-(5-�rum-3-( TRANS-4-methoxycyclohexanone)pyrazine-2-ylamino)acetate (10 g, of 25.7 mmol), methanol (10.5 ml, 259 mmol) and TFA (100 ml) was combined in a sealed reactor with a magnetic stirrer. The system was purged with nitrogen and the resulting mixture was sealed, intensively stirred and heated at 90°C in oil bath for 18.5 hours. The resulting mixture was diluted with methanol and all the solvent removed under reduced pressure. Add methanol (100 ml) and again, all the solvent was removed under reduced pressure. Add methanol (100 ml) and sodium bicarbonate (12,4 g, 147 mmol). The resulting mixture was stirred at room temperature until pH=6 (in water). The resulting mixture is concentrated almost to dryness. Add water (100 ml). The resulting solid brown part harvested using vacuum filtration, and washed with water. Brown solid portion was dissolved in hot methanol and acetonitrile and purified using a C18 column with reversed phase flash chromatography (20-100% acetonitrile in water). Fractions containing the desired product were pooled and concentrated almost to dryness under reduced pressure. The solid part was collected using vacuum filtration, washed with water and dried in a high vacuum, obtaining the target product of 4.88 g, and 14.3 mmol, 55% yield) in the form of a solid substance of a yellowish-brown color.1H NMR (400 MHz, DMSO-d6) δ M. D.) 7,71 (s, 1H), members, 7.59 (s, 1H), 4,66 (TT, J=3,61, 12,20 Hz, 1H), 4,07 (d, J=1,56 Hz, 2H), 3,25 (s, 3H), 3,06-3,17 (m, 1H), 2,42 (square d, J=3.51, your 12,89 Hz, 2H), 2,10 (d, J=10,93 Hz, 2H), to 1.61 (d, J=10,93 Hz, 2H), 1,10-1,24 (m, 2H); MS (ESI) m/z 341,3 [M]+, 343,1 [M+2]+.

C. 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

2-(5-(tributylstannyl)pyridin-2-yl)propan-2-ol (see example 5.(E) (9,43 g, of 31.4 mmol), 7-bromo-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (10,02 g, 29.4 mmol) of the adduct [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (being equal to 2.398 g, to 2.94 mmol) and N,N-dimethylformamide (25 ml) are combined in round bottom flask with a magnetic stirrer. The air in the flask is evacuated, creating a vacuum, then fills the flask three times with nitrogen gas. The resulting mixture was intensively stirred and heated at 120°C in a nitrogen atmosphere for 35 minutes. The resulting mixture was purified using flash chromatography, separated on 4 separate column (2-15% methanol in dichloromethane). Fractions containing the product were pooled and most of the solvent was removed under reduced pressure. The resulting mixture was purified using preparative HPLC with reversed phase (20-40% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min), divided into 6 batches. Fractions containing the product were pooled, and the entire acetonitrile, and some water is removed by the low�nom pressure at 25°C. The remaining yellow solution was placed in 50 g of ion-exchange resin Strata X-C from Phenomenex. The column is washed successively with water, acetonitrile, methanol and then 5% ammonium hydroxide in methanol. Product, eluting with 5% ammonium hydroxide in methanol, washed and concentrated under reduced pressure and dried in high vacuum to give the desired product (4,85 g, 12.20 mmol, 42% yield) as a foamy solid pink.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,03 (d, J=1,56 Hz, 1H), 8,28 (s, 1H), 8,24 (DD, J=2,34, 8,20 Hz, 1H), 7,74 (d, J=7,81 Hz, 1H), 7,61 (s, 1H), 5,26 (s, 1H), 4,90 (TT, J=3,71, 12,10 Hz, 1H), 4,13 (s, 2H), or 3.28 (s, 3H), 3,20 (TT, J=4,00, 10,84 Hz, 1H), 2,58 (square d, J=2,93, 12,82 Hz, 2H), 2,14 (d, J=10,15 Hz, 2H), by 1.68 (d, J=10,93 Hz, 2H), 1,47 (s, 6H), 1,17-of 1.35 (m, 2H); MS (ESI) m/z 398,3 [M+1]+; T a MP 196-198°C (without amendments).

D. 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (alternative approach)

Ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (1 equiv.) andTRANS-4-methoxycyclohexanone hydrochloride (1.5 equiv.), NMP and DIPEA combined and heated to 127°C and kept at this temperature for 18 hours. After completion of the reaction the mixture was cooled to 35°C for 4 hours. The resulting solution was transferred into a mixture of ethyl acetate and 5% salt solution. The aqueous layer removed and the organic layer was washed successively with 5% salt solution by vodoi. The organic layer is concentrated to a small volume using vacuum distillation, cooled to room temperature, and the solid part was collected using vacuum filtration. The resulting solid portion was washed using MTBE and the product was dried in a vacuum thermostat, receiving 41% yield ethyl 2-(5-bromo-3-(TRANS-4-methoxycyclohexanone)pyrazine-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(TRANS-4-methoxycyclohexanone)pyrazine-2-ylamino)acetate (1 equiv.), water and 85% phosphoric acid (3:1) was heated to 80°C for 1 hour. The heating is maintained for 18 hours to achieve completion of the reaction. After completion of the reaction the mixture was cooled to 25°C and filtered, obtaining the crude product in the form of a solid yellow-brown color. The remaining solid was washed with water, suspended in water and filtered. The solid part was washed with water until the pH of the obtained filtrate is between 4 and 8. The resulting material was dried under vacuum to give 89% yield of 7-bromo-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she. 7-bromo-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine (1 equiv.), sodium carbonate (3 equiv.) and PdCl2(AmPhos)2(0,003 equiv.) combined in isopropanol and heating�s at 70°C for 1.5 hours. Due to routine handling and treatment get secure connection to 93% yield.

The removal of the protective group using standard conditions for the removal of the trimethylsilyl groups, and the allocation leads to obtaining specified in the header connection.

Alternatively, the ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (1 equiv.) andTRANS-4-methoxycyclohexanone hydrochloride (1.5 equiv.), NMP and DIPEA combined and heated to 125°C and kept at this temperature for 18 hours. After completion of the reaction the mixture was cooled to room temperature and transferred into a mixture of ethyl acetate and an aqueous solution of sodium chloride. The aqueous layer removed and the organic layer was washed successively with an aqueous solution of sodium chloride and water. The organic layer was concentrated using vacuum distillation to a small volume, cooled to ambient temperature and the solid part was collected and dried, yielding ethyl 2-(5-bromo-3-(TRANS-4-methoxycyclohexanone)pyrazine-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(TRANS-4-methoxycyclohexanone)pyrazine-2-ylamino)acetate (1 equiv.), water (161 equiv.) and 85% phosphoric acid (16.5 equiv.) heated at 80°C. After completion of reaction the mixture was cooled to 25°C, filtered and the solid portion washed with water. The hard part is again suspended in water, and filtering and p�myvcu repeat. The resulting material was dried, yielding 7-bromo-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he. 7-bromo-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1 equiv.), 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-ol (1.08 equiv.) and PdCl2(AmPhos)2(0,0025 equiv.) combined in tetrahydrofuran. The resulting mixture was treated with a solution of potassium carbonate (2.5 equiv.) and heated to reflux. After cooling to 40°C is added toluene, and the layers were separated. The organic layer was washed with a solution of potassium dihydrogen phosphate and treated with acceptor metal (SiliaBond® Thiol). The resulting mixture was filtered and distilled with addition of toluene until then, until the temperature reaches 100°C. After cooling, the remaining solid is collected by filtration and dried. The obtained solid was combined with butilirovannyh hydroxyltoluene (BHT) (9×10-4equiv.) in IPA and water (3×:5× volume). The resulting mixture was heated to 65°C and, while maintaining a specified temperature, add water (5× vol.). Add a small amount specified in the header connection (to 0.02 equiv.) in the water. The resulting mixture is left to stand for 2 hours, cooled to room temperature and stirred. The remaining solid is collected by filtration and dried, yielding 7-(6-(2-hydroxyp�pan-2-yl)pyridin-3-yl)-1-( TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-it is in the form of solid substances not quite white.

Example 10: 9-(6-(4H-1,2,4-triazole-3-yl)-2-methyl-3-pyridyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-he

A. 5-bromo-6-methilpiralidone

3,6-dibrom-2-methylpyridine (4,9 g, 19,53 mmol), copper cyanide(I) (1,75 g, 19,53 mmol) and N,N-dimethylformamide (20 ml) was combined in a sealed reactor with a magnetic stirrer. The resulting mixture was sealed, intensively stirred and heated at 110°C for 4 hours. The resulting mixture was diluted with ethyl acetate, poured into a separatory funnel containing water and the layers were separated. The aqueous layer twice extracted with ethyl acetate. The combined organic portion was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid is purified using chromatography treatment on silica gel (10% ethyl acetate in hexano), receiving specified in the header connection in the form of white solids (1.88 g, 9,54 mmol, 49% yield). MS (ESI) m/z of 197.3 [M]+.

B. Tert-butyl 3-(3,5-dibromopyrazine-2-ylcarbonyl)morpholine-4-carboxylate

A solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (1,500 g, of 6.49 mmol) and 1,1'-carbonyldiimidazole (1,578 g, 9.73 mmol) in N,N-dimethylformamide(2 ml) and dichloromethane (6 ml) was stirred for 4.5 hours at room temperature in a nitrogen atmosphere. Add N,N-diisopropylethylamine (2,260 ml 12,97 mmol), then added 3.5-dibromopyrazine-2-amine (3.28 g, 12,97 mmol). The resulting mixture was stirred and heated at 50°C at reflux in a nitrogen atmosphere for 2 days. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic portion was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified using flash chromatography (20-30-50% ethyl acetate in hexano), obtaining the target product (2,136 g, 4,58 mmol, 71% yield) as slightly yellow foamy solid. MS (ESI) m/z 467 [M+1]+.

C. 9-bromo-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-he

Tert-butyl 3-(3,5-dibromopyrazine-2-ylcarbonyl)morpholine-4-carboxylate (2,132 g, is 4.57 mmol) was dissolved in dichloromethane (45 ml) with stirring at room temperature. Add TFA (9 ml) and the obtained light yellow mixture was sealed and stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure, and the residue was dried in high vacuum at 45°C, yielding a viscous yellow oil. The yellow oil was dissolved in isopropanol (wet) (50 ml) with stirring at room temperature. Add the bicarbonate soda�I (3,84 g, Of 45.7 mmol), palladium acetate(II) (0,103 g, 0,457 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0,239 ml, 1,372 mmol). The air in the flask is removed and replaced with nitrogen. The resulting mixture was intensively stirred and heated at 80°C at reflux in a nitrogen atmosphere for 2 hours. The resulting mixture was cooled to room temperature and diluted with water (30 ml). The remaining solid substance is harvested using vacuum filtration, thoroughly washed with water and diethyl ether and dried in high vacuum to give the desired product with a purity of ~90% (1,441 g, to 5.05 mmol, 99% yield) as a solid yellow color. MS (ESI) m/z 285 [M]+, 287 [M+2]+.

D. 9-(1,1-dimethyl-1-stannates)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-he

9-bromo-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-he (0.30 g, 1,052 mmol), hexamethyldisilane (0,414 g, 1,263 mmol), tetrakis(triphenylphosphine)palladium(0) (0,122 g, 0,105 mmol) and 1,4-dioxane (5 ml) was combined in a sealed reactor with a magnetic stirrer. Gaseous nitrogen was bubbled through the solution for five minutes. The reactor is sealed, intensively stirred and heated at 100°C for 2 hours. The obtained turbid black mixture was diluted with ethyl acetate, filtered and the filter cake washed thoroughly with ethyl acetate. The filtrate obtained is concentrated at lower�nom pressure and purified, using flash chromatography biotage AB (20-80% ethyl acetate in hexano), obtaining the target product (0,350 g, 0,948 mmol, 90% yield) in the form of solids, white and yellow. MS (ESI) m/z 369,5 [M]+.

E. 6-methyl-5-(5-oxo(6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-9-yl))pyridine-2-carbonitril

5-bromo-6-methilpiralidone (0,080 g, 0,406 mmol), 9-(1,1-dimethyl-1-stannates)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-he (0,150 g, 0,406 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,041 g, or 0.045 mmol), tri-o-tolylphosphino (0,027 g, 0,089 mmol) and triethylamine (0,170 ml, 1,219 mmol) placed in a sealed vial and added N,N-dimethylformamide (2 ml). Gaseous nitrogen was bubbled through the reaction mixture for five minutes, and the reaction mixture was sealed and heated at 100°C for 1 hour. The obtained turbid black mixture was diluted with methanol, filtered and the filter cake washed thoroughly with methanol. The filtrate obtained is concentrated under reduced pressure and purified using flash chromatography biotage AB (50-100% ethyl acetate in hexano), obtaining the target product (0,117 g, 0,363 mmol, 89% yield). MS (ESI) m/z 323,5 [M+1]+.

F. 6-methyl-5-(5-oxo(6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-9-yl))pyridine-2-carboxamide

6-methyl-5-(5-oxo(6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-9-yl))pyridine-2-carbonitrile (0.18 g, 0,558 mmol) are placed in a circle�donnow flask and with stirring was added a mixture of TFA (1.6 ml) and sulfuric acid (0.4 ml). The resulting suspension is left under stirring for 16 hours at room temperature. The resulting mixture was poured onto ice, and the excess of acid is carefully neutralized with solid potassium hydroxide. The obtained solid was filtered, washed with water and dried in a high vacuum, obtaining specified in the header connection (0,153 g, is 0.450 mmol, 81% yield) as a solid red color. MS (ESI) m/z 341,5 [M+1]+.

G. 9-(6-(4H-1,2,4-triazole-3-yl)-2-methyl-3-pyridyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-he

6-methyl-5-(5-oxo(6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-9-yl))pyridine-2-carboxamide (0,159 g, 0,467 mmol), Ν,Ν-dimethylformamide dineopentyl (2 ml of 8.85 mmol) and dimethylsulfoxide (0.5 ml) was placed in a flask and heated to 85°C for 1 hour. The resulting solution was diluted with acetic acid (5 ml, 87 mmol) and added dropwise hydrazine (0,468 ml 14,90 mmol). The reaction mixture is left under stirring at 25°C for 30 minutes. The resulting mixture was concentrated under reduced pressure, and the residue was carefully neutralized with a saturated aqueous solution of sodium carbonate. The resulting solution was then extracted three times with ethyl acetate, concentrated under reduced pressure and purified using semi-preparative HPLC with reversed phase (5-50% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 20 minutes), receiving specified in zag�lowke compound (0.03 g, 0,082 mmol, 17,63% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,96 and 8.04 (m, 2H), of 7.88 (s, 1H), 4,33 (DD, J=3,71, 10,74 Hz, 1H), 4,15-to 4.23 (m, 2H), 3,98 (DD, J=3.51, your 11,71 Hz, 1H), 3,51-3,63 (m, 2H), 2,89-to 2.99 (m, 1H), 2,70 (s, 3H); MS (ESI) m/z 365,5 [M+1]+

Example 11: 6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 6-bromo-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

To a solution of N-(3,5-dibromopyrazine-2-yl)-2-iodoacetamide (see example 5.B) (6.6 g, 15.8 per mmol) and diisopropylethylamine (4.0 g, of 31.6 mmol) in acetonitrile (50 ml) was added tetrahydro-2H-Piran-4-amine (6.4 g, 63.2 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue is purified using chromatography treatment on silica gel (5-20% ethyl acetate in petroleum ether) to obtain specified in the title compound (1.98 g, 40% yield). MS (ESI) m/z 313,1 [M+1]+.

B. 4-(tetrahydro-2H-Piran-4-yl)-6-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

Degassed mixture of 6-bromo-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she (1,98 g 6,35 mmol), tetrakis(triphenylphosphine)palladium (1.45 g, of 1.27 mmol) and hexamethyldisilane (4.0 g, 12.7 mmol) in dioxane (10 ml) was heated at 90°C for 3 hours in a nitrogen atmosphere. The reaction mixture was concentrated under pony�enom pressure, and purified using a column with silica gel (10-20% ethyl acetate in petroleum ether) to give product (1,07 g, 42.3 percent yield). MS (ESI) m/z 399,1 [M+1]+.

C. 6-(6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A mixture of 4-(tetrahydro-2H-Piran-4-yl)-6-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she (1 equiv.), 5-bromo-2-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine (1.2 equiv.), Tris(dibenzylideneacetone)diplegia (0.1 equiv.), three-o-tolylphosphino (0.2 equiv.), triethylamine (3 equiv.) and N,N-dimethylformamide is heated at 95°C for 3 hours in a nitrogen atmosphere. Concentration and chromatographic purification give the target product with a 39% yield. MS (ESI) m/z 463,1 [M+1]+.

D. 6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A mixture of 6-(6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she's in methanolic hydrochloride solution was stirred at room temperature for 0.5 hours. The solvent is evaporated under reduced pressure, obtaining the crude product, which was washed with N,N-dimethylformamide, and receive specified in the header connection in the form hydrochloride salt in 34% yield.1H NMR (DMSO-d6, 400 MHz) δ (M. D.) 11,44 (s, 1H), 9,30 (s, 1H), 8,59 (d, J=8,4 �C, 1H), is 8.46 (s, 1H), 8,22 (m, 2H), 4,70 (t, J=10 Hz, 1H), 4,16 (s, 1H), (m, 4H), 3,51 (t, J=11.2 Hz, 2H), to 1.86 (m, 2H), 1,69 (d, J=12,8 Hz, 2H); MS (ESI) m/z 379,1 [M+1]+.

Example 12: 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 7-bromo-1-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A mixture of ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (see example 6.(B) (1 equiv.), etilamingidrokhlorida (3.1 equiv.), N,N-diisopropylethylamine (4 equiv.) in N-methylpyrrolidinone heated at 105°C in a nitrogen atmosphere for 14 hours. The standard treatment with a mixture of ethyl acetate/water gives the crude product with 77% yield. The resulting material was used without further purification. Crude ethyl 2-(5-bromo-3-(ethylamino)pyrazine-2-ylamino)acetate and acetic acid are combined in methanol. The reaction mixture was brought to reflux at 60-62°C in a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was diluted with methanol and concentrated. The remaining residue is dissolved in ethyl acetate, treated with sodium carbonate and stirred for 10 minutes until a pH of~7. The resulting mixture was filtered and washed with ethyl acetate. The obtained filtrate was concentrated and purified using purification on a layer of silica gel, using (0-40% ethyl acetate in hexano), receiving the product as a solid prophetic�STV yellow-brown color. Additionally, the filter cake suspended in water to remove potassium carbonate. The remaining solid product is collected by filtration. The whole process yields a product with a combined yield of 75%.

B. 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A mixture of 3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine (1 equiv.), bis(pinacolato)diboron (of 1.05 equiv.), potassium acetate (2 equiv.), potassium carbonate (3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.1 equiv.) in anhydrous dioxane (300 ml) Tegaserod and heated at 90°C for 2 hours. The resulting mixture was cooled to <40°C and add 7-bromo-1-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1 equiv.), water and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.05 equiv.). The resulting mixture Tegaserod and heated at 65-70°C in a nitrogen atmosphere for 1 hour. The resulting mixture was cooled to <40°C, diluted with water and ethyl acetate. The standard treatment with a mixture of ethyl acetate/water followed by flash column chromatography (0-5% methanol in dichloromethane) and recrystallization from ethanol leads to obtaining specified in the title compound with 57% yield.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,99 (s, 2H), of 7.93 (s, 1H), 7,72 (s, 1H), 4,22 (s, H), 4,05 (kV, J=was 6.77 Hz, 2H), 2,71 (s, 3H), of 1.18 (t, J=of 7.03 Hz, 3H); MS (ESI) m/z 337,6 [M+1]+.

C. 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (Alternative approach)

Ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (1 equiv.), tetrahydrofuran and an aqueous solution of sodium hydroxide (1.1 equiv.) combined and stirred at room temperature over night. The reaction mixture was filtered and the collected solid portion is dried, obtaining 2-(3,5-dibromopyrazine-2-ylamino)sodium acetate in the form of solid substances not quite white. 2-(3,5-dibromopyrazine-2-ylamino)sodium acetate and ethylamine (3 equiv., 70% wt., solution) are combined in water, and the resulting mixture was stirred at 90°C overnight. The reaction mixture was cooled to 80°C, treated with phosphoric acid (10 equiv.) and stirred for 3 hours. The resulting mixture was cooled to room temperature and the solid part was collected by filtration. The resulting product was dried, yielding 7-bromo-1-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he's in a solid gray color. 7-bromo-1-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1 equiv.), bipinchandra (1.5 equiv.) and potassium acetate (3.2 equiv.) combined in tetrahydrofuran. The reaction mixture is heated at reflux and added PdCl2(AmPhos)2(0.002 equiv.). After 4 hours the reaction mixture was cooled to room�Oh temperature. The resulting mixture was filtered and the collected solid portion is washed, using tetrahydrofuran. The filtrate obtained is concentrated under reduced pressure to 50% of the original volume, and add hexane. The remaining solid is collected by filtration and dried, yielding 1-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-it is in the form of a solid yellow-brown color. 1-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1 equiv.) and 3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine (0.96 equiv.) combined in tetrahydrofuran. In a flask is added an aqueous solution of potassium carbonate (2 equiv.) under stirring. The resulting solution was treated with PdCl2(AmPhos)2Of (0.02 equiv.) and heated to 65°C for 1 hour. The resulting solution was treated with MTBE and seeded. An additional amount of MTBE and a seed crystal is added before adding to the reaction mixture a final portion of MTBE. The solid part was collected by filtration and dried, obtaining the desired intermediate compound in a solid yellow-brown color. Specified intermediate compound and reagent alcohol (95% ethanol and 5% isopropanol) were pooled, and the resulting mixture is treated with a concentrated aqueous solution of hydrogen chloride and heated to 60°C. a second portion of the end�tarirovannogo aqueous solution of hydrogen chloride and the substance is heated for 2 hours. The reaction mixture was cooled to room temperature and filtered. The hard part is washed, using IPA, and dried, yielding the hydrochloride of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-it is in the form of a solid pale yellow color. The obtained salt is dissolved in water and tetrahydrofuran and treated with an acceptor metal (SiliaBond® Thiol) (10% wt.) in the course of the night. The slurry was filtered, and the solid portion washed with a mixture of 1:1 tetrahydrofuran/water. The resulting filtrate is treated with an aqueous solution of ammonium hydroxide, concentrated under reduced pressure to 70% of its volume. The resulting solution was cooled to room temperature, and the remaining solid was filtered and washed with water and ethanol. The dried solid part is transferred to a flask, treated with ethanol, and heated to 65°C for 2 hours. The resulting mixture was cooled to room temperature and allowed to stand over night. The solid part was collected using vacuum filtration, and dried, yielding 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-it is in the form of solid substances not quite white.

Example 13: 4-((CIS)-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 5-bromo-6-methylpyridine

p> A solution of 5-bromo-6-methylpyrimidine (1.8 g, 9,14 mmol) in a mixture of TFA and sulfuric acid (30 ml, 4:1, about./about.) was stirred at 40°C for 16 hours. The reaction mixture was poured into ice water. The resulting solid is filtered off and washed with water and dried, obtaining the target product in the form of white solids (1.0 g, 4,65 mmol, 54% yield). MS (ESI) m/z 217,1 [M+2]+.

B. 3-bromo-2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridine

5-bromo-6-methylpyridine (1 g, 4,65 mmol) and Ν,Ν-dimethylformamide, dimethylacetal (20 ml) are combined in a 100 ml round-bottom flask with a magnetic stirrer and heated at 85°C at reflux in a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure and dried under vacuum to give a yellow oil, which was used for next step without purification. The residue was diluted with acetic acid (10 ml) and added dropwise hydrazine (2.5 ml, is 70.3 mmol) and left under stirring at room temperature for 5 hours. The reaction mixture was poured into ice water. The obtained solid was filtered, washed with water and dried, obtaining the target product in the form of white solids. The aqueous filtrate was extracted with dichloromethane. The organic layer was concentrated under reduced pressure almost to dryness, thus obtaining additional substance. The Union of two Porz�th leads to obtaining the desired product (0.7 g, 2,9 mmol, 63% yield). MS (ESI) m/z 241,1 [M+2]+. Alternative approach: 5-bromo-6-methilpiralidone (1 equiv.) and hydrazinoacetate (2.0 equiv.) combined in absolute ethanol (4× volume) and heated to 55°C for 24 hours. The suspension was cooled to room temperature and filtered. The collected solid portion was washed using ethanol and methyl tert-butyl ether, and the solid part was dried, yielding 5-bromo-6-methylpyrimidine in the form of a powder beige color. 5-bromo-6-methylpyrimidine and formic acid (15 equiv.) combined and heated to 100°C with stirring for 6 hours. The reaction solution was cooled to 40°C, treated with methanol, stirred for 30 minutes and concentrated under reduced pressure to 20% of the reaction volume. The resulting mixture was diluted with methanol and again concentrated under reduced pressure to 20% of the reaction volume. The remaining solid was filtered, washed with water and dried, obtaining specified in the title compound in powder form is not white.

C. 3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine

3-bromo-2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridine (0.7 g, of 2.93 mmol) and 3,4-dihydro-2H-Piran (0,493 g, 5,86 mmol) was dissolved in tetrahydrofuran (20 ml). Add TFA (3,34 mg, 0,029 mmol) and the resulting solution was heated to 70°C for 16 hours. The reaction mixture was cooled�claim to room temperature, diluted with ethyl acetate, filtered and poured into a separatory funnel containing water and ethyl acetate. The organic layer was concentrated under reduced pressure. As a result of processing using flash chromatography (0-60% ethyl acetate in hexane) to get the desired product in the form of white solids (0.40 g, 1,23 mmol, 42% yield). MS (ESI) m/z 325,1 [M+2]+. Alternative approach: 3-bromo-2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridine (1 equiv.), 3,4-dihydro-2H-Piran (2 equiv.) and methanesulfonic acid (0,08 equiv.) combined in tetrahydrofuran (8× volume). The resulting solution was heated and stirred at 68°C for 3.5 hours, then cooled to room temperature. Add triethylamine (0.4 equiv.), and the resulting solution was concentrated under reduced pressure to oil. The oil was treated with acetonitrile and re-concentrated under reduced pressure to obtain a solid substance. The obtained solid substance was dissolved in acetonitrile and treated with water. The suspension was filtered and the solid part was collected and dried. The crude product is suspended in hexano, filtered and dried, obtaining specified in purified title compound in the form of a solid light pink color.

D. (CIS)-4-methoxycyclohexylaminehydrochloride

In a round bottom flask in an atmosphere of nitrogen, was placed tert-butyl (CIS)-4-hidroxizina�oxycarbonate (7.8 g, Overall, 36.2 mmol) and suspended in anhydrous tetrahydrofuran (181,0 ml) and cooled to 0°C. Then added sodium hydride (2,174 g, 54.3 per mmol) and the resulting solution is kept under stirring for 5 minutes. In the second flask in an atmosphere of nitrogen was placed methyliodide (2,265 ml of 36.2 mmol) and suspended in anhydrous tetrahydrofuran (10.0 ml). Solution methyliodide in tetrahydrofuran is slowly added dropwise to the first flask for 3 minutes. The reaction mixture is left under stirring at room temperature for 16 hours. Organic volatiles removed under reduced pressure and separated between ethyl acetate (3×) and water. The organic fractions were combined, dried over magnesium sulfate, filtered and condensed under reduced pressure. The resulting material is purified using column chromatography on silica gel (25-50% ethyl acetate in hexano). The desired fractions were pooled and the organic volatiles removed under reduced pressure followed by the addition of hydrochloric acid (4M in 1,4-dioxane, 23,5 ml). The resulting solution was heated to 40°C for 1 h. the organic volatiles removed under reduced pressure, obtaining specified in the title compound (6.0 g, of 36.2 mmol, 100% yield). MS (ESI) m/z of 130.1 [M+1]+.

E. 6-bromo-4-((CIS)-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

To a solution of N-(3,5-dibromopyrazine-2-�l)-2-iodoacetamide (see example 5.In) (1.0 g, 2,376 mmol) and diisopropylethylamine (1,038 ml, 5,94 mmol) in acetonitrile (10 ml) was added hydrochlorideCIS-4-methoxycyclohexanone (0,413 g, 2,495 mmol). The resulting solution was stirred at 55°C for 3 hours. The resulting residue was filtered, washed with acetonitrile and dried under reduced pressure, obtaining specified in the header connection (0,442 g, 1,29 mmol, 55% yield). MS (ESI) m/z 341,3 [M]+, 343,3 [M+2]+.

F. 4-((CIS)-4-methoxycyclohexyl)-6-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

6-bromo-4-((CIS)-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0,442 g, 1,295 mmol), tetrakis(triphenylphosphine)palladium (0.225 g, 0,194 mmol) and hexamethyldisilane (0,322 ml 1,554 mmol) are combined in dioxane (5 ml). The resulting solution was purged with nitrogen gas and heated to 90°C in vials with screw cap for 3 hours. The resulting solution was condensed under reduced pressure and purified using column chromatography biotage AB (0-50% ethyl acetate in hexano), receiving specified in the header connection (0,356 g, 0,837 mmol, 65% yield). MS (ESI) m/z 426,5 [M+1]+, 427,5 [M+1]+.

G. 4-((CIS)-4-methoxycyclohexyl)-6-(2-methyl-6-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

4-((CIS)-4-methoxycyclohexyl)-6-(tributylstannyl)-3,4-dihydropyrido[2,3-b]�irisin-2(1H)-he (0,292 g, 0,687 mmol), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine (0,244 g, 0,756 mmol), Tris(dibenzylideneacetone)dipalladium (0,063 g, 0,069 mmol), tri-o-tolylphosphino (0,042 g, 0,137 mmol), triethylamine (0,287 ml 2,061 mmol) and dimethylformamide (5.0 ml) combine in a flask with screw cap and heated to 95°C for 1 hour. The resulting solution was condensed under reduced pressure and purified using chromatography biotage AB (0-80% ethyl acetate in hexano, then 0-10% methanol in ethyl acetate), obtaining specified in the header connection (0,279 g, 0,687 mmol, 80% yield). MS (ESI) m/z 505,6 [M+1]+.

N. 4-((CIS)-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

4-(CIS)-4-methoxycyclohexyl)-6-(2-methyl-6-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0,279 g, 0,553 mmol) was diluted with ethanol (15 ml) and hydrogen chloride (4.0 n in dioxane, 5 ml). The resulting solution was stirred at 75°C for 1 hour and at 80°C for 2 hours. The resulting solution was condensed to suspension and diluted with ethanol and treated with ultrasound. The precipitate was filtered off and washed with additional amount of ethanol and then acetonitrile. The crude solid is purified using semi-preparative HPLC with reversed phase (10-100% acetonitrile + 0,1% TFA in water + TFA 0,1, within 30 minutes), receiving specified in the header connection (0,040 g, 0,095 mmol, 17% yield).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) of 7.88-8,13 (m, 2H), 7,65 (s, 1H), 4,58 (s, 1H), of 4.16 (s, 2H), 3,47 (user.s, 1H), 3,22-of 3.32 (m, 66H), 2,73 (s, 3H), 2,08 (user.s, 2H), 1.91 a (user.s, 2H), 1.56 to (user.s, 4H); MS (ESI) m/z UAH 421,2 [M+1]+; T. square p. 192-195°C.

Example 14: 1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 1-isopropyl-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

7-bromo-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (see example 7.(B) (0.5 g, 1,844 mmol), hexamethyldisilane (0,725 g, 2,213 mmol), tetrakis(triphenylphosphine)palladium(0) (0,213 g, 0,184 mmol) and 1,4-dioxane (3 ml) was combined in a sealed reactor with a magnetic stirrer. Gaseous nitrogen was bubbled through the solution. The reactor is sealed, intensively stirred and heated at 100°C for 2 hours. The obtained turbid black mixture was diluted with ethyl acetate, filtered and the filter cake washed thoroughly with ethyl acetate. The filtrate obtained is concentrated under reduced pressure and purified using column flash chromatography on silica gel (20-80% ethyl acetate in hexano), obtaining the target product (2,410 g, 77% yield) in the form of solids, white and yellow. MS (ESI) m/z 357,4 [M+2]+.

B. 1-isopropyl-7-(2-methyl-6-(4-(tetrahydro-2H-Piran-2-and�)-4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

The flask was placed 3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine (0,446 g of 1.380 mmol), 1-isopropyl-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0,490 g, 1,380 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,139 g, 0,152 mmol), three-o-tolylphosphino (0,092 g, 0,304 mmol), triethylamine (0,577 ml, 4,14 mmol) and N,N-dimethylformamide (3 ml). Gaseous nitrogen was bubbled through the reaction mixture for 5 minutes, and the resulting mixture was heated to 100°C for 1 hour. After cooling to room temperature the reaction mixture was filtered through celite, washed with MeOH and concentrated to dryness. The resulting residue is purified using column flash chromatography on silica gel (0-80% ethyl acetate in hexano, then 0-10% methanol in dichloromethane) to give the desired product (0.40 g, 0,921 mmol, 66.7% of output). MS (ESI) m/z 435,5 [M+1]+.

C. 1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

To a stirred mixture of 1-isopropyl-7-(2-methyl-6-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she (0.400 g, 0,921 mmol) in ethanol (40 ml) at 50°C add hydrogen chloride (4 M in dioxane, 1,381 ml, 5,52 mmol). The resulting mixture was heated at 50°C in a nitrogen atmosphere for 1 hour. The resulting suspension is concentrated under reduced pressure, and the obtained solid substance was immersed�t in dimethyl sulfoxide and purified, using chromatography treatment on silica gel (0-10% saturated ammonia methanol in dichloromethane) to obtain specified in the title compound (0,200 g, 0,571 mmol, 62,0% yield) in the form of a solid brown-red color, which is treated next, using the process of recrystallization.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,10 (user.s, 1H), 8,01 (user.s, 2H), 7,92 (s, 1H), 5,26 (Quint., J=6,93 Hz, 1H), 4,14 (s, 2H), 3,58 (d, J=5.08 mm Hz, 3H), of 1.47 (d, J=6,64 Hz, 6H); MS (ESI) m/z 351,5 [M+1]+.

D. 1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (alternative approach)

7-bromo-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1 equiv.), bis(pinacolato)dibor (1 equiv.), potassium acetate (3 equiv.) and bis(1,1'-bis(diphenylphosphino)ferrocene)palladium (0.01 equiv.) combined in dioxane (1.2 l), Tegaserod using nitrogen and heated to 95°C in a nitrogen atmosphere. Diluted with ethyl acetate, filtered through celite, concentrated, triturated with ethyl acetate and hexane, filtered and dried, obtaining borodaty ether with 60% yield. Tert-butyl 3-(5-bromo-6-methylpyridine-2-yl)-1H-1,2,4-triazole-1-carboxylate (1 equiv.), 1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1.2 equiv.), tetrakis(triphenylphosphine)palladium(0) (0.05 equiv.), sodium carbonate (3 equiv.) combine in a mixture (3:1) of dimethylacetamide and water. The resulting mixture was de�Airout and heated at 100°C overnight. As a result of standard processing of ethyl acetate/water, followed by a thorough rubbing with ethyl acetate to get the desired product in 41% yield.

Example 15: 7-(1H-imidazo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. Ethyl 2-(5-bromo-3-(2-(tetrahydro-2H-Piran-4-yl)ethylamino)pyrazine-2-ylamino)acetate

Ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (see example 6.(B) (1.0 g, 2,95 mmol) and 2-(tetrahydro-2H-Piran-4-yl)ethanamine (0,381 g, 2,95 mmol) was placed in a microwave vial, was added dimethyl sulfoxide (2 ml) and the resulting mixture was heated in a microwave reactor biotage AB Emrys Optimizer at 150°C for 3600 seconds. The crude reaction mixture was purified using chromatography treatment on silica gel (33% ethyl acetate in hexano), receiving specified in the title compound (0.5 g, 1.3 mmol, 44% yield). MS (ESI) m/z 387,1 [M]+, 389,1 [M+2]+.

B. 7-bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

Ethyl 2-(5-bromo-3-(2-(tetrahydro-2H-Piran-4-yl)ethylamino)pyrazine-2-ylamino)acetate (0.5 g, 1,291 mmol) and hydrochloric acid (6 M in water, 0,215 ml 1,291 mmol) are combined in ethanol (2 ml) and the resulting mixture was heated in a microwave reactor biotage AB Emrys Optimizer at 100°C for 2400 sec. The reaction mixture was concentrated and purified using chromatographic treatment�weave on silica gel (33% ethyl acetate in hexano), receiving specified in the title compound (quantitative yield). MS (ESI) m/z 341,1 [M]+, 343,1 [M+2]+.

C. 1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

7-bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0.4 g, 1,29 mmol), hexamethyldisilane (0,57 g, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0,176 mmol) placed in a sealed flask containing 1,4-dioxane (5 ml). The air in the flask was evacuated, purged with nitrogen, sealed and heated at 110°C for 1 hour. The reaction mixture was cooled to room temperature and filtered through celite, washed with ethyl acetate. The filtrate obtained is concentrated and treated with ultrasound with a small amount of a mixed solvent (50% hexane in ethyl acetate) and isolated by filtration, getting mentioned in the title compound (0,34 g, 0.8 mmol, 54.6% of output). MS (ESI) m/z 427 [M+2]+.

D. 7-(1H-imidazo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1.0 g, 2,352 mmol), 5-bromo-1H-imidazo[2,3-b]pyridine (0,556 g, 2.82 mmol), Tris(dibenzylideneacetone)palladium(0) (0,237 g, 0,259 mmol), tri-o-tolylphosphino (0,158 g, 0,518 mmol) and triethylamine (0,984 ml, 7,06 mmol) combined in a sealed tube, add dim�telharmonic (5 ml). The air from the reactor is evacuated and replaced with nitrogen gas. The reaction mixture was heated to 100°C for 1 hour. After cooling to room temperature the reaction mixture was filtered through celite. The filter cake was washed with ethyl acetate. Washing and the filtrate were pooled and concentrated almost to dryness. The obtained solid substance was dissolved in hot methanol, filtered through celite, and purified using preparative HPLC with reversed phase (5-80% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Pure fractions are collected, neutralized with ammonium hydroxide and concentrated to dryness. The obtained solid was filtered, washed with water and dried in a high vacuum, obtaining specified in the title compound (0.10 g, 0,264 mmol, 11.2% of output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,71 (user.s, 1H), 8,81 (s, 1H), 8,44 (s, 1H), of 8.26 (s, 1H), 7,49 (d, J=10,54 Hz, 2H), 6,48 (user.s, 1H), 4,18 (s, 2H), 4,13 (t, J=6,44 Hz, 2H), 3,82 (d, J=12,89 Hz, 2H), 3,27 (t, J=11,13 Hz, 2H), 1,71 (d, J=12,49 Hz, 2H), 1,60 (user.s, 3H), 1,24 (d, 2H); MS (ESI) m/z 379,2 [M+1]+; T a MP 255-258°C.

Example 16: 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 6-bromo-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

N-(3,5-dibromopyrazine-2-yl)-2-iodoacetamide (see example 5.(B) (8.0 g, 19.01 last mmol), (tetrahydro-2H-Piran-4-yl)IU�anamin (2,63 g, 22,81 mmol) and diisopropylethylamine (6,64 ml, 38,0 mmol) is placed in a 250-ml round bottom flask, suspended in acetonitrile (80.0 ml) and heated to 40°C for 16 hours. The obtained white precipitate was filtered, washed with acetonitrile, then hexane, and dried in vacuum, obtaining specified in the header connection (4,89 g, 14,95 mmol, 79% yield). MS (ESI) m/z 327,4 [M]+, 329,5 [M+2]+.

B. 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

6-bromo-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (35,98 g, 110 mmol), 2-(5-(tributylstannyl)pyridin-2-yl)propan-2-ol (see example 5.(E) (33,0 g, 110 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (8,05 g, 11,00 mmol) combined in a sealed tube and suspended in N,N-dimethylformamide (288 ml). Then the reaction mixture was heated to 125°C for 2 hours. The reaction mixture was cooled slightly and transfer, while it is still warm in the column of silica gel and purified using biotage AB SP1 (0-100% (5% methanol in ethyl acetate) in hexano). The desired fractions were pooled and the organic volatiles removed under reduced pressure. The residue is triturated with 20% ethyl acetate in hexano, then repeatedly washed with denatured ethanol. Slightly yellowish solid substance was dried under reduced pressure, poluchatelej connection (15,08 g, A 39.3 mmol, 35.8% of the output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) made 11.32 (s, 1H), 9,07 (d, J=1,56 Hz, 1H), 8,29 (DD, J=8,59, 2,34 Hz, 1H), with 8.05 (s, 1H), 7,72 (d, J=8,20 Hz, 1H), 5,26 (s, 1H), is 4.21 (s, 2H), 3,83 (d, J=2,73 Hz, 2H), 3,51 (d, J=of 7.42 Hz, 2H), 3,27 (t, J=made 11.32 Hz, 2H), 2,09 (user.s, 1H), to 1.61 (d, J=11.3 Hz, 2H), 1,46 (s, 6H), 1,24-1,38 (m, 2H); MS (ESI) m/z 384,2 [M+1]+; T a MP 268-269°C.

Example 17: 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 7-bromo-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

Ethyl 2-(3,5-dibromopyrazine-2-ylamino)acetate (see example 1.C) (1 equiv.), 2-methoxyethylamine (1 equiv.), diisopropylethylamine (3 equiv.) suspended in dimethylsulfoxide and heated in a microwave reactor biotage AB Emrys at 150°C for 1 hour. As a result of standard processing of ethyl acetate/water is raw substance that is suspended in 99.7% acetic acid. The reaction mixture was sealed, heated to 120°C and left under stirring for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic layers are combined and washed with saturated sodium bicarbonate solution, then brine, and dried over magnesium sulfate. As a result of concentration and flash column-chromatography processing (0-100% ethyl acetate in hexano) get the target product with 27% yield over two steps. MS (ESI) m/z 287,4 [M]+, 289,4 [M+2]+.

B. 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

7-bromo-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1 equiv.), 2-(5-(tributylstannyl)pyridin-2-yl)propan-2-ol (see example 5.(E) (1 equiv.) and dichlorobis(triphenylphosphine)palladium(II) (0.2 equiv.) suspended in dimethylformamide. The reaction mixture was purged with nitrogen and heated to 140°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. Volatiles are removed under reduced pressure, and the resulting suspension Magenta purified using column chromatography on silica gel (0-100% (5% methanol in ethyl acetate) in hexano). The desired fractions were combined, and the organic volatiles removed under reduced pressure. Received the solid is triturated with 5% ethyl acetate in hexano and washed with hexane, obtaining the target product with 38% yield.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,02 (d, J=1.6 Hz, 1H), 8,27 (s, 1H), 8,24 (DD, J=8,6, and 2.3 Hz, 1H), 7,71 (d, J=0.8 Hz, 1H), 7,69 (s, 1H), 5.25 in (s, 1H), 4,28 (t, J=6,2 Hz, 2H), 4,20 (d, 2H), 3,60 (t, J=6,2 Hz, 2H), 3,26 (s, 3H), of 1.46 (s, 6H); MS (ESI) m/z 344,3 [M+1]+.

Example 18: 7-(1H-imidazo[2,3-b]pyridin-4-yl)-1-[2-(tetrahydropyran-4-yl)ethyl]-3,4-dihydro-1H-pyrazino[2,3-b]pyrazine-2-he

A. 7-(1H-imidazo[2,3-b]pyridin-4-yl)-1-[2-(tetrahydropyran-4-yl)ethyl]-3,4-dihydro-1H-feast�Xeno[2,3-b]pyrazine-2-he

A mixture of 1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-it (see example 15.C) (1 equiv.), tert-butyl ether 4-Pomerol[2,3-b]pyridine-1-carboxylic acid (1 equiv.), Tris(dibenzylideneacetone)palladium (0,13 equiv.), three-o-tolylphosphino (0.25 equiv.) and triethylamine (2.8 equiv.) in anhydrous dioxane was purged with nitrogen, Tegaserod for 2 minutes and stirred at 95°C in a nitrogen atmosphere for 3-4 hours. After completion of the reaction according to TLC volatiles removed under reduced pressure, and the residue purified using column chromatography, obtaining the target product with 35% yield. MS (ESI) m/z 479,7 [M+1]+. Tert-butyl 4-(7-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-1H-imidazo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. After completion of the reaction according to TLC, the solvent was removed under reduced pressure, and the residue purified on silica gel, receiving specified in the title compound with 63% yield.1H NMR (DMSO-d6, 400 MHz) δ (M. D.) 11,72 (s, 1H), to 8.38 (s, 1H), of 8.25 (d, J=4,8 Hz, 1H), 7,79 (s, 1H), 7,53-7,51 (m, 2H), 6,97 (kV, J=1.6 Hz, 1H), 4,23 (s, 2H), 4,14 (t, J=1.6 Hz, 2H), 3,81 (DD, J1=2.4 Hz, J2=11,2 Hz, 2H), 3,25 (d, J=10,8 Hz, 2H), 1,67 (d, J=13.2 Hz, 2H), 1.61 of (m, 3H), 1,22 (m, 2H); MS (ESI): m/z 379,2 [M+1]+.

Example 19: 1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

A. 1-(2-methoxyethyl)-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

7-bromo-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (Cm. example 17.(A) (0.5 g, 1,741 mmol), 1,1,1,2,2,2-hexamethyldisilane (0,856 g, 2,61 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,201 g, 0.174 were revealed mmol) are combined in 1,4-dioxane (20 ml) and heated at 140°C for 2 hours. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate obtained is concentrated under reduced pressure. As a result of processing using flash chromatography (0-30% ethyl acetate in hexane) to get the target product as a clear oil (0.5 g, of 1.34 mmol, 77% yield). MS (ESI) m/z 373,0 [M+2]+.

B. 1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

1-(2-methoxyethyl)-7-(tributylstannyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (0.5 g, 1,348 mmol), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine (0,436 g, 1,348 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,123 g, is 0.135 mmol), three-o-tolylphosphino (0,082 g, 0,270 mmol), triethylamine (0,584 ml of 4.04 mmol) and N,N-dimethylformamide (10 ml) are combined in a 75 ml sealed flask, the air in the flask is removed and replaced with nitrogen. The resulting mixture was stirred at 130°C for 3 hours. The resulting mixture was cooled to�room temperature and filtered. The organic layer was concentrated under reduced pressure. The obtained residue was diluted with methanol and dimethylsulfoxide, filtered and purified using preparative HPLC with reversed phase (10-30% acetonitrile + 0,1% TFA in water + 0.1% of TFA, over 30 min). Fractions containing pure product is passed through a solid phase extraction column (Phenomenex Strata-X-C. the Column is washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. Product, eluting with 5% ammonium hydroxide in methanol, concentrated under reduced pressure. The residue was triturated with ethyl ether in hexane, obtaining a fine powder which is dried in vacuo at 50°C, yielding the desired product (0.05 g, 0,136 mmol, 10% yield) in the form of a solid substance of white color.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,10 (user.s, 1H), 7,98 (user.s, 1H), 7,94 (s, 1H), 7,73 (user.s, 1H), 4,13-to 4.28 (m, 4H), 3,55 (t, J=6,25 Hz, 2H), 3,24 (s, 3H), 2,70 (user.s, 3H); MS (ESI) m/z 367,2 [M+1]+.

Example 20: 6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she hydrochloride

A. 6-bromo-4-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

To a solution of 2-bromo-N-(3,5-dibromopyrazine-2-yl)acetamide (Cm. example 4.(A) (1 equiv.) and diisopropylethylamine (3 equiv.) in acetonitrile is added canamingadapter (of 1.05 equiv.). The resulting solution was left to warm up �about 70°C for 30 minutes. The resulting solution was condensed under reduced pressure and purified using column chromatography (0-75% ethyl acetate in hexano), receiving specified in the title compound (36% yield. MS (ESI) m/z 257,5 [M]+, 259,4 [M+2]+.

B. 4-ethyl-6-(4-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he

6-bromo-4-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (1.1 equiv.), 4-(tetrahydro-2H-Piran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole (1 equiv.) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethan (0.05 equiv.) combined in 1,4-dioxane followed by the addition of sodium carbonate (3 equiv.) in the water. The resulting solution was heated in a microwave reactor biotage AB Emrys Optimizer to 120°C for 30 minutes. The resulting solution was condensed under reduced pressure and purified using column chromatography (0-10% methanol in ethyl acetate), obtaining specified in the title compound with 45% yield. MS (ESI) m/z 406,6 [M+1]+.

C. 6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she hydrochloride

4-ethyl-6-(4-(4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he in ethanol is treated with 2n hydrogen chloride in dioxane. The resulting solution was stirred at 75°C for 1 hour. The resulting solution is partially condensed and cooled�. To the resulting suspension add cold ethanol, and the obtained residue was filtered and washed with additional amount of cold ethanol, then hexane, receiving specified in the header connection in the form hydrochloride salt in 82% yield.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 9,18 (s, 1H), 8,22 (d, J=8,59 Hz, 2H), 8,04-8,09 (m, 3H), 7,66-7,74 (m, 1H), 7,58-of 7.64 (m, 1H), 4,24 (s, 2H), 3,74 (kV, J=7,03 Hz, 2H), of 1.29 (t, J=of 7.03 Hz, 4H), 0.79 in-0,98 (m, 4H); MS (ESI) m/z over 322.2 [M+1]+.

The SYNTHESIS of the STRUCTURAL ELEMENTS

The following structural elements is received and used in the examples of the preparation provided in the description, or their variants, known to specialists.

Tert-butyl 4-bromo-1H-imidazo[2,3-b]pyridine-1-carboxylate

A. 4-bromo-1H-imidazo[2,3-b]pyridine

The solution triftormetilfullerenov anhydride (9.3 g, 33 mmol) was added, dropwise, to a mixture of 1H-imidazo[2,3-b]pyridine-7-oxide (3 g, 22 mmol) and tetrabutylammonium (10.8 g, 33 mmol) in N,N-dimethylformamide (30 ml) at 0°C. the resulting mixture was stirred at 0°C for 4 hours and at room temperature over night. The reaction mixture was quenched with water and neutralized with 1N sodium hydroxide to pH=7. The resulting mixture was twice extracted with a mixture of methylene chloride and isopropanol (30 ml, Vm:Vp=4:1). The organic layers were combined, dried over anhydrous sodium sulfate, concentrate and purify, IP�alzua preparative HPLC with reversed phase (0-30%: acetonitrile + 0,1% TFA in water + 0.1% of TFA, within 15 minutes), receiving specified in the title compound (1.5 g, 34.3% of output). MS (ESI) m/z 196,8 [M+1]+, 198,8 [M+3]+.

B. Tert-butyl 4-bromo-1H-imidazo[2,3-b]pyridine-1-carboxylate

A mixture of 4-bromo-1H-imidazo[2,3-b]pyridine (250 mg, of 1.26 mmol), di-tert-BUTYLCARBAMATE (302 mg, 1.38 mmol), dimethylpyridin-4-ylamine (7,6 mg, 0,06 mmol) and triethylamine (127 mg, of 1.26 mmol) in anhydrous methylene chloride (15 ml) was stirred at room temperature for 3 hours. After completion of the reaction according to TLC volatiles removed under reduced pressure, and the residue purified using column chromatography on silica gel (9-25% ethyl acetate in petroleum ether) to give the desired product (230 mg, 61% yield) as an oil. MS (ESI) m/z 242,9 [M-56+1]+.

1-(tetrahydro-2H-Piran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol

A. 4-bromo-1H-indazol

To a solution of 3-bromo-2-methylaniline (5 g, 27 mmol) in chloroform (1 ml) was added acetic anhydride (5 g, 27 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. Add potassium acetate (0.75 g, 7.8 mmol) and isoenergetic (0.78 g, 58 mmol) and the reaction mixture brought to reflux for 18 hours. Volatiles are removed under reduced pressure and adding water (0.65 ml). The resulting mixture was concentrated, diluted with concentrated CL�estevadeordal acid (1 ml) and heated at 50°C for 2 hours. After cooling to room temperature, add aqueous solution of sodium hydroxide (50%)) until pH=10. The aqueous mixture was extracted with ethyl acetate (100 ml × 3). The combined organic layers washed with brine (150 ml), dried over anhydrous sodium sulfate, filtered, evaporated and purified using a column with silica gel (3% ethyl acetate in petroleum ether) to give the desired product (2,69 g, 34% yield) as a solid substance. MS (ESI): m/z 197,0 [M+1]+.

B. 4-bromo-1-(tetrahydropyran-2-yl)-1H-indazol

A solution of 4-bromo-1H-indazole (1,82 g, 9,24 mmol), 3,4-dihydro-2H-PYRAN (1.55 g, 18,48 mmol) and toluene-4-sulfonic acid (0.26 g, of 1.39 mmol) in anhydrous tetrahydrofuran (40 ml) was heated at 80°C over night in a nitrogen atmosphere. The solvent was removed under reduced pressure, and the residue is purified using a column with silica gel (3% ethyl acetate in petroleum ether) to obtain specified in the title compound (2.13 g, 81% yield) in the form of a solid yellow color. MS (ESI): m/z 280,9 [M+1]+.

C. 1-(tetrahydropyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazol

Degassed mixture of 4-bromo-1-(tetrahydropyran-2-yl)-1H-indazole (2.13 g, 7,45 mmol), bis(pinacolato)diboron (3,73 g, 14.9 mmol), potassium phosphate (2.70 g, 12,67 mmol), palladium acetate (0.174 were revealed g, 0.75 mmol) and triphenylphosphine (0.59 g, 2,24 mmol) in 1,2-dimethoxyethane (50 ml) was heated at 100°CIN a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered, concentrated under reduced pressure and purified using a column with silica gel (10-30% ethyl acetate in petroleum ether) to obtain specified in the title compound (1,83 g, 74% yield) as a solid substance. MS (ESI): m/z 329,2 [M+1]+.

3-(4-bromo-2-fluoro-3-methylphenyl)-4-(tetrahydro-2H-pyrazine-2-yl)-4H-1,2,4-triazole

A. 4-bromo-3-fluoro-2-methylaniline

To a stirred solution of 3-fluoro-2-methylaniline (25 g, 200 mmol) in acetic acid (140 ml) at 0-5°C is added methyl hydrogen (100 ml, 200 mmol), then slowly added dropwise dimethyl sulfoxide (72 ml) (reaction isothermal, and therefore at a temperature higher than the 5-15°C is formed dibromethane). The resulting mixture was stirred at 5-15°C for 12 hours the mixture became a clear solution). The resulting solution was cooled to 0°C and neutralized with sodium hydroxide, then sodium bicarbonate to pH 7. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. As a result of processing using flash chromatography (0-10% ethyl acetate in hexane) to get the desired product in the form of white solids (23.3 g, 114 mmol, 57% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,11 (t, J=8,20 Hz, 1H), 6.35 mm (d, J=8,98 Hz, 1H), and 3.72 (user.s, 2H), 2,07 (d, J=1.95 G�, 3H).

B. 4-amino-2-fluoro-3-methylbenzonitrile

A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmol) and copper cyanide (20,19 g, 225 mmol) in N,N-dimethylformamide (200 ml) was heated to 140°C for 7 hours. After cooling to room temperature the mixture was filtered and poured into a separatory funnel containing water and ethyl acetate (1:1). The layers were separated, and the organic layer was concentrated under reduced pressure. As a result of processing using flash chromatography (0-50% ethyl acetate in hexane) to get the desired product (11.4 g, 76 mmol, 67% yield) in the form of a solid brown color.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,22 (t, 1H), 6,45 (d, J=8,59 Hz, 1H), 4,23 (user.s, 2H), 2,07 (s, 3H); MS (ESI) m/z 151,1 [M+1]+.

C. 4-bromo-2-fluoro-3-methylbenzonitrile

A mixture of dimethyl sulfoxide (400 ml) and potassium nitrite (one-22.67 g, 266 mmol) was stirred to dissolve the nitrite of potassium, and add 4-amino-2-fluoro-3-methylbenzonitrile (10 g, 66.6 per mmol) and added copper bromide(I) (1,911 g of 13.32 mmol). Added dropwise 48% aqueous solution of methyl hydrogen (33 ml, 266 mmol), diluted with dimethylsulfoxide (200 ml) and the reaction mixture was stirred for 2 hours. After complete conversion of the starting material the reaction mixture was poured into ice water and neutralized to pH 7 with cold concentrated sodium hydroxide. The obtained solid is collected Phil�trevanian, getting the desired product (11.4 g, is 53.3 mmol, 80% yield) in the form of a solid substance of white color.1H NMR (400 MHz, CHLOROFORM-d) δ (MD), 7,47 (d, J=9,37 Hz, 1H), to 7.33 (t, 1H), 2,39 (d, J=2,34 Hz, 3H).

D. 4-bromo-2-fluoro-3-methylbenzamide

4-bromo-2-fluoro-3-methylbenzonitrile (11 g, 51,4 mmol) in 100 ml of a mixture of TFA-sulfuric acid (4:1, about./about.) was stirred at 40°C for 16 hours. After complete conversion of the starting material the reaction mixture was poured into ice water. The resulting solid substance was filtered off, washed with water and dried, obtaining the target product (11,24 g, 48.4 mmol, 94% yield) in the form of white solids. MS (ESI) m/z 234,1 [M+2]+.

E. 3-(4-bromo-2-fluoro-3-methylphenyl)-1H-1,2,4-triazole

4-bromo-2-fluoro-3-methylbenzamide (11 g, for 47.4 mmol) and Ν,Ν-dimethylformamide, dimethylacetal (60 ml) are combined in a 100 ml round-bottom flask with a magnetic stirrer and heated at 55°C at reflux in a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure and dried under vacuum to give a yellow oil, which was used for next step without purification. The residue was diluted with acetic acid (60 ml) at 0°C and added dropwise hydrazinoacetate (20 ml) and left under stirring at room temperature for 5 hours. After complete conversion of the starting materials, the reaction mixture was poured into ice�th water and neutralized to pH 7 with chilled ice concentrated sodium hydroxide. The remaining solid substance is harvested using vacuum filtration. The hard part was dissolved in ethyl acetate (400 ml) and stirred for 15 minutes, filtered nerastvorim the hard part, the filtrate obtained is dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under vacuum to give pure solid brown color (4.3 g, 16,79 mmol, 35% yield), which was used for next step without purification.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,12 (s, 1H), 7,97 (t, J=8,00 Hz, 1H), 7,52 (d, J=8,59 Hz, 1H), 2,44 (d, 3H).

F. 3-(4-bromo-2-fluoro-3-methylphenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole

Methanesulfonic acid (0,090 ml, 1,390 mmol) was added to a stirred solution of 3-(4-bromo-2-fluoro-3-methylphenyl)-1H-1,2,4-triazole (7.0 g, 27.3 mmol) and 3,4-dihydro-2H-PYRAN (12,68 ml, 139 mmol) in tetrahydrofuran (33 ml). The resulting mixture was stirred at 85°C at reflux in a nitrogen atmosphere for 20 hours. The resulting mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified using flash chromatography (20-30-50% ethyl acetate in hexane). The fractions containing the product were pooled, and the solvent removed under reduced pressure, �aluca the desired product (8.8 g, 95% of output) in the form of a solid yellow color. MS (ESI) m/z 340,0 [M]+.

Note: As should be obvious to specialists in this field, protection of, for example, Boc or THP groups, heterocyclic fragments, which may be the tautomers, for example, triazolyl fragments can potentially lead to the formation of various regioisomers secure connections, which are not easy to describe or to distinguish using standard analytical methods, such as1H-NMR. Such regioisomer in the description is called specific in accordance with the chemical name of only one of regioisomers, however, it should be understood that this term refers to any of all possible regioisomers and their mixtures, which potentially can be formed in the reaction. The only definition of regioisomer, therefore, also applicable to the names of subsequent products formed in the reaction with the protected intermediate compounds. As should be clear to experts in this field, after removal of the protective group formed only one product, regardless of the original regioisomer a secure connection.

3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine

A. 3-bromo-6-iodo-2-methylpyridine

Of sodium iodide (2 equiv.) and 3,6-d�bromo-2-methylpyridine (1 equiv.) unite in propionitrile, and the resulting suspension was stirred in a nitrogen atmosphere for 5 minutes. Add attributively (0.2 equiv.), and the reaction mixture heated at 95°C, under stirring in a nitrogen atmosphere for 24 hours. The resulting suspension was cooled to room temperature, diluted with 1:1 mixture of ethyl acetate and water. The resulting mixture was stirred for 15 minutes, and the aqueous and organic phases separated. The organic layer was washed successively with equal volumes of saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5% aqueous solution), and a saturated aqueous solution of sodium chloride. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, obtaining the target product with 95% yield, as an oil, which crystallized to a solid substance not quite white. MS (ESI) m/z 297,8 [M]+, 299,8 [M+2]+.

B. 5-bromo-6-methilpiralidone

In an inert atmosphere, 3-bromo-6-iodo-2-methylpyridine (1 equiv.) and pooled and the acetonitrile was stirred for 10 minutes, add copper cyanide (0.5 equiv.), sodium cyanide (0.8 equiv.) and acetonitrile. The reaction suspension was heated with stirring at 80°C for 24 hours. The reaction solution was cooled to room temperature and diluted with ammonium hydroxide (0.5 M aqueous solution). The resulting mixture was stirred 1530 minutes filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The obtained filtrate and washings were pooled, then diluted with ethyl acetate and the resulting solution was stirred for 15 minutes. The aqueous and organic phases separated, and the organic layer was washed successively with ammonium hydroxide (0.5 M aqueous solution; four times) and saturated aqueous sodium chloride solution (twice), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, obtaining 5-bromo-6-methilpiralidone with 92% yield, in the form of solid substances not quite white. MS (ESI) m/z 196,9 [M]+, 198,9 [M+2]+.

C. 5-bromo-6-methylpyrimidine

Hydrazinoacetate (2 equiv.) add 1.2 M to a stirred suspension of 5-bromo-6-methylpyrimidine (1 equiv.) in ethanol in a nitrogen atmosphere. The reaction mixture was heated at 50°C for 24 hours. The reaction mixture was cooled to room temperature and then filtered. The collected solid washed with cold ethanol, then with cold tert-butyl methyl ether. The washed solid is dried in vacuum, obtaining specified in the title compound with 89% yield in the form of a solid yellow color. MS (ESI) m/z at 228.9 [M]+That 230,9 [M+2]+.

D. 3-bromo-2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridine

5-bromo-6-methylpyrimidine ( equiv.) and formic acid (15 equiv.) combined and heated with stirring at 100°C for 6 hours. The reaction mixture was cooled to room temperature and diluted with methanol. The resulting suspension was stirred for 30 minutes and then partially concentrated under reduced pressure to ~20% of full volume. The resulting mixture was again diluted with methanol and partially concentrated under reduced pressure to ~20% of full volume. The remaining solid is collected by filtration, washed with water three times and dried under reduced pressure, obtaining the desired product in 84% yield, in the form of solid substances not quite white. MS (ESI) m/z 238,9 [M]+, 240,9 [M+2]+.

E. 3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine

3-bromo-2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridine (1 equiv.), 3,4-dihydro-2H-Piran (2 equiv.) and methanesulfonic acid (0.1 equiv.) combined in tetrahydrofuran, while stirring in a nitrogen atmosphere. The reaction mixture was heated to 68°C for 3.5 hours. After cooling to room temperature over 1 hour is added triethylamine (0.4 equiv.), and the resulting solution was stirred for 10 minutes, and then concentrated under reduced pressure. Add acetonitrile and the excess tetrahydrofuran was removed by the joint distillation under reduced pressure while warming to 35°C (twice). The obtained residue was dissolved in acetonitrile (1 volume) and add water (2.25). The resulting suspension is re�eshivot 30 minutes. The solid part was collected by filtration, washed with 20% solution of acetonitrile in water and dried under reduced pressure. The crude product is triturated with hexane, filtered, then washed with hexane and dried in a vacuum thermostat at 35°C, obtaining the target product with 80% yield in the form of solid substances not quite white. MS (ESI) m/z 324,9 [M+2]+.

3-(4-bromo-2-fluorophenyl)-4H-1,2,4-triazole

A. 4-bromo-2-perbenzoic

A solution of 4-bromo-2-perbenzoate (10.0 g, 50,0 mmol) in 70 ml of a mixture of TFA (56,0 ml, 727 mmol) and sulfuric acid (14,0 ml, 263 mmol) (4:1 vol./about.) was stirred at 40°C for 16 hours. The reaction mixture while it is still warm, poured into ice water. The product precipitates, and the resulting solid was filtered and dried, yielding 4-bromo-2-fermentated (9,53 g, 43,7 mmol, 87% yield) in the form of white solids. MS (ESI) m/z 218,1 [M]+, 220,1 [M+2]+.

B. 3-(4-bromo-2-fluorophenyl)-4H-1,2,4-triazole

4-bromo-2-fermentated (9,53 g, 43,7 mmol) and Ν,Ν-dimethylformamide, dimethylacetal (75,0 ml) are combined in a 500-ml round-bottom flask and purged with nitrogen. The reaction mixture is heated at reflux at 85°C for 2 hours. The resulting mixture was concentrated under reduced pressure and dried under vacuum to give a yellow oil. The oil is suspended in concentrated acetic� acid (75,0 ml) and cooled to 0°C. Added dropwise hydrazine hydrate (21,88 g, 437 mmol) and the resulting mixture is left under stirring at room temperature for 5 hours. The reaction mixture was warm poured over ice and extracted with dichloromethane (3×200 ml). Organic volatiles removed under reduced pressure, obtaining 3-(4-bromo-2-fluorophenyl)-4H-1,2,4-triazole (7,20 g, 29.7 mmol, 68.1% of output) in the form of white solids. MS (ESI) m/z 241,9 [M]+That 243,9 [M+2]+.

2-(4-methyl-5-(tributylstannyl)pyridin-2-yl)propan-2-ol

A. 2-(5-bromo-4-methylpyridine-2-yl)propan-2-ol

2,5-dibrom-4-methylpyridine (4.0 g, 15,94 mmol) was dissolved in toluene (60,0 ml) and the reaction mixture was cooled to -78°C. was added, dropwise butyllithium (7.01 ml, 17,54 mmol) and the reaction mixture is left under stirring for 30 minutes. Then added acetone (4,69 ml of 63.8 mmol) and the reaction mixture is allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with a saturated solution of chloride, extracted with ethyl acetate (3×200 ml) and washed first with water, then brine. The organic portion was dried over magnesium sulfate and volatiles removed under reduced pressure. The compound is purified using chromatography treatment on silica gel (0-50% ethyl acetate in hexano), getting 2-(5-bromo-4-methylpyridine-2-yl)propan-2-ol (2.33 g, 1,13 mmol, 63.5% yield). MS (ESI) m/z 230,3 [M]+, Of 232.3 [M+2]+.

B. 2-(4-methyl-5-(tributylstannyl)pyridin-2-yl)propan-2-ol

2-(5-bromo-4-methylpyridine-2-yl)propan-2-ol (2.33 g, 10,13 mmol) and tetrakis(triphenylphosphine)palladium(0) (1,045 g, 1,013 mmol) is placed in a tubular reactor operating under pressure, and suspended in 1,4-dioxane (33,8 oz). Then add 1,1,1,2,2,2-hexamethyldisilane (2,99 ml, 12,15 mmol) and heated to 150°C for 30 min. the Reaction mixture is allowed to cool to room temperature, filtered through celite and washed with ethyl acetate. Organic volatiles removed under reduced pressure, followed by extraction with ethyl acetate (3×200 ml) and water. Organic volatiles removed under reduced pressure, and the compound is purified using column chromatography on silica gel column (biotage AB (10-50% ethyl acetate in hexano)) to obtain 2-(4-methyl-5-(tributylstannyl)pyridin-2-yl)propan-2-ol (1.75 g, to 5.57 mmol, 55.0% of the output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,31 (s, 1H), 7,51 (s, 1H), (user.s, 1H), is 2.37 (s, 3H), of 1.41 (s, 6H), of 0.65 (user.s, 3H), 0,34 (s, 6H).

Tert-butyl 3-(5-bromo-6-methylpyridine-2-yl)-1H-1,2,4-triazole-1-carboxylate

A. 5-bromo-6-methilpiralidone

A 1-liter three-neck flask equipped with a mechanical stirrer and input for nitrogen load 3,6-dibrom-2-methylpyridine (150 g, of 0.59 mol), copper cyanide (I) (42,8 g, 0.47 mole) and CYANOGEN�d of sodium (23 g, 0.47 mole). To this mixture was added N,N-dimethylformamide (300 ml). The resulting mixture was heated to 95°C and stirred for 48 hours. The reaction mixture was cooled to ambient temperature and poured into ethanol (3 l) with stirring. The resulting mixture was filtered through a layer of celite, the filtrate obtained is concentrated under reduced pressure and separated between water (3 l) and ethyl acetate (3 l). The organic layer was isolated and washed with brine (2×600 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified using a plug of silica gel (0-5% ethyl acetate in hexano), obtaining the product (61,5 g, 45% yield) in the form of white solids. In addition, isolated 19.32 g (14%) of a mixture of starting material and product. Alternative approach: 3,6-dibrom-2-methylpyridine (1 equiv.) and sodium iodide (2 equiv.), unite in propionitrile (15×). The resulting mixture was stirred and added attributively (0.2 equiv). The reaction mixture was heated and stirred at 95°C for 24 hours, cooled to room temperature and diluted with ethyl acetate and water. The organic phase was washed with aqueous sodium bicarbonate solution, an aqueous solution of sodium thiosulfate and an aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure, dobavljac residue ethyl acetate. The resulting product is cured in a vacuum that leads to 3-bromo-6-iodo-2-methylpyridine in the form of solid substances not quite white. 3-bromo-6-iodo-2-methylpyridine (1 equiv.) in acetonitrile (7 × vol.) treated with copper cyanide (0.5 equiv.), the sodium cyanide (0.8 equiv.) and an additional amount of acetonitrile (3 × vol.). The reaction suspension was heated at 80°C for 24 hours. The reaction mixture was cooled to room temperature, treated with an aqueous ammonium hydroxide solution (1.2 equiv.) and filtered through celite. The filtrate obtained was diluted with ethyl acetate and the phases separated. The organic layer was washed with an aqueous solution of ammonium hydroxide and an aqueous solution of sodium chloride, dried over sodium sulfate and filtered. The filtrate obtained is concentrated under reduced pressure, obtaining specified in the title compound in the form of solid substances not quite white.

B. 5-bromo-6-methylpyrrolidinone

In a 500-ml three-neck round bottom flask is loaded 5-bromo-6-methilpiralidone (101,5 g, 0,515 mol), ethanol (122 ml) and hydrazine hydrate (50 ml, 1.03 mole). Received a very thick mixture is left under stirring at room temperature for 24 hours. Add ethanol (50 ml) and the resulting mixture is left under stirring in the course of the weekend. The resulting mixture was filtered and washed with cold�Western ethanol (100 ml) and cold hexane (50 ml). The hard part is dried in a vacuum thermostat, receiving the product (110 g, 93% yield) in the form of solid substances not quite white.

C. 3-bromo-2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridine

500-ml three-neck round bottom flask supplied with a mechanical stirrer, thermocouple connected to a temperature controller J-KEM, and reflux. The flask was loaded with 5-bromo-6-methylpyrrolidinone (100 g, 0,463 mol) and formic acid (250 ml). The resulting solution was heated to 100°C and stirred for 48 hours. Formic acid was removed under reduced pressure, and the resulting suspension was treated with water (1.5 l) with vigorous stirring. The resulting mixture was filtered and washed with water (300 ml). The hard part is transferred to a round bottom flask and treated with water (1 l) and 1 M sodium hydroxide solution to pH 7. The resulting mixture is left under stirring for 30 minutes, filtered, washed with water (300 ml) and dried in a vacuum thermostat at 30-35°C within 48 hours of receiving the product (96 g, 92% yield) in the form of a solid substance of white color.

D. 3-bromo-2-methyl-6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine

To a suspension of 3-bromo-2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridine (96,0 g, 0.4 mol) in tetrahydrofuran (780 ml) was added 3,4-dihydro-2H-Piran (72,5 ml, 0.8 mole) and methanesulfonic acid (3.2 ml). The resulting mixture was heated to 65°C, and rece�th yellow solution left under stirring at 65°C for 6 hours. The resulting mixture was cooled to room temperature, quenched with triethylamine (23 ml), concentrated under reduced pressure and then dried in high vacuum for 1 hour. The resulting oil was dissolved in acetonitrile (250 ml) and the resulting solution was added to water (750 ml) with vigorous stirring. Add acetonitrile (80 ml) and the resulting mixture is left with stirring for 1 hour. The remaining solid was filtered, washed with a mixture 1:4 acetonitrile/water (800 ml) and dried in a vacuum thermostat within 48 hours of receiving the product (110 g, 85% yield) in the form of white solids. The resulting product is then purified using a plug of silica gel (1:1 hexane/ethyl acetate) to obtain 88 g of pure product in the form of white solids and 16.2 g of less pure product. MS (ESI) m/z 239,1 [M]+, 241,1 [M+2]+.

E. Tert-butyl 3-(5-bromo-6-methylpyridine-2-yl)-1H-1,2,4-triazole-1-carboxylate

To a mixture of 3-bromo-2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridine (300 g, 1.25 mole) in dioxane (4 l) was added sodium carbonate (398 g, 3.75 mol), was then added water (4 l). Add di-tert-BUTYLCARBAMATE (274 g, 1.25 mole), and the resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was then diluted with cold water (~10 l) and extracted with ethyl acetate (4 l × 3). United ethylacetate layers washed with brine�m, dried over sodium sulfate, filtered and concentrated, obtaining the product (254 g, 60% yield) as solid slightly yellow color.

4-(tetrahydro-2H-Piran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole

A. Ethyl 4-bromobenzimidazole

A solution of 4-bromobenzonitrile (17,65 g, 97 mmol) in ethanol (500 ml) was acidified with gaseous hydrogen chloride at 0°C for fifteen minutes. The resulting solution is kept under stirring for 16 hours. The resulting solution was condensed under reduced pressure, obtaining specified in the header connection (25,35 g, 99%). MS (ESI) m/z 228,1 [M]+, 230,4 [M+2]+.

B. 3-(4-bromophenyl)-4H-1,2,4-triazole

Ethyl 4-bromobenzimidazole (35,6 g, 135 mmol), formic acid hydrazide (16,16 g, 269 mmol) and triethylamine (75 ml, 538 mmol) combined in a flask with screw cap and heated to 85°C for 16 hours. The resulting solution was condensed under reduced pressure, obtaining a solid substance, which is divided between water and ethyl acetate (3×), dried over magnesium sulfate and the solvent removed under reduced pressure. The obtained solid is treated with ultrasound with 20% ethyl acetate in hexano, filtered and dried, obtaining specified in the title compound (14.6 g, for 65.2 mmol, 48% yield). MS (ESI) m/z 224,1 [M]+, 226,1 [+2] +.

C. 3-(4-bromophenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole

A solution of 3-(4-bromophenyl)-4H-1,2,4-triazole (14.1 g, to 62.9 mmol), 3,4-dihydro-2H-PYRAN (10,59 mmol) and methanesulfonic acid (1.19 g, 6,29 mmol) in tetrahydrofuran (150 ml) heated at 75°C for 2 hours. The resulting solution is condensed and divided between sodium bicarbonate solution and ethyl acetate (3×), the organic portion dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. Received the solid is triturated with 10% ethyl acetate in hexano, receiving specified in the title compound (8.1 g, to 26.3 mmol, 70% yield). MS (ESI) m/z 308,4 [M]+, 310.5 to [M+2]+.

D. 4-(tetrahydro-2H-Piran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole

3-(4-bromophenyl)-4-(tetrahydro-2H-Piran-2-yl)-4H-1,2,4-triazole (8.1 g, to 26.3 mmol), bis(pinacolato)diboron (6,67 g, 26,3 mmol) and potassium acetate (of 10.32 g, 105 mmol) are combined in dimethylformamide (100 ml). The resulting solution was purged with nitrogen gas for 2 minutes. Then add dichloromethane dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (1,07 g, 1,31 mmol) and the resulting solution was heated to 100°C for 16 hours. The resulting solution was filtered through celite, and the obtained filtrate was condensed under reduced pressure, yielding a dark oil. The oil is purified using chromatography biotage AB (0-70%ethyl acetate in hexano), getting after drying the solids. The obtained solid was diluted with hexane, treated with ultrasound, filtered and dried, obtaining specified in the title compound (7.1 g, 20.0 mmol, 71% yield). MS (ESI) m/z 356,5 [M+1]+.

5-bromo-2-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine

A. (E)-5-bromo-N-((dimethylamino)methylene)picolinate

A solution of 5-bromopicolinic (0.500 g, 2.49 mmol) and dimethylformamide of dimethylacetal (20 ml) was heated at 85°C for 3 hours. The reaction mixture was concentrated, and the product was used directly in the next stage (0,604 g, 95% yield). MS (ESI) m/z 257,1 [M+1]+.

B. 5-bromo-2-(1H-1,2,4-triazole-3-yl)pyridine

A solution of (E)-5-bromo-N-((dimethylamino)methylene)picolinate (0,604 mg, 2.36 mmol) and hydrazine (2,12 g, 66.1 per mmol) was stirred at 25°C for 3 hours. The reaction mixture was concentrated and diluted with water. The resulting residue is collected by filtration and dried in vacuum, obtaining specified in the header connection (0,442 g, 83% yield). MS (ESI) m/z 226,1 [M+1]+.

C. 5-bromo-2-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine

A solution of 5-bromo-2-(1H-1,2,4-triazole-3-yl)pyridine (0,342 mg, of 1.52 mmol), 3,4-dihydro-2H-PYRAN (0,256 g, of 3.04 mmol) and 4-methylbenzenesulfonic acid (0,058 g, 0.30 mmol) in tetrahydrofuran was heated at 75°C for 6 hours. The reaction mixture of concentri�comfort and clean, using column chromatography biotage AB (0-20% methanol in dichloromethane) to give a semi-pure product as an oil (0,614 g, 1.9 mmol, >100% yield). The resulting material was used without further purification. MS (ESI) m/z 309,4 [M]+, 311,1 [M+2]+.

Tert-butyl 6-bromo-4-methyl-2-(methylamino)-1H-benzo[d]imidazole-1-carboxylate

A. (6-bromo-4-methylbenzimidazole-2-yl)-N-methylamine

Isothiocyanates (0.055 g, 0,746 mmol) in N,N-dimethylformamide (1.0 ml) dropwise slowly added to a stirred solution of 5-bromo-3-methylbenzol-1,2-diamine (0,150 g, 0,746 mmol) in N,N-dimethylformamide (1.5 ml) at 0°C. the Cooling bath removed, the reaction mixture was sealed and stirred at room temperature for 48 hours. Add the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0,157 g, 0,821 mmol) and the reaction mixture was sealed and heated at 40°C over night. The resulting mixture was diluted with MeOH, filtered and purified using preparative HPLC with reversed phase (10-50% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Fractions containing the product were pooled, and most of the solvent was removed under reduced pressure. Add acetonitrile and the resulting mixture is introduced into the ion exchange column Strata. The column is washed successively with water, acetonitrile, methanol and 5% hydro�sid ammonium in methanol. Product, eluting with 5% ammonium hydroxide in methanol, concentrated under reduced pressure and dried in high vacuum to give the desired product (of 0.128 g, 0.53 mmol, 72% yield) as a slightly yellow waxy solids. MS (ESI) m/z 240 [M]+, 242 [M+2]+.

B. Tert-butyl 6-bromo-4-methyl-2-(methylamino)-1H-benzo[d]imidazole-1-carboxylate

(6-bromo-4-methylbenzimidazole-2-yl)-N-methylamine (of 0.128 g, of 0.533 mmol), diisopropylethylamine (0,464 ml of 2.67 mmol), di-tert-BUTYLCARBAMATE (0,349 g, 1,599 mmol) and N,N-dimethylformamide (5 ml) are combined in a 100-ml round-bottomed flask, sealed and stirred at room temperature for 21 hours. The resulting mixture was separated between water and ethyl acetate. The layers were separated, and the organic portion was washed with water and brine. The organic portion was dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified using flash chromatography (10-30% ethyl acetate in hexano), obtaining the target product (0,092 g, 0.27 mmol, 51% yield) as a yellow waxy solid. MS (ESI) m/z 340 [M]+, 342 [M+2]+.

7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-amine

A. 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-amine

3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-�Jamin (Cm. example 1.(G) (500 mg, 2,015 mmol) and ciambrone (0,484 ml, is 2.418 mmol) was added in a round bottom flask at room temperature, suspended in methanol (10.0 ml) and left under stirring for 1.5 hours. Volatiles are removed under reduced pressure followed by the addition of saturated solution of sodium bicarbonate. The precipitate is collected by filtration, washed with ethyl acetate and dried under reduced pressure, obtaining specified in the title compound (557 mg, 2,039 mmol, quantitative yield). The connection is then used without further purification or characterization. MS (ESI) m/z 273,8 [M+1]+.

4-methyl-1-(tetrahydro-2H-Piran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole

A. 6-bromo-4-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-benzo[d]imidazole

6-bromo-4-methyl-1H-benzo[d]imidazole (1.02 g, a 4.83 mmol) was dissolved in tetrahydrofuran (10 ml) at room temperature under stirring in a nitrogen atmosphere. Add 3,4-dihydro-2H-PYRAN (3.5 ml, 38.4 mmol) and methanesulfonic acid (to 0.032 ml, 0.48 mmol) and the resulting mixture was heated at 75°C for 49 hours. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The organic portion was dried over magnesium sulfate, filtered and concentrated at lower�nom pressure. As a result of processing using flash chromatography (50-100% ethyl acetate in hexano) get the target product (1,32 g, 4,47 mmol, 93% yield) in the form of solid light yellow color. MS (ESI) m/z 295,1 [M]+, 297,3 [M+2]+.

B. 4-methyl-1-(tetrahydro-2H-Piran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole

6-bromo-4-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-benzo[d]imidazole (1,320 g, 4,47 mmol), bis(pinacolato)diboron (1,192 g, 4,70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (183 mg, 0,22 mmol), potassium acetate (1,317 g, 13.4 mmol) and dimethyl sulfoxide (9 ml) combine in a round bottom flask and stirred. The air in the flask was removed under vacuum and replaced with nitrogen three times. The resulting mixture was heated at 90°C in a nitrogen atmosphere for 1.5 hours. The resulting mixture was diluted with ethyl acetate and filtered through celite. The filter cake washed thoroughly with ethyl acetate. The resulting filtrate is washed twice with water, once with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. As a result of processing using flash chromatography (50-100% ethyl acetate in hexano) get the target product ~90% purity (1.31 g, 3,83 mmol, 77% yield) as a foamy solid yellow-brown color. MS (ESI) m/z 343,2 [M+1]+.

5.2 BIOLOGICAL EXAMPLES

TOR HTR-FRET analysis. The following is an example of analysis that can be used to determine the inhibiting activity of the tested compounds against TOR kinase. Inhibitors TOR kinase is dissolved in DMSO and prepared as a 10 mm initial solutions and diluted as appropriate for experiments. The reagents are prepared as follows:

"Simple TOR buffer" (used for dilution TOR fractions with a high content of glycerin): 10 mm Tris, pH of 7.4, 100 mm NaCl, 0,1% Tween-20, 1 mm DTT. Recombinant TOR enzyme (Invitrogen cat. No. PV4753) was diluted in the buffer up to the specified analytical 0,200 concentrations in μg/ml.

ATP/substrate solution: 0.075 mm ATP, 12.5 mm MnCl2, 50 mm Hepes, pH of 7.4, 50 mm β-GOP 250 nm microCISTina LR, 0.25 mm EDTA, 5 mm DTT and 3.5 μg/ml GST-p70S6.

The detecting reagent solution: 50 mm HEPES, pH of 7.4, with 0.01% Triton X-100, 0,01% BSA, 0.1 mm EDTA, to 12.7 μg/ml Cy5-αGST (Amersham cat. no. PA92002V), 9 ng/ml α-phospho p70S6 (Thr389) (mouse monoclonal cell signaling No. 9206L), 627 ng/ml α-mouse Lance Eu (Perkin Elmer cat. no. AD0077).

To 20 μl simple TOR buffer add 0.5 µl of the tested compounds in DMSO. To initiate the reaction, add 5 ál of ATP/substrate solution to 20 ál simple TOR buffer solution (control) and to a previously prepared solution of compound. The analysis is stopped after 60 minutes by adding 5 μl of 60 mm EDTA solution; then add 10 ál detectbrowser� reagent solution, and the resulting mixture is left to rest for at least 2 hours before testimony can be read using the reader for microplates Perkin-Elmer Envision Microplate Reader that is configured to detect LANCE Eu TR-FRET (excitation at 320 nm and emission at 495/520 nm).

5.3 ACTIVITY of HETEROARYL COMPOUNDS

Heteroaryl compounds, as disclosed in the description, test using TOR HTR-FRET analysis, and detect the presence of activity in the above analysis, where all connections demonstrate the value of IC50below 10 μm in the analysis, some compounds, the values of IC50are between of 0.005 nm and 250 nm, others value IC50are between 250 nm and 500 nm, others value IC50are between 500 nm and 1 μm, and the value of IC50are between 1 micron and 10 microns. The values of IC50for compounds of formula (I) and (II) can be found in the patent application U.S. No. 12/605791, filed October 26, 2009 (see table 1 on pages 141-187), which is included in the description by reference in its entirety.

Disclosed in the description of the options should not be considered as limiting the scope of the invention to the specific embodiments presented in the examples are intended to illustrate some aspects of the disclosed variants, and any options that they are functionally equivalent, included in the invent�tion. Indeed, various modifications of the disclosed in the description of the options, in addition to what is presented and disclosed in the description, will be obvious to specialists in this field, and they also fall in the scope of the attached claims.

Presents a number of references cited, the disclosure of which is included in the description by reference in their entirety.

1. The method of obtaining compounds of formula (I)

comprising the implementation of contacting the compound of formula (III)

with R1-Y in a solvent in the presence of dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) or dichlorobis(p-p dimethylaminophenyl(tert-butyl)phosphine)palladium(II), where:
X represents a halogen, B(OH)2B(-OC(CH3)2C(CH3)2O-), Sn(CH3)3or Sn(n-C4H9)3;
Y represents halogen, triflic, B(OH)2B(-OC(CH3)2C(CH3)2O-), Sn(CH3)3or Sn(n-C4H9)3; where
(a) if X represents a halogen, then Y is B(OH)2B(-OC(CH3)2C(CH3)2O-), Sn(CH3)3or Sn(n-C4H9)3; or
(b) if Y represents a halogen or triflic, then X is a B(OH)2B(-OC(CH3)2C(CH3)2O-), Sn(CH3)3or Sn(n-C H9)3; and where the
R1selected from the group consisting of 1H-imidazo[4,5-b]pyridin-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-imidazo[2,3-b]pyridin-3-yl, 1H-imidazo[2,3-b]pyridin-5-yl, 2-amino-7-methyl-1H-benzo[d]imidazol-5-yl, 2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl, 2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl, 2-methyl-6-cyanopyridine-3-yl, 3-(1H-1,2,4-triazole-5-yl)phenyl, 3-aminocarbonylmethyl, 3-cyanophenyl, 3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl, 3-fluoro-2-methyl-4-(4H-1,2,4-triazole-3-yl) phenyl, 3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl, 4-(1H-1,2,4-triazole-5-yl)phenyl, 4-(2-hydroxypropan-2-yl)phenyl, 4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl, 4-(4H-1,2,4-triazole-3-yl) phenyl, 4-aminocarbonylmethyl, 4-methyl-1H-benzo[d]imidazol-6-yl, 4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl, 4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl, 4-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl, 4-methyl-6-aminocarbonylmethyl-3-yl, 5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl, 6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl, 6-(1-hydroxyethyl)pyridin-3-yl, 6-(1-hydroxy-isopropyl)-3-pyridyl, 6-(2-hydroxypropan-2-yl)-4-methylpyridine-3-yl, 6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-yl, 6-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-(4H-1,2,4-triazole-3-yl)-2-methyl-3-pyridyl, 6-(4H-1,2,4-triazole-3-yl) -3-pyridyl, 6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl, benzo[d]imidazolyl, indazole, phenyl and pyridinyl;
R2selected from the group consisting of H, ((1R,3R)-3-methods�bicyclopentyl)bromide, ((1R,3S)-3-methoxycyclohexyl)methyl, ((1S,3R)-3-methoxycyclohexyl)methyl, ((1S,3S)-3-methoxycyclohexyl)methyl, (1R,3R)-3-methoxycyclohexyl, (1R,3S)-3-methoxycyclohexyl, (1S, 3R)-3-methoxycyclohexyl, (1S,3S)-3-methoxycyclohexyl, (CIS-4-hydroxycyclohexyl)methyl, (CIS-4-methoxycyclohexyl)bromide, (tetrahydro-2H-Piran-4-yl)methyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, (TRANS-4-hydroxycyclohexyl)methyl, (TRANS-4-methoxycyclohexyl)methyl, 2-(tetrahydro-2H-Piran-3-yl)ethyl, 2-(tetrahydro-2H-Piran-4-yl)ethyl, 2-methoxyacetyl, 2-methoxyethyl, 2-morpholinoethyl, 3-(trifluoromethyl)benzyl, 3-methoxypropyl, acetyl, benzyl, CIS-4-hydroxycyclohexyl, CIS-4-methoxycyclohexyl, cyclohexyl, cyclohexylmethyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, ethyl, furanyl, isobutyl, isopropyl, methoxy, methyl, neopentyl, Venetia, phenyl, piperidine-4-silt, piperidinyl, propyl, pyranyl, tetrahydro-2H-Piran-4-yl, tetrahydrofuran-3-yl, TRANS-4-hydroxycyclohexyl and TRANS-4-methoxycyclohexyl;
R3and R4each independently represent H or methyl, or R3and R4together with the atom to which they are attached, form a cyclopropane, CYCLOBUTANE or cyclopentane;
where the solvent is a dimethyl formamide, isopropanol, dioxane, toluene, dimethylacetamide, tetrahydrofuran, Il� combinations thereof, in the presence or in the absence of water;
if X or Y represents B(OH)2or B(-OC(CH3)2C(CH3)2O), the said contacting occurs in the presence of sodium carbonate;
if X or Y are Sn(CH3)3or Sn(n-C4H9)3specified contacting optionally occurs in the presence of triethylamine.

2. A method according to claim 1, where if X or Y are halogen, then the halogen is Br.

3. A method according to claim 1, wherein the palladium catalyst is a dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II).

4. A method according to claim 1, wherein the palladium catalyst is dichlorobis(p-p dimethylaminophenyl(tert-butyl)phosphine)palladium(II).

5. A method according to claim 1, further comprising obtaining a compound of formula (III)

where the specified method comprising contacting the compound of formula (IV)

with R2-NH2in acetonitrile or tetrahydrofuran in the presence of triethylamine or Diisopropylamine, where X is a halogen, R3and R4represent H, Hal represents halogen, and Hal2represents Br or I.

6. A method according to claim 5, where X is a halogen, and the halogen is Br.

7. A method according to claim 5, where Hal represents Soboh� Br.

8. A method according to claim 1, further comprising obtaining a compound of formula (III),

where the specified method comprises cyclization of a compound of formula (V)

in acetonitrile in the presence of a palladium catalyst, ligand and sodium bicarbonate, where the said cyclization occurs under conditions suitable to produce compound of formula (III), where X is a halogen; and Hal represents a halogen.

9. A method according to claim 8, wherein X is a halogen, and the halogen is Br.

10. A method according to claim 8, wherein the palladium catalyst is a palladium acetate(II).

11. A method according to claim 8, wherein the ligand is a 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

12. A method according to claim 8, wherein Hal is Br.

13. A method according to claim 1, wherein the compound of formula (I) is a
6-(1H-imidazo[2,3-b]pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((Tran�-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-((TRANS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((TRANS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((CIS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-[TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-((CIS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(CIS-4-hydroxycyclohexyl�yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-ethyl-6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(2-methoxyethyl)-6-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(3-(1H-1,2,4-triazole-5-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
5-(8-(2-methoxyethyl)-6-OK�about-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;
3-(6-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzamide;
3-(6-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzonitrile;
5-(8-(TRANS-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;
6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(1H-indazol-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-((1R,3S)-3-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-((1S,3R)-3-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-((1R,3R)-3-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-((1S,3S)-3-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-ethyl-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(1H-imidazo[2,3-b]pyridin-5-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(1H-indol-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(1H-indol-5-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(((1R,3S)-3-methoxycyclohexyl)methyl)-6-(2-methyl-6-(4H-1,2,4 triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(((1S,3R)-3-methoxycyclohexyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3,3-dimethyl-6-(4-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1R,3S)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((IS,3R)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1S,3S)-3-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3R)-3-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3S)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1R,3R)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3S)-3-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1S,3R)-3-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(3-f�or-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'-((tetrahydro-2H-Piran-4-yl)methyl)-1'H-Spiro[cyclopentane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-he;
7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'-((tetrahydro-2H-Piran-4-yl)methyl)-1'H-Spiro[CYCLOBUTANE-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-he;
4-(cyclopropylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-11H-Spiro[cyclopentane-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-he;
7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'H-Spiro[CYCLOBUTANE-1,2'-pyrazino[2,3-b]pyrazine]-3'(4'H)-he;
7'-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1'H-Spiro[cyclopropane-1,2'-pyrazino[2,3-b]pyrazine]-31(4'H)-he;
(R)-6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(S)-6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(1H-indazol-5-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(6-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzamide;
4-(2-methoxyethyl)-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-ethyl-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he
6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(R)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)-4-methylpyridine-3-yl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)-4-methylpyridine-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-yl)-4-{TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(S)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydrox�propan-2-yl)pyridin-3-yl)-3,3-dimethyl-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(CIS-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(TRANS-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(2-methoxyethyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
9-(6-(4H-1,2,4-triazole-3-yl)-3-pyridyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;
6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
5-(8-(CIS-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-6-methilpiralidone;
6-(6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-3-(2-methoxyacetyl)-6,11,4 a-trihydroxybenzene[1,2-e]pyrazino[2,3-b]pyrazine-5-it;
9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-6,11,4 and trihydroxybenzene[1,2-e]pyrazino[2,3-b]pyrazine-5-it;
9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-3-(2-methoxyethyl)-6,11,4 and trihydroxybenzene[1,2-e]pyrazino[,3-b]pyrazine-5-it;
4-(cyclopentylmethyl)-6-(2-methyl-6-(4H-1,2,4-triazole-3-yl) pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
9-(6-(4H-1,2,4-triazole-3-yl)-2-methyl-3-pyridyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;
4-(TRANS-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(CIS-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(cyclopentylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-neopentyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-isobutyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3-methyl-6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(piperidine-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-3-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)(3aS,2R)-2-methoxy-5,10,3 a-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;
8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)(2R,3aR)-2-methoxy-5,10,-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;
8-(4(4H-1,2,4-triazole-3-yl)-2-methylphenyl)(2S,3aR)-2-methoxy-5,10,3 a-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;
8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)(2S,3aS)-2-methoxy-5,10,3 a-digidropiridina[2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-methoxypropyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-3-methyl-6,11,4 a-trihydroxybenzene[1,2-e]pyrazino[2,3-b]pyrazine-5-it;
9-(4-(4H-1,2,4-triazole-3-yl)phenyl)-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;
9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-6,11,4 a-trihydrobromide[1,2-e]pyrazino[2,3-b]pyrazine-5-it;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenethyl-3,4-
dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(cyclohexylmethyl�)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
9-[6-(1-hydroxyisopropyl)-3-pyridyl]-6,11,4 a-trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-methoxyethyl)-
3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(2-amino-7-methyl-1H-benzo[d]imidazol-5-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
9-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-6,11,4 and trihydrobromide[4,3-e]pyrazino[2,3-b]pyrazine-5-it;
6-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrazine[,3-b]pyrazine-2(1H)-he;
8-(4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl)-5,10,3 a-digidropiridina [2,3-b]pyrrolidino[1,2-e]pyrazine-4-it;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-methyl-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he; or
6-(4-(1H-1,2,4-triazole-5-yl)phenyl)-4-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he.

14. A method for producing a compound of formula (II):

comprising the implementation of contacting the compound of formula (VI)

with R1-Y in a solvent in the presence of dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) or dichlorobis(p-p dimethylaminophenyl(tert-butyl)phosphine)palladium(II), where
a) e�whether X is a halogen, then Y is B(OH)2B(-OC(CH3)2C(CH3)2O-), Sn(CH3)3or Sn(n-C4H9)3; or
(b) if Y represents a halogen or triflic, then X is a B(OH)2B(-OC(CH3)2C(CH3)2O-), Sn(CH3)3or Sn(n-C4H9)3; where:
R1selected from the group consisting of 1H-imidazo[4,5-b]pyridin-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-imidazo[2,3-b]pyridin-3-yl, 1H-imidazo[2,3-b]pyridin-5-yl, 2-amino-7-methyl-1H-benzo[d]imidazol-5-yl, 2-methyl-4-(4H-1,2, 4-triazole-3-yl)phenyl, 2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl, 2-methyl-6-cyanopyridine-3-yl, 3-(1H-1,2,4-triazole-5-yl)phenyl, 3-aminocarbonylmethyl, 3-cyanophenyl, 3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl, 3-fluoro-2-methyl-4-(4H-1,2,4-triazole-3-yl) phenyl, 3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl, 4-(1H-1,2,4-triazole-5-yl)phenyl, 4-(2-hydroxypropan-2-yl)phenyl, 4-(4H-1,2,4-triazole-3-yl)-2-methylphenyl, 4-(4H-1,2,4-triazole-3-yl) phenyl, 4-aminocarbonylmethyl, 4-methyl-1H-benzo[d]imidazol-6-yl, 4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl, 4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl, 4-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl, 4-methyl-6-aminocarbonylmethyl-3-yl, 5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl, 6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl, 6-(1-hydroxyethyl)pyridin-3-yl, 6-(1-hydroxy-isopropyl)-3-pyridyl, 6-(2-hydroxypropan-2-yl)-4-metile�idin-3-yl, 6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-yl, 6-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-(4H-1,2,4-triazole-3-yl)-2-methyl-3-pyridyl, 6-(4H-1,2,4-triazole-3-yl) -3-pyridyl, 6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl, benzo[d]imidazolyl, indazole, phenyl and pyridinyl;
R2selected from the group consisting of H, ((1R,3R)-3-methoxycyclohexyl)methyl, ((1R,3S)-3-methoxycyclohexyl)methyl, ((1S,3R)-3-methoxycyclohexyl)methyl, ((1S,3S)-3-methoxycyclohexyl)methyl, (1R,3R)-3-methoxycyclohexyl, (1R,3S)-3-methoxycyclohexyl, (1S,3R)-3-methoxycyclohexyl, (1S,3S)-3-methoxycyclohexyl, (CIS-4-hydroxycyclohexyl)methyl, (CIS-4-methoxycyclohexyl)methyl, (tetrahydro-2H-Piran-4-yl)methyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, (TRANS-4-hydroxycyclohexyl)methyl, (TRANS-4-methoxycyclohexyl)methyl, 2-(tetrahydro-2H-Piran-3-yl)ethyl, 2-(tetrahydro-2H-Piran-4-yl)ethyl, 2-methoxyacetyl, 2-methoxyethyl, 2-morpholinoethyl, 3-(trifluoromethyl)benzyl, 3-methoxypropyl, acetyl, benzyl, CIS-4-hydroxycyclohexyl, CIS-4-methoxycyclohexyl, cyclohexyl, cyclohexylmethyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, ethyl, furanyl, isobutyl, isopropyl, methoxy, methyl, neopentyl, Venetia, phenyl, piperidine-4-silt, piperidinyl, propyl, pyranyl, tetrahydro-2H-Piran-4-yl, tetrahydrofuran-3-yl, TRANS-4-hydroxycyclohexyl and TRANS-4-methoxycyclohexyl;
R3 represents H or methyl;
where the solvent is a dimethyl formamide, isopropanol, dioxane, toluene, dimethylacetamide, tetrahydrofuran, or combinations thereof, in the presence or in the absence of water;
if X or Y represents B(OH)2or B(-OC(CH3)2C(CH3)2O), the said contacting occurs in the presence of sodium carbonate;
if X or Y are Sn(CH3)3or Sn(n-C4H9)3specified contacting optionally occurs in the presence of triethylamine.

15. A method according to claim 14, where if X or Y are halogen, then the halogen is Br.

16. A method according to claim 14, where the palladium catalyst is a dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II).

17. A method according to claim 14, where the palladium catalyst is dichlorobis(p-p dimethylaminophenyl-tert-butylphosphine)palladium(II).

18. A method according to claim 14, further comprising obtaining a compound of formula (VI)

where the specified method comprises cyclization of a compound of formula (VII)

in the presence of butoxide potassium, acetic acid, TFA, HCl, or phosphoric acid, where Hal represents halogen, and R represents ethyl; and
the cyclization is carried out in methanol or water.

19. A method according to claim 18, DG� Hal represents halogen, and the halogen is Br.

20. A method according to claim 18, further comprising obtaining a compound of formula (VII)

where the specified method comprising contacting the compound of formula (VIII)

with R2-NH2in dimethyl sulfoxide or N-methylpyrrolidinone, optionally in the presence of triethylamine or diisopropylethylamine where the contacting occurs under conditions suitable to produce compound of formula (VII), where Hal represents a halogen.

21. A method according to claim 20, wherein halogen represents Br.

22. A method according to claim 14, where the compound is a
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(CIS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-imidazo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((CIS-4-
methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-ethyl-7-(1H-imidazo[3,2-b]pyridin-5-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-34-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-imidazo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((TRANS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((CIS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((TRANS-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((dis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]Pyra�in-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-
methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-hydroxypyridine-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;
7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-aminopyrimidine-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrazine[23-b]pyrazine-2(1H)-he;
7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-hydroxypyridine-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(pyrimidine-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-methoxypyridine-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(2-methoxyethyl)-7-(1H-imidazo[2,3-b]pyridin-5-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-ethyl-7-(1H-imidazo[2,3-b]pyridin-5-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-methyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
2-(2-hydroxypropan-2-yl)-5-(8-(TRANS-4-methoxycyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)pyridine 1-oxide;
4-methyl-5-(7-oxo-8-((tet�ahydro-2H-Piran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)picolinate;
5-(8-((CIS-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;
7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(TRANS-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3-((7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)methyl)benzonitrile;
1-((TRANS-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
3-(7-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzamide;
5-(8-((TRANS-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)-4-methylpyridine;
3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)methyl)benzonitrile;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrazine�[2,3-b]pyrazine-2(1H)-he;
7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(grance-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(CIS-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-((CIS-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(TRANS-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(CIS-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
4-(7-oxo-8-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazine-2-yl)benzamide;
7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-imidazo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-((1S,3R)-3-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-((1R,3R)-3-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-((1R,3S)-3-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-((1S,3S)-3-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-Piran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-((TRANS-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((CIS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2 (1H)-he;
1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyri�[2,3-b]pyrazine-2(1H)-he;
7-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(3-fluoro-4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(TRANS-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(TRANS-4-methoxycyclohexyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((TRANS-4-methoxycyclohexyl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(4-(2-hydroxypropan-2-yl)φ�Neal)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(4-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-methyl-6-(4H-1,2,4-triazole-3-yl)pyridin-3-yl)-1-(2-(tetrahy�ro-2H-Piran-4-yl)ethyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
(S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
7-(4-(1H-1,2,4-triazole-5-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he;
1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he; or
1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazole-3-yl)pyridin-3-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he.

23. The compound of formula (III):

or its salt, tautomer or stereoisomer, wherein: X represents a halogen, B(OH)2B(-OC(CH3)2C(CH3)2O-), Sn(CH3)3or Sn(n-C4H9)3;
R2selected from the group consisting of H, ((1R,3R)-3-methoxycyclohexyl)methyl, ((1R,3S)-3-methods�bicyclopentyl)bromide, ((1S,3R)-3-methoxycyclohexyl)methyl, ((1S,3S)-3-methoxycyclohexyl)methyl, (1R,3R)-3-methoxycyclohexyl, (1R,3S)-3-methoxycyclohexyl, (IS,3R)-3-methoxycyclohexyl, (1S,3S)-3-methoxycyclohexyl, (CIS-4-hydroxycyclohexyl)methyl, (CIS-4-methoxycyclohexyl)methyl, (tetrahydro-2H-Piran-4-yl)methyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, (TRANS-4-hydroxycyclohexyl)methyl, (TRANS-4-methoxycyclohexyl)methyl, 2-(tetrahydro-2H-Piran-3-yl)ethyl, 2-(tetrahydro-2H-Piran-4-yl)ethyl, 2-methoxyacetyl, 2-methoxyethyl, 2-morpholinoethyl, 3-(trifluoromethyl)benzyl, 3-methoxypropyl, acetyl, benzyl, CIS-4-hydroxycyclohexyl, CIS-4-methoxycyclohexyl, cyclohexyl, cyclohexylmethyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, ethyl, furanyl, isobutyl, isopropyl, methoxy, methyl, neopentyl, Venetia, phenyl, piperidine-4-silt, piperidinyl, propyl, pyranyl, tetrahydro-2H-Piran-4-yl, tetrahydrofuran-3-yl, TRANS-4-hydroxycyclohexyl and TRANS-4-methoxycyclohexyl; and
R3and R4each independently, represents H or methyl, or R3and R4together with the atoms to which they are attached, form a cyclopropane, CYCLOBUTANE or cyclopentane.

24. The compound of formula (IV):

or its salt, tautomer or stereoisomer, wherein: each Hal independently represents a halogen; � Hal 2represents Br or I.

25. The compound of formula (V):

or its salt, tautomer or stereoisomer, where:
R2selected from the group consisting of H, ((1R,3R)-3-methoxycyclohexyl)methyl, ((1R,3S)-3-methoxycyclohexyl)methyl, ((1S,3R)-3-methoxycyclohexyl)methyl, ((1S,3S)-3-methoxycyclohexyl)methyl, (1R,3R)-3-methoxycyclohexyl, (1R,3S)-3-methoxycyclohexyl, (IS,3R)-3-methoxycyclohexyl, (1S,3S)-3-methoxycyclohexyl, (CIS-4-hydroxycyclohexyl)methyl, (CIS-4-methoxycyclohexyl)methyl, (tetrahydro-2H-Piran-4-yl)methyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, (TRANS-4-hydroxycyclohexyl)methyl, (TRANS-4-methoxycyclohexyl)methyl, 2- (tetrahydro-2H-Piran-3-yl)ethyl, 2-(tetrahydro-2H-Piran-4-yl)ethyl, 2-methoxyacetyl, 2-methoxyethyl, 2-morpholinoethyl, 3-(trifluoromethyl)benzyl, 3-methoxypropyl, acetyl, benzyl, CIS-4-hydroxycyclohexyl, CIS-4-methoxycyclohexyl, cyclohexyl, cyclohexylmethyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, ethyl, furanyl, isobutyl, isopropyl, methoxy, methyl, neopentyl, Venetia, phenyl, piperidine-4-silt, piperidinyl, propyl, pyranyl, tetrahydro-2H-Piran-4-yl, tetrahydrofuran-3-yl, TRANS-4-hydroxycyclohexyl and TRANS-4-methoxycyclohexyl;
R3and R4each independently, represents H or methyl, or R3and R4in�with natural atoms, to which they are attached, form a cyclopropane, CYCLOBUTANE or cyclopentane; and
each Hal independently represents a fluorine, chlorine or iodine.

26. The compound of formula (VI):

or its salt, tautomer or stereoisomer, wherein: X represents a halogen, B(OH)2B(-OC(CH3)2C(CH3)2O-), Sn(CH3)3or Sn(n-C4H9)3;
R2selected from the group consisting of H, ((1R,3R)-3-methoxycyclohexyl)methyl, ((1R,3S)-3-methoxycyclohexyl)methyl, ((1S,3R)-3-methoxycyclohexyl)methyl, ((1S,3S)-3-methoxycyclohexyl)methyl, (1R,3R)-3-methoxycyclohexyl, (1R,3S)-3-methoxycyclohexyl, (1S,3R)-3-methoxycyclohexyl, (1S,3S)-3-methoxycyclohexyl, (CIS-4-hydroxycyclohexyl)methyl, (CIS-4-methoxycyclohexyl)methyl, (tetrahydro-2H-Piran-4-yl)methyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, (TRANS-4-hydroxycyclohexyl)methyl, (TRANS-4-methoxycyclohexyl)methyl, 2-(tetrahydro-2H-Piran-3-yl)ethyl, 2-(tetrahydro-2H-Piran-4-yl)ethyl, 2-methoxyacetyl, 2-methoxyethyl, 2-morpholinoethyl, 3-(trifluoromethyl)benzyl, 3-methoxypropyl, acetyl, benzyl, CIS-4-hydroxycyclohexyl, CIS-4-methoxycyclohexyl, cyclohexyl, cyclohexylmethyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, ethyl, furanyl, isobutyl, isopropyl,methoxy, methyl, neopentyl, Venetia, phenyl, piperidin-Il piperidinyl, propyl, pyranyl, tetrahydro-2H-Piran-4-yl, tetrahydrofuran-3-yl, TRANS-4-hydroxycyclohexyl and TRANS-4-methoxycyclohexyl; and
R3represents H or methyl.

27. The compound of formula (VII)

or its salt, tautomer or stereoisomer, wherein: Hal represents halogen; R represents ethyl;
R2selected from the group consisting of H, ((1R,3R)-3-methoxycyclohexyl)methyl, ((1R,3S)-3-methoxycyclohexyl)methyl, ((1S,3R)-3-methoxycyclohexyl)methyl, ((IS,3S)-3-methoxycyclohexyl)methyl, (1R,3R)-3-methoxycyclohexyl, (1R,3S)-3-methoxycyclohexyl, (1S,3R)-3-methoxycyclohexyl, (1S,3S)-3-methoxycyclohexyl, (CIS-4-hydroxycyclohexyl)methyl, (CIS-4-methoxycyclohexyl)methyl, (tetrahydro-2H-Piran-4-yl)methyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, (TRANS-4-hydroxycyclohexyl)methyl, (TRANS-4-methoxycyclohexyl)methyl, 2- (tetrahydro-2H-Piran-3-yl)ethyl, 2-(tetrahydro-2H-Piran-4-yl)ethyl, 2-methoxyacetyl, 2-methoxyethyl, 2-morpholinoethyl, 3-(trifluoromethyl)benzyl, 3-methoxypropyl, acetyl, benzyl, CIS-4-hydroxycyclohexyl, CIS-4-methoxycyclohexyl, cyclohexyl, cyclohexylmethyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, ethyl, furanyl, isobutyl, isopropyl, methoxy, methyl, neopentyl, Venetia, phenyl, piperidine-4-silt, piperidinyl, propyl, PIR�Nile, tetrahydro-2H-Piran-4-yl, tetrahydrofuran-3-yl, TRANS-4-hydroxycyclohexyl and TRANS-4-methoxycyclohexyl; and
R3represents H or methyl.

28. The compound of formula (VIII)

or its salt, tautomer or stereoisomer, where:
each Hal independently represents a fluorine, chlorine or iodine;
R represents ethyl; and
R3represents H or methyl.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: thrombocyte aggregation-inhibiting heteromeric peptides based on imidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane are disclosed: , where R=Phe-Ile-Ala-Asp-Thr; Arg-Tyr-Gly-Asp-Arg; Lys-Ile-Ala-Asp-Asp; His-Ile-Gly-Asp-Asp.

EFFECT: improved properties.

1 dwg, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-carb(arginyl)oxymethylimidazo[4,5-e]benzo[1,2-c; 3,4-c']difuroxane of formula .

EFFECT: improved properties of the compound.

1 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula and to its pharmaceutically acceptable salts, stereoisomers and isomers, wherein T: N, U: N, X: CR3 and Y: N; or T: CR6, U: CR4, X: CR3 and Y: N; or T: CR6, U: N, X: NR3 and Y: C; or T: O, U: N, X: CR3 and Y: C; or T: NR6, U: N, X: CR3 and Y: C; and R1, R2 and R5: H, heteroaryl substituted by 1-2 substitutes; or T: CR6, U: N, X: CR3 and Y: N; or T: N, U: CR4, X: CR3 and Y: N; and R1 and R2: H, heteroaryl substituted by 1-2 substitutes; R5: heteroaryl substituted by 1-2 substitutes; R3: H, bridging (C7-C10)cycloalkyl; (C1-C8)alkyl optionally substituted by 1 substitute; (C3-C10)cycloalkyl optionally substituted by 1 substitute; (C6-C8)cycloalkenyl substituted by two (C1-C6)alkyl; (C6)aryl optionally substituted by 1-2 substitutes; heteroaryl optionally substituted by (C1-C6)alkyl; heterocyclyl optionally substituted by (C1-C6)alkyl or heteroaryl; or R3: -A-D-E-G, wherein: A: a bond or (C1-C6)alkylene; D : (C1-C2)alkylene optionally substituted by (C1-C6)alkyl, bridging (C6-C10)cycloalkylene optionally substituted by (C1-C6)alkyl, (C3-C10)cycloalkylene optionally substituted by 1-2 substitutes, (C4-C6)cycloalkenylene optionally substituted by (C1-C6)alkyl, (C6)arylene, heteroarylene or heterocyclylene optionally substituted by one (C1-C6)alkyl; E: a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)O-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-N(Ra)C(O)ORe- or -Re-N(Ra)S(O)2-Re-; wherein in each case, E is bound to either a carbon atom, or a nitrogen atom in D; G: H, -N(Ra)(Rb), halogen, -ORa, S(O)2Ra, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -C(O)Ra, -CF3, N(Ra)S(O)2Rb, -(C1-C6)alkyl optionally substituted by 1-3 substitutes; -(C3-C6)cycloalkyl optionally substituted by CN; -heteroaryl optionally substituted by 1-2 halogens, CN, -C(O)NH2 or -CF3; -heterocyclyl optionally substituted by 1-5 substitutes, -(C6-C10)aryl optionally substituted by 1-3 substitutes; wherein in a fragment containing -N(Ra)(Rb), nitrogen, Ra and Rb can form a ring so that -N(Ra)(Rb) represents (C3-C6)heterocyclyl optionally substituted by 1 substitute, wherein said (C3-C6)heterocyclyl is bound through nitrogen; R4 and R6: H, (C1-C4)alkyl optionally substituted by -OH, -COOH; (C3-C8)cycloalkyl, phenyl, optionally substituted by -SO2CH3 or -NHSO2CH3, halogen or -J-L-M-Q; wherein: J: (C2-C6)alkenylene; L: a bond; M: a bond; Q: -C(O)ORa; Ra and Rb: H, (C1-C4)alkyl optionally substituted by cyano, -CF3 or cyclopropane; (C6)aryl optionally substituted by halogen or -O(C1-C4)alkyl; and Re: a bond, (C1-C4)alkylene or (C3)cycloalkylene. Besides, the invention refers to specific compounds, a pharmaceutical composition based on the compound of formula I, using the compound of formula I for treating and using the compounds of formulas 2-6

for preparing the compound of formula I.

EFFECT: prepared are the new compounds effective in treating a condition mediated by Jak1, Jak3 or Syk protein kinase activity.

51 cl, 34 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-carboxymethylimidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane by hydrolysis of N-carbethoxymethylimidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane with 10% aqueous hydrochloric acid solution.

EFFECT: high output of the end product.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-carb(glutaminyl)oxymethylimidazo[4,5-e]benzo[1,2-c; 3,4-c']difuroxane of formula .

EFFECT: obtaining a novel compound which can be used as a medicinal preparation which inhibits thrombocyte aggregation.

1 dwg, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or (I'): Z-X1-(-CH2-CH2-O-)n-Yp-D (I), D-Yp-(-CH2-CH2-O-)n-X1-Z (l'), where: Z is a reactive carboxylic ether selected from a group consisting of N-succinimidyl, N-sulphosuccinimidyl, N-phthalimidyl, N-sulphophthalimidyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3-sulpho-4-nitrophenyl, 3-carboxy-4-nitrophenyl and a trifluorophenyl ester, or haloacetamide; D is maytansinoid; X is an aliphatic structural unit; Y is an aliphatic structural unit linked to the maytansinoid through a thioether bond; where said aliphatic structural unit, represented by X or Y, is a simple or branched alkyl group with 1-20 carbon atoms in the chain, a cyclic alkyl group having 3-10 carbon atoms, a simple or branched alkenyl group, having 2-15 carbon atoms in the chain or a simple or branched alkynyl group, having 2-15 carbon atoms in the chain; 1 equals 0 or 1; p equals 0 or 1; and n is an integer from 1 to 2000. The invention also relates to a conjugate of a cell-binding agent, and cytotoxic maytansinoid, where the cell-binding agent is an antibody.

EFFECT: obtaining compounds and conjugates, as well as pharmaceutical compositions based thereon, which can be used in medicine to treat tumours, autoimmune diseases, graft rejection, graft-versus-host disease, viral infections and parasitic infections.

20 cl, 38 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) where values of the substitutes are disclosed in the patent claim.

EFFECT: compounds can be applied for treating the infections caused by Pneumovirinae subfamily viruses (RSV, PCB).

53 cl, 502 ex, 11 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to products of oxidative decomposition of atorvastatin calcium, specifically to 4-[6-(4-fluorophenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoylhexahydro-1,2-dioxa- 5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid, phenylamide 4-(4-fluorophenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxylic acid and 4-[1b-(4-fluorophenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoylhexahydro-1,2-dioxa-5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid. The invention also relates synthesis methods thereof, based on oxidation of an atorvastatin salt.

EFFECT: disclosed are products of oxidative decomposition of an atorvastatin salt, which can be used to identify impurities or a product of decomposition of an atorvastatin salt in accordance with approved analytical procedures.

15 cl, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound (I) or its pharmaceutically acceptable salt, which possess properties of selective phosphodiesterase inhibitors, and can be used for treating male erectile dysfunction. In compound (I) R1 represents C1-C6alkyl; R2 represents C1-6alkyl; R3 represents C1-C6alkyl; R4 represents C1-C6 alkyl; R5 means H. The above salt is formed by the compound of formula (I) and an acid specified in citric acid, oxalic acid, hydrochloric acid, sulphuric acid, phosphoric acid, maleic acid, fumaric acid, tartaric acid, hydroxysuccinic acid, succinic acid, methane sulphonic acid or n-toluene sulphonic acid. A preferential compound is 5-[2-ethoxy-5-(4-methyl-1-homopiperazinylsulphonyl)]phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

EFFECT: preparing the pharmaceutically acceptable salt that possesses the properties of selective phosphodiesterase inhibitors.

7 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula (I), possessing properties, making it possible to inhibit phosphorylation of AKT (proteinkinase B; PKB), to versions of method of their obtaining, as well as to intermediate products for their obtaining. In particular compounds can be applied in treatment of different tumours and/or metastases, as well as in case parasitic diseases such a malaria. In formula (I), R1 stands for -L-phenyl or -L-heteroaryl, with term "heteroaryl" standing for bicyclic radical, containing from 9 to 12 units, L stands for either linear or branched alkyl, containing 1-6 carbon atoms, optionally substituted with hydroxyl, or CO group, or group L'-X, where L' stands for linear or branched alkyl, containing 1-6 carbon atoms, and X stands for oxygen or sulphur atom; with phenyl and heteroaryl being optionally substituted with one or several radicals, similar or different, selected from halogen atoms, -NRxRy, alkoxy and alkyl; with said alkyl being optionally substituted with one or several halogen atoms; R2 stands for hydrogen atom or alkyl; R3 stands for alkyl, optionally substituted with one or several halogen atoms; R4 stands for hydrogen atom or halogen atom; with NRxRy being such that Rx and Ry form together with nitrogen atom, which they are bound to, cyclic radical, including 3-10 units, and optionally oxygen atom; and all alkyl or alkoxy radicals, mentioned above, are linear or branched and contain 1-6 carbon atoms.

EFFECT: compounds can be applied as active component for obtaining medications, intended for treatment or prevention of disease, characterised by deregulation of protein- or lipidkinase activity.

25 cl, 3 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula

,

having Aβ42 secretion inhibiting activity. In formula I , hetaryl I is a five- or six-member heteroaryl group containing 1-3 heteroatoms selected from O, S or N, hetaryl II is a five- or six-member heteroaryl group containing 1-3 heteroatoms as defined above for hetaryl I, or is a bicyclic ring system containing 1-4 heteroatoms selected from S, O or N, where at least one ring is aromatic by nature, R1 is C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted with a halogen, or a halogen; R2 is a halogen, C1-7-alkyl, C1-7-alkoxy, hydroxy, C1-7-alkyl substituted with a halogen, C1-7-alkyl substituted with a hydroxy, or benzo[1,3]dioxolyl or is -(CHR)p-phenyl, optionally substituted with a halogen, C1-7-alkyl, C1-7-alkoxy, S(O)2-C1-7-alkyl, cyano, nitro, C1-7-alkoxy substituted with a halogen, dimethylamino, -(CH2)p-NHC(O)O-C1-7-alkyl or C1-7-alkyl, substituted with a halogen. The values of radicals R, R3, R4,p, n, m, o are given in the claim.

EFFECT: invention relates to a method of producing said compounds, a medicinal agent containing said compounds and a method of treating Alzheimer's disease, cerebral amyloid angiopathy, Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), vascular dementia, dementia pugilistica or Down syndrome, associated with β amyloid activity.

21 cl, 283 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to 5,5-condensed heteroarylene compounds IIIB, where U2, V1, V2 and W1 are selected from O, N, NH, S or CR3a; U1, W2, X1 and X2 represent C or N; R1 and R2 represents hydrogen, -C(O)CH(NR1bR1c)R1a, -C(O)CH(N(R1c)C(O)OR1b)R1a or -C(O)OR1a; R3a represents hydrogen or R3; R3 represents halogen or -C(O)OR1a; L1 and L2 are such as given in invention formula, each Z1 and Z2 represents bond or -O-; each Rla, R1b and R1c represents hydrogen, C1-6 alkyl or C6-14 aryl; or Rlb and Rlc together with N atom, which they are bound to, form 5-6-membered heterocyclyl; q, r, s, t and u equal 1. Invention also relates to pharmaceutical compositions, containing 5,5-condensed heteroarylene compounds, and methods of treating or preventing HCV infection.

EFFECT: 5,5-condensed heteroarylene derivatives, possessing inhibiting activity with respect to hepatitis C virus.

43 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a formula compound. The method includes a stage of binding a formula compound with a formula compound in the presence of a base with the formation of the formula (I) compound. In formula (I) stereochemical configurations in the positions, marked with asterisks, are relative; Rb represents hydrogen; R00 represents a C1-10 aliphatic group or a C6-14 aryl group, including one-three rings; Rd, Re, Re', Rf, Rh, Rh', Rk represent hydrogen; Rg represents chlorine, fluorine, iodine or bromine; Rm represents a protective hydroxyl group; values of radicals Ra, R*, Rc are given in the invention formula. In formulas (II) and (III) Ra, Rb, Rc, Rd, Re, Re', Rf, Rg, Rh, Rh', Rj, Rk and Rm are such as determined in formula (I) and R1 represents -CH2CHO. The invention also relates to methods of obtaining compounds of formulae (V), (VI), (VId) and to a compound of the structural formula (IIa). Structural formulae of compounds (V), (VI), (VId), (IIa) are given in the invention formula.

EFFECT: method makes it possible to carry out synthesis in a regioselective way and use the obtained product without purification.

15 cl, 1 tbl, 26 ex

Ethinyl derivatives // 2553461

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to ethinyl derivatives of formula I, where X represents N or C-R1; Y represents N or C-R2; Z represents CH or N; R4 represents 6-membered ring, containing 0, 1 or 2 nitrogen atoms, possibly substituted with 1-2 groups, selected from halogen, lower alkyl, lower alkoxy or NRR'; R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower cycloalkyl or represents 5-6-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O and N; R2 represents hydrogen, CN; R and R' independently on each other represent hydrogen; or their pharmaceutically acceptable salts or acid-addition salts. Invention also relates to pharmaceutical composition, possessing activity of positive allosteric modulator of mGluR5 receptor, including effective quantity of at least one invention compound, and to application of invention compounds for manufacturing medication for treatment or prevention of diseases, associated with positive allosteric modulators of mGluR5 receptor.

EFFECT: obtained are novel compounds, which can be applied as positive allosteric modulator of mGluR5 receptor.

14 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention describes a method of producing and a method of purifying dialkyl pemetrexed of formula (I) , having antifolate action. The compound can be used to treat non-small-cell cancer and, coupled with cisplatin, to treat malignant pleural mesothelioma of the lungs. The method includes reacting a carboxylic acid of formula (II) with a diester of glutamic acid of formula (III) or an acid-addition salt thereof. The process is carried out in the presence of a substituted triphenyl phosphate of formula (IV) , a base and a solvent. In formulae (I) and (III) each R1 and R2 independently represents alkyl groups. In formula (IV) X, Y and Z assume values given in the claim.

EFFECT: use of safe, mild, cheap, non-oxidising and easy to handle triphenyl phosphate simplifies the process and enables to obtain, for example, diethyl pemetrexed with purity higher than 99%.

14 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to a method of obtaining methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid and benzosulphonate of methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid, which includes the interaction of methyl ether of 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid with an oxidiser and, optionally, processing the reaction product in acidic conditions, as well as to intermediate compounds and .

EFFECT: simplification and reduction of the price of the obtaining method due to the reduction of the number of stages.

13 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: medicine, pharmaceutics.

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

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

18 cl, 1 dwg, 237 ex

Up!