Heteroaryl compounds, compositions containing them and methods of treating with use of such compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

 

This application claims the benefit of Provisional Application U.S. No. 60/853166, filed October 19, 2006, which is incorporated into the present application by reference in its entirety.

In this application presents some of the heteroaryl compounds, compositions comprising an effective amount of one or more such compounds, and methods of treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions that can be treated or prevented by inhibition of kinase way, including the introduction of an effective amount heteroaryl compound to a patient in need of it.

The relationship between abnormal protein phosphorylation and cause or consequence of the disease known for 20 years. Therefore, protein kinases have become a very important group of targets for drugs. Cm. Cohen, Nature, 1: 309-315 (2002). Various inhibitors of protein kinases have found clinical use for the treatment of 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).

Protein kinases represent a large and diverse family of enzymes that catalyze the phosphorylation of proteins and play a critical role in signal transmission in cells. Proteinsin the s can be positive or negative regulatory action, depending on their target protein. Protein kinases are involved in specific signaling pathways that regulate cellular function, such as, but not limited to, metabolism, development, cell cycle, cell adhesion, function of blood vessels, apoptosis and angiogenesis. The disturbance of cellular signaling activity is associated with many diseases, the most characteristic of which include cancer and diabetes. Regulation of signal transduction by cytokines and communication of signaling molecules with many proto-oncogenes and genes suppression of the tumor is sufficiently documented. Similarly, we demonstrated the link between diabetes and the associated state and a violation of the regulation of the level of protein kinases. See, for example, Sridhar et al. Pharmaceutical Research, 17(11): 1345-1353 (2000). Viral infections and their related status is also associated with the regulation of protein kinases. Park et al Cell 101 (7): 777-787 (2000).

Protein kinases can be divided into broad groups based on the identity of amino acids(amino acids)to which they are targeted (serine/threonine, tyrosine, lysine and histidine). For example, include tyrosine kinase tyrosine kinase, which are the receptors (RTK), such as growth factors and tyrosine kinase non-receptor type, such as src family kinases. There are also protein kinase dual specificity to target I have is as tyrosine, and the serine/threonine, such as cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK).

Protein kinase C (PKC) is a family of serine/treoninove kinases that play a Central role in cellular signal transduction. Irie et al, 2005, The Chemical Record 5:185-195. PKC isoenzymes are involved in tumor promotion, as well as in various other biological events and, accordingly, are attractive targets for the treatment of cancer and other disorders, as indicated. One such by PKC isoenzyme, which is activated by tumor promoters, is PKCθ. PKC isoenzymes are also expressed in the epithelial cells of the gastrointestinal tract, especially of the intestine. Farhadi et al, 2006, J. Pharm. Exp. Ther. 316: 1-7. Accordingly, it is considered that the means which modulate the PCK activity should be useful as therapeutic agents against gastro-intestinal disorders such as cancer and inflammatory bowel disease.

mTOR (target of rapamycin in mammals), also known as FRAP, RAFTI or SEPT, contains 2549 amino acids Ser/Thr a protein kinase, which, as shown, is one of the most critical proteins in the PI3K/Akt path, which regulates cell growth and proliferation. Georgakis and Younes, 2006, Expert Rev. Anticancer Ther. (5(7,): 131-140. Because PI3K and Akt participants is comfort in the regulation of certain cellular functions, there may be toxic effects associated with inhibition of these kinases, making inhibition of mTOR also the most attractive approach. Three of the mTOR inhibitor currently in clinical trials for cancer treatment. This CCI-779 (kidney cancer, breast cancer, lymphoma cortex, different glioblastomas and metastatic melanoma), RAD001 (resistant solid tumor, running hematological tumors, GIST and running non-small cell lung cancer), and AP23573 (solid tumor, hematological malignant disease and sarcoma). Preclinical success of these compounds demonstrates the usefulness of mTOR inhibitors in cancer treatment and the need for additional compounds having activity of inhibiting mTOR.

Because protein kinases regulate almost every cellular process, including metabolism, cell proliferation, cell differentiation and cell survival, they are attractive targets for therapeutic intervention in various painful conditions. For example, control of the cell cycle and angiogenesis, in which protein kinases play a Central role, are the cellular processes associated with various painful conditions, such as, but not limited to, cancer, inflammatory diseases, abnormal is migenes and related diseases, atherosclerosis, macular degeneration, diabetes, obesity and pain.

Protein kinases have become attractive targets for cancer treatment. Fabbro et al., Pharmacology & Tharapeutics 93:79-98 (2002). An assumption was made that the participation of protein kinases in the development of malignant diseases can occur in one of the following ways: (1) genomic rearrangement (e.g., BCR-ABL in chronic myelogenous leukemia), (2) mutations leading to constitutive active kinase activity, such as acute myelogenous leukemia and gastrointestinal tumors, (3) dysregulation of kinase activity through activation of oncogenes or loss of tumor-suppressor functions, such as cancers with oncogenic RAS, (4) the dysregulation of kinase activity through overexpression, as in the case of EGFR and (5) ectopic expression of growth factors, which contribute to the development and maintenance of the neoplastic phenotype. Fabbro et al., Pharmacology & Tharapeutics 93:79-98 (2002).

When figuring out intricate ways of the protein kinase and the complexity of the relationships and interactions between different protein kinases and kinase pathways important to the development of pharmaceuticals that can act as modulators, regulators or inhibitors of protein kinases, which have a favorable effect on various kinases or different kinase PU is I. Accordingly, there remains a need for new modulators of kinases.

Quote or indication of any reference document in Section 2 of this application should not be construed as an assumption that this reference document is known from the prior art analogue of this application.

3. Brief description of the invention

In the present application is represented by compounds having the following formula (I):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers and prodrugs, where R1, R2, L, X, Y, Z, Q, A and B have the meanings given in this application.

The compounds of formula (I)or their pharmaceutically acceptable salt, clathrate, solvate, hydrates, stereoisomers, or prodrugs of (each of which is indicated in this application as "Heteroaryl compounds") are useful for the treatment or prevention of cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions that can be treated or prevented by inhibiting the kinase pathway, in one variant embodiment of the invention - PKCθ or mTOR path.

In addition, this application presents a composition comprising an effective amount heteroaryl compounds, compositions comprising an effective amount of heteroa the strong connection and a pharmaceutically acceptable carrier or excipient. The compositions are useful for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions that can be treated or prevented by inhibiting the kinase pathway, in one variant embodiment of the invention - PKCθ or mTOR path.

In addition, this application presents methods of treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions that can be treated or prevented by inhibiting the kinase pathway, in one variant embodiment of the invention - PKCθ or mTOR way, including the introduction of an effective amount heteroaryl compound to a patient in need of such treatment or prevention.

The options presented embodiment of the invention will be best understood by reference to the detailed description and examples, which are intended to illustrate a non-limiting embodiment variants of the invention.

4. Detailed description of the invention

4.1 Definitions

Group "C1-8alkyl represents a saturated linear or branched acyclic hydrocarbon containing from 1 to 8 carbon atoms. A representative of the group -(C1-8alkyl) include-methyl, -ethyl, -n-propyl, n-butyl, -n-pentyl, n-hexyl, n-heptyl and n-octyl; whereas nasy the military branched alkali include-isopropyl, -sec-butyl, -isobutyl, -tert-butyl-isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl etc. Group -(C1-8alkyl) may be substituted or unsubstituted. For example, C1-8the alkyl group may be substituted by phenyl with the formation of the benzyl group.

Group C2-8alkenyl" represents a linear or branched acyclic hydrocarbon containing from 2 to 8 carbon atoms and containing at least one carbon-carbon double bond. Representative linear and branched (C2-8)alkenyl include-vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylene, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl etc. Double bond alkenylphenol group may be unpaired or paired with another unsaturated group. Alchemilla group can be unsubstituted or substituted.

Group "C2-8quinil" represents a linear or branched acyclic hydrocarbon containing from 2 to 8 carbon atoms and containing at least one carbon-carbon triple bond. Representative linear and branched(C2-8)alkinyl include-acetylenyl, -PROPYNYL, -1-butynyl, -2-butynyl, -1-pentenyl, -2-pentenyl, -3-meth is l-1-butenyl, -4-pentenyl, -1-hexenyl, -2-hexenyl, -5-hexenyl, -1-heptenyl, -2-heptenyl, -6-heptenyl, -1-octenyl, -2-octenyl, -7-octenyl etc. Alchemilla group can be unsubstituted or substituted.

The terms "halogen" and "halo" means fluorine, chlorine, bromine and iodine.

Group "aryl" represents an unsaturated aromatic carbocyclic group comprising 6-14 carbon atoms, comprising a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl or until). Specific arily include phenyl, biphenyl, naphthyl, and other Aryl group can be substituted or unsubstituted.

Group "heteroaryl" is an aryl ring system containing from one to four heteroatoms (such as O, S or N) as ring atoms in the heteroaromatic ring system, where the remaining atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. In some embodiments, embodiments of the invention, the heterocyclic ring system is monocyclic or bicyclic. Non-limiting examples include an aromatic group selected from the following:

where Q represents CH2CH=CH, O, S or NH. Other representative examples of heteroaryl groups include, but are not limited to, benzofuranyl, benzothieno is, indolyl, benzimidazolyl, coumarinyl, furanyl, isothiazolin, imidazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiophenyl, pyrimidinyl, ethenolysis, chinoline, pyridinyl, pyrrolyl, pyrazolyl, 1H-indolyl, 1H-indazole, benzo[d]thiazolyl and pyrazinyl. The following are representative examples of heteroaryl groups include groups present in the compounds disclosed in this application. Heteroaryl can be linked via any ring atom (i.e on any carbon atom or heteroatom heteroaryl ring). Heteroaryl group may be substituted or unsubstituted. In one variant embodiment of the invention, the heteroaryl group represents a C3-10heteroaryl group.

Group "cycloalkyl" represents a saturated or unsaturated non-aromatic carbocyclic ring. Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadiene, 1,3,5-cycloheptatriene, cyclooctyl and cyclooctadiene. Cycloalkyl group can be substituted or unsubstituted. In one variant embodiment of the invention, cycloalkyl group represents a C3-8cycloalkyl group.

Group "heterocyclyl the Il represents a nonaromatic cycloalkyl, in which one to four of the ring carbon atoms are independently replaced by a heteroatom selected from the group consisting of O, S and N. Representative examples geteroseksualnoe groups include, but are not limited to, morpholinyl, pyrrolyl, pyrrolidinyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, isothiazolin, isoxazolyl, (1,4)-dioxane, (1,3)-dioxolane, 4,5-dihydro-1H-imidazolyl and tetrazolyl. Heterocicluri can be linked via any ring atom (i.e on any carbon atom or heteroatom of the heterocyclic ring). Heterocytolysine group can be substituted or unsubstituted. In one variant embodiment of the invention heteroseksualci is a 3-7-membered heteroseksualci.

When it is noted that the groups described in this application are "substituted or unsubstituted", when they are substituted, they can be substituted by one or more of any substituents. Examples of the substituents include the substituents, which can be found in the illustrative compounds and variations of the embodiments of the invention disclosed in this application, as well as halogen (e.g. chlorine, iodine, bromine, or fluorine); C1-8alkyl, C2-8alkenyl; C2-8quinil; hydroxyl; C1-8alkoxyl; amino; nitro; thiol; thioether; Imin; C is ANO; amido; phosphonate; phosphine; carboxyl; carbarnoyl; carbamate; acetal; urea; thiocarbonyl; sulfonyl; sulfonamide; sulfinil; ketone; aldehyde; ester; acetyl; acetoxy; oxygen (=O); halogenated (e.g., trifluoromethyl); substituted aminoacyl and aminoalkyl; a carbocyclic cycloalkyl, which may be monocyclic or condensed or unfused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heteroseksualci, which may be monocyclic or condensed or unfused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinil, morpholinyl furanyl, or triazinyl); carbocyclic or heterocyclic, monocyclic or condensed or unfused polycyclic aryl (e.g. phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, chinoline, ethenolysis, acridines, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, sensational, or benzofuranyl); amino (primary, secondary, or tertiary); -O-lower alkyl; -O-aryl; aryl; aryl-lower alkyl; CO2CH3; CONH2; OCH2CONH2; NH2; N(C1-4alkyl)2; NHC(O)C1-4alkyl; SO2NH2; SO2C1-4alkyl; OCHF2; CF3 ; OCF3; and such groups can also be optionally substituted condensed ring structure or bridge, for example-OCH2O - or-O-lower alkylene-O-. These substituents optionally may be additionally substituted by a Deputy selected from such groups.

As used in this application, the term "pharmaceutically acceptable salt(salt)" refers to salts derived from pharmaceutically acceptable non-toxic acids or bases including inorganic acid and base and the organic acid and base. Suitable pharmaceutically acceptable basic additive salt heteroaryl compounds include, but are not limited to, metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts derived from lysine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic, Anthranilic, benzolsulfonat, benzoic, camphorsulfonic, lemon, Tinsulanonda, formic, fumaric, francebuy, galacturonic, gluconic, glucuronic, glutamic, glycolic, Hydrobromic, hydrochloric, setiono the traveler, lactic, maleic, malic, almond, methansulfonate, murinova, nitrogen, Panova, Pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid and p-toluensulfonate acid. Specific non-toxic acids include hydrochloric, Hydrobromic, phosphoric, sulphuric and methansulfonate acid. Examples of specific salts thus include cleaners containing hydrochloride and mesylate salt. Other salts are well known in the prior art, see, for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19' eds., Mack Publishing, Easton PA (1995).

As used in this application, the term "polymorph(polymorphs)" and related terms in this application refers to solid forms of heteroaryl compounds having different physical properties as a result of the arrangement of the molecules in the crystal lattice. The difference in physical properties, which demonstrate solid form, affect pharmaceutical parameters such as storage stability, compressibility and density (important for the formulation of compositions and manufacturing of the product), and the dissolution rate (an important factor in determining bioavailability). The difference in stability can result from changes in the ability to chemical interaction (EmOC is emer, differential oxidation, for example, the dosage form will fade much faster when it consists of one solid form than when it consists of other solid forms) or mechanical changes (e.g., tablets crumble when stored as kinetically preferred polymorph converted to thermodynamically more stable solid form), or both (e.g., tablets of one solid form are more susceptible to damage under conditions of high humidity). As a result of differences in solubility/dissolution, in extreme cases, some transitions of solid forms can lead to a lack of activity, and in the other extreme case, to toxicity. In addition, the physical properties of the crystal can be important when processing, for example, one solid form can more easily form a solvate, or may be more difficult to filter this form and washing to remove impurities (i.e. shape and size distribution of particles can be different in different solid forms).

As used in this application and unless otherwise indicated, the term "clathrate" means a heteroaryl compound or its salt in the form of a lattice, which includes spatial formation (e.g., channels)that contain the “guest” molecule (for example, actuarial or water), captured in them, or lattice, in which the heteroaryl compound is the “guest” molecule.

As it is used in this application and unless otherwise indicated, the term "hydrate" means a heteroaryl compound or its salt, which, in addition, includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

As it is used in this application and unless otherwise indicated, the term "MES" means a heteroaryl compound or its salt, which, in addition, includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.

As it is used in this application and unless otherwise indicated, the term "prodrug" means a derivative heteroaryl compounds, which can be either hydrolyzed, oxidized or any other way to react in biological conditions (in vitro or in vivo) with the formation of active compounds, in particular, the heteroaryl compounds. Examples of podcast include, but are not limited to, derivatives and metabolites heteroaryl compounds that include biohydrology groups, such as biokerosene amides, biohydrology esters, biohydrology carbamates, biohydrology carbonates, ihydrocodeine ureides and biokerosene phosphate analogues. In some embodiments, embodiments of the invention, prodrugs of compounds with carboxyl functional groups are lower alkalemia esters of carboxylic acids. Carboxylate esters are easily formed by the esterification of any of carbonisation groups present in the molecule. Prodrugs, as a rule, can be obtained using well known methods such as methods described in Burger''s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and the Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

As it is used in this application and unless otherwise indicated, the term "stereoisomer" or "stereoisomers clean" means one stereoisomer heteroaryl compounds, which essentially contains no other stereoisomers of the compound. For example, stereoisomers pure compound containing one chiral center, essentially does not contain the opposite enantiomer of the compound. Stereoisomers pure compound containing two chiral center, essentially contains no other diastereomers of the compound. Typical stereoisomer a pure compound comprises greater than about 80% wt. one stereoisomer of the compound and less than about 20% wt. other stereoisomers of the compound, greater than about 90% wt. one stereoisomer of the compound and m is niche than about 10% wt. other stereoisomers of the compound, greater than about 95% wt. one stereoisomer of the compound and less than about 5% wt. other stereoisomers of this compound, or greater than about 97 wt.%. one stereoisomer of the compound and less than about 3% wt. other stereoisomers of the compound. Heteroaryl compounds may contain chiral centers and may exist in the form of the racemates, individual enantiomers or diastereomers and their mixtures. All such isomeric forms are covered by the variant embodiment of the invention disclosed in this application, including mixtures thereof.

Various heteroaryl compounds contain one or more chiral centers and can exist as racemic mixtures of enantiomers, mixtures of diastereoisomers or enantiomeric or optically pure compounds. Use stereoisomers pure forms of such heteroaryl compounds, and the use of mixtures of such forms is covered by a variant embodiment of the invention disclosed in this application. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular heteroaryl compounds can be used in the methods and compositions disclosed in the present application. These isomers can be obtained by asymmetric synthesis, or they can be separated using a hundred of the standard methods, such as chiral column or chiral separation agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S.., et al, Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.., Tables 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 pointed out that heteroaryl compounds can include E and Z isomers or a mixture thereof, and CIS and TRANS isomers or a mixture thereof. In some embodiments, embodiments of the invention, the heteroaryl compounds isolated in the form of either E or Z isomer. In other embodiments, embodiments of the invention, the heteroaryl compounds are a mixture of E and Z isomers.

The term "effective amount" in connection with a heteroaryl compound can mean a quantity that can treat or prevent disease, disclosed in this application, such as cancer, inflammatory conditions, immunological conditions, metabolic conditions or conditions that can be treated or prevented by inhibiting the kinase pathway, in one variant embodiment of the invention - PKCθ or mTOR path.

The term "patient" includes an animal, including, but not limited to, an animal, such as cow, monkey, horse, sheep, pig, chicken, Turkey, quail, cat, dog, mouse, rat, rabbit or Guinea pig, in one variant embodiment of izaberete the Oia - mammal, in another variant embodiment of the invention is the man.

4.2 HETEROARYL COMPOUNDS

In this application presents the heteroaryl compounds of formula (I):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers, enantiomers and prodrugs,

where

X, Y and Z, in each case, independently represent N or CR3where at least one of X, Y and Z represents N and at least one of X, Y and Z represents CR3;

-A-B-Q-taken together form-CHR4C(O)NH-, -C(O)CHR4NH-, -C(O)NH-, -CH2C(O)O-, -C(O)CH2O-, -C(O)O - or C(O)NR3;

L represents a simple bond, NH or O;

R1represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci;

R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci;

R3represents H, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroseksualci, -other4or-N(R4)2; and

R4in each case independently represents a substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In one variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-CH2C(O)NH-.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-C(O)CH2NH-.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-C(O)NH-.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-CH2C(O)O-.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B--, taken together form-C(O)CH2O-.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-C(O)O-.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-C(O)NR3-.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which Y represents CR3.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which X and Z are N and Y is CR3.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which X and Z are N and Y is CH.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which X and Z are CH and Y is N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which Y and Z are CH and X is N.

In another variant of the embodiment from which retene, heteroaryl compounds of formula (I) are those compounds in which X and Y are CH and Z represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which R1represent substituted aryl, such as substituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which R1represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which R1represents a substituted or unsubstituted heteroaryl, such as substituted or an unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which R1represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds, to the which R 2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which R2represents a methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclization.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which R2represents a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which R2represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which L represents a simple link.

In another variant embodiment of the invention, heteroaryl with the organisations of the formula (I) are such compounds, in which-A-B-Q-taken together form-C(O)NH-, X and Z are N and Y is CH, R1represents a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, L represents a simple bond, and R2represents a substituted or unsubstituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-C(O)NH-, X and Z are N and Y is CH, R1represents a substituted or unsubstituted aryl, L is a simple bond and R2represents a substituted or unsubstituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-C(O)NH-, X and Z are N and Y is CH, R1represents a substituted or unsubstituted aryl and R2represents a C1-8alkyl, substituted by one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl or geterotsiklicheskie.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together, education is comfort-C(O)NH-, X and Z are N and Y is CH, R1represents a substituted or unsubstituted aryl and R2represents a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) are those compounds in which-A-B-Q-taken together form-C(O)NH-, X and Z are N and Y is CH, R1is a substituted phenyl, L represents a simple bond, and R2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where X and Z both represent N, and Y is CH, -A-B-Q - is-C(O)NH-, L represents a simple bond, R1represents a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl and R2represents a C1-8alkyl, substituted substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where X and Z both represent N, and Y is CH, -A-B-Q - is-C(O)NH-, L represents a simple bond,R 1represents phenyl, naphthyl, indanyl or biphenyl, each of which is optionally substituted by one or more substituents independently selected from the group comprising substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where X and Z both represent N, and Y is CH, -A-B-Q - is-C(O)NH-, L represents a simple bond, R1represents phenyl, naphthyl or biphenyl, each of which is optionally substituted by one or more substituents, each of which is independently selected from the group consisting of C1-4of alkyl, amino, amino1-12of alkyl, halogen, hydroxy, hydroxys1-4of alkyl, C1-4alkalosis1-4of alkyl, -CF3C1-12alkoxy, aryloxy, arils1-12alkoxy, -CN, -OCF3, -CORg, -COORg, -CONRgRh, -NRgCORh, -SO2Rg, -SO3Rgor-SO2NRgRhwhere each Rgand Rhindependently selected from the group consisting of hydrogen, C1-4of alkyl, C3-6cycloalkyl, aryl, arils1- of alkyl, heteroaryl or heteroaryl1-6of alkyl; or A is a 5-6-membered monocyclic heteroaromatic ring containing one, two, three or four heteroatoms, independently selected from the group consisting of N, O and S, such monocyclic heteroaromatic ring optionally substituted by one or more substituents, each of which is independently selected from the group consisting of C1-6of alkyl, amino, amino1-12of alkyl, halogen, hydroxy, hydroxys1-4of alkyl, C1-4alkalosis1-4of alkyl, C1-12alkoxy, aryloxy, aryl (C1-12alkoxy, -CN, -CF3, -OCF3, -CORi, -COORi, -CONRiRj, -NRiCORj, -NRiSO2RJ, -SO2Ri, -SO3Rior-SO2NRiRjwhere each Riand Rjindependently selected from the group consisting of hydrogen, C1-4of alkyl, C3-6cycloalkyl, aryl, arils1-6of alkyl, heteroaryl or heteroaryl1-6of alkyl; or A is an 8-10-membered bicyclic heteroaromatic ring containing one, two, three or four heteroatoms selected from the group consisting of N, O and S, and optionally can be substituted one, two or three substituents, each independently selected from the group consisting of C1-6of alkyl, amino, amino 1-12of alkyl, halogen, hydroxy, hydroxys1-4of alkyl, C1-4alkalosis1-4of alkyl, C1-12alkoxy, aryloxy, arils1-12alkoxy, -CN, -CF3, -OCF3, -CORk, -COORk, -CNRkRl, -NRkCORl, -NRkSO2Rl, -SO2Rk, -SO3Rkor-SO2NRkRlwhere each Rkand Rlindependently selected from the group consisting of hydrogen, C1-4of alkyl, C3-6cycloalkyl, aryl, arils1-6of alkyl, heteroaryl or heteroaryl1-6of alkyl, and R2represents a C1-8alkyl, substituted substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where X and Y both represent N, and Z represents CH, -A-B-Q - is-C(O)NH-, L represents a simple bond, R1represents a substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, and R2represents a substituted or unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl or ndimethylacetamide.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where X and Y both represent N, and Z represents CH, -A-B-Q - represents a C(O)NH-, L represents a simple bond, R1represents a substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, and R2is a ndimethylacetamide.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where X is N and Y and Z both represent CH, -A-B-Q - is-C(O)NH-, L represents a simple bond, R1is a (2,5'-bi-1H-benzimidazole)-5-carboxamid and R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where one of X and Z represents CH and the other represents N, Y is CH, -A-B-Q - is-C(O)NH-, L represents a simple bond, R1represents an unsubstituted pyridine, and R2represents H, methyl or substituted ethyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where X and Z both represent N, and Y is CH, -A-B-Q - is-C(O)NH-, R1represents H, C1-6alkyl, C2-8alkenyl, aryl or cycloalkyl, and L represents NH.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where X and Z are both PR is astavliaut a N and Y is CH, -A-B-Q - is-C(O)NR3-, R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci, and L represents NH.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include compounds where R1represents a substituted or unsubstituted oxazolidinone.

In another variant embodiment of the invention, the heteroaryl compounds of formula (I) include one or more of the following compounds: 1,7-dihydro-2-phenyl-8H-purine-8-he, 1,2-dihydro-3-phenyl-6H-imidazo[4,5-e]-1,2,4-triazine-6-he, 1,3-dihydro-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-it, 6-(1,3-benzodioxol-5-yl)-1,3-dihydro-1-[(1S)-1-phenylethyl]-2H-imidazo[4,5-b]pyrazin-2 he, 3-[2,3-dihydro-2-oxo-3-(4-pyridinylmethyl)-1H-imidazo[4,5-b]pyrazin-5-yl]-benzamide, 1-[2-(dimethylamino)ethyl]-1,3-dihydro-6-(3,4,5-trimethoxyphenyl)-2H-imidazo[4,5-b]pyrazin-2-it, N-[5-(1,1-dimethylethyl)-2-methoxyphenyl]-N'-[4-(1,2,3,4-tetrahydro-2-occupied[2,3-b]pyrazin-7-yl)-1-naftalina]urea, N-[4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridine-6-yl)-1-naphthalenyl]-N'-[5-(1,1-dimethylethyl)-2-methoxyphenyl]urea, 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-he, 1,3-dihydro-5-phenoxy-2H-imidazo[4,5-b]pyridine-2-he, 1,3-dihydro-1-methyl-6-phenyl-2H-imidazo[4,5-b]PI is one-2-it, 1,3-dihydro-5-(1H-imidazol-1-yl)2H-imidazo[4,5-b]pyridine-2-it, 6-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridine-6-yl)-8-methyl-2(1H)-chinoline and 7,8-dihydro-8-oxo-2-phenyl-9H-purine-9-acetic acid.

In some embodiments, embodiments of the invention, the conditions specified above in respect of the heteroaryl compounds of formula (I)also apply to the heteroaryl compounds of formula (II)-(VIII), where this is appropriate.

In the following variant embodiment of the invention presents heteroaryl compounds of the following formula (II):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers, enantiomers and prodrugs,

where

L represents a simple bond, NH or O;

Y represents N or CR3;

R1represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci;

R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci;

R3p is ecstasy a H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroseksualci, -other4or-N(R4)2; and

R4in each case independently represents a substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In one variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R1represent substituted aryl, such as substituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R1represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R1represents a substituted or unsubstituted heteroaryl, such as substituted or an unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or nezame the military pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R1represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R2represents a methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclization.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R2represents a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R2represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.

In another variant is NTE embodiment of the invention, heteroaryl compounds of formula (II) are such compounds in which R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are those compounds in which Y represents CH.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which L represents a simple link.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents unsubstituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a C1-8alkyl, substituted by one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl or geterotsiklicheskie.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a substituted or n is substituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (II) do not include compounds where Y is CH; L represents a simple bond, R1represents a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and R2represents a C1-8alkyl, substituted substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

In the following variant embodiment of the invention presents heteroaryl compounds of the following formula (III):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers, enantiomers and prodrugs,

where

L represents a simple bond, NH or O;

R1represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci; and

R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or zames the config or an unsubstituted heteroseksualci.

In one variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R1represent substituted aryl, such as substituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R1represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R1represents a substituted or unsubstituted heteroaryl, such as substituted or an unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R1represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds is of formula (III) are such compounds, in which R2represents a methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclization.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R2represents a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R2represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which L represents a simple link.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents unsubstituted C 1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a C1-8alkyl, substituted by one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl or geterotsiklicheskie.

In another variant embodiment of the invention, the heteroaryl compounds of formula (III) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In the following variant embodiment of the invention presents heteroaryl compounds of the following formula (IV):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers, enantiomers and prodrugs,

where

L represents a simple bond, NH or O;

R1represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted, heterocycla the keel; and

R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In one variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R1represent substituted aryl, such as substituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R1represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R1represents a substituted or unsubstituted heteroaryl, such as substituted or an unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R1represents N.

<> In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R2represents a methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclization.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R2represents a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R2represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) represent the hat connection in which L represents a simple link.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents unsubstituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a C1-8alkyl, substituted by one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl or geterotsiklicheskie.

In another variant embodiment of the invention, the heteroaryl compounds of formula (IV) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In the following variant embodiment of the invention presents heteroaryl compounds of the following formula (V):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers, enantiomers and prodrugs,

where

L represents a simple bond, NH is whether O;

R1represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci; and

R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In one variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R1represents a substituted aryl, such as substituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R1represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R1represents a substituted or unsubstituted heteroaryl, such as substituted or an unsubstituted quinoline, substituted or nezameshchenny is pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R1represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R2represents a methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclization.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R2represents a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R2represents a substituted or unsubstituted aryl, such as substituted or resumes the config phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which L represents a simple link.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents unsubstituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a C1-8alkyl, substituted by one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl or geterotsiklicheskie.

In another variant embodiment of the invention, the heteroaryl compounds of formula (V) are such compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In the next version of the incarnation is subramania presents heteroaryl compounds of the following formula (VI):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers, enantiomers and prodrugs,

where

L represents a simple bond, NH or O;

R1represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci; and

R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In one variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R1represents a substituted aryl, such as substituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R1represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In another variant embodiment of the invention, heteroaryl the basic compounds of formula (VI) are such compounds, in which R1represents a substituted or unsubstituted heteroaryl, such as substituted or an unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R1represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R2represents a methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclization.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R2represents a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, heteroaryl the compounds of the formula (VI) are such compounds, in which R2represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which L represents a simple link.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents unsubstituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a C1-8alkyl, substituted by one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl or geterotsiklicheskie.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VI) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a substituted linesamsung cycloalkyl, or substituted or unsubstituted heteroseksualci.

In the following variant embodiment of the invention presents heteroaryl compounds of the following formula (VII):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers, enantiomers and prodrugs,

where

L represents a simple bond, NH or O;

R1represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci; and

R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In one variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R1represent substituted aryl, such as substituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R1represents a substituted or not alseny aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R1represents a substituted or unsubstituted heteroaryl, such as substituted or an unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R1represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R2represents a methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclization.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are particularly which such compounds, in which R2represents a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R2represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which L represents a simple link.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents unsubstituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a C1-8alkyl, substituted by one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl and the and geterotsiklicheskie.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In the following variant embodiment of the invention presents heteroaryl compounds of the following formula (VIII):

and their pharmaceutically acceptable salts, polymorphs, clathrates, solvate, hydrates, stereoisomers, enantiomers and prodrugs,

where

L represents a simple bond, NH or O;

R1represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci; and

R2represents H, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In one variant embodiment of the invention, the heteroaryl compounds of formula (VIII) represents such is soedineniya, in which R1represents a substituted aryl, such as substituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R1represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R1represents a substituted or unsubstituted heteroaryl, such as substituted or an unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R1represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R2represents a substituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R2represents methyl or ethyl, someseni is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclization.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R2represents a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R2represents a substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R2represents N.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which L represents a simple link.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents unsubstituted C1-8alkyl.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VII) are compounds such in which R1represents a substituted or unsubstituted aryl, and R2represents a C1-8alkyl, substituted by one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl or geterotsiklicheskie.

In another variant embodiment of the invention, the heteroaryl compounds of formula (VIII) are those compounds in which R1represents a substituted or unsubstituted aryl, and R2represents a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroseksualci.

Representative heteroaryl compounds are presented in Table 1.

Table 1
ConnectionConnection
(S)-3-(1-hydroxy-3-methylbutane-2-yl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he
1
1-((tetrahydro-2H-Piran-4-yl)methyl)-6-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
2
(R)-6-(naphthalene-1-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
3
1-(3-methoxybenzyl)-6-(4-methylsulphonyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
4
(S)-1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-]pyrazin-2(3H)-he
5
6-(4-hydroxyphenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
6
(S)-6-(naphthalene-1-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
7
(S)-1-(1-hydroxy-3-methylbutane-2-yl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
8
(R)-1-(1-hydroxy-3-methylbutane-2-yl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he
9
(R)-1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
10
(S)-1-(1-hydroxy-3-methylbutane-2-yl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
11
(R)-1-(1-hydroxy-3-methylbutane-2-yl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
12

(R)-1-(1-hydroxy-3-methylbutane-2-yl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
13
1-benzyl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
14
1-(4-methoxybenzyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
15
(R)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
16
(S)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
17
1-isopropyl-6-(5-isopropyl-2-methoxyphenyl)-1H-it is dazo[4,5-b]pyrazin-2(3H)-he
18
1-cyclohexyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
19
5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
20
1-isobutyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
21
1-(2-hydroxyethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
22

6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
23
(R)-1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-C]pyridine-2(3H)-he
24
(S)-1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-C]pyridine-2(3H)-he
25
3-(1-phenylethyl)-5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
26
(R)-3-(1-phenylethyl)-5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he
27
(R)-6-(5-isopropyl-2-methoxyphenyl)-1(3-methylbutane-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
28
(S)-6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
29
(S)-6-(5-isopropyl-2-methoxyphenyl)-1-(3-methylbutane-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
30
1-cyclopentyl-6-(a-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
31
(R)-6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
32

1-(cyclopropylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
33
1-(cyclopentylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
34
1-(cyclohexylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
35
6-(5-isopropyl-2-methoxyphenyl)-1-neopentyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he
36
1-isopropyl-6-(3-isopropylphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
37
1-isopropyl-6-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
38
(S)-3-(1-hydroxy-3-methylbutane-2-yl)-5-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-2(3H)-he
39
(R)-1-(2-hydroxy-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
40
(S)-1-(2-hydroxy-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
41
1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
42

1-benzhydryl-6-(quinoline-5-yl)-1-imidazo[4,5-b]pyrazin-2(3H)-he
43
(S)-1-(1-phenylpropyl)-6-quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
44
(R)-1-(1-phenylpropyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
45
6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-Piran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
46
1-(3-methoxybenzyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
47
(R)-1-methyl-3-(1-phenylethyl)-5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
48
(S)-1-methyl-3-(1-phenylethyl)-5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
49
1-(cyclopentylmethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
50
1-(1-(2-forfinal)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
51
1-(1-(4-forfinal)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
52

1-cyclopentyl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
53
1-(1-(3-forfinal)ethyl)-6-quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
54
1-(3-methoxyphenyl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
55
1-(1-(4-methoxyphenyl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3)-he
56
1-(quinoline-5-yl)-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
57
6-(quinoline-5-yl)-1-(tetrahydro-2H-Piran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
58
1-((1S,4S)-4-hydroxycyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
59
1-((1R,4R)-4-hydroxycyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
60
6-(isoquinoline-5-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
61
(R)-1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he
62
1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he
63
1-isopropyl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
64

1-(1-(4-cyclofenil)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
65
1-(1-(4-methylsulphonyl)phenyl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
66
1-(1-(pyridin-4-yl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
67
5-methyl-1-((S)-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
68
5-methyl-1-((R)-1-phenylethyl)-6-(quinoline-5-yl)-1H-imides the[4,5-b]pyrazin-2(3H)-he
69
1-(1-phenylethyl)-6-(quinoline-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
70
6-(3-forfinal)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
71
6-(2-forfinal)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
72
1-(1-phenylethyl)-6-(quinoline-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
73
1-(piperidine-4-ylmethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
74

1-(1-phenylethyl)-6-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
83
1-(1-(pyridin-2-yl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
75
1-(1-(pyridin-3-yl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
76
1-((1S,4S)-4-hydroxymethyl)cyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
77
N-(4-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide
78
6-(3-(methylsulphonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
79
6-(3-AMINOPHENYL)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
80
6-(3-(dimethylamino)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
81
1-phenyl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
82
N-(3-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide
84

6-(4-(methylsulphonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
85
3-(1-phenylethyl)-5-(quinoline-5-yl)-oxazolo[5,4-b]pyrazin-2(3H)-he
86
1-(cyclopentylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
87
6-(4-hydroxyphenyl)-1-isopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he
88
6-(4-hydroxyphenyl)-1-isobutyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he
89
6-(4-hydroxyphenyl)-1-((tetrahydro-2H-Piran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
90
1-(cyclohexylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
91
5-(3-hydroxyphenyl)-3-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-2(3H)-he
92
4-(3-(3-methoxybenzyl)-2-oxo-2,3-dihydrooxazolo[5,4-b]pyrazin-5-yl)N-methylbenzamide
93
1-cyclopentyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
94
1-cyclohexyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-is n
95
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide
96

methyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate
97
1-(cyclohexylmethyl)-6-(pyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
98
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-methylbenzamide
99
1-(cyclohexylmethyl)-6-(4-(hydroxymethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
100
1-(cyclohexylmethyl)-6-(pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
101
3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile
102
1-(cyclohexylmethyl)-6-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
103
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-isopropylbenzene
104
1-(2-hydroxyethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
105
1-(cyclohexylmethyl)-6-(1H-indol-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
106

3-(3-(cyclohexyl who yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide
107
6-(4-(aminomethyl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
108
6-(4-hydroxyphenyl)-1-((1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
109
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile
110
1-((1S,4S)-4-hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
111
1-(cyclohexylmethyl)-6-(pyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
112
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-ethylbenzamide
113
1-(cyclohexylmethyl)-6-(4-(2-hydroxypropan-2-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
114
1-(cyclohexylmethyl)-6-(4-hydroxy-2-were)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
115
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic acid
116

6-(4-hydroxyphenyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
117
6-(4-hydroxyphenyl)-1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
118
6-(4-hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydro what iresine[2,3-b]pyrazin-2(1H)-he
119
6-(4-hydroxyphenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
120
6-(4-hydroxyphenyl)-1-phenethyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he
121
1-((1R,4R)-4-hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
122
6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
123
1-(cyclohexylmethyl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he
124
1-(cyclohexylmethyl)-6-(1H-pyrazole-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
125
1-(cyclohexylmethyl)-6-(1H-pyrazole-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
126

1-(cyclohexylmethyl)-6-(1-occaisonaly-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
127
6-(3-(1H-tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
128
1-(cyclohexylmethyl)-6-(2-oxindol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
129
1-(cyclohexylmethyl)-6-(1H-indazol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
130
1-(cyclohexylmethyl)-6-(6-methoxypyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
131
6-(4-hydroxyphenyl)-1-(piperidine-4-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
133
1-(((1R,4R)-4-aminocyclohexane)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
134
1-(cyclohexylmethyl)-6-(6-hydroxypyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
135
1-(cyclohexylmethyl)-6-(2-methoxypyridine-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
136

4-(3-((1R,4R)-4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide
137
2-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetic acid
138
2-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)ndimethylacetamide
139
1-(cyclohexylmethyl)-6-(2-oxoindole-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
140
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-3-methylbenzoic acid
141
N-methyl-4-2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide
142
4-(2-oxo-3-((t is trihydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide
143
7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazine-[2,3-b]pyrazin-2(1H)-he
144
6-(4-(2-hydroxypropan-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
145
6-(1H-indol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
146

6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
147
6-(1H-benzo[d]imidazol-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
148
4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide
149
6-(3-(2H-1,2,3-triazole-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
150
6-(4-(1H-imidazol-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
151
6-(4-(2H-1,2,4-triazole-3-yl)phenyl)-1-((1R,4R)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
152
6-(4-(2H-tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
153
1-(cyclohexylmethyl)-6-(2-hydroxypyridine-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
154
6-(4-(2H-1,2,4-triazole-3-yl)phenyl)-1-(2-tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
155
6-(4-(1H-imidazol-2-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
156

6-(4-(1H-1,2,3-triazole-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
157
6-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
158
1-(cyclohexylmethyl)-6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
159
6-(4-(1H-pyrazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
160
6-(4-(1H-pyrazole-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
161
the hydrochloride of 6-(4-(5-(aminomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
162
1-(cyclohexylmethyl)-6-(4-(5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
163
6-(4-hydroxyphenyl)-1-((1R,4R)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
164
6-(4-hydroxyphenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
165
6-(3-(1H-1,2,4-triazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
166

1-((1R,4R)-4-(hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
167
6-(4-hydroxyphenyl)-1-((1S,4S)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
168
6-(4-hydroxyphenyl)-1-((1R,4R)-4-methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
169
6-(1-methyl-1H-pyrazole-4-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
170
1-(((1R,4R)-4-hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
171
6-(4-hydroxyphenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
172
1-(((1S,4S)-4-hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
173
the hydrochloride of 6-(1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
174

6-(4-(5-(morpholinomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
175
6-(4-hydroxyphenyl)-1-(3-(2-ACS is pyrrolidin-1-yl)propyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
176
the hydrochloride of 6-(4-hydroxyphenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
177
1-(cyclohexylmethyl)-6-(4-(oxazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
178
the hydrochloride of 6-(2-methyl-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
179
6-(4-(5-(methoxymethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
180
1-((1S,4S)-4-(hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
181
6-(3-methyl-1H-pyrazole-4-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
182

6-(1H-pyrazole-4-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
183
the dihydrochloride 6-(2-amino-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
184
6-(4-(5-(2-hydroxypropan-2-yl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
185
6-(4-(5-isopropyl-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he 186
the hydrochloride of 4-(2-methoxy-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzamide
187
4(-1-((1S,4S)-4-hydroxycyclohexyl)-2-methoxy-1H-imidazo[4,5-b]pyrazin-6-yl)benzamide
188
6-(4-hydroxyphenyl)-1-((1S,4S)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
189
6-(3H-imidazo[4,5-b]pyridine-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
190

1-(2-(2,2-dimethylether-2H-Piran-4-yl)ethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
191
6-(4-(1H-pyrazole-1-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
192
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
193
6-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
194
the hydrochloride of 6-(4-(1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
195
6-(4-(5-hydroxymethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
196
the hydrochloride of 6-(4-(1 ሺ-imidazol-5-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
197
6-(4-hydroxyphenyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
198
6-(4-(4,5-dimethyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
199
6-(4-(1H-1,2,4-triazole-5-yl)phenyl)-1-((1S,4S)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
200

6-(4-(1H-1,2,4-triazole-5-yl)phenyl)-1-((1R,4R)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
201
6-(6-(1H-1,2,4-triazole-3-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
202
6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
203
6-(4-(5-((dimethylamino)methyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
204
the hydrochloride of 6-(4-hydroxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
205
the dihydrochloride 6-(2-aminobenzimidazole-5-yl)-1-(cyclohexylmethyl)-4-imidazoline[4,5-b]pyrazin-2-it
206
6-(2-dimethylamino)-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
20
6-(4-hydroxyphenyl)-1-(piperidine-3-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
208

the hydrochloride of 6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-piperidine-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
209
1-(cyclohexylmethyl)-6-(2-(methylamino)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
210
6-(3-methyl-4-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
211
1-(cyclohexylmethyl)-6-(2-(2-methoxyethylamine)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
212
6-(4-(5-((methylamino)methyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
213
6-(4-(5-oxopyrrolidin-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
214
6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
215
6-(4-(1H-imidazol-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
216
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-methyl-2-morpholinopropan)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
217
6-(4-(4H-1,2,4-Tr the azole-3-yl)phenyl)-1-(1-morpholinopropan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
218

6-(4-(pyrrolidin-2-yl)phenyl)-1-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
219
6-(4-(5-(aminomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
220
6-(5-(hydroxymethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
221
(1R,4R)-4-(6-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic
222
(1S,4S)-4-(6-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic
223
6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
224
6-(4-(5-oxopyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
225
6-(4-(pyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
226

6-(1H-benzo[d]imidazol-5-yl)-1-(2-tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
227
6-(3-(hydroxymethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-they are the azo[4,5-b]pyrazin-2(3H)-he
228
6-(5-(2-hydroxyethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
229
1-(cyclohexylmethyl)-6-(pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
230
6-(6-herperidin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
231
6-(6-aminopyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
232
6-(4-(5-methyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
233
6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
234
6-(6-(methylamino)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
235
6-(2-aminopyrimidine-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
236

6-(4-(2-hydroxypropan-2-yl)phenyl)-1-(((1R,4R)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
237
6-(4-hydroxyphenyl)-1-((1-methylpiperidin-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
238
6-(2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-the Iran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
239
1-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
240
6-(4-(hydroxymethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
241
6-(1H-benzo[d]imidazol-6-yl)-1-(1R,4R)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
242
6-(4-(4,5-dimethyl-1H-imidazol-2-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
243
6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
244
6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
245
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
246

6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he
247
6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyridine-2(3H)-he
248
(R)-6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
249
(S)-6-(4-(1H-1,2,4-triazole-3-yl)Fe who yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
250
(1R,4R)-4-(6-(4-(2-hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic
251
6-(3-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
252
6-(4-(1H-imidazol-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
253
6-(4-(5-(aminomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
254

tr>
6-(1H-benzo[d]imidazol-5-yl)-1-(2-tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
255
6-(2-aminopyrimidine-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
256
the hydrochloride of 6-(4-hydroxyphenyl)-1-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it
257
6-(3-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
258
1-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
259
6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
260
6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
261
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
262
(R)-6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he
263
(R)-6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
264

(S)-6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
265
(1R,4R)-4-(6-(4-(2-hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic
266
6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he
267

4.3 METHODS of OBTAINING HETEROARYL COMPOUNDS

Heteroaryl compounds can be obtained by experts using conventional methods of organic synthesis and commercially available substances. As an example, but without limitation, the heteroaryl compounds can be obtained, as shown in Schemes 1-12, which are presented below and in the examples that PR is dstanley in section 5.1. You should specify that the person skilled in the art will be able to modify the procedure described for illustrative diagrams and examples to reach the desired product.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

Pharmaceutically acceptable salts heteroaryl compounds can be formed by conventional and known methods, such as the interaction of a heteroaryl compound with an appropriate acid, as disclosed above. Such salts are typically formed in high yields at moderate temperatures, and they are often given simply by highlighting the connection of a suitable acid leaching at the final stage of the synthesis. Salt-forming acid can be dissolved in a suitable organicism solvent or aqueous-organic solvent such as alcohol, keto is or ester. On the other hand, when it is desirable to obtain a heteroaryl compound in free base form, it can be selected at the final stage alkaline leaching, in accordance with known methods. For example, a typical way to obtain cleaners containing hydrochloride salt includes dissolving the free base in a suitable solvent and thorough drying of the solution, for example, over molecular sieves before bubbling through the solution of gaseous hydrogen chloride.

4.4 APPLICATIONS

Heteroaryl compounds described in this application can be used as pharmaceuticals for the treatment or prevention of disease in animals or humans. In addition, the heteroaryl compounds described in this application are active against kinases (e.g. protein kinases, including kinases that participate in such conditions as cancer, inflammatory conditions, immunological conditions, neurodegenerative diseases, cardiovascular diseases, and metabolic status. Not limited to any theory, it is believed that heteroaryl compounds are useful for treatment and prevention of cancer, inflammatory conditions, immunological conditions, neurodegenerative diseases, cardiovascular diseases and metabolic state which deposits, because of their ability to modulate (e.g. inhibit) kinases, which are involved in the etiology of these conditions. Accordingly, the present application provides a wide range of applications heteroaryl compounds, including the treatment or prevention of the diseases mentioned below. The ways provided in this application include the introduction of an effective amount of one or more heteroaryl compounds to a patient in need of it.

Representative immunological status, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiple sclerosis, ordinary erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Grave's disease, and diabetes (such as diabetes type I).

Representative inflammatory condition, for the treatment or prevention of which heteroaryl compounds are useful 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, diabetes (such as diabetes type I and diabetes the IPA II) and obesity.

Representative cardiovascular diseases, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, restenosis, stroke, myocardial infarction or ischemic disease of the heart, lungs, intestines, kidneys, liver, pancreas, spleen or brain.

Representative metabolic state, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, obesity and diabetes (such as diabetes type II).

Representative neurodegenerative diseases, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, Huntington's disease, Alzheimer's disease and HIV-induced encephalitis.

In a particular variant embodiment of the invention in this application provides methods of treatment or prevention of insulin resistance. In some embodiments, embodiments of the invention in this application provides methods of treatment or prevention of insulin resistance that leads to diabetes (e.g. type II diabetes).

In another variant embodiment of the invention in this application provides methods of treatment or prevention of syndrome X or metabolic syndrome.

Another is ariante embodiment of the invention, in this application provides methods of treatment or prevention of diabetes.

In another variant embodiment of the invention in this application provides methods of treatment or prophylaxis of diabetes type II, diabetes type I, slowly developing diabetes type I, diabetes insipidus (e.g., neurogenic diabetes insipidus, nephrogenic diabetes insipidus, dipsogenic diabetes or gestagenna diabetes), diabetes mellitus, gestational diabetes, polycystic ovarian syndrome, diabetes adults, juvenile diabetes, insulin-dependent diabetes, insulin-independent diabetes mellitus, caused by improper diet, cloznogo diabetes, pre-diabetic state (for example, impaired glucose metabolism)associated with cystic fibrosis, diabetes, hemochromatosis and ketosis-resistant diabetes.

In another variant embodiment of the invention in this application provides methods of treatment or prevention of fibrotic diseases and disorders. In a particular variant embodiment of the invention in this application provides methods of treatment or prevention of idiopathic pulmonary fibrosis, myelofibrosis, liver fibrosis, sealifebase and steatohepatitis.

Representative types of cancer, for the treatment or prevention of which heteroaryl soedineniya useful include but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or Central nervous system. Heteroaryl compounds are useful for the treatment or prevention of solid tumors and tumors of the blood and bone.

Specific types of cancer covered by the methods provided in this application include cancer associated with PKCθ, mTOR, Syk and Tyk2 kinases and their mutants or isoforms.

Other types of cancer covered by the methods provided in this application include cancer-related pathways following kinases: IKK1, PKA, Akt, PKC (all isoforms), Aurora, Abα, c-Raf, PI3K (all isoforms), ATM, ATX, DNA-PK and Yes.

More specifically, cancer and related disorders, the treatment or prevention of which can be accomplished using the methods and compositions provided in the present application include but are not limited to, the following: leukemias such as, but not limited to, acute leukemia, acute lymphocytic leukemia, acute miliitary leukemias such as myeloblastic, PR is military, myelomonocytic, monocytic leukemia, erythroleucus and myelodysplastic syndrome or symptom, such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed by sideroblasts (RARS), RA with excess of blasts (RAEB), RAEB in transformation (RAEB-T), prelates and chronic myelomonocytic leukemia (CMML), chronic leukemias such as but not limited to, chronic miliitary (granulocytic) leukemia, chronic lymphocytic leukemia, hairy-cell leukemia; polycythemia vera; lymphomas such as, but not limited to, Hodgkin's disease, non-Hodgkin disease, multiple myeloma, such as, but not limited to smoldering multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, prismatically leukemia, single plasmacytoma and extramedullary plasmacytoma; macroglobulinemia Waldenstrom; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone sarcoma and connective tissue, such as, but not limited to bone sarcoma, osteosarcoma, chondrosarcoma, abnormal Ewing sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, permasteelisa sarcoma, soft tissue sarcoma, angiosarcoma (gemangiosarkoma), Phi is Rosatoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, glioma of the brain stem, ependymoma, oligodendroglioma, non-glial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary lymphoma of the brain; breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease and inflammatory breast cancer; adrenal cancer such as but not limited to, pheochromocytoma and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or insulare-cell tumor; pituitary cancer, t is the cue as, but not limited to, illness Kuchiha, prolactin-secreting tumor, acromegaly, and diabetes insipidus; cancer of the eye, such as, but not limited to, ocular melanoma such as melanoma of the iris, choroid melanoma and cilliary melanoma, and retinoblastoma; vaginal cancers such as this form may cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as this form may cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancers such as but not limited to, this form may cell carcinoma, and adenocarcinoma; cancer of the uterus, such as, but not limited to, endometrial carcinoma and sarcoma of the uterus, cancer of the ovaries, such as, but not limited to, epithelial ovarian carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cancer of the esophagus, such as, but not limited to, squamous cancer, adenocarcinoma, adenomatosna carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucosa carcinoma and asanovic-cell (small cell) carcinoma; cancers of the stomach, such as, but not limited to, adenocarcinoma, the fungus is seen growing (polynoidae), ulcerative, superficial swelling, diffuse growing, malignant lymphoma, liposarcoma, fibrosarcoma and carcinosarcoma; cancer colon cancer; cancer of the rectum; cancer of the liver, such as, but not limited to hepatocellular carcinoma and hepatoblastoma, cancer of the gallbladder, such as adenocarcinoma; cholangiocarcinomas, such as, but not limited to papillary, nodular, and diffuse; lung cancer such as non-small cell lung cancer, this form may cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; testicular cancers such as but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocyte, not-seminoma, embryonal carcinoma, teratoma carcinoma, horiokartsinoma (yolk-sac tumor), cancer of the prostate, such as, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; cancer of the penis; cancer of the oral cavity, such as, but not limited to, this form may cell carcinoma; basal cancers; cancer of the salivary glands, such as, but not limited to, adenocarci the Ohm, mucoepidermoid carcinoma and adeno-cystic carcinoma; cancer of the pharynx, such as, but not limited to, this form may cell carcinoma and verrucose cancer; skin cancers such as but not limited to, basal cell carcinoma, this form may cell carcinoma and melanoma, superficial growing melanoma, nodular melanoma, malignant lentigo, acrolina lentiginosa melanoma; cancers of the kidney, such as, but not limited to, renal cell cancer, adenocarcinoma, renal cell cancer, fibrosarcoma, transtorno cell cancer (renal pelvis and/ or ureter); Wilms ' tumor; cancer of the bladder, such as, but not limited to, transtorno-cell carcinoma, this form may cell carcinoma, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endothelioma, libpango-endothelioma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, carcinoma of the sebaceous glands, papillary carcinoma and papillary adenocarcinomas (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J. B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America)

Accordingly, the methods and compositions provided in the present application, are also useful for the treatment or prevention of various cancers or other abnormal proliferative diseases, including (but not limited to) the following: carcinoma, including carcinoma of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including this form may cell carcinoma; hematopoietic tumors of lymphoid origin, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, lymphoma Burkitts; hematopoietic tumors of myeloid origin, including acute and chronic myelogenous leukemia, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratocarcinoma, neuroblastoma and glioma; tumors of the Central and peripheral nervous system, including astrocytoma, different glioblastoma, neuroblastoma, glioma and swannery; solid and blood tumors; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma and osteosarcoma; and other tumors, including melanoma,xenoderma pegmentosum, keratoacanthoma, Semin is mu thyroid follicular cancer and teratocarcinoma. Also provides that cancers caused by aberrations in apoptosis, can also be treated using the methods and compositions disclosed in the present application. Such cancers may include, but are not limited to, follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis and myelodysplastic syndromes. In specific embodiments, the embodiments of the invention, carry out the treatment or prevention of malignant or deproliferation changes (such as metaplasia and dysplasia), or hyperproliferative disorders of ovary, bladder, breast, colon, lung, skin, pancreas, kidney, or uterus. In other specific embodiments, the embodiments of the invention, carry out the treatment or prevention of sarcoma, melanoma or leukemia.

In a particular variant embodiment of the invention, methods and compositions presented in this application are also useful for the treatment, prevention or care for different types of lymphomas (i.e. heterogeneous group of neoplasms arising in the reticuloendothelial and lymphatic systems), such as not-Hodge is Ty lymphoma (NHL) (i.e. malignant monoclonal proliferation of lymphoid cells in areas of the immune system, including lymph nodes, bone marrow, spleen, liver and gastrointestinal tract). NHL, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, lymphoma cortex, MCL, lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma, ILL, diffuse non-differentiated lymphocytic lymphoma, PDL, centrocytes lymphoma, diffuse small cell lymphoma, DSCCL, follicular lymphoma, and any type of lymphoma of the cerebral cortex which can be discerned under the microscope (nodular, diffuse, blast lymphoma and lymphoma region of the mantle).

In another variant embodiment of the invention in this application are provided methods and compositions useful for administration to patients in need of bone marrow transplantation for treatment of malignant diseases (for example, patients suffering from acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome ("preclaims"), syndrome monosomy 7, non-Hodgkin's lymphoma, neuroblastoma, brain tumors, multiple myeloma, testicular tumor is mi germ cells, breast cancer, lung cancer, ovarian cancer, melanoma, glioma, sarcoma, or other solid tumors), patients in need of bone marrow transplants to treat non-cancerous diseases (for example, patients suffering from hematologic disorders, congenital immune deficiency, mucopolysaccharidosis, lipidosis, osteoporosis, Langerhans cells Langerhans, Lesch-Nyhan syndrome or glycogen disease), patients undergoing chemotherapy or radiation therapy, patients preparing to undergo chemotherapy or radiation therapy, patients who had previously received chemotherapy or radiation therapy.

In another variant embodiment of the invention in this application are provided methods of treating myeloproliferative disorders or myelodysplastic syndromes involving the introduction of a patient in need, an effective amount of heteroaryl compounds or compositions comprising such compound. In some embodiments, embodiments of the invention, the myeloproliferative disorder is a true erythremia; primary trombozitemia; chronic myelogenous leukemia; acute or chronic granulocytic leukemia; acute or chronic myelomonocytic leukemia; maloperro-erythroleucus; or angio is built myeloid metaplasia.

In another variant embodiment of the invention in this application provides methods of treating cancer or tumors that are resistant to other kinase inhibitors, such as treatment by imatinib mesilate (STI-571 or Gleevec™), involving the introduction of a patient in need, an effective amount of heteroaryl compounds or compositions comprising such compound. In a particular variant embodiment of the invention in this application provides methods of treatment of leukemias, including, but not limited to, gastrointestinal stromal tumor (GIST), acute lymphocytic leukemia or chronic miliitary leukemia resistant to treatment by imatinib mesilate (STI-571 or Gleevec™), involving the introduction of a patient in need, an effective amount of heteroaryl compounds or compositions comprising such a connection.

In a particular variant embodiment of the invention in this application provides methods of treatment or prevention of diseases or disorders associated with inhibition of PKCθ or mTOR. Specific diseases that can be treated or prevented by inhibiting PKCθ or mTOR include, but are not limited to, rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; KIS the religious fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; type II diabetes; obesity; atherosclerosis; restenosis after angioplasty; left ventricular hypertrophy of the heart; myocardial infarction; stroke; ischemic heart damage, lung, intestine, kidney, liver, pancreas, spleen and brain; acute or chronic rejection of organ transplant; preservation of the organ for transplantation; organ failure or loss of an organ (e.g., including but not limited to those resulting from ischemic-reperfusion lesions, trauma, severe traumatic injury, automobile accidents, fractures or graft rejection); disease graft-versus-host; endotoxic shock; multiple organ failure; psoriasis; burn caused by heat, chemicals or radiation; eczema; dermatitis; skin graft; ischemia; ischemic conditions associated with surgery or traumatic injury (e.g., car accident, gunshot wound or fracture of extremities); epilepsy; Alzheimer's disease; Parkinson's disease; immune response to bacterial the ing or viral infection; cachexia; angiogenic and proliferative diseases, solid tumors, and cancers of various tissues, such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, throat, esophagus, mouth, larynx, bladder, ovary or uterine.

In a particular variant embodiment of the invention in this application provides methods of treatment or prevention of leukemia (i.e malignant tumors of severe haematopoietic tissues), including, but not limited to, chronic lymphocytic leukemia, chronic miliitary leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia. Leukemia can be recurrent, persistent or resistant to traditional therapy. The term "recurrent" refers to a situation where patients had remission of leukemia after therapy, again appeared leukemia cells in the bone marrow and decreased the number of normal blood cells. The term "persistent or resistant" refers to the fact that patients, even after intensive therapy, there are residual leukemic cells in their bone marrow.

Different types of cancer described in the Provisional Application U.S. No. 60/380842, filed may 17, 2002, full sod the neigh which is incorporated into the present application by reference (see, for example, Section 2.2. Types of Cancers). Specific cancers include, but are not limited to, leukemias such as chronic lymphocytic leukemia, chronic miliitary leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia; running malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, multiform glioblastomas, glioblastoma, glioma of brain stem malignant brain tumor with a poor prognosis malignant glioma, rediculious malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, colorectal cancer Dukes C & D, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotyping acute myeloblastic leukemia, Hodgkin's lymphoma, nahodkinskuju lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma low-grade, malignant melanoma, malignant mesothelioma, malignant pleural effusions mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, sarcoma of soft TC is her scleroderma, cutaneous vasculitis, histiocytosis Langerhans cells, leiomyosarcoma, fibrodysplasia with progressive ossification, hormone-resistant prostate cancer, soft tissue sarcoma with a high risk after resection of nonresectable hepatocellular carcinoma, macroglobulinemia Waldenstrom, slowly developing myeloma, painless myeloma, cancer of the fallopian tubes, androgen-independent prostate cancer, androgen-dependent non-metastatic prostate cancer stage IV, insensitive to hormone prostate cancer, insensitive to chemotherapy prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary carcinoma of the thyroid gland and leiomyoma. In one variant embodiment of the invention, the cancer is primary or metastatic. In another variant embodiment of the invention, the cancer is recurrent, persistent or resistant to chemotherapy or radiation therapy; in particular, resistant to thalidomide.

In addition, the present application provides methods of treatment of patients previously treated for cancer, but who do not respond to standard therapy, and which had not been previously treated. Also in this application are provided methods of treating patients, regardless of the age of the patient, although some cancers are most common in certain age groups. Also, the present application provides methods of treating patients undergoing surgery as a method of treatment of a particular cancer, and patients who did not have surgery. Because patients suffering from cancer, have heterogeneous clinical manifestations and varying clinical outcome, treatment, prescribed different patients may be different, depending on the prognosis for these patients. The person skilled in the art can easily determine, without undue experimentation, specific additional funds, type of operation, and types of non-standard treatment that can effectively be used to treat a particular patient suffering from cancer.

In another variant embodiment of the invention in this application provides methods of treatment or prevention of a disease or disorder (e.g., cancer or tumor)that are associated with the inhibition of IKK1, PKA, Akt, PKC (all isoforms), Aurora, Ab1, c-Raf, PI3K (all isoforms), ATM, ATX, DNA-PK, Syk, PI3K or Yes.

In a particular variant embodiment of the invention in this application provides methods of treatment or prevention of diseases or disorders associated with inhibition of mTOR, which include, but are not limited to, tumor syndromes that result directly or indirectly, genetic defects in PTEN (deletions phosphatase and homolog of Tenzin in chromosome 10), TSCl (Tuberose sclerosis 1), TSC2 (Tuberose sclerosis 2), NFl (neurofibromin 1), AMPK (AMP-dependent protein kinase STK11, serine/trionychinae 11) and LKB1. Not limited to any theory, it is believed that genetic defects associated with these proteins, lead to hyperactivate the mTOR pathway. Specific diseases that can be treated or prevented by inhibiting the mTOR pathway include, but are not limited to, disease Cowden syndrome Cowden, Cowden-like syndrome, Bannayan-Zonana syndrome Bannayan-Riley-Ruvalcaba, disease, Lhermitte-Duclos, endometrial carcinoma, prostatic carcinoma and malignant melanoma, tuberose sclerosis complex, lymphangioleiomyomatosis, neurofibromatosis 1, hereditary hypertrophic cardiomyopathy syndrome Peutz-jeghers, renal cell carcinoma and polycystic kidney disease.

In a particular variant embodiment of the invention in this application provides methods of treatment or prevention of diseases or disorders that are associated with the modulation, for example inhibition of the kinase, including, but not limited to, the tyrosine of the protein kinase (SYK), the tyrosine of the protein kinase (ZAP-70), the tyrosine a protein kinase 2 beta (PYK2), focal adhesion kinase 1 (FAK), a kinase B is impositon (BLK), kinase hematopoietic cells (HCK), a homologue of the oncogene of the Yamaguchi sarcoma virus v-yes-1 (LYN), T-cell-specific the tyrosine a protein kinase (LCK), the proto-oncogenic the tyrosine a protein kinase (YES), the proto-oncogenic the tyrosine a protein kinase(SRC), the proto-oncogenic the tyrosine a protein kinase (FYN), the proto-oncogenic the tyrosine a protein kinase (FGR), the proto-oncogenic the tyrosine a protein kinase (FER), the proto-oncogenic the tyrosine a protein kinase (FES), C-SRC kinase, the tyrosine of the protein kinase (CYL), the tyrosine of the protein kinase (CSK), megakaryocyte-associate the tyrosine a protein kinase (CTK), the tyrosine of a protein kinase receptor (EPH), Ephrin A-type receptor 1, Ephrin A-type receptor 4 (EPHA4), Ephrin B-type receptor 3 (EPHB3), Ephrin A-type receptor 8 (EPHA8), neurotrophic tyrosinekinase-receptor type 1 (NTRK1), the tyrosine of the protein kinase (PTK2), the syk tyrosinekinase (SRK), the tyrosine of the protein kinase (CTK), the tyrosine of the protein kinase tyro3 (TYRO3), tyrosinekinase agammaglobulinemia Bruton (BTK), tyrosinekinase leukocytes (LTK), the tyrosine of the protein kinase (SYK), the tyrosine of the protein kinase (STY), the tek tyrosinekinase (TEK), the elk tyrosinekinase (ERK), tyrosinekinase with homologous domains of immunoglobulin and egf factor (TIE), the tyrosine of the protein kinase (TKF), neurotrophic tyrosinekinase, receptor type 3 (NTRK3), protein kinase-3 mixed origin (MLK3), protein kinase, mitogen-activated 4 (PRKM4), proteine the ABC, activated mitogen 1 (PRKMl), the tyrosine of the protein kinase (PTK7), the tyrosine of the protein kinase (EEK), minimogueva (Drosophila) homolog (MNBH), kinase bone marrow, x-linked (BMX), eph-like tyrosinekinase 1 (ETK1), macrophage-stimulating 1 receptor (MST1R), btk-associated protein of 135 kDa, lymphocyte-specific the tyrosine a protein kinase (LCK), receptor 2 fibroblast growth factor (FGFR2), the tyrosine of the protein kinase-3 (TYK3), the tyrosine of the protein kinase (TXK), the tyrosine of the protein kinase tec (TEC), the tyrosine of the protein kinase-2 (TYK2), ligand 1 tyrosinekinase eph receptor (EPLG1), t-cell tyrosinekinase (EMT), the eph tyrosinekinase 1 (EPHT1), tyrosinekinase-receptor zona pellucida, 95 kDa (ZRK), protein kinase, mitogen-activated, kinase 1 (PRKMKl), the eph tyrosinekinase 3 (EPHT3), specific to stop the growth gene 6 (GAS6), the receptor kinase domain inserts (KDR), axl to tyrosinekinase-receptor (AXL), receptor-1 growth factor fibroblasts (FGFR1), a homolog 2 viral oncogene erythroblastic leukemia birds v-erb-b2 (ERBB2), fms-like tyrosinekinase-3 (FLT3), neuroepithelial tyrosinekinase (NEP), neurotrophic tyrosinekinase-receptor 3 (NTRKR3), ligand 5 tyrosinekinase eph receptor (EPLG5), neurotrophic tyrosinekinase, receptor, type 2 (NTRK2), receptor-like tyrosinekinase (RYK), b-lymphocyte-specific tyrosinekinase (BLK), the eph tyrosinekinase 2 (EPHT2), ligand 2 tyrosinekinase eph receptor (EPLG2), g is imaginova disease VIII, ligand 7 tyrosinekinase eph receptor (EPLG7), janus kinase 1 (JAKl), the fms tyrosinekinase-1 (FLTl), protein kinase, camp-dependent, regulatory, type I, alpha (PRKAR1A), wee-1 tyrosinekinase (WEE1), eph-like tyrosinekinase 2 (ETK2), the musk tyrosinekinase-receptor, insulin receptor (INSR), janus kinase 3 (JAK3), ligand fms tyrosine kinase-3, protein kinase c, beta 1 (PRKCBl), cell-surface receptor tyrosinekinase type (EHR3), janus kinase 2 (JAK2), a kinase 1 Hm domain (LIMKl), phosphatase 1 dual specificity (DUSP1), kinase hematopoietic cells (HCK), a protein activated tyrosine 3-monooxygenase/tryptophan 5-monooxygenase, eta polypeptide (YWHAH), ret proto-oncogene (RET), a protein activated tyrosine 3-monooxygenase/tryptophan 5-monooxygenase, Zeta polypeptide (YWHAZ), a protein activated tyrosine 3-monooxygenase/tryptophan 5-monooxygenase, beta polypeptide (YWHAB), a transmembrane kinase hepatoma (HTK), 6 map kinase kinase, phosphatidylinositol 3-kinase, catalytic, alpha polypeptide (PIK3CA), an inhibitor of cyclin-dependent kinase 3 (CDKN3), diacylglycerides, Delta, 130 kDa protein tyrosinosis, precepting type 13 (PTPN1 3), homolog of the viral oncogene 1 murine leukemia abelson (ABL1), diacylglycerides, alpha (DAGK1), kinase 2 (focal adhesion, receptor 1 epithelial discontinuos domain (EDDR1), kinase anaplastic lymphoma (ALK), phosphatidylinositol 3-kinase, catalytic, DIN is and polypeptide (PIK3CG), regulatory subunit of phosphatidylinositol 3-kinase, (PIK3R1), kinase-1 eph homology (EHK1), homolog of the viral oncogene feline sarcoma v-kit hardy-zuckerman 4 (KIT), receptor-3 fibroblast growth factor (FGFR3), vascular endothelial growth factor c (VEGFC), the receptor for epidermal growth factor (EGFR), oncogene (TRK)associated with growth factor receptor protein 7 (GRB7), activator protein ras p21 (RASA2), met proto-oncogene (MET), src-like adapter (SLA), vascular endothelial growth factor (VEGF)receptor growth factor vascular endothelial (VEGFR), the receptor for nerve growth factor (NGFR), receptor trombozitarnogo growth factor (DERIVED), receptor beta trombozitarnogo growth factor (PDGFRB)with dual specificity regulated tyrosine-(Y)-phosphorylation kinase 2 (DYRK2)with dual specificity regulated tyrosine-(Y)-phosphorylation kinase 3 (DYRK3)with dual specificity regulated tyrosine-(Y)-phosphorylation kinase 4 (DYRK4)with dual specificity regulated tyrosine-(Y)-phosphorylation kinase 1A (DYRK1A)with dual specificity regulated tyrosine-(Y)-phosphorylation kinase 1B (DYRK1B), CDC-like kinase 1 (CLKl), the tyrosine of the protein kinase STY, CDC-like kinase 4 (CLK4), CDC-like kinase 2 (CLK2) or CDC-like kinase 3 (CLK3).

In another variant embodiment of the invention in this application provides methods of treatment or profile is ctice disease or disorder, that are associated with the modulation, for example inhibition of serine/trainingin or related molecules, including, but not limited to, Akt/protein kinase B, protein kinase A (PKA), CK2, the cyclin-dependent kinase 7 (CDK7), serine/threonine the rac protein kinase, serine-threonine the protein kinase n (PKN), serine/threonine a protein kinase 2 (STK2), the zipper protein kinase (ZPK), the tyrosine of the protein kinase (STY), tyrosinekinase agammaglobulinemia bruton (BTK), mkn28 kinase, protein kinase, x-linked (PRKX), elk tyrosinekinase (ERK), ribosomal protein s6 kinase, 90 kDa, polypeptide 3 (RPS6KA3), glycogenosis VIII-related mortality of the protein kinase 1 (DAPK1), pctaire the protein kinase 1 (PCTKl), protein kinase, interferon-inducible double-stranded RNA (PRKR), a receptor activin a type II-like kinase 1 (ACVRLK1), protein kinase, camp-dependent, catalytic, alpha (PRKACA), protein kinase, y-linked (PRKY)associated with G-protein receptor kinase 2 (GPRK21), the protein kinase c, theta form (PRKCQ), kinase 1 lim domain (LIMK1), phosphoglycerides 1 PGK1), kinase 2 lim domain (LIMK2), c-jun kinase, receptor activin a type II-like kinase 2 (ACVRLK2), janus kinase 1 (JAK1), kinase elkl motif (EMK1)associated with male germ cell kinase (MAK), caseinline 2, alpha Prime subunit (CSNK2A2), caseinline 2, beta polypeptide (CSNK2B), caseinline 2, alpha 1 polypeptide (CSNK2A1), ret proto-oncogene (RET), hematopoietics the s predecessor kinase 1, conservative helix-loop-helix ubiquitous kinase (CHUK), caseinline 1, Delta (CSNK1D), caseinline 1, Epsilon (CSNK1E), homolog 1 viral oncogene murine thymoma v-akt (AKTl), tumor protein p53 (TP53 genes), proteinopathy 1, regulatory (inhibitor) subunit 2 (PPP1R2), oncogene pim-1 (PIM1), receptor trasformismo growth factor-beta type II (TGFBR2), receptor trasformismo growth factor-beta type I (TGFBR1), homolog b1 viral oncogene mouse sarcoma v-raf (a skin disease), bone morphogenetic receptor type II (BMPR2), a homolog 1 viral oncogene 3611 murine sarcoma v-raf (ARAF1), homolog 2 viral oncogene 3611 murine sarcoma v-raf (ARAF2), protein kinase C (PKC), a homolog of the viral oncogene of the cat's sarcoma v-kit hardy-zuckerman 4 (KIT) or c-KIT receptor (KITR).

In another variant embodiment of the invention in this application provides methods of treatment or prevention of diseases or disorders that are associated with the modulation, for example inhibition of MAP kinases, including, but not limited to, mitogen-activated protein kinase 3 (MAPK3), p44erk1, p44mapk, mitogen-activated protein kinase 3 (MAP kinase 3; p44), ERK1, PRKM3, P44ERK1, P44MAPK, mitogen-activated protein kinase 1 (MAPK1), kinase 1 mitogen-activated protein kinase (MEK1), MAP2K1 tyrosinemia protein kinases ERK2, mitogen-activated protein kinase 2, regulated extracellular signal kinase 2, tyrosinemia Proteus the kinase ERK2, mitogen-activated protein kinase 2 is regulated by extracellular signal kinase 2, ERK, p38, p40, p41, ERK2, ERT1, MAPK2, PRKM1, PRKM2, P42MAPK, p41mapk, mitogen-activated protein kinase 7 (MAPK7), BMK1 kinase, which is regulated by extracellular signal kinase 5, BMK1, ERK4, ERK5, PRKM7, nemo-like kinase (NLK), possible ortholog of mouse nemo-like kinase, mitogen-activated protein kinase 8 (MAPK8), protein kinase JNK1, JNK1 beta protein kinase, JNK1 alpha protein kinase, c-Jun N-terminal kinase 1, the stress-activated protein kinase JNK1, JNK, JNK1, PRKM8, SAPK1, JNK1 A2, JNK21B1/2, mitogen-activated protein kinase 10 (MAPK10), c-Jun kinase 3, JNK3 alpha protein kinase, c-Jun N-terminal kinase 3, the stress-activated protein kinase JNK3, stress-activated protein kinase beta, mitogen-activated protein kinase 9 (MAPK9), MAP kinase 9, c-Jun kinase 2, c-Jun N-terminal kinase 2 and stress-activated protein kinase JNK2, JNK2, JNK2A, JNK2B, PRKM9, JNK-55, JNK2BETA, p54aSAPK, JNK2ALPHA, mitogen-activated protein kinase 14 (MAPK 14), p38 MAP kinase, MAP kinase Mxi2, Csaids binding protein, MAX-interacting protein 2, stress-activated protein kinase 2A, p38 mitogen-activated protein kinase, protein, binding to the cytokine-suppressive anti-inflammatory drug, RK, p38, EXIP, Mxi2, CSBP1, CSBP2, CSPB1, PRKM14, PRKM15, SAPK2A, p38ALPHA, mitogen-activated protein kinase 11 (MAPK11), stress-activated protein kinase-2, stress-activated protein kinase-2b, mitogen-activated proteinkinase p38-2, mitogen-activated protein kinase RET, P38B, SAPK2, p38-2, PRKM11, SAPK2B, rat, RAT, mitogen-activated protein kinase 13 (MAPK13), stress-activated protein kinase 4 mitogen-activated protein kinase p38 Delta, SAPK4, PRKM1 3, RLT, mitogen-activated protein kinase 12 (MAPK 12), RAM, stress-activated protein kinase 3, mitogen-activated protein kinase 3, ERK3, ERK6, SAPK3, PRKM 12, SAPK-3, P38GAMMA, mitogen-activated protein kinase 6 (MAPK6), MAP kinase isoforms p97, mitogen-activated protein kinase 5, mitogen-activated protein kinase 6, which is regulated by extracellular signal kinase 3, which is regulated by extracellular signal kinase, p97, ERK3, PRKM6, p97MAPK, mitogen-activated protein kinase 4 (MAPK4), Erk3 protein kinase, mitogen-activated protein kinase 4 (MAP kinase 4; p63), PRKM4, p63MAPK, ERK3, or regulated by extracellular signal kinase 8 (ERK7).

Heteroaryl compound can be combined with other pharmacologically active compounds ("second active agent") in methods and compositions described in this application. Consider that some combinations may work synergistically in the treatment of specific types of diseases or disorders as well as conditions and symptoms associated with such diseases or disorders. Heteroaryl compound can also work to alleviate adverse effects associated with some and second active substances, and Vice-versa.

In the methods and compositions described in this application, you can use one or more second active ingredients or agents. The second active substance can be large molecules (e.g. proteins) or small molecules (e.g., synthetic inorganic, ORGANOMETALLIC or organic molecules).

Examples of large molecules of second active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Specific examples of active agents include anti-CD40 monoclonal antibodies (such as, for example, SGN-40); inhibitors discontiuation (such as, for example, SAHA and lunar abyss 824); inhibitors of the protein 90 heat shock (such as, for example, 17-AAG); inhibitors of kinase receptor insulin-like growth factor-1; kinase inhibitors of growth factor receptor vascular endothelium (such as, for example, PTK787); inhibitors of growth factor receptor insulin; inhibitors of acyltransferase lysophosphatidic acid; inhibitors of IkB kinase; p38MAPK inhibitors; inhibitors of EGFR (such as, for example, gefitinib and erlotinib HCL), antibody to HER-2 (such as, for example, trastuzumab (Herceptin®) and pertuzumab (Omnitarg™)); antibodies to VEGFR (such as, for example, bevacizumab (Avastin™)); VEGFR inhibitors (such as, for example, flk-1 specific is inhibitory kinase, SU5416 and ptk787/zk222584); P13K inhibitors (such as, for example, wortmannin); inhibitors of C-Met (such as, for example, PHA-665752); monoclonal antibodies (such as, for example, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab (Panorex®) and G250); and anti-TNF-α antibodies. Examples of active substances, which are small molecules include, but are not limited to, cancer funds, representing small molecules, antibiotics (eg, clarithromycin).

Specific second active compounds that can be used in combination with a heteroaryl compound vary depending on the specific indications in respect of which need treatment, prevention or relief.

For example, to implement treatment, prevention, or care for cancer, the second active substance include, but are not limited to: semaxanib; cyclosporine; etanercept; doxycycline; bortezomib; activity; aclarubicin; acetasol hydrochloride; Acronis; adozelesin; aldeslakin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; astromicin; asparaginase; aspirin; azacytidine; asettaa; azotomycin; batimastat; benzodepa; bikalutamid; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; to replacin; carmustin; karubitsin hydrochloride; carzelesin; Cedeira; celecoxib; chlorambucil; cirolemycin; cisplatin; cladribine; kristana mesilate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; decompletion; deazaguanine; deazaguanine mesilate; diazinon; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; deatomizer; edatrexate; eflornithine hydrochloride; elsamitrucin; anoplate; Promat; epirubicin; epirubicin hydrochloride; arbolada; zorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; atopen; fadrozole hydrochloride; fazarabine; phenetidine; floxuridine; fludarabine phosphate; fluorouracil; fluorocytosine; poquito; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubitsin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; lioresal hydrochloride; lometrexol sodium; lomustin; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; Matorin; matureup; maintain; metatarsi; cytochromes; mitogillin; mitomycin; mitomycin; mit is sper; mitotane; mitoxantrone hydrochloride; mycophenolate acid; nocodazole; nogalamycin; ormaplatin; oxysure; paclitaxel; pegaspargase; polymycin; pentamycin; peplomycin sulfate; perforated; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomelin; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; ibuprin; safingol; safingol hydrochloride; semustine; contrast; spartacat sodium; sparsomycin; spirogermanium hydrochloride; spiramycin; spiroplatin; streptonigrin; streptozocin; alienor; talisayan; tecogen sodium; Taxotere; tegafur; Alexandre hydrochloride; ]; teniposide; teraxion; testolactone; timipre; tioguanin; thiotepa; teatterin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate the glucuronate; triptorelin; tubulosa hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; benefitin sulfate; Inglesina sulfate; winnersin sulfate; vinorelbine tartrate; vinosity sulfate; ventolin sulfate; vorozole; senility; zinostatin and zorubicin hydrochloride.

Other second means include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-itinerarary; abiraterone; alarabi is in; allfusion; Adelina; adozelesin; aldeslakin; ALL-TK antagonists; altretamine; ambamustine; amidax; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; Andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antranilic; anti-dorkalicious morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; gene modulators of apoptosis; regulators of apoptosis; apurinovaya acid; ara-CDP-DL-PTBA; argininosuccinate; isolagen; atamestane; attemptin; achinstein 1; 2 achinstein; achinstein 3; azasetron; anatoxin; asteroid; derivatives baccatin III; balana; batimastat; antagonists BCR/ABL; benzocaine; benzoyltartaric; beta-lactam derivatives, beta-alamin; butaclamol B; Betulinol acid; an inhibitor of bFGF; bikalutamid; bisantrene; besuseradminclient; bisnafide; bitraten A; bizelesin; Brevet; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; derivatives camptothecin; capecitabine; carboxamid-amino-triazole; carboxamidates; CaRest M3; CARN 700; inhibitor, cartilaginous origin; carzelesin; inhibitors caseinline (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chlorination the sulfonamide; cicaprost; CIS-porphyrin; cladribine; clatronic is; analogues clomiphene; clotrimazole; colimycin a; colimycin B; combretastatin A4; similar combretastatin; convenin; kambezidis 816; Kristol; cryptophycin 8; derivatives cryptophycin a; curacin a; cyclopentadecanone; cyclopean; cephamycin; cytarabine actstat; cytolytic factor; cytostatin; daclizumab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; Taxifolin; dexrazoxane; dexverapamil; diazinon; didemnin B; detox; diethylnitrosamine; dihydro-5-azacytidine; dihydroxy-9; dioxazine; diphenyl spiramycin; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; elastin; edelfosine; edrecolomab; eflornithine; elements; Amateur; epirubicin; epristeride; similar estramustine; agonists of estrogen; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; phenetidine; filgrastim; finasteride; flavopiridol; fileselection; fluasterone; fludarabine; forceunauthorized hydrochloride; forenames; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; Galitsin; ganirelix; inhibitors gelatinase; gemcitabine; inhibitors of glutathione; HaSulam; heregulin; hexamethylene biocetamol; hypericin; ibandronate acid; idarubitsin; idoxifene; Idamante; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod is; peptide Immunostimulants; inhibitor of insulin-like growth factor receptor-1; interferon agonists; interferons; interleukins; iobenguane; iododeoxyuridine; ipomeanol-4; isoplast; irsogladine; isomerases; isohemagglutinins B; fusetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; lanemile; lenograstim; lentinan sulfate; leptostachys; letrozole; factor inhibiting leukemia; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leiprorelina; levamisole; lioresal; similar linear polyamine; lipophilic disaccharide glycosides peptide; lipophilic platinum compounds; lissoclinum 7; lobaplatin; lombrici; lometrexol; lonidamine; losoxantrone; doxorubin; lurtotecan; lutetium texaphyrin; lisofylline; lytic peptides; maytansine; sandostatin a; marimastat; masoprocol; maspin; inhibitors matrilysin; inhibitors of matrix metalloproteinases; menogaril; merbanan; peterlin; methionine; metoclopramide; inhibitor of MIF; mifepristone; miltefosin; Miramistin; mitoguazone; mitolactol; analogues of mitomycin; mitonafide; mycotoxicosis the fibroblast growth factor-saporin; mitoxantrone; Maarten; molgramostim; Erbitux, human chorionic gonadotropin; monophosphoryl lipid A+sk cell membrane myobacteria; mopidamol; mustard anticancer agent; megaproxy B; extract mikeb sterelny cell membranes; mylapore; N-azetidinone; N-substituted benzamide; nafarelin; Agresti; naloxone+pentazocine; Naveen; Natterer; nartograstim; nedaplatin; nemorubicin; Nejdanov acid; nilutamide; nizamettin; modulators of nitric oxide; nitroxide antioxidant; nitrolon; oblimersen (Genasense®); O6-benzylguanine; actuated; okizeme; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral inducer of cytokines; ormaplatin; asteron; oxaliplatin; axiomized; paclitaxel; analogues of paclitaxel, derivatives of paclitaxel; palyulin; palmitoylation; pamidronovu acid; panaxytriol; promife; pyrabactin; pallidin; pegaspargase; peltatin; pentosan polysulfate sodium; pentostatin; petrosal; perflubron; perforated; parallelly alcohol; fansinating; phenylacetate; inhibitors of phosphatase; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placedin a; placein B; inhibitor of plasminogen activator; a complex of platinum; platinum compounds; platinum complex analogue; porfimer sodium; porfiromycin; prednisone; propyl bis-acridan; prostaglandin J2; proteasome inhibitors; immunomodulator on the basis of protein A, an inhibitor of protein kinase C, inhibitors of protein kinase C, on the basis of microalgae; inhibitors patientinitiated; inhibitors polynucleotides; purpurin; pyrazoloacridine; to nyugat pyridoxamine hemoglobin and polyoxyethylene; antagonists raf; raltitrexed; ramosetron; inhibitors farnesyltransferase ras; ras inhibitors; inhibitors of ras-GAP; reality demetilirovanny; rhenium Re-186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romantic; roquinimex; rubiginosa B1; robaxin; safingol; sinepin; SarCNU; sarcophyton A; sargramostim; Sdi 1 mimetics; semustine; inhibitor of aging 1; sense oligonucleotides; inhibitors of signal transduction; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solvera; somatomedin-binding protein; sonarmen; spartenvol acid; spicamycin D; spiramycin; splenopathy; spongistatin 1; squalamine; stipend; inhibitors stromelysin; solifenacin; super active vasoactive intestinal peptide antagonist; coralista; suramin; swainsonine; tallimustine; tamoxifen methiodide; terramycin; tazarotene; tecogen sodium; tegafur; tellurium; telomerase inhibitors; ]; teniposide; tetrachlorodecaoxide; tetrasomy; teleblaster; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; agonist receptor tipepidine; timorian; thyroid-stimulating hormone; utilityperson tin; tirapazamine; titanocene bichloride; topsentin; toremifene; inhibitors broadcast; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; inhibitors tirosint is called; tyrphostin; inhibitors UBC; ubenimex; factor inhibiting the growth of urogenital sinus; antagonists of the receptor for urokinase; vapreotide; variolin B; valarezo; vermin; virgins; verteporfin; vinorelbine; Wincanton; vitaxin; vorozole; sonotron; senility; salaskar and zinostatin stimulater.

Specific second active substances include, but are not limited to, 2-methoxyestradiol, teamstation, inducers of apoptosis in multiple myeloma cells (such as, for example, TRAIL), bortezomib, statins, semaxanib, cyclosporine, etanercept, doxycycline, bortezomib, oblimersen (Genasense®), Remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®, Taxol, Taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, docetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zolendronic acid, palpitant, biaxin, busulfan, prednisone, a bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt is), sulindac and etoposide.

Also, specific examples of the second means in accordance with the indications that you need the treatment, prevention or relief can be found in the following reference documents, which are all included in the present application in their entirety: U.S. Patent No. 6281230 and 5635517; Patent application U.S. No. 10/411649, 10/483213, 10/411656, 10/693794, 10/699154 and 10/981189; and Provisional patent application U.S. No. 60/554923, 60/565172, 60/626975, 60/630599, 60/631870 and 60/533862.

Examples of additional second active agents include, but are not limited to, traditional therapeutic agent used for the treatment or prevention of pain, such as antidepressants, anticonvulsants, antihypertensives, aksiomaticheskie tools, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatories, cox-2 inhibitors, immune modulators, agonists or antagonists, alpha-adrenergic receptor, immunosuppressive means corticosteroids, hyperbaric oxygen, ketamine, other anesthetics, antagonists of NMDA and other therapeutic agents, which can be found, for example, in Physician''s Desk Reference 2003. Specific examples include, but are not limited to, acetate, salicylic acid (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin (Neurontin®), phenytoin (Dilantn®), carbamazepine (Tegretol®), oxcarbazepine (Trileptal®), valproate acid (Depakene®), morphine sulfate, hydromorphone, prednisone, griseofulvin, penthium, alendronate, difengidramin, guanethidine, Ketorolac (Acular®), thyrocalcitonin, dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin, reserpin, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®), imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®), fluoxetine (Prozac®), sertraline (Zoloft®), nefazodone (Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion (Wellbutrin®), meksiletin, nifedipine, propranolol, tramadol, lamotrigine, ziconotide, ketamine, dextromethorphan, benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of additional second active agents include, but are not limited to, a steroid, svetolinerior, an integrin, an antioxidant, an interferon, xantinove derivative, a growth hormone-derived neurotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or compound against angiogenesis, or a combination of such means. Specific examples include, but are not limited to, verteporfin purlytin, angiostatin steroid, rhuFab, interferon-2y, pentoxifylline, adipocere tin, motexafin lutetium, 9-fluoro-l1,21-is hydroxy-16,17-1-methylethylidene(hydroxy)pregna-l,4-diene-3,20-dione, latanoprost (see U.S. Patent No. 6225348), tetracycline and its derivatives, rifamycin and its derivatives, macrolides, metronidazole (U.S. Patent No. 6218369 and 6015803), genistein, genistin, 6'-OMaI, genistin, 6'-0-Ac genistin, daidzein, daidzin, 6'-OMaI daidzin, 6'-0-Ac daidzin, glycitein, glycitin, 6'-O-MaI glycitin, biochanin A, formononetin (U.S. Patent No. 6001368), triamcinolone of acetonide, dexamethasone (U.S. Patent No. 5770589), thalidomide, glutathione (U.S. Patent No. 5632984), basic fibroblast growth factor (bFGF), transforming growth factor b (TGF-b), neurotrophic factor brain (BDNF), a factor plasminogen activator type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and RETISERT implant (Bausch & Lomb). All references mentioned above are included in the present application in their entirety by reference.

Examples of additional second active agents include, but are not limited to, keratolytic tools, retinoids, α-hydroxy acid, antibiotics, collagen, toxin botulinum, interferon and immune modulating means. Specific examples include, but are not limited to, 5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lactic acid, ammonium lactate, urea, tretinoinretin, antibiotics, collagen, toxin botulinum, interferon, corticosteroids, transretinoic acid and collagen, such as human placental the th collagen, placentally collagen of animal origin, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast and Isolagen.

Examples of additional second active agents include, but are not limited to, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, analogues of prostacyclin, endothelin antagonists, phosphodiesterase inhibitors (e.g., inhibitors of PDE V)inhibitors endopeptidase, means for reducing the level of lipid inhibitors of thromboxane and other therapeutic agents, known as reducing pulmonary blood pressure. Specific examples include, but are not limited to, warfarin (Coumadin®), a diuretic, cardiac glycoside, digoxin oxygen, diltiazem, nifedipine, a vasodilator, such as prostacyclin (for example, prostaglandin 12 (PGI2), epoprostenol (EPO, Floran®), treprostinil (Remodulin®), nitric oxide (NO), bosentan (Tracleer®), Almaden, epoprostenol (Floran®), treprostinil (Remodulin®), prostacyclin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®), irbesartan (Avapro®), pravastatin (Pravachol®), digoxin, L-arginine, iloprost, beraprost and sildenafil (Viagra®).

Examples of additional second active agents include, but are not limited to, anthracycline, platinum, alkylating agent, oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, Tamka is even, topotecan, methotrexate, Taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, docetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, pamidronate, biaxin, busulfan, prednisone, a bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline and gemcitabine.

Examples of additional second active agents include, but are not limited to, chlorquin, quinine, quinidine, pyrimethamine, sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine, primaquine, hydroxychloroquin, proguanil, atovaquone, azithromycin, suramin, pentamidine, melarsoprol, nifurtimox, benznidazole, amphotericin B, compounds of pentavalent antimony (for example, stibogluconate sodium), interferon gamma, Itraconazole, the combination of the dead promastigote forms and BCG, leucovorin, corticosteroids, sulfonamide, spiramycin, IgG (serology), trimethoprim and sulfamethoxazole.

Examples of additional second active agents include, but are not limited to: antibiotiki (therapeutic or prophylactic), such as, but not limited to, ampicillin, clarithromycin, tetracycline, penicillin, cephalosporin, streptomycin, kanamycin erythromycin; antiviral agents, such as, but not limited to, amantadine, rimantadine, acyclovir, and ribavirin; immunoglobulin; plasma; immunostimulatory drugs, such as, but not limited to, levamisole and isoprinosine; biological means, such as, but not limited to, gammaglobulin, transfer factor, interleukins, and interferons; hormones such as, but not limited to, thymic; and other immunologic agents such as, but not limited to, stimulants B-cells (e.g., BAFF/BlyS), cytokines (for example, IL-2, IL-4 and IL-5), growth factors (e.g., TGF-y), antibodies (e.g., anti-CD40 and IgM), oligonucleotides containing neetilirovannye CpG motifs, and vaccines (e.g., antiviral and anticancer peptide vaccine).

Examples of additional second active agents include, but are not limited to: the agonist or antagonist of dopamine, such as, but not limited to, levodopa, 1-DOPA, cocaine, α-methyltyrosine, reserpine, tetrabenazine, benzotropine, pargyline, findalbum mesilate, cabergoline, pramipexol the dihydrochloride, ropinerole, amantadine hydrochloride, selegiline hydrochloride, carbidopa, pergolid mesilate, Sinemet CR and Symmetrel; a MAO inhibitor, such as, but not limited to, iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor, such as, but not limited to takapo and entakapon; the cholinesterase inhibitor, such as, but not limited to, physostigmine salicylate, physostigmine sulfate, physostigmine bromide, neostigmine bromide, neostigmine methyl sulfate, ambenonium chloride, edrophonium chloride, taken, pralidoxime chloride, obidoxime chloride, trimedoxime bromide, diacetyl monoxime, andropodium, pyridostigmine and demecarium; anti-inflammatory agent, such as, but not limited to, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, Rho-D immune Globulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamico acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, gold Nutritionals, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone or betamethasone and other glucocorticoids; and contradictory, which now means, such as, but not limited to, metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benchenane, beatnuts, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, difenidol, dolasetron, meclizine, metallical, metopimazine, nabilone, oxybenzyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, triterpenoid, thioproperazine, tropisetron, and a mixture of such funds.

Examples of additional second active agents include, but are not limited to, immunomodulators, immunosuppressive tools, antihypertensives, anti-convulsants, anti-fibrinolytic tools, anti-platelet aggregation, antipsychotics, antidepressants, benzodiazepines, buspirone, amantadine and other known or conventional means used for patients with lesions/damage to the Central nervous system and related syndromes. Specific examples include, but are not limited to: steroids (e.g., glucocorticoids, such as, but not limited to, methylprednisolone, dexamethasone and betamethasone); anti-inflammatory agent, including, but not limited to, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprost is h, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, RHo-D immune Globulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamico acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon zileuton, aurothioglucose, gold Nutritionals, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone; the analogue of cAMP, including, but not limited to, db-cAMP; means, including a drug on the basis of methylphenidate, which includes 1 threo-methylphenidate, d-threo-methylphenidate, dl-threo-methylphenidate, l-Erythro-methylphenidate, d-Erythro-methylphenidate, dl-Erythro-methylphenidate, and the mixture of such funds; and diuretic, such as, but not limited to, mannitol, furosemide, glycerol and urea.

Examples of additional second active agents include, but are not limited to, a tricyclic antidepressant, a selective inhibitor of reuptake of CE is Tonina, antiepileptic drug (gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam, topiramate), anti-arrhythmia, a blocker of sodium channels, selective inhibitor of mediator of inflammation, opioid agent, a second immunomodulatory compound, agent combinations, and other known or conventional means used in the treatment of long sleep. Specific examples include, but are not limited to, Neurontin, oxycontin, morphine, topiramate, amitriptyline, nortriptyline, carbamazepine, Levodopa, L-DOPA, cocaine, α-methyltyrosine, reserpine, tetrabenazine, benzotropine, pargyline, findalbum mesilate, cabergoline, pramipexol the dihydrochloride, ropinerole, amantadine hydrochloride, selegiline hydrochloride, carbidopa, pergolid mesilate, Sinemet CR, Symmetrel, iproniazid, clorgyline, phenelzine, isocarboxazid, tolkapon, entacapone, physostigmine salicylate, physostigmine sulfate, physostigmine bromide, neostigmine bromide, neostigmine methyl sulfate, ambenonium chloride, andropodium chloride, taken, pralidoxime chloride, obidoxime chloride, trimedoxime bromide, diacetyl monoxime, andropodium, pyridostigmine, demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, with lipaslazel, gold salts, RHo-D immune Globulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamico acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, gold Nutritionals, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon, benzbromarone, betamethasone and other glucocorticoids, metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benchenane, beatnuts, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, difenidol, dolasetron, meclizine, metallical, metopimazine, nabilone, oxybenzyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, triterpenoid, thioproperazine, tropisetron, and a mixture of such funds.

Examples of additional second active agents include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12 and L-18; interferons, such as interferon Alfa-2a, interferon alpha-2b, interferon alpha-nl, interferon alpha-n3, interferon beta-Ia, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrate or derivatives butyrate; nitric oxide; HEMOXIN™ (NIPRISAN™; see U.S. Patent No. 5800819); antagonists of Gardos channels, such as clotrimazole, triarylmethane derivatives; Deferoxamine; protein C; and transfusion of blood or blood substitute, such as Hemospan™ or Hemospan™ PS (Sangart).

The introduction of a heteroaryl compound and the second active means the patient can be performed simultaneously or sequentially, the same or different routes of administration. Is suitable the particular route of administration used for a specific active funds, depends on the active funds as such (for example whether it can be administered orally without its decomposition before entering the bloodstream) and from diseases that are treated. The preferred route of administration for the heteroaryl compounds is oral. The preferred route of administration for the second active agents or ingredients of the present invention known to specialists in this field. See, for example, Physicians' Desk Reference, 1755-1760 (56th ed., 2002).

In one variant embodiment of the invention, the second active agent is administered intravenously or subcutaneously. In another variant embodiment of the invention, the second activeassist administered intravenously or subcutaneously once or twice a day number, comprising from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. of a Specific amount of the second active means depends on the particular tool that you use, the type of disease being treated or in which help, severity and stage of the disease and the number(quantity) heteroaryl compound and any optional additional active while the input to the patient.

In addition, the present application provides methods of reducing, treating and/or prophylaxis of adverse or unwanted effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biotherapy and immunotherapy. Heteroaryl compounds and other active ingredients can enter the patient before, during or after the manifestation of adverse effects associated with conventional therapy.

4.5 PHARMACEUTICAL COMPOSITIONS AND routes of administration

Heteroaryl compounds can enter the patient orally or parenterally in conventional dosage form such as capsules, microcapsules, tablets, granules, powder, tablets, pills, suppositories, injections, suspensions and syrups. Suitable compositions can to get tra the investment of ways using traditional organic or inorganic additives, such as excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polipropilenglicol, polyvinylpyrrolidone, gelatin, Arabic gum, polyethylene glycol, sucrose or starch), baking powder (for example, starch, carboxymethylcellulose, hydroxypropylmethyl, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), grease (for example, magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulphate), perfume (for example, citric acid, menthol, glycine or powdered orange flavoring), preservatives (e.g. sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (for example, citric acid, sodium citrate or acetic acid), suspendisse substance (for example, methylcellulose, polyvinylpyrrolidone or aluminum stearate), a dispersing agent (e.g. hypromellose), a diluent (e.g. water) and wax base (e.g. cocoa butter, petrolatum or polyethylene glycol). An effective amount heteroaryl compounds in the pharmaceutical composition may be at a level that will give the desired effect; for example, from about 0.005 m is/kg of patient's body weight to about 10 mg/kg of body weight of the patient in the standard dosing dosage form for oral, and for parenteral administration.

Dose heteroaryl compounds for administration to the patient varies in a rather wide limits and is determined by the physician. As a rule, the heteroaryl compounds can enter the patient from one to four times per day at a dose of from about 0.005 mg/kg of patient's body weight to about 10 mg/kg of body weight of the patient, doses above these limits can be appropriately selected depending on the age, bodyweight and medical condition of the patient and on the type of injection. In one variant embodiment of the invention, the dose is about 0.01 mg/kg of patient's body weight to about 5 mg/kg of body weight of the patient, from about 0.05 mg/kg of patient's body weight to about 1 mg/kg of body weight of the patient, from about 0.1 mg/kg of body weight of the patient to about 0.75 mg/kg of body weight of the patient, or from about 0.25 mg/kg of patient's body weight to about 0.5 mg/kg of body weight of the patient. In one variant embodiment of the invention, is administered one dose per day. In this case, the number of input heteroaryl compounds depends on such factors as the solubility of the active component, the composition and the way of introduction.

In another variant embodiment of the invention in this application provides methods of treatment or prevention of diseases or disorders involving the introduction of from about 0.375 mg/day to about 750 mg/d is Ni, from about 0.75 mg/day to about 375 mg/day, from about 3.75 mg/day to about 75 mg/day, from about 7.5 mg/day to about 55 mg/day or from about 18 mg/day to about 37 mg/day heteroaryl compound to a patient in need of it.

In another variant embodiment of the invention in this application provides methods of treatment or prevention of diseases or disorders involving the introduction of from about 1 mg/day to about 1200 mg/day, from about 10 mg/day to about 1200 mg/day, from about 100 mg/day to about 1200 mg/day, from about 400 mg/day to about 1200 mg/day, from about 600 mg/day to about 1200 mg/day, from about 400 mg/day to about 800 mg/day or from about 600 mg/day to about 800 mg/day heteroaryl compound to a patient in need. In a particular variant embodiment of the invention, the methods disclosed in this application include the introduction of 400 mg/day, 600 mg/day or 800 mg/day heteroaryl compound to a patient in need of it.

In another variant embodiment of the invention in this application provides for a standard dosage form, which include from about 1 mg to 200 mg, from about 35 mg to about 1400 mg, about 125 mg to about 1000 mg, from about 250 mg to about 1000 mg, or from about 500 mg to about 1000 mg heteroaryl compounds.

In a particular variant embodiment of the invention in this application provides a standard drug is the first form, comprising about 100 mg or 400 mg heteroaryl compounds.

In another variant embodiment of the invention in this application provides for a standard dosage form, which includes 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg heteroaryl compounds.

Heteroaryl connection, you can enter one, two, three, four or more times a day. In a particular variant embodiment of the invention, doses of 600 mg or less is injected in the form of a single daily dose, and doses greater than 600 mg administered twice daily in a quantity equal to half the total daily dose.

Heteroaryl compound can be administered orally for the sake of convenience. In one variant embodiment of the invention, when administered orally, heteroaryl compound is administered together with food and water. In another variant embodiment of the invention, the heteroaryl compound is dispersed in water or juice (such as Apple juice or orange juice) and administered orally in suspension.

Heteroaryl connection you can also enter intradermal, intramuscular, intraperitoneal, percutaneous, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectally, by injection through the mucous, putaminal or local path to the ears, nose, eyes, or skin. The route of administration depends on the choice of the treating physician and depends in part on a medical condition.

In one variant embodiment of the invention in the present application is provided with capsules containing heteroaryl compound without an additional carrier, excipient or filler.

In another variant embodiment of the invention in this application are provided compositions comprising an effective amount heteroaryl compounds and pharmaceutically acceptable carrier or excipient, where the pharmaceutically acceptable carrier or excipient may include excipient, diluent or a mixture of such substances. In one variant embodiment of the invention, the composition is a pharmaceutical composition.

The composition can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, drops, suppositories and suspensions and the like, the Composition can be formulated so that they contain daily dose or convenient to introduce the fraction of the daily dose in a standard dosage form, which can be a single tablet or capsule or convenient for the introduction of fluid volume. In one variant embodiment of the invention, the solutions prepared from water-soluble salts, such as cleaners containing hydrochloride salt. As a rule, all songs and receive in accordance with the methods, known in pharmaceutical chemistry. Capsules can be obtained by mixing heteroaryl compound with a suitable carrier or diluent and the introduction of the desired amount of the mixture in capsules. Conventional carriers and diluents include, but are not limited to, inert powdered substances such as starch of all kinds, powdered cellulose, in particular, crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, flour from cereals and similar edible powders.

Tablets can be obtained by direct pressing, by wet granulation, or by dry granulation. Their compositions typically include diluents, binders, lubricants and disintegrating agents, as well as connection. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, phosphate, or calcium sulfate, inorganic salts such as sodium chloride and powdered sugar. Also useful are powdered cellulose derivatives. In one variant embodiment of the invention, the pharmaceutical composition does not contain lactose. Typical binders for tablets include such substances as starch, gelatin and sugars such as lactose, fructose, glucose, etc. are Also suitable for use are natural and synthetic resins,including the Arabian gum, alginates, methylcellulose, polyvinylpyrrolidine etc. Glycol, ethylcellulose and waxes can also serve as a binder.

Grease may be necessary in the composition of the tablets to prevent sticking of tablets and stamp the form. The lubricating substance can be selected from such agents slip as talc, magnesium stearate and calcium, stearic acid and hydrogenated vegetable oils. Leavening agents for tablets are substances which swell when wetted with the destruction of the tablet and release of the connection. They include starches, clays, cellulose derivatives, substances algae and resin. More specifically, it is possible to use, for example, corn and potato starch, methylcellulose, agar, bentonite, wood pulp, powdered natural sponge, katiana-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, and sodium lauryl sulfate. Tablets can be sugar coated as odorants and seal, or may have a film coating using the protective film-forming substances, for modification of the properties of solubility of the tablets. The compositions can also be formulated as chewable tablets, for example, in compositions such is exist, as mannitol.

When desirable, the introduction of a heteroaryl compound in the form of a suppository, you can use a typical basis. Cocoa butter is a traditional basis for suppositories, which can be modified by adding wax to a small increase of the melting temperature. Widely used mixed with water bases for suppositories, including, in particular, polyethylene glycols of various molecular weights.

The effect of the heteroaryl compounds can be delayed or prolonged by providing a suitable composition. For example, you can get slowly dissolving granular particles heteroaryl compounds and include in tablet or capsule, or in the form of the implantable device slow release. The method also includes obtaining granular particles, which have different speeds of dissolution, and filling capsules with a mixture of these granular particles. Tablets or capsules may have a film coating, which is resistant to dissolution within a certain period of time. Even the parenteral preparations can be made sustainable by dissolution or suspension heteroaryl compound in oily or emulsified fillers that make it possible slow distribution in serum.

5. POR WHAT MEASURES

The following examples are provided to illustrate and not to limit.

5.1 Examples of synthesis

General procedure A.

In a vessel made of thick borosilicate glass (5-10 ml) was added 2-amino-3,5-dibromo-pyrazin desired amine and diisopropylethylamine in n-butanol. The reaction vessel was tightly closed and placed in a microwave reactor and irradiated at 220°C for 3600 sec. The solution are condensed under reduced pressure, dissolved in ethyl acetate, washed with saturated brine, separated, was extracted with ethyl acetate (2×), the organic layers were combined, dried over sodium sulfate, filtered and are condensed to obtain the crude product.

General procedure B.

The substrate (1 equiv.) and boranova acid (1.2 EQ.) was dissolved in DMF (15 ml). After the solution was barbotirovany nitrogen for 2 minutes. Added a suitable base in water (5 ml) and Pd catalyst (0.1 EQ.). The solution is then heated to 85-95°C in nitrogen atmosphere. When the starting material was completely consumed, the solution are condensed under reduced pressure. The resulting material was diluted with ethyl acetate and filtered through celite, or a strong stream was passed through available for use extraction column Bakerbond SPE with SiOH. The filtrate are condensed under reduced pressure to get crude product.

General PR is the procedure B.

Bromide, the desired Bronevoy acid, Pd catalyst, an aqueous solution of the base (1 M) and dioxane were heated together in a microwave reactor Biotage Emrys Optimizer at 150°C for 20 minutes. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate and then concentrated.

General procedure B2.

The substrate (1 equiv.) and boranova acid (1.2 EQ.) was dissolved in DMF (10 ml). After the solution was barbotirovany nitrogen for 2 minutes. Solution was added a suitable base in water (5 ml) and Pd catalyst (0.1 EQ.). The resulting solution was then heated in a microwave reactor Biotage Emrys Optimizer at 120°C for 15 minutes. When the starting material was completely consumed, the solution are condensed under reduced pressure. The resulting material was diluted with ethyl acetate and filtered through celite. The filtrate are condensed under reduced pressure to get crude product.

General procedure B3.

The substrate (1 equiv.) and boranova acid (1.2 EQ.) was dissolved in DMF (10 ml). After the solution was barbotirovany nitrogen for 2 minutes. Sodium carbonate (1M) (5 ml), acetonitrile (5 ml) and dichlorobis(triphenylphosphine)palladium(II) is 0.05 EQ.). The solution is then heated together in a microwave reactor Biotage Emrys Optimizer at 120°C for 15 minutes. When the starting material was completely consumed, the solution are condensed at ponie nom pressure. The resulting material was diluted with ethyl acetate and filtered through celite. The filtrate are condensed under reduced pressure to get crude product.

General procedure C.

Bromide, the desired Bronevoy acid (or ester Bronevoy acid) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane were combined in DMF. Potassium phosphate was dissolved in water and added to the reaction mixture and left to stir at 100°C for 16 hours. The reaction solution are condensed under reduced pressure and diluted with 10% methanol in ethyl acetate and a strong stream was passed through available for use extraction column Bakerbond SPE with SiOH. The filtrate are condensed under reduced pressure to get crude product.

General procedure D1.

In a vessel made of thick borosilicate glass (5-10 ml) was added to the substrate and 1,1'-carbonyldiimidazole in THF. The reaction vessel was tightly closed and placed in a microwave reactor and irradiated at 180°C for 3600 sec. The reaction solution are condensed under reduced pressure to get crude product.

General procedure D2.

In a vessel made of thick borosilicate glass (5-10 ml) was added to the substrate, urea and formamide. The reaction vessel was tightly closed and placed in a microwave reactor and irradiated at 220°C in ECENA 2700 sec. The solution are condensed under reduced pressure to get crude product.

General procedure E.

A solution of N-bis-boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) and the desired amine in ethanol (4 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 4 hours.

General procedure E1.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 26.E) and the desired amine (or amine salt and triethylamine) in ethanol was heated in a microwave reactor Emrys at 150°C for 4 hours. The product was isolated using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O+0.1% of TFA, over 30 min). The fractions containing pure product was passed through the extraction column with the solid phase Phenomenex Strata-X-C to remove TFA. The product was isolated from the column using 2M ammonia in methanol. The solution was concentrated under reduced pressure and dried in vacuum to obtain the product as a white solid.

General procedure F.

The substrate (1 equiv.) and triethylamine (20 EQ.) was dissolved in methanol (3.0 ml) in a sealed tube and stirred for 5 minutes. Added hydrazine (4.0 EQ.) and the reaction mixture was heated to 100°C for 18 hours. When the starting material was completely consumed, the solution are condensed under reduced pressure obtained with the eating of the crude product.

5.1.1 EXAMPLE 1: SYNTHESIS of 1-(4-METHOXYBENZYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-N2-(4-methoxybenzyl)pyrazin-2,3-diamine.

2-Amino-3,5-dibromopyrazine (3.0 g, 11,95 mmol) and 4-methoxybenzylamine (2,13 g, 15,53 mmol) was subjected to interaction in accordance with the General Procedure A and was carried out by purified using chromatography on silica gel Biotage (30-100% ethyl acetate in hexane) to obtain the specified title compound (1.75 g, 47% yield). MS (ESI) m/z 311,2 [M+1]+.

B. (3-Amino-6-(5-chinolin)pyrazin-2-yl)[(4-methoxyphenyl)methyl]amine.

6-Bromo-N2-(4-methoxybenzyl)pyrazin-2,3-diamine (0,928 g, 3.00 mmol), quinoline-5-Bronevoy acid (0,675 g, 3.9 mmol), tetrakis(triphenylphosphine)palladium (0,306 g, 0,265 mmol), potassium carbonate (1.10 g, of 7.95 mmol), water (7 ml) and dimethylformamide (35 ml) was subjected to interaction in accordance with the General Procedure B. the Crude product was subjected to purification using chromatography on silica gel Biotage (0-10% methanol in dichloromethane) followed by kneading the powder with water/methanol to obtain specified in the connection header (0,165 g, 15% yield). MS (ESI) m/z 358,3 [M+1]+.

C. 1-(4-Methoxybenzyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(3-Amino-6-(5-chinolin)pyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (0,200 g, 0,560 mmol) and urea (0,67 g, 1.12 mmol) was subjected to interaction in accordance with the General Procedure D2. The solution which was undesirable under reduced pressure and triturated to powder with water/methanol to obtain specified in the connection header (0,180 g, 84% yield). 1 N. NMR (300 MHz, CD3OD) δ 8,88 (m, 1H), of 8.47 (d, 1H), 8,19 (s, 1H), 8,12 (d, 2H), 7,86 (m, 1H), 7,56 (d, 1H), 7,46 (m, 1H), 7,38 (d, 2H), 6,91 (d, 2H), 5,07 (s, 2H), of 3.78 (s, 3H); MS (ESI)m/z384,4 [M+1]+.

5.1.2 EXAMPLE 2: SYNTHESIS of (R)-1-(1-PHENYLETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (R)-6-Bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine.

Specified in the title compound was obtained using (R)-α-methylbenzylamine (2,28 ml, 17,93 mmol), 2-amino-3,5-dibromopyrazine (3.00 g, 11,96 mmol) and n-BuOH (30 ml)as described in General Procedure A. the Crude compound was purified using chromatography on silica gel (20%-30% EtOAc in hexane). Pure fractions were combined and are condensed with further kneading the powder from methanol with water, while processing the ultrasound, to obtain 1.92 g (6,54 mmol, 55%) of (R)-6-bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine. MS (ESI) m/z 294,0 [M+1]+.

B. (R)-N2-(1-Phenylethyl)pyrazin-2,3-diamine.

Specified in the title compound was obtained by dissolving (R)-6-bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine (1,00 g, 3,37 mmol) in pure formic acid (15 ml) and add 10% Pd/C (0.34 mmol). This solution was purged with gaseous hydrogen at 1 ATM and was stirred for 4 hours at room temperature. Upon completion of this procedure, the reaction mixture was filtered through celite and concentrated. The crude substance was purified using chromatography on silica gel (-10% methanol in dichloromethane). Pure fractions were combined and are condensed to obtain 0.65 g (3.03 mmol, 90%) of (R)-N2-(1-phenylethyl)pyrazin-2,3-diamine. MS (ESI) m/z 215,4 [M+1]+.

C. (R)-1-(1-Phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Specified in the title compound was obtained using (R)-N2-(1-phenylethyl)pyrazin-2,3-diamine (0.65 g, 3.03 mmol), 1,1'-carbonyldiimidazole (0,62 g, with 3.79 mmol) and tetrahydrofuran (10 ml)as described in General Procedure D1. After cooling to room temperature, volatiles were removed under reduced pressure. The crude oil was purified using chromatography on silica gel (10-70% EtOAc in hexane). Pure fractions were combined and are condensed to obtain 0.10 g (0.42 mmol, 40%) of (R)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she. 1 N. NMR (400 MHz, DMSO-d6) δ 12,08 (s, 1H), 7,89 (s, 1H), 7,43 (d, 2H), 7,33 (t, 2H), 7,26 (t, 1H), 5,67 (DD, 1H), was 1.94 (d, 3H); MS (ESI)m/z241,3 [M+1]+.

5.1.3 EXAMPLE 3: SYNTHESIS of (S)-1-(1-PHENYLETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (S)-6-Bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine.

Specified in the title compound was obtained using (S)-α-methylbenzylamine (2,28 ml, 17,93 mmol), 2-amino-3,5-dibromopyrazine (3.00 g, 11,96 mmol) and n-BuOH (30 ml)as described in General Procedure A. the Crude molecule was purified using chromatography on silica gel (20-30% EtOAc in hexane). Pure fractions were combined and are condensed, followed by kneading powder of the metal is Nola with water, while processing the ultrasound, to obtain 1.52 g (5.18 mmol, 43%) of (S)-6-bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine. MS (ESI) m/z 294,0 [M+1]+.

B. (S)-N2-(1-Phenylethyl)pyrazin-2,3-diamine.

Specified in the title compound was obtained by dissolving (S)-6-bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine (1,00 g, 3,37 mmol) in pure formic acid (15 ml) and add 10% Pd/C (0.34 mmol). This solution was purged with gaseous hydrogen at 1 ATM and was stirred for 4 hours at room temperature. Upon completion of this procedure, the reaction mixture was filtered through celite and concentrated. The crude substance was purified using chromatography on silica gel (0-10% methanol in dichloromethane). Pure fractions were combined and are condensed with the receipt of 0.47 g (2,19 mmol, 65%) of (S)-N2-(1-phenylethyl)pyrazin-2,3-diamine. MS (ESI) m/z 215,4 [M+1]+.

C. (S)-1-(1-Phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Specified in the title compound was obtained using (S)-N2-(1-phenylethyl)pyrazin-2,3-diamine (0.40 g, of 1.87 mmol), 1,1'-carbonyldiimidazole (0,38 g of 2.33 mmol) and tetrahydrofuran (7 ml)as described in General Procedure D1. After cooling to room temperature, volatiles were removed under reduced pressure. The crude oil was purified using chromatography on silica gel (10-70% EtOAc in hexane). Pure fractions were combined and con who was netravali to obtain 0.18 g (0,74 mmol, 40%) of (S)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she. 1 N. NMR (400 MHz, DMSO-d6) δ 12,08 (s, 1H), 7,89 (s, 1H), 7,43 (d, 2H), 7,33 (t, 2H), 7,26 (t, IH), 5,67 (DD, 1H), was 1.94 (d, 3H); MS (ESI)m/z241,3 [M+1]+.

5.1.4 EXAMPLE 4: SYNTHESIS of 5-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 5-(5-Chinolin)pyrazin-2,3-diamine.

(3-Amino-6-(5-chinolin)pyrazin-2-yl)[(4-methoxy-phenyl)methyl]amine (see Example 1.B) (0,210 g, 0,588 mmol) was dissolved in triperoxonane acid/dichloromethane (2 ml:2 ml) using PS-thiophenol as acceptor. The solution was heated to 70°C in a sealed tube for two hours and then concentrated under reduced pressure and diluted with methanol. A solution of methanol/product filtered through the extraction column with the solid phase Phenomenex Strata-X-C to remove TFA. Added additional amount of water to lirovannomu connection to the sediment. The precipitate was filtered and dried in vacuum to obtain specified in the connection header (0,080 g, 57% yield). MS (ESI) m/z 238,1 [M+1]+.

B. 5-(Quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

5-(5-Chinolin)pyrazin-2,3-diamine (0,080 g of 0.337 mmol) and urea (0,061 g, 1.01 mmol) was subjected to interaction, as described in the General Procedure D2. Was added in portions water in the reaction vessel to cause the precipitation of the product. The precipitate was filtered and dried in vacuum to obtain specified in sialometaplasia (by 0.055 g, 62% yield). 1 N. NMR (400 MHz, DMSO-d6) δ 11,89 (Sirs, 2H), to 8.94 (d, 1H), 8,56 (d, 1H), 8,14 (s, 1H), 8,10 (d, 1H), to 7.84 (t, 1H), 7,72 (d, 1H), 7,54 (DD, 1H). MS (ES)m/zAZN 264.2 [M+1].

5.1.5 EXAMPLE 5: SYNTHESIS of 1-(2-HYDROXYETHYL)-6-(5-ISOPROPYL-2-METHOXYPHENYL)-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine.

5-Bromopyrazine-2-amine (5.7 g, 33 mmol), 5-isopropyl-2-methoxybenzeneboronic acid (6.4 g, 33 mmol), tetrakis (triphenylphosphine)palladium(0) (1.9 g, 1.6 mmol) and sodium carbonate (99 ml, 99 mmol) and dioxane (300 ml) were heated together at 90°C for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate and then concentrated. Carried out the purification of the residue by chromatography on silica gel Biotage (0-60% ethyl acetate in hexane) to give oil (4.1 g, 51% yield). 1 N. NMR (300 MHz, CD3OD) δ at 8.36 (d, J=1,2, 1H), 8,00 (d, J=1,2, 1H), 7,46 (d, J=2,4, 1H), 7,20 (DD, J=8,1, 2,1, 1H), 7,00 (d, J=8,1, 1H), 3,83 (s, 3H), 2,86-of 2.93 (m, 1H), 1,25 (d, J=6,9, 6N); MS (ESI)m/z244,4 [M+1]+.

B. 3-Bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine.

5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (4.1 g, a 16.8 mmol) was dissolved in DMSO (20 ml) and stirred in a water bath. Was added N-bromosuccinimide (3.6 g, a 20.2 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water. Emulsified solid substances is the primary objective was filtered. The organic layer was dried over magnesium sulfate, filtered and then concentrated. Carried out the purification of the residue by chromatography on silica gel Biotage (0-60% ethyl acetate in hexane) to obtain the solid reddish-brown (4 g, 74% yield). 1 N. NMR (400 MHz, DMSO-d6) δ of 8.47 (s, 1H), of 7.48 (d, J=2,3, 1H), 7,22 (DD, J=8,6, 2,3, 1H), 7,05 (d, J=8,6, 1H), 6,78 (s, 2H), 3,82 (s, 3H), 2,86-of 2.93 (m, 1H), 1,20 (d, J=6,8, 6H); MS (ESI)m/z322,0, 324,1 [M+1]+.

C. N-bis-Boc-3-Bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine.

3-Bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (1 g, 3.1 mmol), di-tert-BUTYLCARBAMATE (1.6 g, 8 mmol), 4-dimethylaminopyridine (38 mg, 0.3 mmol) and acetonitrile (15 ml) was heated to 50°C for 30 minutes. The reaction mixture was concentrated and carried out the purification of the residue by chromatography on a Biotage silica gel (0-40% ethyl acetate in hexane) to give a yellow oil (1.6 g, 99% yield). 1 N. NMR (300 MHz, DMSO-d6) δ is 9.09 (s, 1H), 7,65 (d, J=2,4, 1H), 7,42 (DD, J=9,0, 2,7, 1H), 7,18 (d, J=8,1 Hz, 1H), a 3.87 (s, 3H), 2,86-of 2.93 (m, 1H), 1,40 (s, 18H), 1,22 (d, J=6,8, 6N). MS (ESI)m/z424,5 [M+1]+.

D. 1-(2-Hydroxyethyl)-6-(5-isopropyl-2-methoxyphenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-it.

N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (150 mg, 0.29 mmol), 2-hydroxyethylamine (0,177 ml, 2.9 mmol) and ethanol (4 ml) was heated in accordance with the General Procedure E. the Product was purified using reversed-phase polypr paratively HPLC (5-70% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (20 mg, 21% yield). 1 N. NMR (400 MHz, DMSO-d6) δ 11,90 (s, 1H), 8,28(s, 1H), 7,50 (d, J=2,3, 1H), 7,21 (DD, J=8,5, 2,4, 1H), 7,02 (d, J=8,4, 1H), 4,81 (t, J=6,0, 1H), a 3.87 (t, J=6,0, 2H), 3,76 (s, 3H), 3,70 (sq, J=5,9, 2H), 2,85 (s, 1H), 1,16 (d, J=6,8, 6H); MS (ESI)m/z329,3 [M+1]+.

5.1.6 EXAMPLE 6: SYNTHESIS of 1-((R)-1,2-DIMETHYLPROPYL)-6-(5-ISOPROPYL-2-METHOXYPHENYL)-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-((R)-1,2-Dimethylpropyl)-6-(5-isopropyl-2-methoxyphenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-it.

N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol) and (R)-1,2-dimethylpropylene (0,336 ml, 2.9 mmol) and ethanol (4 ml) was heated in accordance with the General Procedure E. the Product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (36 mg, 35% yield). 1 N. NMR (400 MHz, DMSO-d6) δ 11,96 (s, 1H), of 8.37 (s, 1H), 7,58 (d, J=2,3, 1H), 7,26 (DD, J=8,7, 2,2, 1H), was 7.08 (d, J=8,4,1H), 4,11 (DQC., J=9,6, 6,9, 1H), 3,82 (s, 3H), 2,86-to 2.94 (m, 1H), 2,39-2,47 (m, 1H), 1.55V (d, J=6,8, 3H), 1,22 (d, J=7,0, 6H), of 1.02 (d, J=6,8, 3H), of 0.77 (d, J=6,6, 3H); MS (ESI)m/z355,4 [M+1]*.

5.1.7 EXAMPLE 7: SYNTHESIS of 6-(5-ISOPROPYL-2-METHOXYPHENYL)-1-(S)-TETRAHYDRO IS FURAN-3-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 6-(5-isopropyl-2-methoxyphenyl)-1-(S)-tetrahydro-furan-3-yl-1,3-dihydro-imidazo[4,5-b]pyrazin-2-it.

N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), (S)-3-aminotetrahydrofuran in the form tosylate salt (0.75 g, 2.9 mmol), triethylamine (1 ml) and ethanol (4 ml) was heated in accordance with the General Procedure E. the Product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (44 mg, 43% yield). 1 N. NMR (400 MHz, DMSO-d6) δ 11,92 (s, 1H), of 8.37(s, 1H), to 7.61 (d, J=2,5, 1H), 7,20 (DD, J=8,7, 2,2, 1H), 7,02 (d, J=8,6, 1H), 3,85-of 3.97 (m, 3H), of 3.78 (s, 3H), 2,85 (dt, J=13,7, 6,9, 1H), 2,46-2,52 (m, 1H), 2,20-of 2.28 (m, 1H), 1,17 (d, J=7,0, 6H); MS (ESI)m/z355,5 [M+1]+.

5.1.8 EXAMPLE 8: SYNTHESIS of 1-((S)-1,2-DIMETHYLPROPYL)-6-(5-ISOPROPYL-2-METHOXYPHENYL)-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-((S)-1,2-Dimethylpropyl)-6-(5-isopropyl-2-methoxyphenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-it.

N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), (S)-1,2-dimethylpropyl (0,336 ml, 2.9 mmol) and ethanol (4 ml) was heated in accordance with the General Procedure E. the Product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 minutes). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (56 mg, 55% yield). 1 N. NMR (400 MHz, DMSO-d6) δ of $ 11.97 (s, 1H), of 8.37 (s, 1H), 7,58 (d, J=2,3, 1H), 7,26 (DD, J=8,6, 2,5, 1H), was 7.08 (d, J=8,6, 1H), 4,10 (DQC., J=9,5, 7,0, 1H), 3,82 (s, 3H), 2,87-to 2.94 (m, 1H), 2,43 (m, 1H), 1.55V (d, J=7,0, 3H), 1,22 (d, J=6,8, 6H), of 1.02 (d, J=6,6, 3H), of 0.77 (d, J=6,6, 3H). MS (ESI)m/z355,4 [M+1]+.

5.1.9 EXAMPLE 9: SYNTHESIS of 6-(5-ISOPROPYL-2-METHOXYPHENYL)-1-(R)-TETRAHYDROFURAN-3-yl-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 6-(5-isopropyl-2-methoxyphenyl)-1-(R)-tetrahydrofuran-3-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), (R)-3-aminotetrahydrofuran in the form tosylate salt (0.75 g, 2.9 mmol), triethylamine (1 ml) and ethanol (4 ml) was heated in accordance with the General Procedure E. the Product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (31 mg, 30% yield). 1 N. NMR (400 MHz, DMSO-d6) δ 11,96 (s, 1H), of 8.37 (s, 1H), to 7.61 (d, J=2,5, 1H), 7,19 (DD, J=8,9, 2,4, 1H), 7,02 (d, J=8,6, 1H), 4,96-to 5.03 (m, 1H), 4,16 (sq, J=7,5, 1H), 3,85-of 3.97 (m, 3H), of 3.78 (s, 3H), 2,82-2,89 (m, 1H), 2,46-2,50 (m, 1H), 2,20-of 2.28 (m, 1H), 1,17 (d, J=6,8, 6H); MS (ESI)m/z355,5 [M+1]+.

5.1.10 EXAMPLE 10: SYNTHESIS of 1-CEC is OPENTIMER-6-(5-ISOPROPYL-2-METHOXYPHENYL)-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-Cyclopentylmethyl-6-(5-isopropyl-2-methoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), cyclopentylamine (0,287 ml, 2.9 mmol) and ethanol (4 ml) was heated in accordance with the General Procedure E. the Product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (77 mg, 75% yield). 1 N. NMR (300 MHz, DMSO-d6) δ 11,98(s, lH), at 8.36 (s, 1H), 7,60 (d, J=2,5,1H), 7,26 (DD, J=8,7, 2,6, 1H), was 7.08 (d, J=8,5, 1H), 3,82 (s, 3H), of 3.78 (d, J=7,4, 2H), 2,45 (d, J=7,1, 1H), 1,58 is 1.70 (m, 4H), 1,53 (d, J=9,3, 2H), to 1.38 (d, J=4,4, 2H), 1,22 (d, J=6,9, 6H); MS (ESI)m/z367,5 [M+1]+.

5.1.11 EXAMPLE 11: SYNTHESIS of 1-CYCLOHEXYLMETHYL-6-(5-ISOPROPYL-2-METHOXYPHENYL)-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-Cyclohexylmethyl-6-(5-isopropyl-2-methoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), cyclohexanemethylamine (0,287 ml, 2.9 mmol) and ethanol (4 ml) was heated in accordance with the General Procedure E. the Product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Contains the product of the fraction of concentri is ovale and then was ground into powder with 50% methanol in H 2O obtaining a white solid (76 mg, 74% yield). 1 N. NMR (300 MHz, DMSO-d6,)- δ of $ 11.97 (s, 1H), 8,35 (s, 1H), 7,60 (d, J=2,5, 1H), 7,26 (DD, J=8,7, 2,6, 1H), was 7.08 (d, J=8,5, 1H), 3,82 (s, 3H), 3,71 (d, J=7,4, 2H),2,90 (d, J=7,1, 1H), 1,90(m, 1H), 1.5 and 1.7 (m, 5H), 1,0-1,3 (m, 11H); MS (ESI)m/z381,3 [M+1]+.

5.1.12 EXAMPLE 12: SYNTHESIS of 1-(2,2-DIMETHYLPROPYL)-6-(5-ISOPROPYL-2-METHOXYPHENYL)-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-(2,2-Dimethylpropyl)-6-(5-isopropyl-2-methoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), 2,2-dimethylpropylene (0,341 ml, 2.9 mmol) and ethanol (4 ml) was heated in accordance with the General Procedure E. the Product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (69 mg, 67% yield). 1 N. NMR (400 MHz, DMSO-d6) δ 11,96 (s, 1H), 8.34 per (s, 1H), 7,58 (d, J=2,5, 1H), 7,19 (DD, J=8,8, 2,3, 1H), 7,01 (d, J=8,4, 1H), 3,76 (s, 3H), 3,61 (s, 2H)and 1.15 (d, J=7,0, 6H), is 0.96 (s, 9H); MS (ESI)m/z355,4 [M+l]+.

5.1.13 EXAMPLE 13: SYNTHESIS of 1-ISOPROPYL-6-(3-ISOPROPYL-PHENYL)-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 5-Bromo-3-isopropyl-pyrazin-2,3-diamine. 2-Amino-3,5-dibromopyrazine (0.9 g, 3.5 mmol) and Isopropylamine (1 g, 18 mmol) were heated together up to 150°C for 16 hours. Intermediate prod the CT was purified using chromatography on a Biotage silica gel (0-60% ethyl acetate in hexane) to give the oil a dark color (0.56 g, 69% yield). MS (ESI) m/z 233,1 [M+1]+.

B. 6-Bromo-1-isopropyl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

To 5-bromo-3-isopropyl-pyrazin-2,3-diamine was added 1,1'-carbonyldiimidazole (0,86 g, 5.3 mmol) and DMSO (3 ml) and then heated in a microwave reactor Emrys at 150°C for 1 hour. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated and then carried purified using chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane) to give white solid (370 mg, 60% yield). 1 N. NMR (400 MHz, DMSO-d6) δ 12,1 (s, 1H), 8,01 (s, 1H), 4,55 (sq, J=6,8, 1H), 1,46 (d, J=6,8, 6H); MS (ESI)m/z259,1 [M+1]+.

C. 1-isopropyl-6-(3-isopropylphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

6-Bromo-1-isopropyl-1,3-dihydroimidazo[4,5-b]pyrazin-2-he (65 mg, 0.4 mmol), 3-isopropylaniline acid (0,92 mg, 0.4 mmol), tetrakis-(triphenylphosphine)palladium(0) (42 mg, being 0.036 mmol) and sodium carbonate (2.1 ml, 1M, 2.1 mmol) and dioxane (6 ml) was subjected to interaction in accordance with the General Procedure B2. The product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (24 mg, 23% yield). 1 N. I Is R (300 MHz, (400 MHz, DMSO-d6) δ 11,96 (s, 1H), of 8.47 (s, 1H), 7,78 (s, 1H), 7,81 (d, J=6,8,1H), 7,40 (t, J=7,7, 1H), 7,28 (d, J=7,5, 1H), 4,66 (sq, J=6,9, 1H), 2,98 (sq, J=6,9,1H), 1.55V (d, J=6,9, 6H), 1,25 (d, J=6,9, 6H); MS (ESI)m/z297,3 [M+1]+.

5.1.14 EXAMPLE 14: SYNTHESIS of (R)-1-(2-HYDROXY-1-PHENYLETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (R)-2-(3-Amino-6-bromopyrazine-2-ylamino)-2-phenylethanol.

2-Amino-3,5-dibromopyrazine (1.0 g, 3,98 mmol) and (R)-(-)-2-phenylglycinol (1,09 g of 7.96 mmol) was subjected to interaction in accordance with the General Procedure A and was carried out by purified using chromatography on silica gel Biotage (40-100% ethyl acetate/hexane, 25M column) to obtain specified in the connection header (0,700 g, 57% yield). MS (ESI) m/z 309,2 [M+1]+, 31 1,2[M+2]+.

B. (R)-2-(3-Amino-6-(quinoline-5-yl)pyrazin-2-ylamino)-2-phenylethanol.

(R)-2-(3-Amino-6-bromopyrazine-2-ylamino)-2-phenylethanol (0,700 g of 2.26 mmol), quinoline-5-Bronevoy acid (0,431 g, 2.48 mmol), tetrakis(triphenylphosphine)-palladium (0,287 g, 0,226 mmol), potassium carbonate (1.24 g, 9,04 mmol), water (8 ml) and dimethylformamide (35 ml) was subjected to interaction in accordance with the General Procedure B. the Crude product was subjected to purification using chromatography on silica gel Biotage (40-100% ethyl acetate/hexane, 40S column) to obtain specified in the connection header (0,546 g, 67% yield). MS (ESI) m/z 358,3 [M+1]+.

C. (R)-1-(2-Hydroxy-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(R)-2-(3-Amino-6-(hin is Lin-5-yl)pyrazin-2-ylamino)-2-phenylethanol (0,546 g, 1.53 mmol) and urea (0,183 g of 3.05 mmol) was subjected to interaction in accordance with the General Procedure D2. The solution are condensed under reduced pressure and triturated to powder with water/methanol to obtain specified in the connection header (0,150 g, 26% yield). 1 N. NMR (300 MHz, CD3OD) δ to 8.94 (s, 1H), 8,56 (d, 1H), of 8.27 (s, 1H), 8,14 (d, 1H), a 7.85 (m, 2H), 7,51 (t, 3H), 7,39 (m, 3H), 5,65 (m, 1H), amounts to 4.76 (t, IH), 4,14 (s, 3H); MS (ESI)m/z384,3 [M+1]+.

5.1.15 EXAMPLE 15: SYNTHESIS of (S)-1-(2-HYDROXY-1-PHENYLETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (S)-2-(3-Amino-6-bromopyrazine-2-ylamino)-2-phenylethanol.

2-Amino-3,5-dibromopyrazine (1.0 g, 3,98 mmol) and (S)-(+)-2-phenylglycinol (1,09 g of 7.96 mmol) was subjected to interaction in accordance with the General Procedure A and was carried out by purified using chromatography on silica gel Biotage (40-100% ethyl acetate/hexane, 25M column) to obtain specified in the connection header (0,882 g, 72% yield). MS (ESI) m/z 309,2 [M+1]+, 311,2[M+2]+.

B. (S)-2-(3-Amino-6-(quinoline-5-yl)pyrazin-2-ylamino)-2-phenylethanol.

(S)-2-(3-Amino-6-bromopyrazine-2-ylamino)-2-phenylethanol (0,882 g of 2.26 mmol), quinoline-5-Bronevoy acid (0,544 g, 2.48 mmol) tetrakis(triphenylphosphine)-palladium (0,331 g, 0,287 mmol), potassium carbonate (1.25 g, the remaining 9.08 mmol), water (8 ml) and dimethylformamide (30 ml) was subjected to interaction in accordance with the General Procedure B. the Crude product was subjected to purification using chromatography on silica compound is hardly Biotage (0-10% methanol/dichloromethane, 40S column) to obtain specified in the connection header (0,524 g, 51% yield). MS (ESI) m/z 358,3 [M+1]+.

C. (S)-1-(2-Hydroxy-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(S)-2-(3-Amino-6-(quinoline-5-yl)pyrazin-2-ylamino)-2-phenylethanol (0,524 g of 1.46 mmol) and urea (0,176 g of 2.93 mmol) was subjected to interaction in accordance with the General Procedure D2. The solution are condensed under reduced pressure and triturated to powder with water/methanol to obtain specified in the connection header (0,103 g, 18% yield). 1 N. NMR (300 MHz, CD3OD) δ 8,95 (m, 1H), 8,56 (d, 1H), 8,28 (s, 1H), 8,16 (d, 1H), 7,86 (m, 2H), 7,51 (t, 3H), 7,39 (m, 3H), 5,67 (m, 1H), amounts to 4.76 (t, 1H), 4,12 (m, 2H); MS (ESI)m/z384,4 [M+l]+.

5.1.16 EXAMPLE 16: SYNTHESIS of 1-(DIPHENYLMETHYL)-6-(5-CHINOLIN)-4-IMIDAZOLINE[4,5-B]PYRAZIN-2-It

A. (3-Amino-6-bromopyrazine-2-yl)(diphenylmethyl)Amin.

2-Amino-3,5-dibromopyrazine (1.0 g, 3,98 mmol) and aminodiphenylamine (1,82 g, 10.0 mmol) was subjected to interaction in accordance with the General Procedure A and was carried out by purified using chromatography on silica gel Biotage (5-70% ethyl acetate in hexane, 25M column) to obtain specified in the connection header (1,00 g, 71% yield). MS (ESI) m/z 355,3 [M+1]+, 357,3[M+2]+.

B. (3-Amino-6-(5-chinolin)pyrazin-2-yl)(diphenylmethyl)Amin.

(3-Amino-6-bromopyrazine-2-yl)(diphenylmethyl)amine (1.0 g, 2.82 mmol), quinoline-5-Bronevoy acid (0,537 g, 3.1 mmol), tetrakis(triphenylphosphine)palladium (0,325 g, 0,282 mm is l), potassium carbonate (1.55 g, 11,28 mmol), water (8 ml) and dimethylformamide (35 ml) was subjected to interaction in accordance with the General Procedure B. the Crude product was subjected to purification using chromatography on silica gel Biotage (10-100% ethyl acetate/hexane, 40S column) to obtain specified in the connection header (0,539 g, 47% yield). MS (ESI) m/z 404,6 [M+1]+.

C. 1-(Diphenylmethyl)-6-(5-chinolin)-4-imidazoline[4,5-b]pyrazin-2-it.

(3-Amino-6-(5-chinolin)pyrazin-2-yl)(diphenylmethyl)Amin (0,539 g of 1.33 mmol) and urea (0,160 g, to 2.67 mmol) was subjected to interaction in accordance with the General Procedure D2. The solution are condensed under reduced pressure and triturated to powder with methanol:ethyl acetate (1:1) to obtain specified in the connection header (of € 0.195 g, 34% yield). 1 N. NMR (300 MHz, CD3OD) δ 8,84 (m, 1H), they were 8.22 (s, 1H), 8,09 (m, 2H), 7,82 (t, 1H), of 7.70 (d, 1H), of 6.96 (s, 1H), 4,25 (m, 1H); MS (ESI)m/z430,3 [M+1]+.

5.1.17 EXAMPLE 17: SYNTHESIS of (S)-1-(1-PHENYLPROPYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (S)-6-bromo-N2-(1-phenylpropyl)pyrazin-2,3-diamine.

2-Amino-3,5-dibromopyrazine (1.0 g, 3,98 mmol) and (S)-(-)-α-ethylbenzylamine (2.15 g, 15,93 mmol) was subjected to interaction in accordance with the General Procedure A and was carried out by purified using chromatography on silica gel Biotage (10-80% ethyl acetate/hexane, 25S column) to obtain specified in the connection header (0,560 g, 47% yield). MS (ESI) m/z 307,4 [M+1]+, 309,4[M+2] +.

B. (S)-N2-(1-phenylpropyl)-6-(quinoline-5-yl)pyrazin-2,3-diamine.

(S)-6-Bromo-N2-(1-phenylpropyl)pyrazin-2,3-diamine (0,560 g and 1.83 mmol), quinoline-5-Bronevoy acid (0,348 g, a 2.01 mmol), tetrakis(triphenylphosphine)palladium (0,211 g, 0,183 mmol), potassium carbonate (1.01 g, to 7.32 mmol), water (8 ml) and dimethylformamide (30 ml) was subjected to interaction in accordance with the General Procedure B. the Crude product was subjected to purification using chromatography on silica gel Biotage (0-10% methanol/dichloromethane, 40S column) to obtain specified in the header connection (0,500 g, 77% yield). MS (ESI) m/z 356,3 [M+1]+.

C. (S)-1-(1-Phenylpropyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(S)-N2-(1-Phenylpropyl)-6-(quinoline-5-yl)pyrazin-2,3-diamine (0,500 g of 1.40 mmol) and urea (0,170 g of 2.81 mmol) was subjected to interaction in accordance with the General Procedure D2. The solution are condensed under reduced pressure and triturated to powder with water/methanol to obtain specified in the connection header (of € 0.195 g, 36% yield). 1 N. NMR (300 MHz, CD3OD) δ 8,89 (d, 1H), 8,44 (d, 1H), to 8.20 (s, 1H), 8,12 (d, 1H), 7,87 (t, 1H), 7,76 (d, 1H), 7,51 (m, 3H), 7,34 (m, 2H), 5,50 (DD, 1H), 0,981 (t, 3H), 2,39 (m, 2H); MS (ESI)m/z382,5 [M+1]+.

5.1.18 EXAMPLE 18: SYNTHESIS of (R)-1-(1-PHENYLPROPYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-b]PYRAZIN-2(3H)-It

A. (R)-6-bromo-N2-(1-phenylpropyl)pyrazin-2,3-diamine.

2-Amino-3,5-dibromopyrazine (1.0 g, 3,98 mmol) and (R)-(+)-α-ethylbenzylamine (2.15 g, 15.9 mmol) was subjected to interaction in accordance with the General Procedure A and was carried out by purified using chromatography on silica gel Biotage (10-80% ethyl acetate/hexane, 25S column) to obtain specified in the connection header (0,440 g, 36% yield). MS (ESI) m/z 307,4 [M+1]+, 309,4[M+2]+.

B. (R)-N2-(1-phenylpropyl)-6-(quinoline-5-yl)pyrazin-2,3-diamine.

(R)-6-Bromo-N2-(1-phenylpropyl)pyrazin-2,3-diamine (0,440 g of 1.43 mmol), quinoline-5-Bronevoy acid (0,273 g, was 1.58 mmol), tetrakis(triphenylphosphine)palladium (0,165 g, 0,143 mmol), potassium carbonate (0,789 g, 5,72 mmol), water (8 ml) and dimethylformamide (30 ml) was subjected to interaction in accordance with the General Procedure B. the Crude product was subjected to purification using chromatography on silica gel Biotage (0-10% methanol/dichloromethane, 40S column) to obtain specified in the header connection (0,476 g, 93% yield). MS (ESI) m/z 356,4 [M+1]+.

C. (R)-1-(1-Phenylpropyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(R)-N2-(1-Phenylpropyl)-6-(quinoline-5-yl)pyrazin-2,3-diamine (0,476 g of 1.34 mmol) and urea (0,160 g, 2.68 mmol) was subjected to interaction in accordance with the General Procedure D2. The solution are condensed under reduced pressure and triturated to powder with water/methanol to obtain specified in the connection header (0,105 g, 20% yield).lH NMR (300 MHz, CD3OD) δ 8,89 (d, 1H), 8,44 (d, 1H), to 8.20 (s, 1H), 8,12 (d, 1H), 7,87 (t, 1H), 7,76 (d, 1H), 7,51 (m, 3H), 7,34 (m, 2H), 5,50 (DD, 1H), 0,981 (t, 3H), 2,39 (m, 2H); MS (ES)m/z382 [M+1]+.

5.1.19 EXAMPLE 19: SYNTHESIS of 6-(5-ISOPROPYL-2-METHOXYPHENYL)-1-(TETRAHYDRO-2H-PIRAN-3-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-is On

A. 6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-Piran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

N-Bis-Boc-3-Bromo-5-(5-isopropyl-2-methoxyphenyl)pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), hydrochloride tetrahydropyran-3-ylamine (0,395 g, 2.9 mmol) and triethylamine (1 ml) was subjected to interaction in accordance with the General Procedure E. the Product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with 50% methanol in H2O obtaining a white solid (53 mg, 50% yield).lH NMR (300 MHz, DMSO-d6) δ 12,04 (s, 1H), 8,40 (s, 1H), 7,65 (d, J=2,5, 1H), 7,27 (DD, J=8,4, 2,3, 1H), to 7.09 (d, J=8,5, 1H), 4,30-to 4.41 (m, 1H), of 4.05 (t, J=10,7, 1H), 3,86-3,95 (m, 2H), 3,83 (s, 3H), of 2.93 (DD, J=13,8, 6,8, 1H), of 1.23 (d, J=6,9, 6H), 2,60 (DD, J=12,1, 5,2,1H), 1.93 and-2,02 (m, 1H), 1.77 in (s, 2H); MS (ESI)m/z369,0 [M+1]+.

5.1.20 EXAMPLE 20: SYNTHESIS of (S)-1-METHYL-3-(1-PHENYLETHYL)-5-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (S)-6-Bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Specified in the title compound was obtained using (S)-6-bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine (see Example 3.A) (0.50 g, 1,71 mmol), 1,1'-carbonyldiimidazole (0.35 g, 2,13 mmol) and tetrahydrofuran (7 ml)as described in General Procedure Dl. The crude substance was dissolved in methanol (5 ml) and the product was ground into powder with H2O, processing the ri this ultrasound. The precipitate was filtered and dried in a vacuum oven overnight to obtain 0.34 g (1.07 mmol, 62%) of (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she. MS (ESI) m/z 319,4 [M+1]+.

B. (S)-5-Bromo-1-methyl-3-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

To a solution of (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she (0,300 g, 0,943 mmol) in dimethylformamide (3 ml) was added cesium carbonate (excess) followed by the addition of dimethylsulfate (0,130 g of 1.03 mmol). The solution was heated to 55°C in a test tube with a screw cap. After one hour the solution was filtered to remove salts of cesium carbonate. The filtrate are condensed under reduced pressure and the crude product was subjected to purification using chromatography on silica gel Biotage (5-50% ethyl acetate/hexane) to obtain specified in the connection header (0,306 g, 83% yield).lH NMR (300 MHz, DMSO-d6) δ to 7.99 (s, 1H), EUR 7.57 (d, 2H), 7,32 (m, 3H), 5,77 (kV, 1H), 3,42 (s, 3H), 2,04 (d, 3H);13C NMR (75 MHz, CHCl3) δ 52,6 (C=O); MS (ESI)m/zto 333.3 [M+1]+, 335,3 [M+2]+.

C. (S)-1-Methyl-3-(1-phenylethyl)-5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(S)-5-Bromo-1-methyl-3-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0,276 g, 0,831 mmol), quinoline-5-Bronevoy acid (0,158 g, 0,914 mmol), tetrakis(triphenylphosphine)palladium (0,096 g, 0,083 mmol), potassium carbonate (0,458 g of 3.32 mmol), water (8 ml) and dimethylformamide (30 ml) was subjected interaction is the influence of in accordance with the General Procedure B and purified using preparative HPLC (5-70% acetonitrile/water, 60 ml/min) to obtain specified in the connection header (0,130 g, 43% yield).lH NMR (300 MHz, CD3OD) δ 8,86 (d, 1H), at 8.36 (d, 1H), 8,23 (s, 1H), 8,10 (d, 1H), a 7.85 (t, 1H), 7,74 (d, 1H), 7,51 (d, 2H), 7,41 (m, 1H), 7,33 (m, 3H), of 5.85 (q, 1H), 3,53 (s, 3H), 2,01 (d, 3H); MS (ESI) 10m/z382,4 [M+1]+.

5.1.21 EXAMPLE 21: SYNTHESIS of (R)-1-METHYL-3-(1-PHENYLETHYL)-5-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (R)-5-Bromo-1-methyl-3-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

To a solution of (R)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she (0,360 g, 1.13 mmol) in dimethylformamide (3 ml) was added cesium carbonate (excess) followed by the addition of dimethylsulfate (0,150 g, 1.13 mmol). The solution was heated to 55°C in a test tube with a screw cap. After one hour the solution was filtered to remove salts of cesium carbonate. The filtrate are condensed under reduced pressure and the crude product was subjected to purification using chromatography on silica gel Biotage (5-50% ethyl acetate/hexane) to obtain specified in the connection header (0,306 g, 83% yield). 1 N. NMR (300 MHz, DMSO-d6)δ to 7.99 (s, 1H), EUR 7.57 (d, 2H), 7,32 (m, 3H), 5,77 (kV, 1H), 3,42 (s, 3H), 2,04 (d, 3H);13C NMR (75 MHz, CHCl3) δ 52,6 (C=O); MS (ESI)m/zto 333.3 [M+1]+, 335,3 [M+2]+.

B. (R)-1-Methyl-3-(1-phenylethyl)-5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(R)-5-Bromo-1-methyl-3-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0,283 g, 0,849 mmol), quinoline-5-Bronevoy acid (0,161 g, 0.33 mmol), tetrakis(triphenyl phosphine)palladium (0,161 g, 0,933 mmol), potassium carbonate (0,468 g, 3,39 mmol), water (8 ml) and dimethylformamide (30 ml) was subjected to interaction in accordance with the General Procedure B and purified using preparative HPLC (5-70% acetonitrile/water, 60 ml/min) to obtain specified in the connection header (0,137 g, 42% yield). 1 N. NMR (300 MHz, CD3OD) δ 8,86 (d, 1H), at 8.36 (d, 1H), 8,24 (s, 1H), 8,10 (d, 1H), a 7.85 (t, 1H), of 7.75 (d, 1H), 7,51 (d, 2H), 7,41 (m, 1H), 7,34 (m, 3H), of 5.85 (q, 1H), 3,53 (s, 3H), 2,01 (d, 3H); MS (ESI)m/z382,4 [M+1]+.

5.1.22 EXAMPLE 22: SYNTHESIS of 1-CYCLOPENTYLMETHYL-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. Quinoline-5-yl triftorbyenzola.

The quinoline-5-ol (5 g, 34 mmol) was dissolved in pyridine (5.6 ml, 69 mmol) and dichloromethane (100 ml). The solution was cooled in an ice bath, was added via syringe triftormetilfullerenov anhydride (7 ml, 41 mmol). The reaction mixture was stirred for 30 minutes and then the reaction is extinguished by water. The reaction mixture was extracted with saturated sodium bicarbonate solution, water and saturated salt solution. The organic layer was dried over magnesium sulfate and then concentrated. The obtained residue was purified using chromatography on a Biotage silica gel (0-60% ethyl acetate in hexane) to give the product as a yellow oil (9.5 g, 100% yield). 1 N. NMR (400 MHz, DMSO-d6) δ 9,10 (DD, J=4,4, 1,6, 1H), 8,42 (dt, J=8,4, 1,2, 1H), 8,21 (dt, J=8,8, 0,8, 1H), to 7.93 (DD, =8,0, 1H),7,82 (m, 2H); MS (ESI)m/z278,0 [M+1]+.

B. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline.

The quinoline-5-intraformational (9.5 g, 34 mmol), bis(pinacolato)LIBOR (18.2 g, 51 mmol), dichloro[1,1'-bis(diphenyl-phosphino)ferrocene]palladium(II) dichloromethane (753 mg, 1 mmol), triethylamine (14 ml, 102 mmol) and dioxane (100 ml) was heated to boiling point under reflux in nitrogen atmosphere for 16 hours. The reaction mixture was concentrated and the resulting residue was purified using chromatography on a Biotage silica gel (0-60% ethyl acetate in hexane) to give the product as a yellow oil (7.0 g, 80% yield). 1 N. NMR (300 MHz, DMSO-d6) δ 9,00 (d, J=9,3, 1H), 8,93 (DD, J=4,1, 1,9, 1H), 8,15 (d, J=8,2, 1H), of 8.06 (DD, J=6,9, 1,4, 1H), 7,78 (DD, J=8,5, 6,9, 1H), to 7.61 (DD, J=8,5, 4,1, 1H), 1.39 in (s, 12H); MS (ESI)m/zfigure of € 256.4 [M+1]+.

C. 5-(Quinoline-5-yl)pyrazin-2-amine.

A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (5.5 g, 21 mmol), 5-bromopyrazine-2-amine (3.8 g, 21 mmol), tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1 mmol) and sodium carbonate (63 ml, 1M, 63 mmol) in dioxane (240 ml) was heated to boiling point under reflux for 16 hours under nitrogen atmosphere. The reaction mixture was cooled and was extracted using EtOAc and water. The emulsion, which is formed in the extraction process, was filtered and then dried to obtain a reddish solid (3.2 g, 67% yield). 1 N. NMR (300 MHz, DMSO- 6)δ 8,93 (DD, J=4,1, 1,6, 1H), at 8.60 (d, J=8,5, 1H), 8,24 (d, J=1,4,1H), 8,03-8,08 (m, 2H), a 7.85 (m, 1H); MS (ESI)m/z223,2 [M+1]+.

D. 3-Bromo-5-(quinoline-5-yl)pyrazin-2-amine.

A solution of 5-(quinoline-5-yl)pyrazin-2-amine (1.1 g, 5 mmol) and N-bromosuccinimide (882 mg, 5 mmol) in DMF (50 ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (300 ml) and then filtered through celite. The filtrate is brought to pH 8 with saturated sodium bicarbonate solution (100 ml) and then diluted using EtOAc (100 ml). The mixture was stirred for 2 hours and the resulting solid precipitate was filtered, washed with the aid of EtOAc and then dried in vacuum to obtain an orange solid (300 mg, 20% yield). 1 N. NMR (400 MHz, DMSO-d6)δ to 8.94 (d, J=3,2, 1H), 8,56 (d, J=8,4, 1H), with 8.33 (s, 1H), 7,83 (d, J=7,2, 1H), 7,73 2(d, J=6,8, 1H), EUR 7.57 (DD, J=8,8, 4,0, 1H), 6,98 (s, 2H); MS (ESI)m/z301,4 [M+1]+.

E. N-Bis-Boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine.

3-Bromo-5-(quinoline-5-yl)pyrazin-2-amine (1.5 g, 5.0 mmol), di-tert-BUTYLCARBAMATE (2.7 g, 12.5 mmol), 4-dimethylaminopyridine (61 mg, 0.5 mmol) and acetonitrile (15 ml) was heated to 50°C for 30 minutes. The reaction mixture was concentrated and the resulting residue was purified using chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane) to give yellow solid (2.4 g, 96% yield). 1 N. NMR (300 MHz, DMSO-d6)δ the remaining 9.08 (s, 1H), 9,02 (DD, J=4,1, 14, 1H), 8,49 (d, J=8,5, 1H), 8,25 (d, J=8,0,1H), to $ 7.91-8,02 (m, 2H), 7,68 (DD, J=8,7, 4,3, 1H), USD 1.43 (s, 18H); MS (ESI)m/z501,3 [M+1]+.

F. 1-Cyclopentylmethyl-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (150 mg, 0.29 mmol), hydrochloride of cyclopentylamine (268 mg, 2 mmol) and triethylamine in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 25 mg (36% yield) of a white solid. 1 N. NMR (300 MHz, DMSO-d6)δ 8,96 (DD, J=4,1, 1,6, 1H), 8,54-8,61 (m, 2H), 8,12 (d, J=8,2, 1H), to 7.77-of 7.90 (m, 2H), 7,47-to 7.59 (m, 2H), 3,11-3,19 (m, 2H), 1,98-2,12 (m, 1H), 1,67-to 1.77 (m, 2H), 1,49-of 1.65 (m, 4H), 1,15-1,30 (m, 2H); MS (ESI)m/z346,4 [M+1]+.

5.1.23 EXAMPLE 23: SYNTHESIS of 1-[1-(2-FORFINAL)ETHYL]-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-[1-(2-Forfinal)ethyl]-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-(2-forfinal)ethylamine (278 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 55 mg (36% yield) of a white solid. 1 N. NMR (300 MHz, DMSO-d6)δ 12,27 (s, 1H), to 8.94 (DD, J=4,1, 1,6, 1H), with 8.33 (d, J=8,0, 1H), they were 8.22 (s, 1H), 8,10 (d, J=8,2, 1H), 7,81-to $ 7.91 (m, 1H), 7,72 for 7.78 (m, 1H), 7,60-of 7.69 (m, 1H), 7,37-7,49 (m, 2H), 7,17-7,26 (m, 2H), 5,94 (sq, J=7,1, 1H), 1,90 (d, J=7,1, 3H); MS (ESI)m/z386,0 [M+1]+.

5.1.24 EXAMPLE 24: SYNTHESIS of 1-[1-(4-FORFINAL)ETHYL]-6-QUINOLINE-5-the L-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-[1-(4-Forfinal)ethyl]-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-(4-forfinal)ethylamine (278 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 75 mg (49% yield) of a white solid. 1 N. NMR (300 MHz, DMSO-d6)δ 12,29 (s, 1H), 8,91-9,01 (m, 1H), 8,32 (d, J=8,5, 1H), they were 8.22 (s, 1H), 8,10 (d, J=8,2, 1H), 7,80-to $ 7.91 (m, 1H), 7,72-7,79 (m, 1H), 7,41-7,53 (m, 3H), 7,19 (t, J=8,9, 2H), 5,72 (kV, J=7,2, 1H), 1.91 a (l, J=7,1, 3H); MS (ESI)m/z385,9 [M+1]+.

5.1.25 EXAMPLE 25: SYNTHESIS of 1-[1-(3-FORFINAL)ETHYL]-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-[1-(3-Forfinal)ethyl]-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-(3-forfinal)ethylamine (278 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 53 mg (69% yield) of a white solid. 1 N. NMR (400 MHz, DMSO-d6)δ 8,93 (DD, J=4,1, 1,6, 1H), 8,31-to 8.34 (m, 1H), they were 8.22 (s, 1H), 8,10 (d, J=8,4, 1H), 7,82-7,86 (m, 1H), of 7.75 (DD, J=7,1, 1,3, 1H), 7,39-7,44 (m, 2H), 7.23 percent-7,31 (m, 2H), 7,13-7,19 (m, 1H), 5,73 (kV, J=7,4, 1H), at 1.91 (d, J=7,2, 3H); MS (ESI)m/z386,1 [M+1]+.

5.1.26 EXAMPLE 26: SYNTHESIS of 1-[1-(3-METHOXYPHENYL)ETHYL]-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-[1-(3-Methoxyphenyl)ethyl]-6-quinoline-5-yl-1,3-dihydroimidazo[4,-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-(3-methoxyphenyl)ethylamine (278 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 44 mg (38% yield) of a white solid. 1 N. NMR (400 MHz, DMSO-d6)δ 8,93 (DD, J=4,1, 1,8, 1H), 8,35 is 8.38 (m, 1H), they were 8.22 (s, 1H), 8,10 (d, J=8,4, 1H), 7,82-7,86 (m, 1H), 7,76 (DD, J=7,1, 1,3, 1H), 7,42 (DD, J=8,6, 4,1, 1H), 7,26-7,31 (m, 1H), 6,97-7,00 (m, 2H), 6.87 in-6,91 (m, 1H), 5,67 (kV, J=7,3, 1H), 3,68 (s, 3H), of 1.92 (d, J=7,2, 3H); MS (ESI)m/z398,4 [M+1]+.

5.1.27 EXAMPLE 27: SYNTHESIS of 1-[1-(4-METHOXYPHENYL)ETHYL]-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-[1-(4-Methoxyphenyl)ethyl]-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-(4-methoxyphenyl)ethylamine (278 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 44 mg (38% yield) of a white solid. 1 N. NMR (400 MHz, DMSO-d6)δ 12,24 (s, 1H), to 8.94 (DD, J=4,1, 1,8, 1H), 8,33-at 8.36 (m, 1H), 8,21 (s, 1H), 8,10 (d, J=8,4, 1H), a 7.85 (DD, J=8,4, 7,2, 1H), of 7.75 (DD, J=7,2, 1,2, 1H), 7,44 (DD, J=8,6, 4,1, 1H), 7,35-7,38 (m, 2H), 6.90 to-6,94 (m, 2H), 5,67 (kV, J=7,2,1H), 3,74 (s, 3H), at 1.91 (d, J=7,2, 3H); MS (ESI)m/z397,9 [M+1]+.

5.1.28 EXAMPLE 28: SYNTHESIS of 6-QUINOLINE-5-YL-1-(TETRAHYDRO-PIRAN-3-YL)-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 6-Quinoline-5-yl-1-(tetrahydro-Piran-3-yl)-1,3-dihydroimidazo[4,5-b]p the Razin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol), hydrochloride tetrahydro-Piran-3-ylamine (278 mg, 2 mmol) and triethylamine (1 ml) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 21 mg (21% yield) of a white solid. 1 N. NMR (400 MHz, MSO-d6)δ 12,22 (s, 1H), 8,96 (DD, J=4,1, 1,8, 1H), 8,61 (d, J=8,0, 1H), they were 8.22 (s, 1H), 8,12 (d, J=8,4, 1H), 7,87 (DD, J=8,4, 7,0, 1H), 7,78 (DD, J=7,1, 1,3, 1H), 7,58 (DD, J=8,6, 4,1, 1H), or 4.31-4,39 (m, 1H), 3,89-to 3.99 (m, 2H), 3,82 (DD, J=11, 0,4, 0,1H), 3,21 (TD, J=11,6, 2,8, 1H), 2,54 (d, J=4,7, 1H), 1,99 (d, J=12,1, 1H), 1,63 is 1.75 (m, 2H); MS (ESI)m/z348,4 [M+1]+.

5.1.29 EXAMPLE 29: SYNTHESIS of 1-((1S,4S)-4-HYDROXYCYCLOHEXYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-((1S,4S)-4-Hydroxycyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol), hydrochloride, (1S,4S)-4-aminocyclohexanol (278 mg, 2 mmol) and triethylamine (1 ml) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 50 mg (35% yield) of a white solid. 1 N. NMR (400 MHz, MSO-d6)δ 12,16 (s, 1H), 8,96 (DD, J=4,1, 1,8, 1H), 8,58-to 8.62 (m, 1H), to 8.20 (s, 1H), 8,12 (d, J=8,4, 1H), 7,85-7,89 (m, 1H), 7,78 (DD, J=7,2, 1,2, 1H), EUR 7.57 (DD, J=8,8, 4,1, 1H), to 4.62 (d, J=4,5, 1H), 4,21 (TT, J=12,3, 4,3, 1H), 3.33 and-3,39 (m, 1H), 2,27-of 2.38 (m, 2H), 1.91 a (d, J=10,9, 2H), 1,81 (d, J=11,7, 2H), 1,24 is 1.34 (m, 2H); MS (ESI)m/z362,0 [M+1]+.

5.1.30 EXAMPLE 30: SYNTHESIS of 1-((1's,4R)-4-HYDROXYCYCLOHEXYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-((1R,4R)-4-Hydroxycyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol), hydrochloride, (1R,4R)-4-aminocyclohexanol (278 mg, 2 mmol) and triethylamine (1 ml) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 55 mg (38% yield) of a white solid. 1 N. NMR (400 MHz, MSO-d6)δ 12,13 (s, 1H), 8,95 (DD, J=4,2,1, 7, 1H), 8,66 (DD, J=8,8, 1,3, 1H), 8,19 (s, 1H), 8,12 (d, J=8,4, 1H), 7,84-7,88 (m, 1H), to 7.77-7,80 (m, 1H), 7,55 (DD, J=8,8, 4,1, 1H), 4,18-to 4.28 (m, 2H), 3,83 (s, 1H), 2,64 is 2.75 (m, 2H), 1,76 (d, J=12,3, 2H), 1,47 is 1.58 (m, 4H); MS (ESI)m/z362,4 [M+1]+.

5.1.31 EXAMPLE 31: SYNTHESIS of 6-(5-ETHANOLIC)-1-(PHENYLETHYL)-4-IMIDAZOLINE[4,5-B]PYRAZIN-2-It

A. 6-Bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine.

α-Methylbenzylamine (1.3 ml, of 10.21 mmol) was added to 2-amino-3,5-dibromopyrazine (2.00 g, of 7.97 mmol) in n-BuOH (10 ml) and the resulting mixture was heated at 220°C for 4500 seconds in a microwave reactor Emrys Optimizer. The reaction mixture are condensed to obtain a brown oil. Purification using flash column-chromatography on silica gel (10-80% EtOAc in hexane) gave 1.65 g (5,62 mmol, 71%) of 6-bromo-N2-(1-phenylethyl)pyrazin-2,3-diamine. MS (ESI) m/z 293,0 [M+1]+.

B. 6-Bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1,1'-Carbonyldiimidazole (1,14 g? 7.04 baby mortality mmol) was added to 6-bromo-N2-(1-phenylethyl)pyrazin-2,diamino (1.65 g, 5,63 mmol) was dissolved in THF (15 ml). The resulting mixture was heated for 3600 seconds at 180°C in a microwave reactor Emrys Optimizer. The reaction mixture are condensed to obtain a brown oil. Was carried out by absorption of the crude oil in a minimum amount of methanol and, while processing the ultrasound was added to the water to cause precipitation. The formed solid substance was collected by filtration and dried in a vacuum oven overnight to obtain 1.54 g (a 4.83 mmol, 86%) specified in the connection header. MS (ESI) m/z 319,1 [M+1]+.

C. 6-(5-ethanolic)-1-(phenylethyl)-4-imidazoline[4,5-b]pyrazin-2-it.

A solution of 6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she (0.5 g, 1,567 mmol), isoquinoline-5-Bronevoy acid (0.4 g, of 2.35 mmol), potassium phosphate (1.6 g, 7.8 mmol) and complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) methylene chloride (0,13 g, 0.16 mmol) in dimethylformamide (10 ml) was heated at 130°C for 1 hour in a microwave reactor Emrys Optimizer. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude substance was purified column chromatography (SiO2, 20-100% ethyl acetate in hexane). The resulting material was subjected to additional purification using column chromatography (SiO2, 2% methanol in methylene chloride). Pure fractions were combined, the solvent deletion is whether under reduced pressure and the resulting solid was subjected to ultrasonic treatment in the presence of acetonitrile. The precipitate was filtered and dried in high vacuum to obtain specified in the title compound with a purity of 99.9% (by 33.7 mg, 6%).1H NMR (400 MHz, CD3OD) δ 9,29 (s, 1H), 8,32 (d, J=6,2, 1H), 8,18 (users, 2H), to 7.93 (DD, J=7,1, 1,2 1H), 7,82 (d, J=6,1, 1H), 7,78 (DD, J=8,2, 7,2, 1H), 7,51 (d, J=6,6, 2H), 7,34 (m, 3H), of 5.83 (q, J=7,22, 1H), 2,03 (d, J=7,22, 3H); MS (ESI) m/z 368,1 [M+1]+.

5.1.32 EXAMPLE 32: SYNTHESIS of 1-[1-(4-CHLOROPHENYL)ethyl]-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-[1-(4-Chlorophenyl)ethyl]-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-(4-chlorophenyl)ethylamine (278 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 49 mg (42% yield) of a white solid.1H NMR (400 MHz, MSO-d6) δ 12,29 (s, 1H), to 8.94 (DD, J=4,1, 1,8, 1H), 8,29 (DD, J=9,2, 1,2, 1H), they were 8.22 (s, 1H), 8,10 (d, J=8,2, 1H), to 7.84 (DD, J=8,4, 7,2,1H), of 7.75 (DD, J=7,1, 1,3, 1H), 7,40-7,46 (m, 5H), 5,68-5,74 (m, 1H), 1,90 (d, J=7,2, 3H); MS (ESI)m/z402,3 [M+1]+.

5.1.33 EXAMPLE 33: SYNTHESIS of 1-[1-(4-METHANESULFONYL)ethyl]-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-[1-(4-Methanesulfonyl)ethyl]-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-(4-methanesulfonyl)ethylamine (400 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified in with the accordance with the General Procedure E2 to obtain 33 mg (37% yield) of a white solid. 1H NMR (400 MHz, MSO-d6) δ 12,31 (s, 1H), 8,88 (DD, J=4,1, 1,6, 1H), compared to 8.26-8,29 (m, 1H), 8,21 (s, 1H), of 8.06 (d, J=8,4, 1H), 7,89 (dt, J=8,6, 2,0, 2H), 7,78-7,83 (m, 1H), 7,71 (DD, J=7,1, 1,3, 1H), 7,66 (d, J=8,4, 2H), 7,40 (DD, J=8,6, 4,1, 1H), 5,78 (kV, J=7,3, 1H), 3,18 (s, 3H), of 1.92 (d, J=7,2, 3H); MS (ESI)m/zKZT 446.4 [M+1]+.

5.1.34 EXAMPLE 34: SYNTHESIS of 1-(1-PYRIDINE-4-RETIL)-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-(1-Pyridin-4-yl-ethyl)-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b] pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-pyridin-4-ylethylamine (250 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 15 mg (20% yield) of a white solid.1H NMR (400 MHz, MSO-d6) δ 12,30 (s, 1H), 8,87 (d, J=3,9, 1H), charged 8.52 (d, J=6,1, 2H), to 8.20 (s, 1H), 8,18 (s, 1H), with 8.05 (d, J=8,4, 1H), 7,79 (t, J=7,7, 1H), of 7.70 (d, J=7,0, 1H), 7,37 (d, J=6,1, 2H), 7,33 (DD, J=8,7, 4,2, 1H), 5,69 (d, J=7,2, 1H), 1,86 (d, J=7,2, 3H); MS (ESI)m/z369,4 [M+1]+.

5.1.35 EXAMPLE 35: SYNTHESIS of 5-METHYL-1-((S)-1-PHENYLETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Methylpyridin-2-ylamine.

To a solution containing 6-chloro-2-pyrazinamid (5.0 g, 38,75 mmol) in 1,4-dioxane (70 ml)was added [1,3-bis(diphenylphosphino]Ni(II)Cl2(2.10 g, 38,76 mmol), followed by adding dropwise dimethylzinc in toluene (38,75 ml, 2.0 M, 77,50 mmol) for 15 minutes. The solution was left for stirring at 105°C for 16 hours. The solution is then are condensed with onigen the m pressure, was diluted with ethyl acetate and filtered through celite to remove salts of Nickel. The resulting suspension was purified using chromatography on silica gel Biotage (0-8% methanol in dichloromethane) to obtain the specified title compound as an orange solid (1.18 g, 28% yield). MS (ESI) m/z 110,3 [M+1]+.

B. 3,5-Dibromo-6-methylpyridin-2-ylamine.

6-Methylpyridin-2-ylamine (1.18 g, was 10.82 mmol) and pyridine (1,79 g, 22,72 mmol) were combined in chloroform (100 ml) at ambient temperature. Then was added dropwise bromine (3,63 g, 22,72 mmol) in chloroform (5 ml) for 5 minutes. When the starting material was completely consumed, as shown by TLC analysis, the reaction solution was transferred into a separating funnel and the organic layer was washed twice with water. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to obtain specified in the title compound (2.70 g, 95% yield). MS (ESI) m/z 268,0 [M+2]+.

C. (S)-6-Bromo-5-methyl-N2-(1-phenylethyl)pyrazin-2,3-diamine.

3,5-Dibromo-6-methylpyridin-2-ylamine (1.45 g, the 5.45 mmol) and (S)-(-)-α-methylbenzylamine (1.65 g, 13,62 mmol) was subjected to interaction in accordance with the General Procedure A and was carried out by purified using chromatography on silica gel Biotage (5-75% ethyl acetate in hexane, 40M column) to obtain specified in the connection header (0,975 g, 65% yield). MS (ESI) m/z 39,4 [M+2] +.

D. 5-Methyl-N2-((S)-1-phenylethyl)-6-(quinoline-5-yl)pyrazin-2,3-diamine.

A solution of (S)-6-bromo-5-methyl-N2-(1-phenylethyl)pyrazin-2,3-diamine (0,975 g, 3,19 mmol), quinoline-5-Bronevoy acid (0,606 g, 3.50 mmol), tetrakis(triphenylphosphine)palladium (0,368 g, 0,319 mmol) and potassium carbonate (1,76 g of 12.76 mmol) in water (8 ml) and dimethylformamide (30 ml) was subjected to interaction in accordance with the General Procedure B and has been purified using chromatography on silica gel Biotage (0-10% methanol in dichloromethane, 40M column). The obtained solid was ground into powder with water/methanol to obtain specified in the connection header (0,200 g, 18% yield). MS (ESI) m/z 356,5 [M+1]+.

E. 5-Methyl-1-((S)-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

5-Methyl-N2-((S)-1-phenylethyl)-6-(quinoline-5-yl)pyrazin-2,3-diamine (0,200 g, 0,563 mmol) and urea (0,067 g, 1.12 mmol) was subjected to interaction in accordance with the General Procedure D2 and has been purified using chromatography on silica gel Biotage (0-10% methanol in dichloromethane, 25M column) to obtain specified in the connection header (0,063 g, 30% yield).1H NMR (300 MHz, MSO-d6) δ 12,10 (Sirs, 1H), of 8.92 (DD, 1H), 8,10 (d, 2H), to 7.84 (m, 2H), a 7.62 (d, 1H), 7,41 (m, 1H), 7,30 (m, 6H), 5,63 (kV, 1H), 3,32 (s, 2H), of 1.85 (d, 3H); MS (ESI)m/z382,5 [M+1]+.

5.1.36 EXAMPLE 36: SYNTHESIS of 5-METHYL-1-((R)-1-PHENYLETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (R)-6-Bromo-5-ethyl-N 2-(1-phenylethyl)pyrazin-2,3-diamine.

3,5-Dibromo-6-methylpyridin-2-ylamine (see Example 35.B) (to 0.900 g, to 3.38 mmol) and (R)-(+)-α-methylbenzylamine (1.63 g, 13,52 mmol) was subjected to interaction in accordance with the General Procedure A and was carried out by purified using chromatography on silica gel Biotage (5-80% ethyl acetate in hexane, 40S column) to obtain the specified title compound (0.534 g, 52% yield). MS (ESI) m/z 309,4 [M+2]+.

B. 5-Methyl-N2-((R)-1-phenylethyl)-6-(quinoline-5-yl)pyrazin-2,3-diamine.

(R)-6-Bromo-5-methyl-N2-(1-phenylethyl)pyrazin-2,3-diamine (0.534 g, of 1.74 mmol), quinoline-5-Bronevoy acid (0,331 g, at 1.91 mmol), tetrakis(triphenylphosphine) palladium (0.20 g, 0,175 mmol) and potassium carbonate (0.96 g, of 6.96 mmol) in water (4 ml) and dimethylformamide (15 ml) was subjected to interaction in accordance with the General Procedure B and has been purified using chromatography on silica gel Biotage (0-10% methanol in dichloromethane, 40M column) and the resulting solid was ground in a the powder with water/methanol to obtain specified in the connection header (0,42 g, 67% yield). MS (ESI) m/z 356,4 [M+1]+.

C. 5-Methyl-1-((R)-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

5-Methyl-N2-((R)-1-phenylethyl)-6-(quinoline-5-yl)pyrazin-2,3-diamine (0,418 g, 1.11 mmol) and urea (0,141 g of 2.35 mmol) was subjected to interaction in accordance with the General Procedure D2. The solution are condensed under reduced pressure and was diluted with methanol and triturated in water with the powder, while processing the ultrasound. The precipitate was filtered and dried to obtain specified in the connection header (0,142 g, 32% yield).1H NMR (300 MHz, DMSO) δ 12,10 (Sirs, 1H), of 8.92 (DD, 1H), 8,10 (d, 2H), to 7.84 (m, 2H), a 7.62 (d, 1H), 7,41 (m, 1H), 7,30 (m, 6H), 5,63 (kV, 1H), 3,32 (s, 2H), of 1.85 (d, 3H). MS (ESI)m/z382,5 [M+1]+.

5.1.37 EXAMPLE 37: SYNTHESIS of 1-(1-PHENYLETHYL)-6-(QUINOLINE-4-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(1-Phenylethyl)-6-(quinoline-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Specified in the title compound was obtained using 6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (see Example 31.B) (0.50 g, 1.57 mmol), 4-henrikromby acid (0.27 g, 1,89 mmol), potassium carbonate (1,00 g, 4,71 mmol), tetrakis(triphenylphosphine)palladium(0) (0,13 g, 0.16 mmol), dimethylformamide (7 ml) and water (4 ml), as described in General Procedure B. the Crude substance was purified using chromatography on silica gel (20-70% EtOAc in hexane). Pure fractions were combined and are condensed to obtain 0.1 g (0.27 mmol, 17%) 1-(1-phenylethyl)-6-(quinoline-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she. 1 N. NMR (300 MHz, CD3OD) δ 8,91 (d, 1H), of 8.27 (s, 1H), 8,09 (m, 2H), 7,81 (m, 1H), 7,63 (d, 2H), 7,53 (m, 2H), 7,34 (m, 2H), of 5.83 (m, 1H), 2,03 (d, 3H); MS (ESI)m/z368,4 [M+1]+; TPL 252-254°C.

5.1.38 EXAMPLE 38: SYNTHESIS of 6-(2-FORFINAL)-1-(1-PHENYLETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(2-Forfinal)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 6-bromo-1-(1-phenylethyl)-1H-imides the[4,5-b]pyrazin-2(3H)-it (see Example 31.B) (0.125 g, 0,393 mmol), 2-ftorhinolonovy acid (0,065 g, 0,470 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-product join dichloromethane (0,032 g 0,039 mmol) and potassium phosphate (of 0.333 g, 1.57 mmol) in water (0.6 ml) and dimethylformamide (2 ml) was subjected to interaction in accordance with the General Procedure C and purified using preparative HPLC (10-100% acetonitrile/water, 60 ml/min) to obtain the specified in the title compound (0,050 g, 38% yield).1H NMR (300 MHz, MSO-d6) δ 12,10 (s, 1H), 8,35 (s, 1H), a 7.85 (t, 1H), 7,45 (t, 3H), 7,37 (m, 3H), 7,30 (m, 1H), 5,77 (kV, 1H), 2,00 (d, 3H), MS (ESI)m/z335,1 [M+1]+.

5.1.39 EXAMPLE 39: SYNTHESIS of 1-(1-PHENYLETHYL)-6-(QUINOLINE-6-YL)-1H-imidazo[4,5-B]PYRAZIN-2(3H)-It

A. 4,4,5,5-Tetramethyl-2-(6-chinolin)-1,3,2-dioxaborolan.

To a suspension of 6-brainline (0.9 g, 4.35 mmol), bis(pinacolato)Debora (cent to 8.85 g, 34.8 mmol) and potassium acetate (2,56 g, with 5.22 mmol) in DMF (50 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) in the form of an adduct with dichloromethane (355 mg, 0,435 mmol) and the reaction mixture was heated in a microwave reactor Emrys Optimizer at 1000C for 30 minutes. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude substance was purified column chromatography (SiO2, 20-50% ethyl acetate in hexane) to obtain the specified title compound (1.1 g, 99% yield). MS (ESI) m/z 256,5 [M+1]+.

B. -(1-Phenylethyl)-6-(quinoline-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (see Example 35.B) (0.5 g, 1,567 mmol), 4,4,5,5-tetramethyl-2-(6-chinolin)-1,3,2-dioxaborolane (0.6 g, 2,35 mmol), potassium phosphate (1.6 g, 7.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)the product of the merger dichloromethane (of 0.13 g, 0.16 mmol) in a mixture of 10:1 DMF:water (10 ml) was heated at 130°C for 1 hour in a microwave reactor Emrys Optimizer. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude substance was purified using column chromatography (SiO2that 1:1 n-hexane:ethyl acetate). Subsequent purification using column chromatography (SiO2, 2% methanol in methylene chloride) followed by passing through a C18 column using acetonitrile as eluent gave specified in the title compound with a purity of 98.9 per cent (3 mg, 0.5%).1H NMR (400 MHz, CD3OD) δ 8,84 (DD, J=4,3, of 1.6,1H), 8,61 (s, 1H), 8,53 (d, J=7,9, 1H), 8,46 (d, J=7,2, 1H), to 8.41 (DD, J=8,9, 2,2, 1H), 8,11 (d,J=8,8, 1H), to 7.59 (user. s, 3H), 7,35 (t, J=7,7,2H), 7,28 (t, J=7,2, 1H), by 5.87 (kV J=7,4, 1H), 2,03 (d, J=7,4, 3H); MS (ESI)m/z368,3 [M+1]+.

5.1.40 EXAMPLE 40: SYNTHESIS of 1-PIPERIDINE-4-YLMETHYL-6-QUINOLINE-5-YL-1,3-DIHYDROIMIDAZO[4,5-B]PYRAZIN-2-It

A. 1-piperidine-4-ylmethyl-6-quinoline-5-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-it.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol), and require the-butyl 4-(aminomethyl)piperidine-1-carboxylate (400 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2. The reaction mixture was ground into powder with a mixture of 1:1 DMSO:methanol to obtain 19 mg (26% yield) of a white solid.1H NMR (400 MHz, DMSO-d6) δ to 8.94 (DD, J=4,1, 1,8, 1H), 8,59-8,61 (m, 1H), 8,10 (s, 1H), 8,08 (d, J=7,2, 1H), 7,82-7,86 (m, 1H), 7,73 (DD, J=7,2, 1,2, 1H), 7,51 (DD, J=8,8, 4,1, 1H), 3,68 (d, J=6,8, 1H), 2,96 totaling 3.04 (m, 2H), 1,94-2,04 (m, 1H), 1.56 to of 1.64 (m, 2H), 1,12-1,24 (m, 2H); MS (ESI) m/z to 405.5 [M+1]+.

5.1.41 EXAMPLE 41: SYNTHESIS of 1-(1-(PYRIDIN-2-YL)ETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Pyridine-2-yl)ethanamine.

2-Acetylpyridine (0.5 g, 4.1 mmol), potassium carbonate (1.7 g, 12.3 mmol), hydroxylamine hydrochloride (342 mg, 5 mmol) and methanol (10 ml) was stirred together at room temperature for 16 hours, then the reaction mixture was filtered. To the filtrate was added zinc dust (1.3 g, 21 mmol) and ammonium chloride (1.1 g, 21 mmol). The resulting suspension was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (10 ml) and then filtered. The filtrate was concentrated and dried to obtain 300 mg (60% yield) of a white solid.1H NMR (300 MHz, DMSO-d6) δ of 8.47 (d, J=4,9, 1H), 7,73 (TD, J=7,7, 1,9, 1H), 7,45 (d, J=7,7, 1H), 7,20 (DDD, J=7,5, 4,9, 1,1, 1H), 3,98 (kV, J=6,0, 1H), 1.27mm (d, J=6,6, 3H); MS (ESI)m/z123,6 [M+1]+.

B. 1-(1-(Pyridin-2-yl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of N-bis-boc-3-bromo-5-(hin is Lin-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and 1-(pyridine-2-yl)ethanamine (250 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 53 mg (48% yield) of a white solid.1H NMR (400 MHz, DMSO-d6) δ 12,27 (s, 1H), 8,88 (DD, J=4,1, 1,6, 1H), 8,50-charged 8.52 (m, 1H), 8,21 (s, 1H), 8,16 (d, J=8,4, 1H), of 8.06 (d, J=8,4, 1H), 7,79-to 7.84 (m, 2H), 7,71-7,73 (d, J=7,5, 1H), of 7.48 (d, J=8,5,1H), 7,30 and 7.36 (m, 2H,), 5,72 is 5.77 (DD, J=9,0, 1H), 1,94 (d, J=9,0, 3H); MS (ESI)m/z369,5 [M+1]+.

5.1.42 EXAMPLE 42: SYNTHESIS of 1-(1-(PYRIDIN-3-YL)ETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Pyridine-3-yl)ethanamine.

3-Acetylpyridine (0.5 g, 4.1 mmol), potassium carbonate (1.7 g, 12.3 mmol), hydroxylamine hydrochloride (342 mg, 5 mmol) and methanol (10 ml) was stirred together at room temperature for 16 hours, then the reaction mixture was filtered. To the filtrate was added zinc dust (1.3 g, 21 mmol) and ammonium chloride (1.1 g, 21 mmol). The solution was stirred at room temperature for 24 hours. To the reaction mixture were added water (10 ml) and then filtered. The filtrate was concentrated and dried to obtain 300 mg (60% yield) of a white solid.1H NMR (300 MHz, DMSO-d6) δ charged 8.52 (d, J=4,9, 1H), 8,32 (TD, J=7,7, 1,9, 1H), 7,68 (d, J=7,7, 1H), 7,28 (DDD, J=7,5, 4,9, 1,1, 1H), 4,6 (kV, J=6,0, 1H), 1,25 (d, J=6,6, 3H); MS (ESI)m/z123,4 [M+1]+.

B. 1-(1-(Pyridin-3-yl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-lamina (see Example 22.E) (150 mg, 0.29 mmol) and 1-(pyridine-3-yl)ethanamine (250 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 15 mg (14% yield) of a white solid.1H NMR (400 MHz, DMSO-d6) δ 12,29 (s, 1H), 8,93 (m, 1H), at 8.60 (d, J=2,0, 1H), charged 8.52-8,54 (d, J=6,0, 1H), 8,30 (d, J=10,0, 1H), they were 8.22 (s, 1H), of 8.09 (d, J=10,5, 1H), 7,82-7,86 (m, 2H), 7,73 (d, J=8,5, 1H), 7,38-7,46 (m, 2H), 5,75-of 5.81 (DD, J=9,0, 1H), 1,94 (d, J=9,5, 3H); MS (ESI)m/z369,5 [M+1]+.

5.1.43 EXAMPLE 43: SYNTHESIS of 1-((1S,4S)-4-(HYDROXYMETHYL)CYCLOHEXYL)-6-(QUINOLINE-5-YL)-1H-imidazo[4,5-B]PYRAZIN-2(3H)-It

A. ((1S,4S)-4-Aminocyclohexane)methanol.

To ((1S,4S)-4-(Dibenzylamino)cyclohexyl)methanol (2 g, 6.5 mmol) was added methanol (50 ml) and 10% Pd/C (100 mg). The reaction mixture was shaken in hydrogenator Parra with gaseous hydrogen (40 psi (2,812 kg/cm2)) for 16 hours. The reaction mixture was filtered through celite and then concentrated to obtain oil.1H NMR (300 MHz, DMSO-d6) δ of 4.49 (s, 1H), 3,25 (s, 2H), 2,81 (s, 1H), 1,38 (m, 8H); MS (ESI)m/z130,3 [M+1]+.

B. 1-((1S,4S)-4-(Hydroxymethyl)cyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)pyrazin-2-ylamine (see Example 22.E) (150 mg, 0.29 mmol) and ((1S,4S)-4-aminocyclohexane)methanol (250 mg, 2 mmol) in ethanol (4 ml) was subjected to interaction and purified according to General Procedure E2 to obtain 40 mg (36% yield) of a white solid substances is A. 1H NMR (400 MHz, DMSO-d6) δ 12,14 (s, 1H), 8,96 (DD, J=4.2, and the 1.7, 1H), 8,69 (d, J=8,0, 1H), they were 8.22 (s, 1H), 8,21 (d, J=8,4, 1H), 7,84-7,88 (m, 1H), 7,78-7,80 (m, 1H), 7,58 (DD, J=8,8, 4,1, 1H), of 8.06 (t, J=5,6, 1H), 4,24 (dt, J=8,0, 4,4, 1H), 3,50-to 3.41 (m, 2H), and 3.16 (d, J=5,2, 1H), 2,31-2,48 (m, 2H), 1,79-of 1.85 (m, 2H), 1,71 (Sirs, 1H), 1,45-of 1.62 (m, 4H); MS (ESI)m/z376,4 [M+1]+.

5.1.44 EXAMPLE 44: SYNTHESIS of 6-(3-(METHYLSULPHONYL)PHENYL)-1-(1-PHENYLETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(3-(Methylsulphonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 31.B) (of 0.13 g, 0.40 mmol), (3-methylsulfinylphenyl)baronova acid (0,094 g, 0.47 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0,032 g 0,039 mmol) and potassium phosphate (of 0.333 g, 1.57 mmol) was dissolved in water (0.6 ml) and DMF (4 ml)were subjected to interaction in accordance with the General Procedure C and purified using preparative HPLC (10-100% acetonitrile/water, 60 ml/min) to obtain specified in the connection header (of 0.038 g, 0.1 mmol, 24% yield).1H NMR (400 MHz, DMSO-d6) δ 12,23 (s, 1H), to 8.62 (s, 1H), charged 8.52 (s, 1H), of 8.37 (d, 1H), of 7.97 (d, 1H), 7,79 (t, 1H), EUR 7.57 (d, 2H), 7,38 (2, t), 7,29 (m, 1H), of 5.75 (m, 1H), 3,29 (d, 3H), from 2.00 (d, 3H); MS (ESI)m/z395,4 [M+1]+.

5.1.45 EXAMPLE 45: SYNTHESIS of 3-(1-PHENYLETHYL)-5-QUINOLINE-5-YL-3H-OXAZOLO[4,5-B]PYRAZIN-2-It

A. 5-(Quinoline-5-yl)pyrazin-2-amine.

The quinoline-5-Voronovo acid (2.0 g, 11.5 mmol), 5-bromopyrazine-2-amine (2.0 g, 11.5 mmol), dichloro[1,1'-bis(WPPT is siltstone)ferrocene]palladium(II) in the form of an adduct with dichloromethane (252 mg, 0.34 mmol), 1M sodium carbonate (35 ml, 35 mmol) and dioxane (120 ml) were heated together to 100°C for 2 hours in nitrogen atmosphere. The reaction mixture was concentrated to a paste and then was ground into powder with water. The residue was filtered and washed with water to obtain a dark brown solid (2.2 g, 90% yield).1H NMR (400 MHz, DMSO-d6) δ 8,93 (DD, J=4,1, 1,8, 1H), at 8.60 (d, J=7,8, 1H), 8,24 (d, J=1,6, 1H), with 8.05 (m, 2H), 7,81 (m, 1H), 7,69 (d, J=5,9, 1H), 7,53 (DD, J=8,6, 4,3, 1H), 6,69 (s, 2H); MS (ESI)m/z223,3 [M+1]+.

B. 5-Quinoline-5-yl-1H-pyrazin-2-it.

5-(Quinoline-5-yl)pyrazin-2-amine (2.2 g, 10 mmol) and sodium nitrite (1.4 g, 20 mmol) were added together and cooled in an ice bath. To the mixture was added concentrated sulfuric acid (6 ml). The reaction mixture was slowly heated to 50°C in a water bath for 30 minutes. The reaction mixture was poured into crushed ice (50 g) and the pH was brought to 7 by using 1M NaOH. The resulting solid was filtered, washed with water and then dried to obtain solid reddish-brown, (1.4 g, 65% yield).1H NMR (400 MHz, DMSO-d6) δ 8,93 (DD, J=4,3, 1,6, 1H), 8,53 (d, J=8,6, 1H), 8,19 (s, 1H), of 8.06 (d, J=8,6, 1H), 7,81 (m, 2H), 7,69 (d, J=6,2, 1H), 7,54 (DD, J=8,6, 3,9, 1H); MS (ESI)m/z224,4[M+1]+.

C. 3-Bromo-5-quinoline-5-yl-1H-pyrazin-2-it.

5-Quinoline-5-yl-1H-pyrazin-2-er (600 mg, 2.6 mmol), N-bromosuccinimide (480 mg, 2.6 mmol) and DMF (7 ml) was stirred at room temperature in temnote for 3 hours. The reaction mixture was concentrated under reduced pressure and then was ground into powder with water. The mixture was filtered, washed with water and then dried to obtain solid reddish-brown color (380 mg, 47% yield).1H NMR (400 MHz, DMSO-d6) δ 8,88 (DD, J=4,1, 1,8, 1H), 8,69 (d, J=8,6, 1H), 7,92 (m, 2H), 7,74 (DD, J=8,4, 7,2, 1H), 7,58 (DD, J=7,0, 1,2, 1H), 7,52 (DD, 7=8,6, 4,3, 1H); MS (ESI)m/z304,0 [M+1]+.

D. 3-(1-Phenyl-ethylamino)-5-quinoline-5-yl-1H-pyrazin-2-it.

3-Bromo-5-quinoline-5-yl-1H-pyrazin-2-he (0,82 g, 2.7 mmol), 1-fenilatilamin (394 mg, 3.3 mmol) and diisopropylethylamine (2 ml) were heated together up to 130°C for 16 hours. The reaction mixture was ground into powder with water and EtOAc to obtain a solid substance. The mixture was filtered and dried to obtain a dark brown solid (0.74 g, 80% yield).1H NMR (400 MHz, DMSO-d6) δ 11,94 (s, 1H), 8,83 (s, 1H), 8,29 (d, J=9,0, 1H), 7,95 (d, J=8,6, 1H), of 7.70 (t, J=7,6, 1H), 7,60 (d, J=7,4, 1H), 7,55 (d, J=7,0, 1H), was 7.36 (d, J=3,9, 3H), 7,28 (DD, J=7,8, 3,5, 1H), 7,18 (DD, J=8,2, 3,9, 1H), 6,86 (s, 1H), to 5.03 (m, 1H), 1,50 (d, J=6,6, 3H); MS (ESI)m/z343,1 [M+1]+.

E. 3-(1-Phenyl-ethyl)-S-quinoline-5-yl-3H-oxazolo[4,5-b]pyrazin-2-it.

3-(1-Phenyl-ethylamino)-5-quinoline-5-yl-1H-pyrazin-2-he (50 mg, 0.15 mmol), 1,1'-carbonyldiimidazole (470 mg, 1.5 mmol) and dioxane (5 ml) were heated together in a high pressure tube to 150°C for 20 hours. The reaction mixture was filtered through celite, washed with the aid of EtOAc and then concentrated. Carried out the cleaning of the residue by chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane). The fractions containing the product were concentrated and then triturated to powder with simple ether to obtain a white solid (28 mg, 52% yield).1H NMR (400 MHz, CD3OD) δ 9,73 (DD, J=4,1, 1,8, 1H), 9,11 (s, 1H), which is 9.09 (d, J=8,2, 1H), 8,93 (d, J=8,6, 1H), 8,66 (m, 1H), 8,58 (DD, J=7,2, 1,4, 1H), 8,31 (m, 2H), compared to 8.26 (DD, J=8,6, 4,3, 1H), 8,17 (m, 2H), to 6.43 (kV, J=7,0, 1H), 2,71 (d, J=7,0, 3H); MS (ESI)m/z369,4 [M+1]+.

5.1.46 EXAMPLE 46: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-ISOPROPYL-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (4 Bromophenoxy)triisopropylsilane.

4-Bromophenol (5.5 g, 32 mmol), imidazole (5.4 g, 80 mmol) and dichloromethane (200 ml) was stirred in nitrogen atmosphere. Added triisopropylsilane (8.1 ml, 38 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with water, 1M sodium hydroxide solution and saturated saline solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain a colorless oil (10 g, 100% yield).1H NMR (400 MHz, DMSO-d6) δ 7,42 (d, J=9,0, 2H), 6,83 (d, J=9,0, 2H), 1,23 (DQC, J=14,7, 7,3, 3H), of 1.05 (d, J=7,4, 18H).

B. Triisopropyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)silane.

(4 Bromophenoxy)triisopropylsilane (10 g, 32 mmol), bis(pinacolato)LIBOR (8,1 g, 32 mmol), potassium acetate (9.4 g, 96 mmol) and dioxane (200 ml) were added together and were degirolami in vacuum. Added dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the IDA adduct with dichloromethane (0.7 g, 0.96 mmol) and the reaction mixture was heated to 100°C in nitrogen atmosphere for 20 hours. After cooling to room temperature the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated and the resulting material was purified using chromatography on a Biotage silica gel (0-20% ethyl acetate in hexane) to give colorless oil (10.1 g, 84% yield).1H NMR (400 MHz, DMSO-d6) δ 7,58 (d, J=8,6, 2H), 6.87 in (d, J=8,6, 2H), 1.27mm (s, 15H), of 1.05 (d, J=7,4, 18H).

C. 5-(4-(Triisopropylsilyl)phenyl)pyrazin-2-amine.

Triisopropyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)silane (1.1 g, 2.9 mmol), 5-bromopyrazine-2-amine (507 mg, 2.9 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (64 mg, 0,087 mmol), 1M sodium carbonate (8.7 ml to 8.7 mmol) and dioxane (10 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 120°C for 10 minutes. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified using chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane) to give a reddish brown solid (0.8 g, 80% yield).1H NMR (400 MHz, DMSO-d6) δ 8,42 (s, 1H), 7,92 (s, 1H), 7,80 (d, J=8,6, 2H), make 6.90 (d, J=8,6, 2H), 6,45 (s, 2H), 1.26 in (kV, J=7,4, 7,2, 3H), of 1.08 (d, J=7,4, 18H); MS (ESI)m/zto 344.4 [M+1]+.

D. 3-Bromo-5-(4-(is diisopropylethylamine)phenyl)pyrazin-2-amine.

5-(4-(Triisopropylsilyl)phenyl)pyrazin-2-amine (1.6 g, 4.7 mmol), N-bromosuccinimide (830 mg, 4.7 mmol) and dimethylformamide (10 ml) was stirred together at room temperature for 1 hour. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane) to give a dark solid (1.1 g, 56% yield).1H NMR (400 MHz, DMSO-d6) δ 8,51 (s, 1H), 7,78 (d, J=8,6, 2H), 6,93 (d, J=9,0, 2H), 6.75 in (s, 2H), to 1.21 to 1.31 (m, 3H), of 1.08 (d, J=7,0, 18H); MS (ESI)m/z422,4 [M+1]+.

E. 3-Bromo-N,N-bis-boc-5-(4-(triisopropylsilyl)phenyl)pyrazin-2-amine.

3-Bromo-5-(4-(triisopropylsilyl)phenyl)pyrazin-2-amine (1.1 g, 2.6 mmol), di-tert-BUTYLCARBAMATE (2.8 g, 13 mmol), 4-dimethylaminopyridine (32 mg, 0.26 mmol) and acetonitrile (30 ml) were heated together to 50°C for 2 hours. The reaction mixture was concentrated and then purified using chromatography on a Biotage silica gel (0-20% ethyl acetate in hexane) to give a dark oil (1.6 g, 99% yield).1H NMR (400 MHz, DMSO-d6) δ 9,29 (s, 1H), they were 8.22 (d, J=8,6, 2H), 7,42 (d, J=8,6, 2H), to 1.38 (s, 18H), 1,20-1,30 (m, 3H), was 1.04 (d, J=7,4, 18H).

F. 4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol.

3-Bromo-N,N-bis-boc-5-(4-(triisopropylsilyl)phenyl)pyrazin-2-amine (1.6 g, 2.6 mmol) was dissolved in tetrahydrofuran (20 ml) and dobblemoneycreditcard (0.68 g, 2.6 mmol). After starting material was completely consumed (monitored by using TLC), the reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified using chromatography on a Biotage silica gel (0-50% ethyl acetate in hexane) to give white solid (1.1 g, 92% yield).1H NMR (400 MHz, DMSO-d6) δ 9,13 (s, 1H), 8,02 (d,J=8,6, 2H), 6,93 (d, J=8,6, 2H), to 1.38 (s, 18H).

G. 6-(4-Hydroxyphenyl)-1-isopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (150 mg, 0.32 mmol), Isopropylamine (0,272 ml, 3.2 mmol) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 3 hours. The reaction mixture was concentrated and then triturated to powder with water and simple ether. The solid was filtered and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (14 mg, 16% yield).1H NMR (400 MHz, DMSO-d6) δ 11,88 (s, 1H), RS 9.69 (s, 1H), 8,35 (s, 1H), 7,83-7,88 (m, 2H), 6,85-6,89 (m, 2H), 4,60-4,69 (m, 1H), 1.55V (d, J=6,6, 6H); MS (ESI)m/z271,3 [M+1]+; TPL 323-324°C.

5.1.47 EXAMPLE 47: SYNTHESIS of 1-(CYCLOPENTYLMETHYL)-6-(4-HYDROXYPHENYL IS)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclopentylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (150 mg, 0.32 mmol), hydrochloride of cyclopropanemethylamine (438 mg, 3.2 mmol), triethylamine (0.5 ml) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 3 hours. The reaction mixture was concentrated and then triturated to powder with water and simple ether. The solid was filtered and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (25 mg, 25% yield).1H NMR (400 MHz, DMSO-d6) δ 11,91 (s, 1H), 9,67 (s, 1H), 8,35 (s, 1H), to 7.84 (s, 2H), 6,86 (s, 2H), 3,79 (s, 2H), 1,65 (s, 5H), of 1.52 (s, 2H), 1,34 (s, 2H); MS (ESI)m/z311,3 [M+1]+; TPL 296-297°C.

5.1.48 EXAMPLE 48: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-ISOBUTYL-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-Hydroxyphenyl)-1-isobutyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (150 mg, 0.32 mmol), 2-methylpropan-1-amine (MX 0.317 ml, 3.2 mmol) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 3 hours. The reaction mixture was concentrated and then triturated to powder with water and simple ether. The solid was filtered and then ciali using reversed-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (21 mg, 23% yield).1H NMR (400 MHz, DMSO-d6) δ 11,92 (s, 1H), RS 9.69 (s, 1H), at 8.36 (s, 1H), 7,83-7,86 (m, 2H), 6,84-to 6.88 (m, 2H), 3,68 (d, J=7,4, 2H), 2,24 (dt, J=13,7, 6,8, 1H), 0,92 (d, J=6,6, 6H); MS (ESI)m/z285,5 [M+1]+; TPL 290-291°C.

5.1.49 EXAMPLE 49: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((TETRAHYDRO-2H-PIRAN-3-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-HE

A. 6-(4-Hydroxyphenyl)-1-((tetrahydro-2H-Piran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (150 mg, 0.32 mmol), (tetrahydro-2H-Piran-3-yl)methanamine (368 mg, 3.2 mmol) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 3 hours. The reaction mixture was concentrated and then triturated to powder with water and simple ether. The solid was filtered and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (25 mg, 24% yield).1H NMR (400 MHz, DMSO-d6) δ 11,94 (s, 1H), to 9.70 (s, 1H), at 8.36 (s, 1H), a 7.85 (d, J=8,6, 2H), 6.87 in (d, J=8,6, 2H), of 3.73-3,82 (m, 3H), of 3.69 (DDD, J=11,1, 3,7, 3,5, 1H), 3,35 is 3.40 (m, 1H), 3,25 (DD, J=11,3, 9,0, 1H), 2,10-to 2.18 (m, 1H), of 1.74(s, IH), and 1.63 (d, J=3,9, 1H), 1,39-1,49 (m, 1H), 1,26-of 1.35 (m, 1H); MS (ESI)m/z327,5 [M+1]+; TPL 271-272°C.

5.1.50 EXAMPLE 50: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(4-HYDROXYPHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (226 mg, 0.48 mmol), cyclohexylamine (629 mg, 4.8 mmol) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 3 hours. The reaction mixture was concentrated and then triturated to powder with water and simple ether. The solid was filtered and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (45 mg, 29% yield).1H NMR (400 MHz, DMSO-d6) δ 11,92 (s, 1H), RS 9.69 (s, 1H), 8,35 (s, 1H), to 7.84 (d, J=8,6, 2H), 6.87 in (d, J=8,6, 2H), 3,71 (d, J=7,4, 2H), 1,89 (s, 1H), 1,58 was 1.69 (m, 6H), of 1.17 (t, J=8,4, 3H), 0,98-1,08 (m, 2H); MS (ESI)m/z325,4 [M+1]+; TPL 302-303°C.

5.1.51 EXAMPLE 51: 5-(3-HYDROXYPHENYL)-3-(2-METHOXYPHENYL)-1H-imidazo[4,5-B]PYRIDINE-2(3H)-HE

A. 6-Chloro-N-(2-methoxyphenyl)-3-nitropyridine-2-amine.

2,6-Dichloro-3-nitropyridine (3.0 g, 15,54 mmol) was dissolved in tetrahydrofuran (50 ml) and was cooled to -78°C. was Added dropwise a solution of o-anisidine (1,91 g, 15,54 mmol) and Diisopropylamine (2.10 g, to 16.31 mmol) in tetrahydrofuran (5 ml) and the Mixture was stirred at ambient temperature for 16 hours. The solution are condensed under reduced pressure and distributed between water and ethyl acetate (3×), the organic layers were combined and dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to get crude product. The solid was ground into powder with ethyl acetate/hexane and the resulting precipitate was filtered to obtain specified in the connection header (3,53 g, 81%). MS (ESI) m/z 280,1 [M+1]+.

B. 3-(6-(2-Methoxyphenylazo)-5-nitropyridine-2-yl)phenol.

6-Chloro-N-(2-methoxyphenyl)-3-nitropyridine-2-amine (2,03 g, 7,27 mmol), 3-hydroxyphenylarsonic acid (1.50 g, 10,90 mmol), palladium(II) acetate (0,489 g, 0,727 mmol), 1,1'-(bis(di-tert-butyl)phosphine)ferrocene (0,344 g, 0,727 mmol) and potassium phosphate (4,62 g, 21,81 mmol) were combined in dioxane and heated to 98°C in nitrogen atmosphere for 16 hours. After starting material was completely consumed (monitored by using TLC), the reaction mixture was filtered through celite. The filtrate are condensed under reduced pressure to get crude product. The crude substance was purified using chromatography on silica gel Biotage (10-40% ethyl acetate in hexane) to obtain the specified title compound (1.48 g, 59%). MS (ESI) m/z 338,4 [M+1]+.

C. 3-(5-Amino-6-(2-methoxybenzylamine)pyridine-2-yl)phenol.

3-(6-(2-Methoxyphenyl-amino)-5-nitropyridine-2-yl)phenol(1.48 g, 4,39 mmol) was dissolved in glacial acetic acid (120 ml). Then was added iron powder (0,489 g, 8,78 mmol) and the solution was heated to 80°C. the Reaction was monitored by thin layer chromatography on the expenditure of the original substance. After 2 hours the solution was cooled, filtered through celite and are condensed under reduced pressure. The resulting oil was distributed between sodium bicarbonate solution and ethyl acetate (3×). The organic layers were combined, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to obtain specified in the connection header (1,15 g, 85%). MS (ESI) m/z 308,4 [M+1]+.

D. 5-(3-Hydroxyphenyl)-3-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-2(3H)-he.

3-(5-Amino-6-(2-methoxybenzylamine)pyridine-2-yl)phenol (1.08 g, 3,51 mmol) and urea (0,528 g, 8,79 mmol) was subjected to interaction in accordance with the General Procedure C. the Crude product was purified using reverse-phase preparative HPLC (5-65% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 39 min) to obtain specified in the connection header (0,056 g, 5%).1H NMR (400 MHz, DMSO-d6) δ to 11.28 (s, 1H), 9,43 (s, 1H), 7,51 (t, J=8,1, 2H), 7,42 (t, J=8,1, 2H), 7.23 percent (m, 3H), 7,12 (m, 2H), 6,70 (d, J=7,80, 1H), of 3.73 (s, 3H); MS (ESI)m/z334,0 [M+1]+; TPL 240-242°C.

5.1.52 EXAMPLE 52: SYNTHESIS of 4-(3-(3-METHOXYBENZYL)-2-OXO-2,3-DIHYDROOXAZOLO[5,4-B]PYRAZIN-5-yl)-N-METHYLBENZAMIDE

A. Methyl 4-(5-aminopyridin-2-yl)Ben is oat.

4-(Methoxycarbonyl)phenylboronic acid (1.8 g, 9.7 mmol), 5-bromopyrazine-2-amine (1.8 g, 9.7 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (213 mg, 0.29 mmol), 1M sodium carbonate (29 ml, 29 mmol) and dioxane (100 ml) were heated together to 100°C for 16 hours under nitrogen atmosphere. The reaction mixture was filtered through celite and then added water and ethyl acetate to obtain a solid substance. The solid was filtered and dried to obtain a black solid (1.1 g, 50% yield).1H NMR (400 MHz, DMSO-d6) δ 8,63 (s, 1H), 8,07 (s, 2H), 7,99 (s, 3H), 6,78 (s, 2H), 3,86 (s, 3H); MS (ESI)m/z230,4 [M+1]+.

B. 4-(5-Hydroxypyridine-2-yl)benzoic acid.

Methyl 4-(5-aminopyridin-2-yl)benzoate (1.1 g, 4.8 mmol) and sodium nitrite (6.6 g, 9.6 mmol) were combined and cooled in an ice bath. To the mixture was added concentrated sulfuric acid (6 ml). The reaction mixture was slowly heated to 50°C in water banev for 30 minutes. The reaction mixture was poured into crushed ice (50 g) and water mixture is brought to pH 7 using 1M sodium hydroxide. The resulting solid was filtered, washed with water and then dried to obtain the product as a reddish brown solid (0.4 g, 36% yield).1H NMR (400 MHz, DMSO-d6) δ to 8.20 (s, 1H), 8,14 (s, 1H), with 8.05 (d, J=8,2, 2H), 7,87 (d,J=7,8, 2H); MS (ESI) m/z 217,1 [M+1]+.

C. 4-(5-Hydroxypyrazol--yl)-N-methylbenzamide.

4-(5-Hydroxypyridine-2-yl)benzoic acid (0.4 g, 1.8 mmol), methylaminopropane (149 mg, 2.2 mmol), hexaflurophosphate O-(benzotriazol-1-yl)-N,N,N, N'-tetramethylurea (824 mg, 2.2 mmol), triethylamine (0.8 ml, 1 mmol) and dimethylformamide (20 ml) was stirred together at room temperature for 16 hours. The reaction mixture was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated to obtain a reddish brown solid (250 mg, 59% yield).1H NMR (400 MHz, DMSO-d6) δ 8,46 (sq, J=4,4, 1H), 8,17 (s, 1H), 8,13 (m, 1H), 7,93-to 7.99 (m, 2H), 7,86-to $ 7.91 (m, 2H), and 2.79 (d, J=4,7, 3H); MS (ESI)m/z230,4 [M+1]+.

D. 4-(6-Bromo-5-hydroxypyridine-2-yl)-N-methylbenzamide.

A solution of 4-(5-hydroxypyridine-2-yl)-N-methylbenzamide (250 mg, 1.1 mmol) and N-bromosuccinimide (233 mg, 1.3 mmol) in DMF (4 ml) was stirred at room temperature in the dark for 30 minutes. The reaction mixture was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated to obtain a reddish brown solid (195 mg, 58% yield).1H NMR (400 MHz, DMSO-d6) δ 8,49 (s, 1H), 8,23 (s, 1H), of 7.90 (s, 4H), and 2.79 (d, J=3,9, 3H); MS (ESI)m/z308,1 [M+1]+.

E. 4-(5-Hydroxy-6-(3-methoxybenzylamine)pyrazin-2-yl)-N-methylb same.

4-(6-Bromo-5-hydroxypyridine-2-yl)-N-methylbenzamide (195 mg, to 0.63 mmol), 3-methoxybenzylamine (130 mg, 0.95 mmol), diisopropylethylamine (2 ml) and dimethylsulfoxide (1 ml) were heated together up to 130°C for 16 hours. The reaction mixture was ground into powder with water and ethyl acetate to obtain a solid substance. The mixture was filtered and dried to obtain a dark brown solid (101 mg, 44% yield).1H NMR (400 MHz, DMSO-d6) δ of 8.40 (s, 1H), 7,88 (d, J=7,8, 3H), 7,78-to 7.84 (m, 2H), 7,31 (s, 1H), 7,22 (t, J=7,6, 1H), 6,97-7,03 (m, 2H), 6,78 (d, J=7,8, 1H), 4,56 (s, 2H), 3,71 (s, 3H), 2.77-to of 2.81 (m, 3H); MS (ESI)m/z365,3 [M+1]+.

F. 4-(3-(3-Methoxybenzyl)-2-oxo-2,3-dihydrooxazolo[5,4-b]pyrazin-5-yl)-N-methylbenzamide.

4-(5-Hydroxy-6-(3-methoxybenzylamine)pyrazin-2-yl)-N-methylbenzamide (100 mg, 0.27 mmol), 1,1'-carbonyldiimidazole (445 mg, 2.7 mmol) and dioxane (2 ml) were heated together in a sealed tube to 150°C for 16 hours. The reaction mixture was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated to obtain a white solid (27 mg, 25% yield).1H NMR (400 MHz, DMSO-d6) δ 8,71 (s, 1H), 8,51-8,59 (m, 1H), 8,15 (d, J=8,5, 2H), 7,95 (d, J=8,5, 2H), 7,26-7,33 (m, 1H),? 7.04 baby mortality for 7.12 (m, 2H), 6.89 in (DD, J=7,8, 2,9, 1H), 5,07 (s, 2H), 3,74 (s, 3H), of 2.81 (d, J=4,4, 3H); MS (ESI)m/z391,0 [M+1]+; TPL 168-169°C.

5.1.53 EXAMPLE 53: SYNTHESIS of 1-CYCLOPENTYL-6-(4-HYDROXYPHENYL)-1-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-Cyclopentyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-Boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (200 mg, 0.43 mmol), cyclopentylamine (365 mg, 4.3 mmol) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 4 hours. The reaction mixture was concentrated and then purified using chromatography on silica gel Biotage (0-10% methanol in ethyl acetate) to obtain white solid (46 mg, 36% yield).1H NMR (300 MHz, DMSO-d6) δ to 9.70 (s, 1H), 8,35 (s, 1H), to 7.84 (d, J=8,8, 2H), 6,86 (d, J=8,5, 2H), 4.75 V-a 4.86 (m, 1H), 2,14-of 2.28 (m, 2H), 1,90-2,04 (m, 4H), 1.60-to of 1.73 (m, 2H); MS (ESI)m/z297,3 [M+1]+; TPL 299-301°C.

5.1.54 EXAMPLE 54: SYNTHESIS of 1-CYCLOHEXYL-6-(4-HYDROXYPHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-Cyclohexyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (200 mg, 0.43 mmol), cyclohexylamine (425 mg, 4.3 mmol) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 4 hours. The reaction mixture was concentrated and then purified using chromatography on silica gel Biotage (0-10% methanol in ethyl acetate) to obtain white solid (50 mg, 37% yield).1H NMR (300 MHz, DMSO-d6) δ 11,90 (s, 1H), to 9.70 (s, 1H), 8,35 (s, 1H), a 7.85 (d, J=8,5, 2H), 6.87 in (d, J=8,5, 2H), 4,24 (t, J=11,9, 1H), 2,25-2,39 (m, 2H), 1,76-1,90 (m, 6H), 1.30 and USD 1.43 (m, 2H); MS (ESI)m/z311,5 [M+1]+; MP 318-320°C.

5.1.55 EXAMPLE 55: SI IS PROC. of 4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZAMIDE

A. 6-Bromo-N2(cyclohexylmethyl)pyrazin-2,3-diamine.

3,5-Dibromopyridin-2-amine (5.0 g, 19,92 mmol) and cyclohexylamine (of 3.25 ml of 24.90 mmol) was dissolved in n-butanol (120 ml). To the mixture was added diisopropylethylamine (8.34 per ml, 47,88 mmol) and stir the reaction mixture was heated at 130°C for 2 days. After starting material was completely consumed (monitored by using IHMS), the reaction mixture was allowed to cool to room temperature and volatiles were removed under reduced pressure. Semi-solid oil was dissolved in ethyl acetate and triturated to powder from the hexane, while processing the ultrasound. The precipitate was filtered to obtain specified in the connection header (4,85 g, 86%). MS (ESI) m/z 285,0 [M]+, 287,2 [M+2]+

B. 6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-N2(cyclohexylmethyl)pyrazin-2,3-diamine (4,85 g, 17,01 mmol) was dissolved in THF (50 ml)was added 1,1'-carbonyldiimidazole (3,45 g, 21.26 mmol) and the reaction solution was distributed in 4 different vessel. Each fraction was heated in a microwave reactor Biotage Emrys Optimizer at 120°C for 30 minutes. Unreacted fractions were combined and are condensed under reduced pressure. The crude substance was dissolved in minimum amount of DMF and precipitated using deionized water, while processing the ultrasound. Otfit is consistent the product was dried in a vacuum oven at 60°C overnight with obtaining specified in the connection header (4.72 in) 89%). MS (ESI) m/z 311,3 [M]+, 313,5 [M+2]+

C. 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (200 mg, 0.64 mmol), (4-aminosulphonylphenyl)baronova acid (128 mg, 0.77 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (53 mg, 0.06 mmol) and potassium phosphate (550 mg, 2.58 mmol) in DMF (15 ml) and water (1 ml) was subjected to interaction in accordance with General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The desired product was collected by means of filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (35 mg, 15% yield) as a white loose powder.1H NMR (300 MHz, DMSO-d6) δ 12,18 (s, 1H), 8,66 (s, 1H), 8,19 (d, J=8,7, 2H), of 8.06 (d, J=8,7, 2H), 7,51 (s, 2H), 3,82 (d, J=8,7, 2H), up to 1.98 (m, 1H), 1,76 (m, 5H), 1.26 in (m, 5H); MS (ESI)m/z352,2 [M+1]+; TPL 293-295°C.

5.1.56 EXAMPLE 56: SYNTHESIS of METHYL 4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZOATE

A. Methyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (1, g, up 3.22 mmol), (4-ethoxycarbonylphenyl)baronova acid (0,77 g, a 3.87 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (263 mg, 0.32 mmol) and potassium phosphate (2,73 g, 12,88 mmol) in DMF (30 ml) and water (4 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The desired product was collected by means of filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (360 mg, 31% yield) as a white loose powder.1H NMR (300 MHz, DMSO-d6) δ 12,23 (s, 1H), 8,69 (s, 1H), 8,27 (d, J=8,7,2H), 8,15 (d, J=8,7, 2H), 3,83 (d, J=6,9, 2H), 1,99 (m, 1H), 1,76 (m, 5H), 1.26 in (m, 5H); MS (ESI)m/z367,2 [M+1]+; TPL 253-255°C.

5.1.57 EXAMPLE 57: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(PYRIDIN-4-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(pyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,250 g, 0.80 mmol), pyridine-4-Bronevoy acid (amount of 0.118 g, 0.96 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane(1:1) (0,065 g, 0.08 mmol), potassium phosphate (0,678 g, 3.2 mmol), water (2 ml) and dimethylformamide (10 ml) under the Yergali interaction in accordance with the General Procedure B. The solution are condensed under reduced pressure and was purified using chromatography on silica gel Biotage (0-10% methanol in dichloromethane). The fractions containing the product were concentrated and recrystallized from methanol to obtain (0,057 g, 23% yield).1H NMR (300 MHz, CD3OD) δ to 8.62 (m, 3H), 8,08 (m, 2H), a 3.87 (d, J=7,5, 2H), 2,01 (m, 1H), 1,75 (m, 5H), of 1.28 (m, 6H); MS (ESI)m/z310,4 [M+1]+; TPL 267-269°C.

5.1.58 EXAMPLE 58: SYNTHESIS of 4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-imidazo[4,5-B]PYRAZIN-5-YL)-N-METHYLBENZAMIDE

A. 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-methylbenzamide.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (200 mg, 0.64 mmol), [4-(N-methylaminomethyl)phenyl]Bronevoy acid (139 mg, 0.77 mmol), dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II)dichlormethane (53 mg, 0.06 mmol) and potassium phosphate (550 mg, 2.58 mmol) in DMF (15 ml) and water (1 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The desired product was collected by means of filtration under vacuum, washed with water and dried in high vacuum to give the desired product (85 mg, 36% of you who ar). 1H NMR (300 MHz, DMSO-d6) δ 12,18 (s, 1H), 8,65 (s, 1H), 8,58 (s, 1H), 8,19 (d, J=8,4, 2H), 8,02 (d, J=8,4, 2H), 3,83 (d, J=6,9, 2H), 2,89 (s, 3H), 2,00 (m, 1H), 1,76 (m, 5H), 1.26 in (m, 5H); MS (ESI)m/z366,3 [M+1]+; TPL 273-275°C.

5.1.59 EXAMPLE 59: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(4-(HYDROXYMETHYL)PHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(4-(hydroxymethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (200 mg, 0.64 mmol), 4-(hydroxymethyl)phenylboronic acid (118 mg, 0.77 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (53 mg, 0.06 mmol) and potassium phosphate (550 mg, 2.58 mmol) in DMF (15 ml) and water (1 ml) subjected interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The formed solid substance was collected by means of filtration under vacuum, washed with water and dried in high vacuum to give the desired product (66 mg, 30% yield).1H NMR (300 MHz, DMSO-d6) 12,01 (s, 1H), of 8.47 (s, 1H), of 7.97 (d, J=8,4, 2H), 7,42 (d, J=8,4, 2H), 5,22 (t, J=5,6, 1H), 4,53 (d, J=8,4, 2H), of 3.73 (J=5,6, 2H), 1,90 (m, 1H), 1,67 (m, 5H), 1,17 (m, 5H); MS (ESI)m/z339,1 [M+1]+; TPL 275-277°C

5.1.60 EXAMPLE 60: SYNTHESIS of 1-(CYCLOHEXYLMETHYL is)-6-(PYRIDIN-3-yl)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,250 g, 0.80 mmol) and pyridine-3-Bronevoy acid (0,098 g, 0.80 mmol), dichlorobis(triphenylphosphine)palladium(II) (0,028 g of 0.004 mmol), sodium carbonate (4.5 ml, 1M in water) and acetonitrile (4.5 ml) was subjected to interaction in accordance with the General Procedure B3. The solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate and extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried in vacuum to obtain (0,069 g, 28% yield).1H NMR (300 MHz, CD3OD) δ to 9.15 (d, J=2,1, 1H), 8,54 (m, 1H), of 8.47 (m, 2H), 7,55 (m, 2H), 3,85 (d, J=7,2, 2H), 2,03 (m, 1H), 1,74 (m, 5H) of 1.27 (m, 5H); MS (ESI)m/z310,4 [M+1]+; TPL 205°C.

5.1.61 EXAMPLE 61: SYNTHESIS of 3-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZONITRILE

A. 3-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (1.0 g, up 3.22 mmol), 3-cyanoaniline acid (0,57 g, a 3.87 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (23 mg, 0.32 mmol) and potassium phosphate (2,73 g, 12,88 mmol) in DMF (30 ml) and water (4 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The formed solid substance was collected by means of filtration under vacuum, washed with water and dried in high vacuum to give the desired product (164 mg, 16% yield).1H NMR (300 MHz, DMSO-d6) δ 12,23 (s, 1H), 8,71 (s, 1H), 8,53 (s, 1H), 8,46 (d, J=7,8, 1H), 7,95 (d, J=7,2, 1H), 7,78 (d, J=7,2, 2H), 3,82 (d, J=8,4, 2H), up to 1.98 (m, 1H), 1,76 (m, 5H), 1.26 in (m, 5H); MS (ESI)m/z334,2 [M+1]+; TPL 228-230 °C.

5.1.62 EXAMPLE 62: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(1H-INDOL-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,250 g, 0.80 mmol), indole-5-Bronevoy acid (0,155 g, 0.96 mmol), tetrakis(triphenylphosphine)palladium(0) (0,092 g, 0.08 mmol), sodium bicarbonate (0,268 g, 3.2 mmol), water (2 ml) and dimethyl ether of ethylene glycol (10 ml) was subjected to interaction in accordance with the General Procedure B2. The product was besieged from the reaction mixture and was filtered and dried to obtain (0,048 g, 17% yield).1H NMR (300 MHz, the MCO-d 6) δ 11,9 (s, 1H), and 11.2 (s, 1H), 8,44 (s, 1H), 8,19 (s, 1H), 7,79 (DD, J=1,5, and 8.4, 2H), 7,50 (d, J=8,4, 1H), 7,40 (m, 1H), of 6.52 (s, 1H), 3,76 (d, J=6,9, 1H), 1.93 and (m, 1H), 1.69 in (m, 5H), of 1.18 (m, 5H); MS (ESI)m/z348,4 [M+1]+; TPL 343-346°C.

5.1.63 EXAMPLE 63: SYNTHESIS of 4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)-N-ISOPROPYLBENZENE

A. 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic acid.

A solution of methyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate (see Example 56.A) (350 mg, 0.95 mmol) in 1 N. solution of lithium hydroxide (4.5 ml) and tetrahydrofuran (4.5 ml) was left to stir at room temperature for 19 hours. After the reaction was completed, the volatiles were removed under reduced pressure. The residue was treated with 1 n hydrochloric acid solution and subjected to ultrasonic treatment. The precipitate was collected through filtration under vacuum and dried in high vacuum to obtain specified in the title compound (300 mg, 90% yield) as a reddish brown solid. MS (ESI) m/z 353,3 [M+1]+.

B. 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-isopropylbenzene.

4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic acid (150 mg, 0.42 mmol), diisopropylethylamine (47 μl, 0.55 mmol) and hexaphosphate benzotriazol-1-elox the-Tris(dimethylamino)phosphonium (243 mg, 0.55 mmol) in DMF (3 ml) was left to stir at room temperature for 19 hours. The crude product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The formed solid substance was collected by means of filtration under vacuum, washed with water and dried in high vacuum to give the desired product (42 mg, 25% yield) as a tan solid.1H NMR (300 MHz, DMSO-d6) δ 12,18 (s, 1H), 8,66 (s, 1H), 8,35 (d, J=7,5, 1H), to 8.20 (d, J=8,4, 2H), 8,03 (d, J=8,4, 2H), 4,20 (m, 1H), 3,83 (d, J=8,9, 1H), 2,01 (m, 1H), 1,76 (m, 5H), 1,25 (d, J=9,0, 6H), of 1.16 (m, 5H); MS (ESI)m/z394,2 [M+1]+; TPL 264-268°C.

1.64 EXAMPLE 64: SYNTHESIS of 1-(2-HYDROXYETHYL)-6-(4-HYDROXYPHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(2-Hydroxyethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (200 mg, 0.43 mmol), ethanolamine (262 mg, 4.3 mmol) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 4 hours. The reaction mixture was concentrated and then triturated to powder with 10% methanol in water to obtain a white solid (50 mg, 42% yield).1H NMR (300 MHz, DMSO-d6) δ 9,68 (s, 1H), 8,35 (s, 1H), a 7.85 (d, J=8,8, 2H), 6,86 (d, J=8,8,2H), 4,88 (t, J=5,9, 1H), 3,93 (t, J=5,8, 4H), 3,76 (sq, J=6,1, 4H); MS (ESI)m/z273,3 [M+1]+; TPL 308-310°C.

5.1.65 EXAMPLE 65: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(1H-INDOL-6-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(1H-indol-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,250 g, 0.80 mmol), indole-6-Bronevoy acid (0,155 g, 0.96 mmol), tetrakis (triphenylphosphine)palladium(0) (0,092 g, 0.08 mmol), sodium bicarbonate (0,268 g, 3.2 mmol), water (2 ml) and dimethyl ether of ethylene glycol (10 ml) was subjected to interaction in accordance with the General Procedure B2. The product was besieged from the reaction mixture and was filtered and dried to obtain (0,088 g, 32% yield).1H NMR (300 MHz, CD3OD) δ 11,94 (s, 1H), 11,27 (s, 1H), 8,46 (s, 1H), of 8.06 (s, 1H), 7,68 (DD, J=15,0, and 8.4, 2H), 7,42 (m, 1H) 6,46 (s, 1H) 3,76 (d, J=7,2, 1H) of 1.93 (m, 1H) 1.69 in (m, 5H) of 1.18 (m, 5H); MS (ESI)m/z348,4 [M+1]+; TPL 359-363°C.

5.1.66 EXAMPLE 66: SYNTHESIS of 3-(3-(CYCLOHEXYLMETHYL-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZAMIDE

A. 3-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (500 mg, 1.6 mmol), 3-aminocarbonylmethyl acid (318 mg, of 1.93 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (131 mg, 0.16 mmol) and potassium phosphate (1.35 g, 6.4 mmol) in DMF (30 ml) and water (4 ml) was subjected to interaction in compliance and General Procedure B. The product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The desired product was collected by means of filtration under vacuum, washed with water and dried in high vacuum to give the desired product (272 mg, 48% yield) as a tan solid.1H NMR (300 MHz, DMSO-d6) δ 12,06 (s, 1H), 8,55 (s, 1H), of 8.47 (s, 1H), 8,16 (d, J=8,4, 1H), of 8.09 (s, 1H), 7,89 (d, J=7,4, 1H), 7,58 (t, J=8,0, 1H), 7,45 (s, 1H), 3,74 (d, J=7,2, 2H), 1.91 a (m, 1H), 1,67 (m, 5H), 1,17 (m, 5H); MS (ESI)m/z352,2 [M+1]+.

5.1.67 EXAMPLE 67: SYNTHESIS of 6-(4-(AMINOMETHYL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzylcarbamoyl.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (200 mg, 0.64 mmol), [4-(N-boc-aminomethyl)phenyl]Bronevoy acid (195 mg, 0.77 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (53 mg, 0.06 mmol) and potassium phosphate (550 mg, 2.58 mmol) in DMF (15 ml) and water (1 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions conc who was narrowly approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The desired product was collected by means of filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the connection header. This product was used directly in the next stage without further purification or analysis. MS (ESI) m/z 438,1 [M+1]+.

B. 6-(4-(Aminomethyl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

tert-Butyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzylcarbamoyl were processed using TFA (2 ml) in methylene chloride (2 ml) for 4 hours at room temperature. The product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one-third the original volume and was treated with potassium carbonate (1,75 M). The desired product was collected by means of filtration under vacuum, washed with water and dried in high vacuum to give the desired product (42 mg, 19% yield from two steps) as a tan solid.1H NMR (300 MHz, DMSO-d6) δ with 8.33 (s, 1H), to $ 7.91 (d, J=8,0, 2H), 7,40 (d, J=8,4, 2H), of 7.75 (s, 2H), 3,68 (d, J=7,2, 2H), 1,90 (m, 1H), 1,65 (m, 5H), of 1.16 (m, 5H); MS (ESI)m/z339,1 [M+1]+.

5.1.68 EXAMPLE 68: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((1-METHYLPIPERIDIN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl pyridine-4-illecillewaet.

To 4-(Amin is Teal)pyridine (1.08 g, 10 mmol) was added 2-propanol (20 ml), was added di-tert-BUTYLCARBAMATE (2.4 g, 11 mmol) and stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain oil and used without further purification. MS (ESI) m/z 209,3 [M+1]+.

B. 4-((tert-butoxycarbonylamino)methyl)-1-methylpyridinium.

To tert-butylpyridinium-4-illecillewaet (of 2.08 g, 10 mmol) was added acetonitrile (8 ml) followed by the addition of iodomethane (0,94 ml, 15 mmol). The reaction mixture was heated in a microwave reactor Biotage Emrys Optimizer at 100°C for 10 minutes. The reaction mixture was concentrated to obtain a residue Magenta and used without additional purification. MS (ESI) m/z 223,4 [M+1]+.

C. (1 Methylpiperidin-4-yl)methanamine hydrochloride.

4-((tert-Butoxycarbonylamino)methyl)-1-methylpyridinium (3.5 g, 10 mmol) was dissolved in methanol (200 ml) was added platinum oxide (IV) (200 mg). The reaction mixture was shaken in hydrogenator Parra under hydrogen pressure of 40 psi (2,812 kg/cm2) for 20 hours. The reaction mixture was concentrated and then extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain oil. The oil obtained was treated with a 4 n solution of hydrochloric acid in dioxane to obtain amine. The reaction is ionic and the mixture was concentrated and then triturated to powder with 20% methanol in ethyl acetate to obtain a white solid (1.2 g, 75% yield from 3 stages). MS (ESI) m/z 128,9 [M+1]+.

D. 6-(4-Hydroxyphenyl)-1-((1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (200 mg, 0.43 mmol), hydrochloride (1 methylpiperidin-4-yl)methanamine (262 mg, 4.3 mmol), triethylamine (1 ml) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 4 hours. The reaction mixture was concentrated and then triturated to powder with 10% methanol in water to obtain a white solid (50 mg, 37% yield).1H NMR (400 MHz, DMSO-d6) δ RS 9.69 (s, 1H), 8.34 per (s, 1H), to 7.84 (d, J=8,6, 2H), 6.87 in (d, J=8,6, 2H), 3,74 (d, J=7,4, 2H), 2,72 (d, J=11,3, 2H), 2,11 (s, 3H), 1,74-of 1.85 (m, 3H), 1,58 (d, J=10,9, 2H), 1,22-of 1.33 (m, 2H); MS (ESI)m/z340,1 [M+1]+; TPL 292-294°C.

5.1.69 EXAMPLE 69: SYNTHESIS of 4-(3-(CYCLOHEXYLMETHYL-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZONITRILE

A. 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b] pyrazin-5-yl)benzonitrile.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,500 g of 1.61 mmol), 4-cyanoaniline acid (0,283 g of 1.93 mmol), the complex bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,132 g, 0,161 mmol), potassium phosphate (1,37 g, 6,44 mmol), water (2 ml) and dimethylformamide (10 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was purified using reversed-phase the howling prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate and extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated and dried in vacuum to obtain the product (0,144 g, 27% yield).1H NMR (400 MHz, DMSO-d6) δ at 8.60 (s, 1H) 8,23 (d, J=7,2, 2H), 7,95 (d, J=8,0, 2H), and 3.72 (d, J=7,2, 2H), 3,85 (d, J=7,2, 2H), 1,90 (m, 1H), 1,67 (m, 5H) of 1.18 (m, 5H); MS (ESI)m/z334,4 [M+1]+; TPL 255-257°C.

5.1.70 EXAMPLE 70 SYNTHESIS of 1-((1S,4S)-4-HYDROXYCYCLOHEXYL)-6-(4-HYDROXYPHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-((1S,4S)-4-Hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (200 mg, 0.43 mmol), hydrochloride, (1S,4S)-4-aminocyclohexanol (0.65 g, 4.3 mmol), triethylamine (1 ml) and ethanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 4 hours. The reaction mixture was concentrated and then triturated to powder with 10% solution of methanol in water to obtain a white solid (50 mg, 37% yield).1H NMR (400 MHz, DMSO-d6) δ 11,88 (s, 1H), RS 9.69 (s, 1H), 8,35 (s, 1H), 7,88 (d, J=8,6, 2H), 6,83-6,87 (m, 2H), 4,46 (s, 1H), 4,23 (t, J=12,1, 1H), 3,90 (s, 1H), 2,74-2,84 (m, 2H), 1,82 (d, J=14,8, 2H), 1,54-to 1.61 (m, 2H), 1,49(d, J=18,0, 2H); MS (ESI)m/z327,1 [M+1]+; TPL 328-338°C.

5.1.71 EXAMPLE 71: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(PYRIDIN-2-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(pyridin-2-yl)-1H-imidazo[4,5-b]feast the Zin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,200 g, 0,643 mmol) 2-(tributylstannyl)pyridine (0,101 g of 1.93 mmol), copper iodide(I) (0.008 g, 0.01 mmol) and dichlorobis(triphenylphosphine)palladium(II) was added to triethylamine (5 ml). The resulting solution was subjected to interaction in a microwave reactor Biotage Emrys Optimizer at 120°C for 30 minutes. The solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate, extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated and dried in vacuum to obtain (0,032 g, 16% yield).1H NMR (400 MHz, DMSO-d6) δ cent to 8.85 (s, 1H), at 8.60 (d, J=4, 1H), 8,29 (d, J=8,0, 1H), 7,94(m, 1H), 7,40 (m, 1H), a 3.87(d, J=7,2, 2H), 2,02 (m, 1H), 1,74 (m, 5H), of 1.28 (m, 5H); MS (ESI)m/z334,4 [M+1]+; TPL 194-196°C.

5.1.72 EXAMPLE 72: SYNTHESIS of 4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)-N-ETHYLBENZAMIDE

A. 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-ethylbenzamide.

4-[3-(Cyclohexylmethyl)-2-oxo-4-imidazoline[4,5-e]pyrazin-5-yl]benzoic acid (see Example 63.A.) (150 mg, 0.42 mmol), ethylamine (2,0M in MeOH, 276 μl, 0.55 mmol) and hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium (243 mg, 0.55 mmol) in dim is telharmonic (3 ml) was left to stir at room temperature for 19 hours. The crude product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated to approximately one third of the original volume, were processed using a 1.75 M potassium carbonate. The desired product was collected by means of filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (8 mg, 5% yield) as a tan solid.1H NMR (300 MHz, DMSO-d6) δ 12,18 (s, 1H), 8,66 (s, 1H), 8,35 (d, J=7,5, 1H), to 8.20 (d, J=8,4, 2H), 8,03 (d, J=8,4, 2H), 4,20 (m, 1H), 3,83 (d, 7=8,9, 1H), 2,01 (m, 2H), 1,76 (m, 5H), 1,25 (m, 3H), of 1.16 (m, 5H); MS (ESI)m/z380,1 [M+1]+.

5.1.73 EXAMPLE 73: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(4-(2-HYDROXYPROPAN-2-YL)PHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(4-(2-hydroxypropan-2-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Methyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate (see Example 56.A) (0.075 g, 0,205 mmol) was dissolved in tetrahydrofuran (5 ml) and cooled to -78°C. was Added methylmagnesium (1,4M in toluene/tetrahydrofuran, 0,410 ml, 0,410 mmol) and the reaction mixture was stirred at -78°C for 3 hours. The reaction was not completed, and added an extra amount of methylacrylamide (1,4M in toluene/tetrahydrofuran, 0,410 ml, 0,410 mmol). After another 2 hours the reactions is extinguished with water and was extracted with methylene chloride. The product was purified using reverse-phase prepreparation HPLC (30-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 40 min). The fractions containing the desired substance were combined and concentrated under reduced pressure. The obtained residue was dissolved in hot DMSO and added water to cause precipitation. The solid was filtered and washed with water and dried in vacuum to obtain specified in the connection header (to 0.055 g, 0,150 mmol, 73% yield).1H NMR (400 MHz, DMSO-d6) δ 12,01 (s, 1H), 8,45 (s, 1H), to 7.93 (d, J=8,6, 2H), EUR 7.57 (d, J=8,6, 2H), 4,95-5,14 (m, 1H), of 3.73 (d, J=7,0, 2H), 1,84 is 1.96 (m, 1H), 1,54-1,72 (m, 5H), 1,45 (s, 6H), 1,12-1,22 (m, 3H), and 0.98 (PI)-1.09 (m, 2H); MS (ESI)m/z367,3 [M+1]+; TPL 226-228°C.

5.1.74 EXAMPLE 74: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(4-HYDROXY-2-WERE)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(4-hydroxy-2-were)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,300 g, 0.96 mmol), 4-hydroxy-2-methylphenylimino acid (0,175 g, 1.15 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (78 mg, 0,096 mmol) and potassium phosphate (814 mg, of 3.84 mmol) in DMF (20 ml) and water (4 ml) were subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase preparative HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fraction of the oxygen which has demonstrated and neutralized using saturated sodium bicarbonate solution. The product was extracted with ethyl acetate and dried in high vacuum to obtain specified in the title compound (152 mg, 47% yield).1H NMR (400 MHz, DMSO-d6) δ 11,95 (s, 1H), 9,52 (s, 1H), 7,92 (s, 1H), 7,21 (d, J=8,2, 1H), 6,64 to 6.75 (m, 2H), 3,66 (d, J=7,4, 2H), 2,28 (s, 3H), 1,81-of 1.94 (m, 1H), 1,54 is 1.70 (m, 5H), 1,09-1,19 (m, 3H), 0,93-of 1.05 (m, 2H); MS (ESI)m/z339,3 [M+1]+; TPL 212-214°C.

5.1.75 EXAMPLE 75: SYNTHESIS of 4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-imidazo[4,5-B]PYRAZIN-5-YL)BENZOIC ACID

A. 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic acid.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,300 g, 0.96 mmol), 4-carboxybenzeneboronic acid (0,192 g, 1.15 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (79 mg, 0,096 mmol) and potassium phosphate (814 mg, of 3.84 mmol) in DMF (20 ml) and water (4 ml) was subjected to interaction in according to the General Procedure B. the Product was purified using reverse-phase preparative HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the desired substance were combined and concentrated under reduced pressure. The obtained residue was dissolved in hot DMSO and added water to cause precipitation. The solid was filtered and washed with water and dried to obtain specified in the connection header (0,047 g, 14% yield).1H NMR (400 MHz, DMSO-d6) δ 8,58 (s, 1H), 8,14(d, J=an 8.4, 2H), 8,03 (d, J=8,4, 2H), 3,74 (d, J=7,4, 2H), 1,86-of 1.97 (m, 1H), 1,54-1,72 (m, 6H), 1,13-of 1.23 (m, 4H), 0,99-1,10 (m, 2H); MS (ESI)m/z353,3 [M+1]+; TPL >350°C.

5.1.76 EXAMPLE 76: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(2-METHOXYETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-Hydroxyphenyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (200 mg, 0.4 mmol), 2-methoxyethylamine (0.27 g, 4 mmol) and N,N-dimethylformamide (4 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture was extracted with water and ethyl acetate. The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (35 mg, 29% yield).1H NMR (400 MHz, DMSO-d6) δ 5 11,95 (s, 1H), to 9.70 (s, 1H), of 8.37 (s, 1H), a 7.85 (d, J=8,6, 2H), 6,86 (d, J=9,0,2H), Android 4.04 (t, J=5,7, 2H), of 3.73 (t, J=5,7, 2H), 3,26 (s, 3H); MS (ESI)m/z287,5 [M+1]+; TPL 236-237°C.

5.1.77 EXAMPLE 77: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(3-METHOXYPROPYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-Hydroxyphenyl)-1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (200 mg, 0.4 mmol), 3-methoxypropylamine (0,44 g, 4 mmol) and N-methylpyrrolidinone (4 ml) was heated in mi is Romanova reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture was extracted with water and ethyl acetate. The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (83 mg, 66% yield).1H NMR (400 MHz, DMSO-d6) δ 11,90 (s, 1H), RS 9.69 (s, 1H), 8,35 (s, 1H), 7,86 (d, J=9,0, 2H), 6,86 (d, J=9,0, 2H), 3,93 (t, J=7,0, 2H), 3,39 (t, J=6,1, 2H), 3,19 (s, 3H), 1,95-2,02 (m, 2H); MS (ESI)m/z301,5 [M+1]+; TPL 208-210°C.

5.1.78 EXAMPLE 78: SYNTHESIS of 6-(4-HYDROXYPHENYL)-4-(3-METHOXYBENZYL)-3,4-DIHYDROPYRIDO[2,3-B]PYRAZIN-2(1H)-It

A. 6-Bromo-4-(3-methoxybenzyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he.

3,5-Dibromopyridin-2-amine (1.0 g, 4 mmol) was dissolved in acetonitrile (6 ml) was added bromoxynil anhydride (1.0 g, 4 mmol). The reaction mixture was heated to 50°C for 16 hours. To the reaction mixture were added 3-methoxybenzylamine (1.6 g, 12 mmol) and continued heating at 50°C for 1 hour. The reaction mixture was diluted with water and ethyl acetate, followed by filtration to obtain a reddish brown solid (0.45 g, 32% yield). MS (ESI) m/z 350,9 [M+1]+.

B. 6-(4-Hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he.

4-Hydroxyphenylarsonic acid (196 mg, 1.4 mmol), 6-bromo-4-(3-methoxybenzyl)-3,4-dihyd is pyrazino[2,3-b]pyrazin-2(1H)-he (450 mg, 1.3 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (28 mg, 0.04 mmol), 1M sodium carbonate (4 ml, 4 mmol) and dioxane (8 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 120°C for 10 minutes. The reaction mixture was filtered through celite. The filtrate is brought to pH 7 using saturated solution of ammonium chloride and then allowed to stand for 1 hour. The precipitated solid was filtered and then was ground into powder in 10% dimethyl sulfoxide and methanol to obtain a reddish brown solid (102 mg, 21% yield).1H NMR (400 MHz, DMSO-d6) δ 11,23 (s, 1H), 9,65 (s, 1H), of 7.96 (s, 1H), 7,82 (d, J=8,6, 2H), 7,26 (s, 1H), 7,00 (d, J=1,6, 2H), 6,78-6,87 (m, 3H), 4,79 (s, 2H), 4,06 (s, 2H), 3,71 (s, 3H); MS (ESI)m/z363,3 [M+1]+; TPL 282-283°C.

5.1.79 EXAMPLE 79: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-Hydroxyphenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (100 mg, 0.2 mmol), 2-(tetrahydro-2H-Piran-4-yl)ethanamine (0.28 g, 2 mmol) and N-methylpyrrolidinone (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture was extracted with water and ethyl acetate. The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile is a + 0,1% TFA in H 2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (45 mg, 62% yield).1H NMR (400 MHz, DMSO-d6) δ 11,92 (s, 1H), to 9.70 (s, 1H), of 8.37 (s, 1H), to 7.84 (d, J=8,6, 2H), 6,86 (d, J=8,6, 2H), 3,91 (t, J=7,0, 2H), 3,79-of 3.85 (m, 2H), 3,21 (TD, J=11,7, 2,0, 2H), 1,67 is 1.75 (m, 4H), 1,44-of 1.53 (m, 1H), 1,15-1,25 (m, 2H); MS (ESI)m/z341,0 [M+1]+; TPL 276-277°C.

5.1.80 EXAMPLE 80: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-PHENETHYL-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-Hydroxyphenyl)-1-phenethyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (100 mg, 0.2 mmol), phenethylamine (0.26 g, 2 mmol) and N-methylpyrrolidinone (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture was extracted with water and ethyl acetate. The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (36 mg, 51% yield).1H NMR (400 MHz, DMSO-d6) δ 11,88 (s, 1H), RS 9.69 (s, 1H), with 8.33 (s, 1H), 7,83 (d, J=9,0, 2H), 7,19-7,27 (m, 5H), 7,17 (d, J=1,0,1H), 6.87 in (d, J=9,0, 2H), 4,12 (t, J=7,2, 2H), 3,11 (t, J=7,2, 2H); MS (ESI)m/zto 333.3 [M+1]+; TPL 283-284°C

5.1.81 EXAMPLE 81: SYNTHESIS of 1-((1R,4R)-4-HYDROXYCYCLOHEXYL)-6-(4-HYDROX IS PHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-((1R,4R)-4-Hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (100 mg, 0.2 mmol), hydrochloride, (1R,4R)-4-aminocyclohexanol (0.32 g, 2 mmol), triethylamine (0.5 ml) and N-methylpyrrolidinone (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture was extracted with water and ethyl acetate. The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (33 mg, 49% yield).1H NMR (400 MHz, DMSO-d6) δ 11,90 (s, 1H), RS 9.69 (s, 1H), 8.34 per (s, 1H), a 7.85 (d, J=8,6, 2H), 6.87 in (d, J=8,6, 2H), 4,69 (d, J=4,3, 1H), 4,22 (t, J=12,3, 1H), 3,54 (d, J=4,7, 1H), 2,35-2,47 (m, 2H), 1,96 (d, J=11,3, 2H), 1,76 (d, J=11,7, 2H), 1,28-of 1.39 (m, 2H); MS (ESI)m/z327,4 [M+1]+; TPL 348-350°C.

5.1.82 EXAMPLE 82: SYNTHESIS of 6-(4-(1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (E)-4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-((dimethylamino)methylene)benzamide.

4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide (see Example 55.C) (0,456 g of 1.30 mmol) was added to dimethylformamidine (50 ml) and was heated to 85°C for 18 hours. The product was besieged by the from the reaction mixture and was filtered and dried to obtain (0,209 g, 40% yield). MS (ESI) m/z of 407.5 [M+1]+.

B. 6-(4-(1H-1,2,4-Triazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Hydrazine (0,452 ml, 14.4 mmol) was added dropwise to a solution of (E)-4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-((dimethylamino)methylene)benzamide (0,209 g, 0,514 mmol) in acetic acid (10 ml). After stirring at room temperature for 2 hours the solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate and extracted with ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting substance was dried in vacuum to obtain (0,020 g, 10% yield).1H NMR (400 MHz, CD3OD) δ 8,49 (s, 1H) 8,39 (s, 1H), 8,16 (m, 4H), a 3.87 (d, J=7,2,2H), 2,02 (m, 1H), 1,74 (m, 5H) of 1.26 (m, 5H); MS (ESI)m/z334,4 [M+1]+; TPL 336-338°C.

5.1.83 EXAMPLE 83: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-PHENYL-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (150 mg, 0.48 mmol), phenylboronic acid (71 mg, of 0.58 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(I)·dichloromethane (40 mg, 0.05 mmol) and potassium phosphate (407 mg, 1.92 mmol) in DMF (10 ml) and water (1 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml)was heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (22 mg, 15% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ a 12.03 (s, 1H), 8,49 (s, 1H), 8,02 (d, J=8,8, 2H), 7,49 (t, J=7,6, 2H), 7,40 (d, J=7,2, 1H), of 3.73 (d, J=6,8, 2H), 1,90 (m, 1H), 1,67 (m, 5H), 1,17 (m, 3H), of 1.05 (m, 2H); MS (ESI)m/z309,1 [M+1]+; TPL 253-255°C.

5.1.84 EXAMPLE 84: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(1H-PYRAZOLE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(1H-pyrazole-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (250 mg, 0.80 mmol), pyrazole-4-Bronevoy acid (108 mg, 0.96 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (66 mg, 0.08 mmol) and potassium phosphate (680 mg, 3.2 mmol) in DMF (10 ml) and water (1 ml) was subjected interaction in accordance with the General Procedure B. About the SPS was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (93 mg, 39% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 13,01 (s, 1H), of $ 11.97 (s, 1H), 8,44 (s, 1H), 7,82 (s, 1H), 6.75 in (s, 1H), 3,70 (d, J=7,2, 2H), 1,90 (m, 1H), 1,65 (m, 5H), 1,17 (m, 3H), 1.06 a-a 1.01 (m, 2H); MS (ESI)m/z299,1 [M+1]+; TPL 264-266°C.

5.1.85 EXAMPLE 85: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(1H-PYRAZOLE-4-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(1H-pyrazole-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (250 mg, 0.80 mmol), pyrazole-4-Bronevoy acid (108 mg, 0.96 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (66 mg, 0.08 mmol) and potassium phosphate (680 mg, 3.2 mmol) in DMF (10 ml) and water (1 ml) was subjected interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. On the Les cooling was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (17 mg, 7% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 12,97 (s, 1H), 11,85 (s, 1H), 8,15 (m, 2H), of 7.96 (s, 1H), 3,65 (d, J=5,4, 2H), of 1.88 (m, 1H), 1,66-to 1.59 (m, 5H), of 1.16 (m, 3H), 1.04 million is 0.99 (m, 2H); MS (ESI)m/z299,1 [M+1]+; TPL 246-248°C.

5.1.86 EXAMPLE 86: SYNTHESIS of 6-(3-(1H-TETRAZOL-5-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(3-(1H-Tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 3-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile (see Example 61.A) (140 mg, 0.42 mmol) in anhydrous toluene (2 ml) were processed using usedatabaseyou (350 μl, of 1.26 mmol) in 21 hours at 110°C. the Toluene was removed under reduced pressure. Added dioxane (3 ml) and 6 n HCl solution (2 ml) and the resulting reaction mixture was stirred at room temperature for 3 hours. Volatiles were removed under reduced pressure, the crude product was dissolved in DMSO and purified via reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml)was heated at 100°C until complete dissolution. After cooling, was added water and the desired product Osage is Ali from solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (22 mg, 14% yield) as a white powder.1H NMR (400 MHz, DMSO-d6) δ 8,68 (s, 1H), 8,51 (s, 1H), they were 8.22 (d, J=8,4, 1H), 8,04 (d, 7=8.0 a, 1H), 7,69 (t, J=8,0, 1H), a 3.87 (d, J=7,2, 2H), 2,02 (m, 1H), about 1.75 (m, 4H), of 1.66 (m, 1H), 1,25 (m, 3H), 1.14 in (m, 2H); MS (ESI)m/z364,2 [M+1]+; TPL 248-250°C.

5.1.87 EXAMPLE 87: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(2-OXINDOL-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-it.

Bis(pinacolato)LIBOR (1.31 g, 4,71 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (385 mg, 0.47 mmol) and potassium acetate (1,38 g, 14.1 mmol) was sequentially added to a solution of 5-brooksi-indole (1.0 g, 4,71 mmol) in methylene chloride (25 ml), followed by addition of DMSO (15 ml). The crude mixture was diluted with water, extracted with methylene chloride (3×). The combined organic fractions were washed with water, saturated salt solution, dried over magnesium sulfate, filtered and volatiles removed under reduced pressure. The crude product was ground into powder with diethyl ether, subjected to ultrasound treatment and the precipitate was collected by filtration to obtain specified in the title compound (165 mg, 14%). MS (ESI) m/z 260,3 [M+1]+.

B. 1-(Cyclohexylmethyl)-6-(2-oxindol-5-yl)-1H-imidazo[4,5-b]feast the Jn-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (165 mg, of 0.53 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-he (165 mg, 0,63 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (41 mg, 0.05 mmol) and potassium phosphate (450 mg, mmol 2,12) in DMF (12 ml) and water (5 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml)was heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (25 mg, 13% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ 11,95 (s, 1H), 10,52 (s, 1H), scored 8.38 (s, 1H), a 7.85 (d, J=8,0, 2H), 6,92 (d, J=8,0, 2H), and 3.72 (d, J=7,2, 2H), only 3.57 (s, 2H), 1,89 (m, 1H), of 1.66 (m, 5H), 1,17 (m, 3H), of 1.03 (m, 2H); MS (ESI)m/z364,2 [M+1]+; TPL-316°C.

5.1.88 EXAMPLE 88: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(1H-INDAZOL-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(1H-indazol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,300 g, 0.96 mmol), indazole-5-Boro the OIC acid (0,283 g, to 1.16 mmol) and the complex[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,082 g, 0.1 mmol), potassium phosphate (0,818 g, 3,86 mmol), water (2 ml) and dimethylformamide (10 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate and extracted with ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dried in high vacuum to obtain the product (0,020 g, 10% yield).1H NMR (400 MHz, CD3OD), δ 8,44 (s, 1H) to 8.40 (s, 1H), 8,14 (s, 1H), 8,07 (DD, J=8,8, 1,6, 1H), to 7.64 (d, J=8,8, 2H), a 3.87 (d, J=7,2, 2H), 2,03 (m, 1H), 1,74 (m, 5H) of 1.26 (m, 5H); MS (ESI)m/z349,4, [M+1]+; TPL 311-313°C.

5.1.89 EXAMPLE 89: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(6-METHOXYPYRIDINE-3-YL)-1H-imidazo[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(6-methoxypyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,300 g, 0.96 mmol), 2-methoxypyridine-5-Bronevoy acid (0,177 g of 1.16 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,082 g, 0.1 mmol), FOSFA the potassium (0,818 g, 3,86 mmol), water (2 ml) and dimethylformamide (10 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate and extracted with ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dried in high vacuum to obtain the product (of 0.133 g, 40% yield).1H NMR (400 MHz, CD3OD), δ 8,44 (s, 1H), a total of 8.74 (d, J=2,4, 1H), 8,35 (s, 1H), 8,28 (DD, J=8,8, 2,4, 1H), 6,91 (d, J=8,8, 1H), 3.96 points (s, 3H), of 3.84 (d, J=7,2, 2H), 2,02 (m, 1H), 1,73 (m, 5H), of 1.28 (m, 5H); MS (ESI)m/z340,4 [M+1]+; TPL 235-237°C.

5.1.90 EXAMPLE 90: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(TETRAHYDRO-2H-PIRAN-4-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-Hydroxyphenyl)-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (100 mg, 0.2 mmol), tetrahydro-2H-Piran-4-amine (0,22 g, 2 mmol) and N-methylpyrrolidinone (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Received mod is to purified using chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane) to give white solid. Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (36 mg, 54% yield).1H NMR (400 MHz, DMSO-d6) δ 11,96 (s, 1H), 9,71 (s, 1H), at 8.36 (s, 1H), a 7.85 (d, J=9,0, 2H), to 6.88 (d, J=8,6, 2H), 4,49 (TT, J=12,4, 4,4, 1H), 4,01 (DD, J=11,5, 3,3, 2H), 3,47 (t, J=11,1, 2H), 2,60 (TD, J=12,6, 4,5, 1H), 1,73 (DD, J=12,3, 2,9, 2H); MS (ESI)m/z313,4 [M+1]+; TPL 382-383°C.

5.1.91 EXAMPLE 91: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(PIPERIDINE-4-YLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-Hydroxyphenyl)-1-(piperidine-4-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (100 mg, 0.2 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0,46 g, 2 mmol) and N-methyl, pyrrolidine (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified using chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane) to obtain the oil. The oil obtained was treated with a 4 n solution of hydrochloric acid in dioxane. The reaction mixture was concentrated and then passed through the ion exchange column Strata XC. The product was isolated from the column using ammonium hydroxide in methanol (5%). The fractions containing the product were combined and concentrated under reduced is the first pressure. The resulting material was ground into powder with simple ether to obtain a yellow solid (56 mg, 80% yield).1H NMR (400 MHz, DMSO-d6) δ 8,31 (s, 1H), 7,83 (d, 7=to 8.6, 2H), 6,86 (d, J=9,0, 2H), and 3.72 (d, J=7,0, 2H), 2,94 (d, J=12,1, 2H), 2,43 (t, J=10,7,2H), 2,00 (m, 1H), 1.55V (d, J=13.3-inch, 2H), 1,11-to 1.21 (m, 2H); MS (ESI)m/zto 326.1 [M+1]+; TPL 300°C.

5.1.92 EXAMPLE 92: SYNTHESIS of 1-(((1R,4R)-4-AMINOCYCLOHEXANE)METHYL)-6-(4-HYDROXYPHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 2-(((1R,4R)-4-(Dibenzylamino)cyclohexyl)methyl)isoindoline-1,3-dione.

((1R,4R)-4-(Dibenzylamino)cyclohexyl)methanol (5.0 g, 16 mmol), phthalimide (2.6 g, 18 mmol) and triphenylphosphine (4.7 g, 18 mmol) was dissolved in tetrahydrofuran. Added diisopropylethylamine (3.4 ml, 18 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with 1 n hydrochloric acid and ethyl acetate. The aqueous layer was neutralized using 1M sodium hydroxide and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain a white solid (3.1 g, 44% yield). MS (ESI) m/z 439,1 [M+1]+.

B. (1R,4R)-4-(Aminomethyl)-N,N-dibenzylhydroxylamine.

A solution of 2-(((1R,4R)-4-(dibenzylamino)cyclohexyl)methyl)-isoindoline-1,3-dione (1.5 g, 3.4 mmol) and hydrazine hydrate is added (2 ml) in ethanol (10 ml) was heated to 50°C for 1 hour. The reaction mixture which was asterili in the powder with water and ethyl acetate to obtain a white solid (0.7 g, 69% yield). MS (ESI) m/z 309,3 [M+1]+.

C. 1-(((1R,4R)-4-(Dibenzylamino)cyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (100 mg, 0.2 mmol), (1R,4R)-4-(aminomethyl)-N,N-dibenzylhydroxylamine (0.32 g, 2 mmol) and N-methylpyrrolidinone (2 ml) was heated on an oil bath to 150°C for 16 hours. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane) to give white solid (100 mg, 60% yield). MS (ESI) m/z 520,3 [M+1]+.

D. 1-(((1R,4R)-4-Aminocyclohexane)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

l-(((1R,4R)-4-(Dibenzylamino)cyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (100 mg, 0.2 mmol), palladium hydroxide (100 mg) and methanol (5 ml) was stirred in hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite and the filtrate was concentrated, and then has been purified using reverse-phase prepreparation HPLC (5-40% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fraction was passed through ion-exchange column StrataXC to remove triperoxonane acid and then was isolated by treatment with a solution of 2M hydroxide is ammonium in methanol. The solution was concentrated and then triturated to powder with simple ether to obtain a white solid (17 mg, 26% yield).1H NMR (400 MHz, DMSO-d6) δ compared to 8.26 (s, 1H), 7,81 (d, J=8,6, 2H), 6,85 (d, J=9,0, 2H), to 3.67 (d, J=7,0, 2H), 2,58 (m, 1H), 1,78 (m, 3H), of 1.64 (m, 2H), of 1.05 (m, 4H); MS (ESI)m/z340,5 [M+1]+; TPL 290°C.

5.1.93 EXAMPLE 93: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(1-OCCAISONALY-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 5-Promisingly-1-it.

A solution of methyl 4-bromo-2-bromoethylamine (2.0 g, 6.5 mmol) was treated with a solution of ammonia in methanol (7,0 M, 5 ml) and ammonium hydroxide (1 ml). The resulting reaction mixture was left to stir over night at room temperature. The reaction mixture was distributed between water and methylene chloride. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered and volatiles removed under reduced pressure. The crude product (620 mg) was used without additional purification. MS (ESI) m/z 212,0 [M+1]+.

B. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-it.

Bis(pinacolato)LIBOR (815 mg, is 3.21 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (240 mg, 0.29 mmol) and potassium acetate (860 mg, 8,76 mmol) was sequentially added to a solution of 5-promisingly-1-she (620 mg, of 2.92 mmol) in methylene chloride (15 ml), followed by addition of DMSO (5 ml). The reaction to the offer was heated at 100°C for 4 hours. After cooling, the crude mixture was diluted with water, extracted with methylene chloride (3×); the combined organic fractions were washed with water, saturated salt solution, dried over magnesium sulfate, filtered and volatiles removed under reduced pressure. The crude product was taken for absorption in hexane, subjected to ultrasound treatment and the precipitate was collected by filtration to give the desired product (250 mg, 33%). MS (ESI) m/z 260,3 [M+1]+.

C. 1-(Cyclohexylmethyl)-6-(1-occaisonaly-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (250 mg, 0.80 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-he (250 mg, 0.96 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (65 mg, 0.08 mmol) and potassium phosphate (680 mg, 3.2 mmol) in DMF (25 ml) and water (4 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum obtained with the eat stated in the title compound (51 mg, 17% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) ∆ 12,12 (s, 1H), 8,61 (s, 1H), 8,58 (s, 1H), to 8.20 (s, 1H), 8,14 (d, J=8,0, 2H), 7,76 (d, J=8,0,2H), 4,46 (s, 2H), 3,74 (d, J=7,2,2H), 1.91 a (m, 1H), 1,68 (m, 4H), to 1.60 (m, 1H), 1,17 (m, 3H), 1,05 (m, 2H); MS (ESI)m/z364,2 [M+1]+; TPL 337-339°C.

5.1.94 EXAMPLE 94: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(2-METHOXYPYRIDINE-4-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(2-methoxypyridine-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,300 g, 0.96 mmol), 2-methoxypyridine-4-Bronevoy acid (0,177 g of 1.16 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane(1:1) (0,082 g, 0.1 mmol), potassium phosphate (0,818 g, 3,86 mmol), water (2 ml) and dimethylformamide (10 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was isolated using chromatography on silica gel Biotage (0-10% methanol in dichloromethane). The fractions containing the product were concentrated to obtain the product (0,145 g, 44% yield).1H NMR (400 MHz, CD3OD), δ 8,65 (s, 1H) compared to 8.26 (DD, J=5,6, and 1.6, 1H), to 7.64 (DD, J=5,6, and 1.6, 1H), 7,43 (d, J=0,8, 1H), 3,90 (s, 3H), 3,74 (d, J=7,2, 2H), 1,92 (m, 1H), 2,02 (m, 1H) 1,68 (m, 5H), of 1.18 (m, 5H); MS (ESI)m/z340,4 [M+1]+; TPL 295-297°C.

5.1.95 EXAMPLE 95: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(6-HYDROXYPYRIDINE-3-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(-hydroxypyridine-1-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(Cyclohexylmethyl)-6-(2-methoxypyridine-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 94.A) (0.125 g, 0,369 mmol) was added to the aqueous 48% solution of Hydrobromic acid (6 ml) and heated to 100°C for 1 hour. The solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate and extracted with ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dried in high vacuum to obtain the product (0.008 g, 8,0% yield).1H NMR (400 MHz, CD3OD), δ 8,32 (s, 1H), 8,12 (DD, J=9,6, 2,8, 1H), 8,02 (s, 1H), 6.48 in (d, J=9,2, 1H), 3,70 (d, J=7,2, 2H), 3,84 (d, J=7,2, 2H), 1,90 (m, 1H), 1,65 (m, 5H), 1,19 (m, 3H), of 1.05(m, 2H); MS (ESI)m/z326 [M+1]+; TPL >400°C.

5.1.96 EXAMPLE 96: SYNTHESIS of 4-(3-((1R,4R)-4-HYDROXYCYCLOHEXYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZAMIDE

A. (1R,4R)-4-(3-Amino-6-bromopyrazine-2-ylamino)cyclohexanol.

3,5-Dibromopyridin-2-amine (5,00 g to 19.9 mmol), (1R,4R)-4-aminocyclohexanol (4,58 g, 39.8 mmol), diisopropylethylamine (3,842 g, 39.8 mmol) and n-butanol (120 ml) was heated in a sealed tube at 130°C for 18 hours. The solution are condensed under reduced pressure and the product in the eyes of the Ali using reverse-phase preparative HPLC (30-100% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). The fractions containing the product were concentrated to obtain specified in the title compound (3.9 g, 68% yield). MS (ESI) m/z 288,2 [M+1]+.

B. 6-Bromo-1-((1R,4R)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(1R,4R)-4-(3-Amino-6-bromopyrazine-2-ylamino)cyclohexanol (3,90 g of 13.6 mmol), 1,1'-carbonyldiimidazole (2.76 g, 17,0 mmol) and tetrahydrofuran (60 ml) was heated in a sealed tube at 120°C for 18 hours. The solution are condensed under reduced pressure and the product was purified using reverse-phase preparative HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the product were concentrated to obtain the product (0,884 g, 21% yield). MS (ESI) m/z 314,2 [M+1]+.

C. 4-(3-((1R,4R)-4-Hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b] pyrazin-5-yl)benzamide.

6-Bromo-1-((1R,4R)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0,300 g, 0.96 mmol), 4-carboxamid-phenylboronic acid (0,190 g, 1.15 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane(1:1) (0,082 g, 0.1 mmol), potassium phosphate (0,812 g, a 3.83 mmol), water (2 ml) and dimethylformamide (7 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was led from ethyl acetate to obtain the product (0,302 g, 89% yield).1H NMR (400 MHz, CD3 OD), δ a 8.34 (s, 1H) 8,08 (d, J=8,4, 2H), of 7.96 (d, 7=8,8, 2H), 7,43 (d, J=0,8, 1H), to 4.41 (m, 1H), 3,74 (m, 1H), 2,66 (m, 2H), 2,12 (d, J=10,4, 2H) to 1.87 (d, J=10,8, 2H), of 1.52 (m, 2H); MS (ESI)m/z354,4 [M+1]+; TPL 301-303°C.

5.1.97 EXAMPLE 97: SYNTHESIS of 2-(4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)PHENYL)ACETIC ACID

A. Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.

In a tightly closed vessel a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (650 mg, 2,47 mmol) in methanol (10 ml) was treated with concentrated hydrochloric acid (few drops). The resulting reaction mixture was left for stirring at room temperature. After the reaction was completed, the volatiles were removed under reduced pressure. The crude product (650 mg, 100% yield) was used without purification in the next stage. MS (ESI) m/z making up 277.3 [M+1]+.

B. Methyl 2-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetate.

Bromo-1-(cyclohexylmethyl)-4-imidazoline[4,5-b]pyrazin-2-he (200 mg, 0.64 mmol), methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (213 mg, 0.77 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (53 mg, 0.06 mmol) and potassium phosphate (543 mg, 2.56 mmol) in DMF (20 ml) and water (5 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reversed-phase polyprop the operational HPLC (30-100% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (95 mg, 39 yield) as a reddish brown solid. MS (ESI) m/z 381,4 [M+1]+.

C. 2-(4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetic acid

A solution of methyl 2-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetate (40 mg, 0.13 mmol) in tetrahydrofuran (1 ml) was treated with 1 n solution of lithium hydroxide (1 ml). After 2 hours the reaction was completed. The tetrahydrofuran was removed under reduced pressure and the residue was treated with acetic acid to pH~5. There was a formation of white precipitate and was collected by filtration to obtain specified in the title compound (20 mg, 55% yield).1H NMR (400 MHz, DMSO-d6) δ 12,38 (s, 1H), 12,02 (s, 1H) of 8.47 (s, 1H), of 7.96 (d, J=8,4, 2H), 7,37 (d, J=8,4, 2H), of 3.73 (d, J=12,2H), 3,62 (s, 2H), 2,08 (m, 1H), of 1.66 (m, 5H), 1,17 (m, 3H)and 1.15 (m, 2H); MS (ESI) m/z 367,2 [M+1]+.

5.1.98 EXAMPLE 98: SYNTHESIS of 2-(4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)PHENYL)NDIMETHYLACETAMIDE

A. 2-(4-(3-(Cyclohexylmethyl)-2-oxo-2,3-what ihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl) ndimethylacetamide.

A solution of methyl 2-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetate (see Example 97.B) (40 mg, 0.13 mmol) was treated with a solution of ammonia in methanol (7 N., 2 ml) and ammonium hydroxide. The resulting solution was left to stir at room temperature. After the reaction was completed, the volatiles were removed under reduced pressure. The residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (50 mg, 47% yield).1H NMR (400 MHz, DMSO-d6) δ 12,01 (s, 1H), 8,46 (s, 1H), 7,94 (d, J=8,0, 2H), 7,49 (s, 1H), 7,37 (d, J=8,4 2H), 6,92 (s, 1H), of 3.73 (d, J=7,2, 2H), 3,62 (s, 2H), 1,90 (m, 1H), of 1.66 (m, 5H), 1,17 (m, 3H), of 1.03 (m, 2H); MS (ESI)m/z366,1 [M+1]+; TPL 272-274°C.

5.1.99 EXAMPLE 99: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(2-OXOINDOLE-6-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(Tributylstannyl)indolin-2-it.

A solution of 6-bromoindole (0.5 g, of 2.35 mmol) in anhydrous toluene (30 ml) were processed using hexamethyldisilane (1.07 g, 3,29 mmol) and tetrakis(triphenylphosphine)palladium(0) (271 mg, 0.23 mmol) in a sealed tube at 92°C for 1.5 hours. Volatiles were removed under reduced pressure and the crude product was purified with SIP the soup Biotage chromatography (0-30% EtOAc in hexane) to obtain the specified title compound (265 mg, 38%). MS (ESI) m/z 298,2 [M+1]+.

B. 1-(Cyclohexylmethyl)-6-(2-oxoindole-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (100 mg, 0.32 mmol), 6-(tributylstannyl)indolin-2-he (114 mg, 0.38 mmol), dichlorobis(triphenylphosphine)palladium(II) (44 mg, 0.06 mmol) in DMF (5 ml) was subjected to interact for 1 hour at 115°C. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (29 mg, 24% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ a 12.03 (s, 1H), 10,49 (s, 1H), 8,42 (s, 1H), 7,58 (d, J=8,0,1H), 7,44 (s, 1H), 7,39 (d, J=8,0, 1H), and 3.72 (d, J=7,2, 2H), 3,52 (s, 2H), 1,90 (m, 1H), of 1.66 (m, 5H), 1,17 (m, 3H), of 1.03 (m, 2H); MS (ESI)m/z364,0 [M+1]+; TPL 334-336°C.

5.1.100 EXAMPLE 100: SYNTHESIS of 4-(3-(CYCLOHEXYLMETHYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)-3-METHYLBENZOIC ACID

A. 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid.

Bis(pinacolato)LIBOR (of 3.07 g, 12,09 mmol), dichloro[1,1'-bis(diphenylprop the but)ferrocene]palladium(II)·dichloromethane (114 mg, 0.14 mmol) and triethylamine (1,95 ml, to 13.95 mmol) was sequentially added to a solution of 4-bromo-3-methylbenzoic acid (1.0 g and 4.65 mmol) in dioxane (15 ml). The resulting reaction mixture was left for stirring at room temperature for 20 min, and then heated at 80°C in a sealed tube. Volatiles were removed under reduced pressure and the oily residue was distributed between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The crude product was used without additional purification. MS (ESI) m/z 263,2 [M+1]+.

B. 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-3-methylbenzoic acid.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (300 mg, 0.96 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (303 mg, 1.15 mmol), dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II)·dichloromethane (80 mg, 0.09 mmol) and potassium phosphate (815 mg, of 3.84 mmol) in DMF (25 ml) and water (5 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and load the Wali at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (43 mg, 12% yield) as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 12,99 (s, 1H), 12,11 (s, 1H), 8,07 (s, 1H), 7,88 (s, 1H), a 7.85 (d, J=8,0, 1H), 7,53 (d, J=8,0, 1H), to 3.67 (d, J=7,2, 1H), of 1.88 (m, 1H), 1,64 (m,2H), 1.61 of (m, 2H), 1.14 in (m, 3H), 1,01 (m, 2H); MS (ESI)m/z367,2 [M+1]+; TPL 244-247°C.

5.1.101 EXAMPLE 101: the SYNTHESIS of N-METHYL-4-(2-OXO-3-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZAMIDE

A. 6-Bromo-N2-((tetrahydro-2H-Piran-4-yl)methyl)pyrazin-2,3-diamine.

In a sealed tube a solution of 5-bromopyrazine-2,3-diamine (6,98 g, 2,78 mmol), (tetrahydro-2H-Piran-4-yl)methanamine (4.0 g, 3,47 mmol), diisopropylethylamine (6,06 ml, 3,47 mmol) in n-butanol (100 ml) was heated at 120°C for 17 hours. Volatiles were removed under reduced pressure. The residue was taken for absorption in hexane/diethyl ether and subjected to ultrasonic treatment. The precipitate was collected by filtration to give the desired product (5.10 g, 64% yield). MS (ESI) m/z 289,1 [M+1]+.

B. 6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

In a sealed tube a solution of 6-bromo-N2-((tetrahydro-2H-Piran-4-yl)methyl)pyrazin-2,3-diamine (of 5.05 g ,017 mmol), 1,1'-carbonyldiimidazole (3,52 g 0,021 mmol) in tetrahydrofuran (40 ml) was heated at 95°C. was Added an additional amount of 1,1'-carbonyldiimidazole (1.7 g, 10 mmol) and the reaction mixture was heated for another 12 hours. Volatiles were removed under reduced pressure. The residue was taken for absorption in hexane/diethyl ether and subjected to ultrasonic treatment. The precipitate was collected by filtration, washed with hexane and dried in a vacuum oven to obtain specified in the title compound (3.5 g, 67% yield) as a reddish brown solid. MS (ESI) m/z 315,9 [M+1]+.

C. N-Methyl-4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (300 mg, 0.95 mmol), [4-(N-methylaminomethyl)phenyl]Bronevoy acid (205 mg, 1.15 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (80 mg, 0.09 mmol) and potassium phosphate (805 mg, 3.8 mmol) in DMF (30 ml) and water (8 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml)was heated at 100°C until complete dissolution. After cooling, was added water and wish the product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (165 mg, 47% yield) as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 12,11 (s, 1H), 8,58 (s, 1H), and 8.50 (d, J=4,8, 1H), 8,12 (d, J=8,4, 1H), to 7.93 (d, J=8,4,1H), 3,82 (m, 2H), 3,79 (d, J=7,2, 2H), 3,25 (m, 2H), and 2.14 (m, 1H), 1.57 in (m, 2H), 1,31 (m, 2H); MS (ESI)m/z368,1 [M+1]+; TPL 328-330°C.

5.1.102 EXAMPLE 102: SYNTHESIS of 4-(2-OXO-3-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZAMIDE

A. 4-(2-oxo-3-((Tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 101. B) (500 mg, of 1.59 mmol), (4-aminosulphonylphenyl)baronova acid (317 mg, 1.92 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (130 mg, 0.16 mmol) and potassium phosphate (1.35 g, 6,36 mmol) in DMF (40 ml) and water (10 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed and water and dried in high vacuum to obtain specified in the title compound (165 mg, 47% yield) as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 12,11 (s, 1H), 8,59 (s, 1H), 8,12 (d, J=8,4, 2H), 8,03 (s, 1H), of 7.97 (d, J=8,4, 2H), 7,42 (s, 1H), 3,82 (m, 2H), 3,79 (d, J=7,2, 2H), 3,25 (m, 2H), and 2.14 (m, 1H), 1.57 in (m, 2H), 1,32 (m, 2H); MS (ESI)m/z354,1 [M+1]+; TPL 273-275°C.

5.1.103 EXAMPLE 103: SYNTHESIS of 7-(4-HYDROXYPHENYL)-1-(3-METHOXYBENZYL)-3,4-DIHYDROPYRIDO[2,3-B]PYRAZIN-2(1H)-It

A. Methyl 2-(3,5-dibromopyridin-2-ylamino)acetate.

3,5-Dibromopyridin-2-amine (2.5 g, 26 mmol), ethyl glyoxylate (50% in toluene, 8 ml, 39 mmol), dichloride dibutyrate (0.4 g, 1.3 mmol) and methanol (20 ml) was stirred together at room temperature for 16 hours. Added borohydride sodium (1.5 g, 39 mmol) in small portions. The reaction mixture was concentrated and then purified on a column of silica gel (0-100% ethyl acetate in hexane) to give the desired product (0.8 g, 19% yield) as a white solid. MS (ESI) m/z 246,1 [M+1]+.

B. 7-Bromo-1-(3-methoxybenzyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he.

Methyl 2-(3,5-dibromopyridin-2-ylamino)acetate (0,58 g, 1.8 mmol), 3-methoxybenzylamine (227 μl, 1.8 mmol), diisopropylethylamine (1 ml) and dimethylsulfoxide (1 ml) was heated to 100°C for 3 days under nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and concentrated. The residue was purified on a column of silica gel (0-100% ethyl acetate is hexane) to obtain the specified title compound (124 mg, 20% yield) as a pink solid. MS (ESI) m/z 349,0 [M+1]+.

C. 7-(4-Hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he.

7-Bromo-1-(3-methoxybenzyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he (124 mg, 0.35 mmol), 4-hydroxyphenylarsonic acid (54 mg, 0,39 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (13 mg, of 0.017 mmol), 1M sodium carbonate (1 ml, 0.8 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using chromatography on a Biotage silica gel (0-100% ethyl acetate in hexane) to give white solid (49 mg, 38% yield).1H NMR (400 MHz, DMSO-d6) δ of 9.56 (s, 1H), of 8.09 (s, 1H), 7,71 (d, J=8,6, 2H), 7,45 (s, 1H), 7,21 (t, J=7,8, 1H), of 6.96 (s, 1H), 6,92 (d, J=7,8, 1H), 6,78 (d, J=8,6, 2H), 5,23 (s, 2H), 4,25 (s, 2H), 3,69 (s, 3H); MS (ESI)m/z363,0 [M+1]+.

5.1.104 EXAMPLE 104: SYNTHESIS of 6-(4-(2-HYDROXYPROPAN-2-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. Methyl 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate.

6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B (500 mg, to 1.59 mmol), 4-(methoxycarbonyl)phenylboronic acid (317 mg, 1.92 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (130 mg, 0.16 mmol) and potassium phosphate (1.35 g, 6,36 mmol) in DMF (40 ml) and water (10 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (180 mg, 31% yield) as a colorless solid. MS (ESI) m/z 369,2 [M+1]+.

B. 6-(4-(2-Hydroxypropan-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Methyl 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate (0,150 g, 0,408 mmol) was dissolved in tetrahydrofuran (15 ml) and cooled to -78°C. was Added methylmagnesium (1,4M in toluene/tetrahydrofuran, of 1.16 ml, and 1.63 mmol) and the reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction extinguished with water and was extracted with ethyl acetate. The product was purified COI is whether the reversed-phase prepreparation HPLC (30-70% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 40 min). The fractions containing the desired substance were combined and concentrated under reduced pressure. The obtained residue was dissolved in hot DMSO and added water to cause precipitation. The resulting solid was filtered, washed with water and dried in vacuum to obtain specified in the connection header (0,067 g, 45% yield).1H NMR (400 MHz, DMSO-d6) δ 12,02 (s, 1H), 8,45 (s, 1H), 7,94 (d, J=8,4, 2H), 8,03 (s, 1H), 7,56 (d, J=8,4, 2H), 3,82 (m, 2H), 3,78 (d, J=6,8, 2H), 3,25 (m, 2H), and 2.14 (m, 1H), 1.57 in (m, 2H), 1,45 (s, 6H), 1.32 to (m, 2H); MS (ESI)m/z369,1 [M+1]+; TPL-214°C.

5.1.105 EXAMPLE 105: SYNTHESIS of 6-(1H-INDOL-5-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(1H-Indol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo [4,5-b] pyrazin-2(3H)-he.

6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 101. B) (300 mg, 0.95 mmol), 5-indeliberately acid (185 mg, 1.15 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (80 mg, 0.09 mmol) and potassium phosphate (812 mg, a 3.83 mmol) in DMF (20 ml) and water (4 ml) was subjected to interaction in accordance with the General Procedure B. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After about what ladenia was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (89 mg, 24% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ 11,93 (s, 1H), 11,21 (s, 1H), 8,45 (s, 1H), to 8.20 (s, 1H), 7,78 (DD, J=8,4, 1,6, 1H), of 7.48 (d, J=8,4, 1H), 7,39 (m, 1H), of 6.52 (s, 1H), 3,84 (m, 2H), 3,80 (d, J=7,2, 2H), 3,26 (t, J=10, 2H), 2,15 (m, 1H), 1,58 (m, 2H), 1,33 (m, 2H); MS (ESI)m/z350,1 [M+1]+; TPL 305-308°C.

5.1.106 EXAMPLE 106: SYNTHESIS of 6-(4-(4H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(4H-1,2,4-Triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide (see Example 102.A) (300 mg, 0.84 mmol) in DMF (3 ml) was treated with dineopentyl N,N-dimethylformamide (2 ml). The resulting reaction mixture was heated at 80°C for 1.5 hours and the volatiles were removed under reduced pressure. The oily residue was taken for absorption in hydrazine (3 ml) was added acetic acid (10 drops). After 1.5 hours, it was determined that the reaction was completed. Volatiles were removed under reduced pressure. The product was purified using reverse-phase preparative HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the STATCOM took for acquisitions in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (39 mg, 12% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ 12,09 (s, 1H), 8,65 (s, 1H), 8,56 (s, 1H), they were 8.22 (d, J=8,8, 1H), 8,08 (m, 4H), 3,85 (m, 2H), 3,80 (d, J=7,2,2H), 3,26 (m, 2H), 2,15 (m, 1H), 1,58 (m, 2H), 1,32 (m, 2H); MS (ESI)m/z378,1 [M+1]+; TPL 342-345°C.

5.1.107 EXAMPLE 107: SYNTHESIS of 6-(1H-BENZO[D]IMIDAZOL-5-YL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 5-bromo-1H-benzo[d]imidazol-1-carboxylate.

5-Bromo-1H-benzo[d]imidazole (0,300 g of 1.52 mmol), di-tert-BUTYLCARBAMATE (0,397 g, 1.82 mmol), triethylamine (0,307 g, 3.04 from mmol) and tetrahydrofuran (10 ml) was stirred at 25°C for 18 hours. The solution are condensed under reduced pressure and the product was isolated using chromatography on silica gel Biotage (0-80% ethyl acetate in hexane). The fractions containing the product were concentrated to obtain (0,398 g, 88% yield). MS (ESI) m/z 298 [M+1]+.

B. tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-carboxylate.

tert-Butyl 5-bromo-1H-benzo[d]imidazol-1-carboxylate (0,300 g, 1.01 mmol), bis(pinacolato)LIBOR (0,283 g, 1.11 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,074 g, 0.09 mmol), and the Etat potassium (0,297 g, 3.03 mmol), dichloromethane (2 ml) and methylsulfoxide (1 ml) were combined in a sealed tube and heated to 100°C for 18 hours. The solution are condensed under reduced pressure and the product was used without purification in the next stage (0,363 g). MS (ESI) m/z 345 [M+1]+.

C. 6-(1H-Benzo[d]imidazol-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,219 g, 0.70 mmol), tert-butyl 5-(4,4,5-,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-carboxylate (0,290 g, 0.84 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,057 g, 0.07 mmol), potassium phosphate (0,596 g of 2.81 mmol), water (2 ml) and dimethylformamide (7 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate and extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated and dried in vacuum to obtain (to 0.060 g, 20% yield).1H NMR (400 MHz, CD3OD), δ 8,44 (s, 1H) compared to 8.26 (s, 1H), they were 8.22 (s, 1H), 7,94(DD, J=8,8, 1,6, 1H), of 7.70 (s, 1H), 3,88 (d, J=7,2, 2H), 2,04 (m, 1H), 1,76 (m, 5H), of 1.29 (m, 5H); MS (ESI)m/z349 [M+1]+; TPL 217 to 220°C.

5.1.108 NOTE THE P 108: SYNTHESIS of 4-(2-OXO-3-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)BENZAMIDE

A. 6-Bromo-N2-(2-(tetrahydro-2H-Piran-4-yl)ethyl)pyrazin-2,3-diamine.

3,5-Dibromopyridin-2-amine (of 5.05 g of 20.1 mmol), 2-(tetrahydro-2H-Piran-4-yl)ethanamine (4,00 g, 24,1 mmol), N,N-diisopropylethylamine (5,19 g, with 40.2 mmol) and n-butanol (120 ml) was heated in a sealed tube at 130°C for 18 hours. The solution are condensed under reduced pressure and the product recrystallized from methanol to obtain (5.8 g, 96% yield). MS (ESI) m/z 302,2 [M+1]+.

B. 6-Bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-N2-(2-(tetrahydro-2H-Piran-4-yl)ethyl)pyrazin-2,3-diamine (5,80 g, and 19.3 mmol), 1,1'-carbonyldiimidazole (to 3.92 g, 24,1 mmol) and tetrahydrofuran (40 ml) was heated in a sealed tube at 120°C for 18 hours. The solution are condensed under reduced pressure and the product was purified using reverse-phase preparative HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the product was recrystallized from methanol to obtain (5,3 g, 84% yield). MS (ESI) m/z 328,2 [M+1]+.

C. 4-(2-oxo-3-(2-(Tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

6-Bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0.400 g, 1,22 mmol), 4-carboxamid-phenylboronic acid (0,241 g of 1.46 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,098 is, 0.12 mmol), potassium phosphate (1,03 g, 4,88 mmol), water (2 ml) and dimethylformamide (7 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was led from dichloromethane to obtain (0.400 g, 89% yield).1H NMR (400 MHz, CD3OD), δ 8,54 (s, 1H) to 8.40 (s, 1H), of 8.09 (d, J=8,4, 2H), 7,94 (d, J=8,4, 1H), 4,08 (t, J=6,8, 2H), 3,92 (DD, J=11, 2,3, 2,2H), to 3.64 (m, 2H)and 1.83 (m, 4H), to 1.59 (m, 1H), 1,38 (sq, d, J=12,8, 4,4, 2H); MS (ESI)m/z368,4 [M+1]+; TPL 233-236°C.

5.1.109 EXAMPLE 109: SYNTHESIS of 6-(3-(2H-1,2,3-TRIAZOLE-4-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 6-bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (100 mg, 0.32 mmol), hexamethylditin (150 mg, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (37 mg, to 0.032 mmol) in toluene (10 ml) was heated at 100°C for 2 hours. After the reaction was completed, toluene was removed under reduced pressure and the residue was purified using Biotage chromatography (0-50% ethyl acetate in hexane) to obtain the specified title compound (100 mg, 79%). MS (ESI) m/z 309,2[M+1]+.

B. 6-(3-(2H-1,2,3-Triazole-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 1-(cyclohexylmethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (100 mg, 0.25 mmol), 4-(3-bromophenyl)-2H-1,2,3-triazole (70 mg, 0.30 mmol) and dichlorobis(trip nilpotent)palladium(II) (18 mg, 0.02 mmol) in DMF (5 ml) was heated for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (4 mg, 4% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ a 12.03 (s, 1H), 10,49 (s, 1H), 8,42 (s, 1H), 7,58 (d, J=8,0, 1H), 7,44 (s, 1H), 7,39 (d, J=8,0, 1H), and 3.72 (d,J=7,2, 2H), 3,52 (s, 2H), 1,90 (m, 1H), of 1.66 (m, 5H), 1,17 (m, 3H), of 1.03 (m, 2H); MS (ESI)m/z316,2[M+1]+; TPL 299-301°C.

5.1.1 10 EXAMPLE 110: SYNTHESIS of 6-(4-(1H-IMIDAZOL-1-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(1H-Imidazol-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(Cyclohexylmethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 109.A) (200 mg, 0,506 mmol), 1-(4-bromophenyl)imidazole (94 mg, 0.42 mmol), dichlorobis(triphenylphosphine)palladium(II) (104 mg, 0.10 mmol) in DMF (10 ml) was subjected to interaction for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2+ 0,1% TFA, within 30 minutes). The desired fractions were concentrated, the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (16 mg, 10% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ 12,11 (s, 1H), 8,61 (s, 1H), 8,24 (d, J=8,8, 2H), 7,87 (d, J=8,8,2H), was 4.02 (d, J=8,8, 1H, in), 3.75 (d, J=8,8, 1H), 1,68 (m, 2H), 1,24 (m, 4H), 1,17 (m, 4H); MS (ESI)m/z375,1 [M+1]+; TPL 284-287°C.

5.1.111 EXAMPLE 111: SYNTHESIS of 6-(4-(1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-((1R,4R)-4-HYDROXYCYCLOHEXYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (1R,4R)-4-(3-Amino-6-bromopyrazine-2-ylamino)cyclohexanol.

3,5-Dibromopyridin-2-amine (5,00 g to 19.9 mmol), 4-aminocyclohexane-1-ol (4,58 g, 39.8 mmol), diisopropylethylamine (3,84 g, 39.8 mmol) and n-butanol (120 ml) was heated at 130°C for 18 hours. The solution are condensed under reduced pressure and the product was purified using reverse-phase preparative HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the product are condensed to obtain (3.9 g, 68% yield). MS (ESI) m/z 288,2 [M+1]+.

B. 6-Bromo-1-((1R,4R)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(1R,4R)-4-(3-Amino-6-bromopyrazine-2-ylamino)cyclohexanol (3,90g, to 13.6 mmol), and 1,1'-carbonyldiimidazole (2.76 g, 17,0 mmol) and tetrahydrofuran (60 ml) was heated in a sealed tube at 120°C for 18 hours. The solution are condensed under reduced pressure and the product was purified using reverse-phase preparative HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the product are condensed with obtaining (0,884 g, 21% yield). MS (ESI) m/z 314,2 [M+1]+.

C. 4-(3-((1R,4R)-4-Hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyrazin-5-yl)benzamide.

6-Bromo-1-((1R,4R)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0,300 g, 0.96 mmol), 4-carboxamid-phenylboronic acid (0,19O g, 1.15 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane(1:1) (0,082 g, 0.10 mmol), potassium phosphate (0,812 g, a 3.83 mmol), water (2 ml) and dimethylformamide (7 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was led from ethyl acetate to obtain (0,297 g, 88% yield). MS (ESI) m/z 354,4 [M+1]+.

D. (E)-N-((Dimethylamino)methylene)-4-(3-((1R,4R)-4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

4-(3-((1R,4R)-4-Hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide (0,272 g, 0.77 mmol) and dineopentyl N,N-dimethylformamide (5.0 ml, of 17.9 mmol) were heated together in a microwave react the e Biotage Emrys Optimizer at 100°C for 45 minutes. When the starting material was completely consumed, the product was filtered to obtain (0,249 g, 79% yield). MS (ESI) m/z 409,5 [M+1]+.

E. 6-(4-(1H-1,2,4-Triazole-3-yl)phenyl)-1-((1R,4R)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(E)-N-((Dimethylamino)methylene)-4-(3-((1R,4R)-4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide (0,249 g, 0.61 mmol) was added to acetic acid (10 ml) and cooled to 0°C. was Added dropwise hydrazine (0,548 g of 17.1 mmol) and the reaction mixture was stirred at 25°C for 4 hours. The solution are condensed under reduced pressure and the product was purified using reverse-phase preparative HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the product are condensed and transformed to a cleaners containing hydrochloride salt with ethanol (300 ml) and 12M HCl (10 ml) to obtain (0,010 g, 4.3% yield).lH NMR (400 MHz, CD3OD), δ of 8.95 (s, 1H) charged 8.52 (s, 1H), 8,23 (d, J=6,4, 2H), 8,13 (d, J=6,4, 1H), 4,45 (m, 1H, in), 3.75 (m, 1H), 2,65 (square d, J=12,8, 2,8, 2H), and 2.14 (m, 2H) of 1.93 (m, 2H), and 1.54 (m, 2H); MS (ESI)m/z378,4 [M+1]+; TPL 303-305°C.

5.1.112 EXAMPLE 112: SYNTHESIS of 6-(4-(2H-TETRAZOL-5-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(2H-tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,300 g, 0,964 mmol), 4-tetraselenafulvalene acid (0,220 g, 1,164 mmol) complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,082 g, 0.1 mmol), potassium phosphate (0,812 g, a 3.83 mmol), water (2 ml) and dimethylformamide (7 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product, neutralized with potassium carbonate, extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated and dried in vacuum to obtain (0,184 g, 51% yield).lH NMR (400 MHz, CD3OD), δ 8,24 (s, 1H) 8,11 (d, J=8,4, 2H), 8,04 (d, J=8,4, 2H), 3,84 (d, J=7,6, 2H), 1,73 (m, 5H), of 1.27 (m, 6H); MS (ESI) m/z 349 [M+1]+; TPL >400°C.

5.1.113 EXAMPLE 113: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(2-HYDROXYPYRIDINE-4-YL-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(2-hydroxypyridine-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(Cyclohexylmethyl)-6-(2-methoxypyridine-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 94.A) (0,120 g, 0,354 mmol) was added to a solution of Hydrobromic acid/acetic acid (10 ml) and heated at 100°C for 0.5 hours. The solution are condensed under reduced pressure and the product was purified using reverse-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the product are condensed and transformed to a cleaners containing hydrochloride with the ü using ethanol (300 ml) and 12M HCl (10 ml) to obtain (0,045 g, 39% yield).lH NMR (400 MHz, CD3OD), δ to 8.70 (s, 1H) with 8.05 (d, J=6,4, 2H), 7,774 (m, 2H), 3,85 (d, J=7,2, 2H), 2,01 (m, 1H), 1,75 (m, 5H), of 1.28 (m, 6H); MS (ESI)m/z326,4[M+1]+; TPL 311-313°C.

5.1.114 EXAMPLE 114: SYNTHESIS of 6-(4-(1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (E)-N-((Dimethylamino)methylene)-4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

4-(2-Oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide (see Example 108.C) (0.40 g, of 1.09 mmol), dineopentyl N,N-dimethylformamide (10.0 ml, 35.8 mmol) were heated together at 100°C for 180 minutes. When the starting material was completely consumed, the product was filtered to obtain (0,539 g, crude product). MS (ESI) m/z 423,5 [M+1]+.

B. 6-(4-(1H-1,2,4-Triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(E)-N-((Dimethylamino)methylene)-4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide (0,250 g, 0,592 mmol) was added to acetic acid (10 ml) and cooled to 0°C. was Added dropwise hydrazine (0,532 g of 16.6 mmol) and the reaction mixture was stirred at 25°C for 4 hours. The solution are condensed under reduced pressure and the product was purified using reverse-phase preparative HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Fractions, provided the product are condensed and transformed to a cleaners containing hydrochloride salt with ethanol (300 ml) and 12M HCl (10 ml) to obtain (0,091 g, 39% yield).1H NMR (400 MHz, CD3OD), δ 9,18 (s, 1H) 8,56 (s, 1H), 8,27 (m, 2H), 8,13 (m, 2H), 4,11 (t, J=7,2, 2H), 3,93 (m, 2H), 3,80 (m, 2H), of 1.85 (m, 4H), to 1.61 (m, 1H), 1.39 in (m, 2H); MS (ESI)m/z378,4 [M+1]+; TPL 263-266°C.

5.1.115 EXAMPLE 115: SYNTHESIS of 6-(4-(1H-IMIDAZOL-2-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(1H-Imidazol-2-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(Cyclohexylmethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 109.A) (200 mg, 0,506 mmol), 1-(4-bromophenyl)imidazole (94 mg, 0.42 mmol), dichlorobis(triphenylphosphine)palladium(II) (104 mg, 0.10 mmol) in DMF (10 ml) was subjected to interaction for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to give the desired product (5 mg, 3% yield) as a tan solid.

1H NMR (400 MHz, DMSO-d6) δ 12,1 (s, 1H), at 8.60 (s, 1H), 8,19 (d, J=8,4, 1H), 8,07 (d, J=8,4, 1H), 7,45 (s, 1H), 375 (d, J=7,2,2H), 1.91 a (m, 1H), 1,68 (m, 4H), to 1.60 (m, 1H), of 1.85 (m, 3H), 1.06 a (m, 2H); MS (ESI)m/z375,1 [M+1]+; TPL 349-351°C.

5.1.116 EXAMPLE 116: SYNTHESIS of 6-(4-(1H-1,2,3-TRIAZOLE-1-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1 Azido-4-Brabanthal.

tert-Butanol(8 ml) was added to azide sodium (1.13 g, 17,43 mmol) followed by addition of water (1.7 ml), 4-bromaniline (1 g, of 5.81 mmol) and tert-butylnitrite (8,35 ml, was 69.7 mmol). The reaction mixture is brought to 70°f within 2 hours. Was added water (20 ml) and the reaction mixture was extracted with ethyl acetate (3×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using Biotage chromatography (0-40% ethyl acetate in hexane) to give the desired product (730 mg, 63% yield).

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

In a sealed tube a solution of 1-azido-4-bromine benzol and vinyl acetate was heated at 100°C for 14 hours. After removal of volatiles under reduced pressure the residue was recrystallized from methanol to obtain specified in the title compound (430 mg, 52%).

C. 1-(4-(Tributylstannyl)phenyl)-1H-1,2,3-triazole.

A solution of 1-(4-bromophenyl)-1H-1,2,3-triazole (0,43 g, at 1.91 mmol) in anhydrous toluene (30 ml) were processed using hexamethyldisilane (0.75 g, to 2.29 mmol) and tetrakis(triphenylphosphine)palladium(0) (220 mg, 0,19 shall mol) in a sealed tube at 110°C for 2.5 hours. Volatiles were removed under reduced pressure and the crude product was purified using Biotage chromatography (0-35% ethyl acetate in hexane) to give the desired product (447 mg, 76%). MS (ESI) m/z 309,2 [M+1]+.

D. 6-(4-(1H-1,2,3-Triazole-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 6-bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (see Example 55.B) (235 mg, 0.75 mmol), 1-(4-(tributylstannyl)phenyl)-1H-1,2,3-triazole (300 mg, 0.97 mmol) and dichlorobis(triphenylphosphine)palladium(II) (53 mg, of 0.075 mmol) in DMF (10 ml) was heated for 1.5 hours at 110°C. the Product was purified using reversed-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated. The residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (17 mg, 6% yield) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ 12,19 (s, 1H), 8,98 (s, 1H), to 8.70 (s, 1H), 8.34 per (d, J=11,2, 2H), 8,13 (d, J=1,2, 2H), 8,10 (s, 1H), 3,84 (d, J=9,6, 2H), 2.0 (m, 1H), 1,78 (m, 5H), 1.27mm (m, 3H)and 1.15 (m, 2H); MS (ESI)m/z375,1 [M+1]+; TPL 276-278°C.

5.1.117 EXAMPLE 117: SYNTHESIS of 6-(4-(2-HYDROXYPROPAN-2-YL)PHENYL)-1-(2-(TETRAHYDRO-2-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. Methyl 4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate.

6-Bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 108.B) (0.400 g, 1,22 mmol), 4-methoxycarbonylpropionyl acid (0,262 g of 1.46 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,098 g, 0.12 mmol), potassium phosphate (1,03 g, 4,88 mmol), water (2 ml) and dimethylformamide (7 ml) was subjected to interaction in accordance with the General Procedure B. the Solution are condensed under reduced pressure and the product was purified using chromatography on silica gel Biotage (0-80% ethyl acetate in hexane). The fractions containing the product were concentrated to obtain (0,058 g, 12% yield). MS (ESI) m/z 383,4 [M+1]+.

B. 6-(4-(2-Hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Methyl 4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate (0,058 g, 0,152 mmol) was added to tetrahydrofuran (5 ml) and cooled to -78°C. Methylmagnesium (3.0 M, 0,073 g, 0.61 mmol) was added dropwise and the reaction mixture was stirred and allowed to cool to

25°C for 18 hours. The solution extinguished with methanol are condensed under reduced pressure and the product was purified using reverse-phase preparative HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Faction, with the holding of the product, neutralized with ammonium hydroxide, are condensed and recrystallized from methylsulfoxide and water with the receipt (or 0.027 g, 47% yield).1H NMR (400 MHz, DMSO-d6) δ of 8.40 (s, 1H) to 7.95 (d, J=8,4,2H), to 7.59 (d, J=8,4,2H), 4.09 to (m, 2H), 3,92 (m, 2H), 3,37 (m, 2H)and 1.83 (m, 4H), to 1.59 (m, 1H), equal to 1.59 (s, 6H), 1,38 (sq,d, J=12,4, 4,4, 2H); MS (ESI)m/z392,4 [M+1]+; TPL 263-266°C.

5.1.118 EXAMPLE 118: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(4-(5-METHYL-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. Hydrochloride ethyl-4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate.

4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile (see Example 69.A) (0,142 g, 0.43 mmol) was added to ethanol (100 ml) and cooled to 0°C. Gaseous hydrogen chloride was barbotirovany through the solution for 15 minutes. The solution was left to stir at room temperature for 18 hours. The solution are condensed under reduced pressure to obtain (of 0.182 g). MS (ESI) m/z 380,4 [M+1]+.

B. 1-(Cyclohexylmethyl)-6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Hydrochloride ethyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (of 0.182 g, to 0.480 mmol), acetic hydrazide (0,142 g, 1.92 mmol) and methanol (4 ml) was subjected to interaction in accordance with the General Procedure F. the Solution are condensed under reduced pressure and the product was purified PR is using chromatography on silica gel Biotage (0-80% ethyl acetate in hexane). The fractions containing the product were concentrated to obtain (0,488 g, 37% yield).1H NMR (400 MHz, CD3OD) δ of 8.47 (s, 1H) 8,13 (DD, J=18,4, 8,4, 4H), a 3.87 (d, J=7,2, 2H), 2,50 (s, 3H), 2,02 (m, 1H), 1,75 (m, 5H), of 1.29 (m, 5H); MS (ES)m/z390,5 [M+1]+; TPL 315-318°C.

5.1.119 EXAMPLE 119: SYNTHESIS of 6-(4-(1H-PYRAZOLE-3-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 3-(4-(Tributylstannyl)phenyl)-1H-pyrazole.

A solution of 3-(4-bromophenyl)-1H-pyrazole (0.50 g, 2,24 mmol) in anhydrous toluene (15 ml) were processed using hexamethyldisilane (0.88 g, 2.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (255 mg, 0.22 mmol) in a sealed tube at 110°C for 2.5 hours. Volatiles were removed under reduced pressure and the crude product was purified using Biotage chromatography (0-35% ethyl acetate in hexane) to give the desired product (420 mg, 76%). MS (ESI) m/z 307,2 [M+1]+.

B. 6-(4-(1H-Pyrazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (250 mg, 0.81 mmol), 3-(4-(tributylstannyl)phenyl)-1H-pyrazole (212 mg, of 0.68 mmol), dichlorobis(triphenylphosphine)palladium(II) (57 mg, of 0.081 mmol) in DMF (10 ml) was subjected to interaction for 1.5 hours at 110°C. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, the OST is OK took for acquisitions in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (28 mg, 11% yield) as a colorless solid. 1 N. NMR (400 MHz, CD3OD) δ to 8.41 (s, 1H), 8,00 (m, 4H), of 7.69 (d, J=8,4, 2H), 3,85 (d, J=7,2, 2H), 2,02 (m, 1H), 1,74 (m, 4H), to 1.67 (m, 1H), 1,25 (m, 3H), of 1.13 (m, 2H); MS (ESI)m/z375,1 [M+1]+; TPL 292-294°C.

5.1.120 EXAMPLE 120: SYNTHESIS of 6-(4-(1H-PYRAZOLE-4-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 4-(4-(Tributylstannyl)phenyl)-1H-pyrazole.

A solution of 4-(4-bromophenyl)-1H-pyrazole (1.0 g, 4,48 mmol) in anhydrous toluene (20 ml) were processed using hexamethyldisilane (1.8 g, 5,38 mmol) and tetrakis(triphenylphosphine)palladium(0) (510 mg, 0.44 mmol) in a sealed tube at 110°C for 2.5 hours. Volatiles were removed under reduced pressure and the crude product was purified using Biotage chromatography (0-35% ethyl acetate in hexane) to give the desired product (940 mg, 76%). MS (ESI) m/z 307,2 [M+1]+.

B. 6-(4-(1H-Pyrazole-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (250 mg, 0.81 mmol), 4-(4-(tributylstannyl)phenyl)-1H-pyrazole (212 mg, of 0.68 mmol), dichlorobis(triphenylphosphine)palladium(II) (57 mg, of 0.081 mmol) in DMF (10 ml) was subjected entries batch is Yu for 1.5 hours at 110°C. The product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (28 mg, 1 1% yield) as a colorless solid. 1 N. NMR (400 MHz, CD3OD) δ 8,98 (s, 1H), to 8.70 (s, 1H), of 8.06 (m, 2H), to $ 7.91 (m, 2H), 7,71 (s, 1H), 6.73 x (s, 1H), 3,86 (d, J=7,2, 2H), 2,03 (m, 1H), about 1.75 (m, 4H), to 1.67 (m, 1H), 1,25 (m, 3H), of 1.13 (m, 2H); MS (ESI)m/z375,1 [M+1]+; TPL 305-307°C.

5.1.121 EXAMPLE 121: SYNTHESIS of 6-(4-(5-(AMINOMETHYL)-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl (3-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)-1H-1,2,4-triazole-5-yl)methylcarbamate.

Hydrochloride ethyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (see Example 118.A) (0,196 g, 0,517 mmol) and boc-glycerides (0,392 g 2,07 mmol) (0,392 g 2,07 mmol) and methanol (4 ml) was subjected to interaction in accordance with the General Procedure F. the Solution are condensed under reduced pressure and the product was purified using chromatography on a Biotage silica gel (0-20% methanol in dichloro ethane). The fractions containing the product were concentrated to obtain (0,099 g, 39% yield). MS (ESI) m/z 505,5 [M+1]+.

B. Hydrochloride 6-(4-(5-(aminomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

tert-Butyl (3-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)-1H-1,2,4-triazole-5-yl)methylcarbamate (0,099 g, 0,196 mmol) and 4.0 M of hydrogen chloride in dioxane (5 ml) was stirred at 25°C for 90 minutes. The solution are condensed under reduced pressure to obtain (0,071 g, 90% yield) cleaners containing hydrochloride salt. 1 N. NMR (400 MHz, CD3OD) δ 8,51 (s, 1H) 8,21 (d, J=8,8,4H), 8,10 (d, J=8,8, 2H), or 4.31 (s, 2H), 3,86 (d, J=7,2, 2H), 2,02 (m, 1H), 1,75 (m, 5H), of 1.28 (m, 5H); MS (ESI)m/zto 405.5 [M+1]+; TPL 326-329°C.

5.1.122 EXAMPLE 122: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(4-(5-(TRIFLUOROMETHYL)-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(4-(5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Hydrochloride ethyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (see Example 118.A) (0,196 g, 0,517 mmol), triperoxonane hydrazine (0,265 g 2,07 mmol) and methanol (4 ml) was subjected to interaction in accordance with the General Procedure F. the Solution are condensed under reduced pressure and the product was purified using reverse-phase preparative HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Fraction, the content is the following product neutralized with ammonium hydroxide, are condensed and recrystallized from methylsulfoxide and water getting is 0.019 g, 8% yield). 1 N. NMR (400 MHz, CD3OD) δ charged 8.52 (s, 1H) 8,21 (d, J=8,4, 2H), 8,10 (d, J=8,4, 2H), a 3.87 (d, J=7,2, 2H), 2,02 (m, 1H), 1,76 (m, 5H), 1.26 in (m, 5H); MS (ESI)m/z444,7 [M+1]+; TPL 303-305°C.

5.1.123 EXAMPLE 123: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((1R,4R)-4-METHOXYCYCLOHEXYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl (1R,4R)-4-hydroxycyclohexanecarboxylate.

(1R,4R)-4-Aminocyclohexanol (2.9 g, 25 mmol) was stirred in 2-propanol (30 ml). Was added di-tert-BUTYLCARBAMATE (1 1 g, 50 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated and the product was purified on a column of silica gel (0-10% ethyl acetate in methanol) to obtain white solid (4.5 g, 83% yield).

B. (1R,4R)-4-Methoxycyclohexanone hydrochloride.

tert-Butyl (1R,4R)-4-hydroxycyclohexanecarboxylate (4.5 g, 21 mmol) was dissolved in tetrahydrofuran (100 ml) followed by addition of 15-crown-5 (4,4 ml, 22 mmol) and 95% solution of sodium hydride (0.75 g, 31 mmol). Added logmean (1.3 ml, 21 mmol) and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid substances is about was purified by chromatography on silica gel (0-100% ethyl acetate in hexane) to give the methylated product as a solid. The solid was treated with a 4 n solution of hydrogen chloride in dioxane for 2 hours. The solvent was removed under reduced pressure and the residue was ground into powder with simple ether to obtain a solid (2.5 g, 65% yield from the two stages).

C. 6-Bromo-N2-((1R,4R)-4-methoxycyclohexyl)pyrazin-2,3-diamine.

3,5-Dibromopyridin-2-amine (253 mg, 1 mmol), hydrochloride, (1R,4R)-4-methoxycyclohexanone (165 mg, 1 mmol), diisopropylethylamine (0.5 ml) and n-butanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 2 hours. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (210 mg, 70% yield). MS (ESI) m/z 303,3 [M+1]+.

D. 6-Bromo-1-((1R,4R)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he

6-bromo-N2-((1R,4R)-4-methoxycyclohexyl)pyrazin-2,3-diamine (210 mg, 0.7 mmol), 1,1'-carbonyldiimidazole (340 mg, 2 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 1 hour. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (130 mg, 57% yield). MS (ESI) m/z 327,0 [M+1]+.

E. 6-(4-Hydroxyphenyl)-1-((1R,4R)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-((1R,4R)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (130 mg, 0.4 mmol),4-hydroxyphenylarsonic acid (55 mg, 0.44 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (15 mg, 0.02 mmol), 1M sodium carbonate (1 ml, 0.8 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layers were combined, concentrated and then purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (70 mg, 52% yield).1H NMR (400 MHz, DMSO-d6) δ 11,92 (s, 1H), to 9.70 (s, 1H), 8,35 (s, 1H), a 7.85 (d, J=8,6, 2H), 6,85-6,89 (m, 2H), 4.26 deaths (t, J=12,3, 1H), 3,23-of 3.32 (m, 5H), 2,35 is 2.46 (m, 2H), 2,15 (d, J=11,7, 2H), 1,82 (d, J=11,3, 2H), 1,24-of 1.35 (m, 2H); MS (ESI)m/z341,0 [M+1]+; TPL 288-290°C

5.1.124 EXAMPLE 124: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((TETRAHYDROFURAN-2-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-Hydroxyphenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(6-Bromo-5-(N,N-bis-boc-amino)pyrazin-2-yl)phenol (see Example 46.F) (466 mg, 1 mmol), (tetrahydrofuran-2-yl)methanamine (1 g, 10 mmol) and n-butanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 4 hours. The reaction mixture was purified using reversed-f the new prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (98 mg, 32% yield).1H NMR (400 MHz, DMSO-d6) δ 11,95 (s, 1H), to 9.70 (s, 1H), of 8.37 (s, 1H), 7,83-7,88 (m, 2H), 6,84-of 6.90 (m, 2H), 4,29 is 4.36 (m, 1H), 3,94 (DD, J=14,1, 7,4, 1H), of 3.77-a-3.84 (m, 2H), 3,60-3,66 (m, 1H), 1,88 of 1.99 (m, 2H), 1,79-to 1.87 (m, 1H), 1,68-of 1.78 (m, 1H); MS (ESI)m/z313,1 [M+1]+; TPL 256-258°C.

5.1.125 EXAMPLE 125: SYNTHESIS of 6-(3-(1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

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

In a sealed tube, a solution of 3-bromobenzaldehyde (1.0 g, 5.0 mmol) was treated with dimethylphenylpiperazinium (5 ml) at 100°C for 6 hours. After the reaction was completed, the volatiles were removed under reduced pressure. The crude product was treated with hydrazine (2 ml) and acetic acid (10 drops) at room temperature for 1 hour. Volatiles were removed under reduced pressure. The crude product was dried in high vacuum and used without further purification in the next stage. MS (ESI) m/z 226,1 [M+1]+.

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

A solution of 3-(3-bromophenyl)-1H-1,2,4-triazole (0.5 g, 2.25 mmol) in anhydrous toluene (20 ml) were processed using hexamethyldisilane (0.88 g, 2,70 mmol) and tetrakis(triphenylphosphine)palladium(0) (255 mg, 0.22 mmol) in hermit is a rule a sealed tube at 110°C for 2.5 hours. Volatiles were removed under reduced pressure and the crude product was purified using Biotage chromatography (0-50% ethyl acetate in hexane) to give the desired stannane (200 mg, 29%). MS (ESI) m/z 310,3[M+1]+.

C. 6-(3-(1H-1,2,4-Triazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (253 mg, 0.81 mmol), 3-(3-(tributylstannyl)phenyl)-1H-1,2,4-triazole (300 mg, 0.97 mmol), dichlorobis(triphenylphosphine)palladium(II) (57 mg, of 0.081 mmol) in DMF (10 ml) was subjected to interaction for 1.5 hours at 110°C. the Product was purified using reversed-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the residue was taken for absorption in DMSO (2 ml) and heated at 100°C until complete dissolution. After cooling, was added water and the desired product was besieged from the solution. The precipitate was collected through filtration under vacuum, washed with water and dried in high vacuum to obtain specified in the title compound (11 mg, 11% yield) as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 12,09 (s, 1H), 8,64 (s, 1H), 8,51 (s, 1H), 8,04 (m, 3H),7,60 (m, 1H, in), 3.75 (d, J=6,8, 2H),of 1.93 (m, 1H), 1,68 (m, 3H), of 1.59 (m, 2H), 1,18 (m, 3H), of 1.07(m, 2H); MS (ESI)m/z376,2 [M+1]+; TPL 305-307°C.

5.1.126 EXAMPLE 126: SYNTHESIS of 1-((1R,4R)-4-(HYDROXYMETHYL)CYCLOHEXYL)-6-(4-HYDROXYPHENYL)-H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (1R,4R)-4-(tert-Butoxycarbonylamino)-cyclohexanecarbonyl acid

(1R,4R)-4-Aminocyclohexanecarboxylic acid (2 g, 14 mmol) were placed in THF (30 ml). Was added an aqueous solution of sodium hydroxide (14 ml, 1M) followed by addition of di-tert-BUTYLCARBAMATE (6.7 g, 31 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate, the aqueous layer was acidified to pH 4 using 1 n hydrochloric acid and was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The resulting material was ground into powder with hexane to obtain specified in the title compound as a white solid (1.2 g, 35% yield).1H NMR (300 MHz, DMSO-d6) δ 6,72 (d, J=8,1, 1H), 3,13 (m, 1H), 2.06 to (m, 1H), of 1.84 (m, 4H), to 1.37 (s, 9H), of 1.33 (m, 2H)and 1.15 (m, 2H).

B. tert-Butyl (1R,4R)-4-(hydroxymethyl)cyclohexylcarbamate

A solution of (1R,4R)-4-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid (1.2 g, 4.9 mmol), isobutylparaben (0,65 ml, 4.9 mmol) and N-methylmorpholine (1.6 ml, 15 mmol) in anhydrous tetrahydrofuran (10 ml) was stirred at room temperature under nitrogen atmosphere for 30 minutes. Added borohydride sodium (0.56 g, 15 mmol) in small portions and the mixture was stirred for another 30 minutes. The reaction was suppressed methanol and processing ivali water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain specified in the connection header in the form of oil (of 1.05 g, 95% yield).1H NMR (400 MHz, MSO-d6) δ 6,72 (d, J=8,1, 1H),4,36 (m, 1H), 3,18 (m, 2H), 3,12 (m, 1H), 1,72 (m, 4H), 1,1 (m, 2H), and 0.9 (m, 2H).

C. Hydrochloride ((1R,4R)-4-aminocyclohexane)methanol

tert-Butyl (1R,4R)-4-(hydroxymethyl)cyclohexylcarbamate (0.33 g, 1,45 mmol) were placed in 1,4-dioxane (4 ml) and the solution was added 1M hydrochloric acid in 1,4-dioxane (1 ml). The reaction mixture was stirred over night. The solvent was removed, the residue was treated with ethyl acetate, filtered and dried to obtain specified in the title compound as a solid (0,13 g, 56% yield).1H NMR (400 MHz, DMSO-d6) δ 7,81 (Sirs, 3,2 (m, 2H), 2,89 (m, 1H), 1,92 (m, 2H), of 1.75 (m, 2H), 1.27mm (m, 3H), of 0.93 (m, 2H).

D. ((1R,4R)-4-(3-Amino-6-bromopyrazine-2-ylamino)cyclohexyl)methanol.

2-Amino-3,5-dibromopyrazine (0.3 g, 1.2 mmol), hydrochloride ((1R,4R)-4-aminocyclohexane)methanol (0,22 g of 1.33 mmol) and diisopropylethylamine (0.51 g, 4 mmol) was subjected to interaction in accordance with the General Procedure A and purified using chromatography on silica gel (30-100% ethyl acetate in hexane) to obtain specified in the connection header (0,19 g, 47.7% of output). MS (ESI) m/z 301 [M+1]+.

E. ((1R,4R)-4-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexyl)methyl-1H-imidazol-1-carbox the lat.

((1R,4R)-4-(3-Amino-6-bromopyrazine-2-ylamino) cyclohexyl)methanol (0,19 g to 0.63 mmol) and 1,1'-carbonyldiimidazole (0,13 g of 0.79 mmol) was subjected to interaction in tetrahydrofuran in accordance with the General Procedure Dl and was purified using chromatography on silica gel (50-100% ethyl acetate in hexane) to obtain the specified title compound (0.2 g, 75% yield). MS (ESI) m/z 421 [M+1]+.

F. 1-((1R,4R)-4-(Hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

((1R,4R)-4-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexyl)methyl 1H-imidazole-1-carboxylate (0.2 g, 0.47 mmol), 4-hydroxybenzophenone acid (0,065 g, 0.47 mmol), 4-hydroxybutanone acid (0,065 g, 0.47 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0,038 g 0,047 mmol) and sodium carbonate (0.25 g, 2,35 mmol) were combined in 1,4-dioxane (6 ml) and water (2 ml) and heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 20 minutes. The product was purified using reverse-phase prepreparation HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and triturated to powder with ethyl ether to obtain not quite white solid (22,4 mg, 14% yield).1H NMR (400 MHz, DMSO-d6) δ 11,90 (s, 1H), RS 9.69 (s, 1H), 8,35 (s, 1H), a 7.85 (d, J=8,8, 2H), 6.87 in (d, J=8,8, 2H), 4,48 (t, J=5,0, 1H), 4,21 (t, J=12, 1H), or 3.28 (t, J=6,2H), 2,39 (who, 2H), 1,89 (d, J=12,2H), 1,81 (d, J=12, 2H), 1,47 (m, 1H), 1,08 (m, 2H); MS (ESI)m/z341,3 [M+1]+; TPL 324-326°C.

5.1.127 EXAMPLE 127: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((1S,4S)-4-METHOXYCYCLOHEXYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl (1S,4S)-4-hydroxycyclohexanecarboxylate.

Hydrochloride, (1S,4S)-4-aminocyclohexanol (4 g, 26 mmol) was stirred in a solution of 1M sodium hydroxide (26 ml, 26 mmol) and 2-propanol (30 ml). Was added di-tert-BUTYLCARBAMATE (7 g, 32 mmol) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain a white solid (4.3 g, 77% yield).

B. Hydrochloride (1S,4S)-4-methoxycyclohexanone.

tert-Butyl (1S,4S)-4-hydroxy-cyclohexylcarbamate (3.8 g, 17.6 mmol) was dissolved in tetrahydrofuran (50 ml) followed by addition of 15-crown-5 (0.35 ml, 2 mmol) and 95% solution of sodium hydride (850 mg, 17 mmol). Added logmean (1.2 ml, 19 mmol) and the reaction mixture was stirred for 6 hours at room temperature. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified by chromatography on silica gel (0-20% ethyl acetate in hexane) to give the methylated product in the form of oil. The solid is first substance was treated with 4 N. a solution of hydrogen chloride in dioxane for 2 hours. The solvent was removed under reduced pressure and the residue was ground into powder with simple ether to obtain a solid (2.3 g, 79% yield from 2 stages).

C. 6-Bromo-N2-((1S,4S)-4-methoxycyclohexyl)pyrazin-2,3-diamine.

3,5-Dibromopyridin-2-amine (253 mg, 1 mmol), hydrochloride, (1S,4S)-4-methoxycyclohexanone (200 mg, 1.2 mmol), diisopropylethylamine (0.5 ml) and n-butanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 2 hours. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (110 mg, 36% yield). MS (ESI) m/z 301,0 [M+1]+.

D. 6-Bromo-1-((1S,4S)-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-N2-((1S,4S)-4-methoxycyclohexyl)pyrazin-2,3-diamine (110 mg, 0.36 mmol), 1,1'-carbonyldiimidazole (178 mg, 1.1 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 1 hour. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (75 mg, 63% yield). MS (ESI) m/z 327,0 [M+1]+.

E. 6-(4-Hydroxyphenyl)-1-((1S,4S)-4-methoxycyclohexyl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he.

6-Bromo-1-((1S,4S)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (75 mg, 0.22 mmol), 4-hydroxyphenylarsonic acid (35 mg, 0.25 IMO the b) dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (8 mg, 0.01 mmol), 1M sodium carbonate (0.6 ml, 0.8 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layer was concentrated and the resulting material was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and the resulting residue was ground into powder with simple ether to obtain a white solid (70 mg, 52% yield).1H NMR (400 MHz, DMSO-d6) δ 11,88 (s, 1H), to 9.70 (s, 1H), at 8.36 (s, 1H), 7,89 (d, J=9,0, 2H), 6,86 (d, J=8,6, 2H), 4,24-4,32 (m, 1H), 3,47 (s, 1H), 3,30 (s, 3H), 2,60-of 2.72 (m, 2H), 2,03 (d, J=12,9, 2H), 1,47-of 1.57 (m, 4H); MS (ESI)m/z341,0 [M+1]+; TPL 256-258°C

5.1.128 EXAMPLE 128: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((1R,4R)-4-(METHOXYMETHYL)CYCLOHEXYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl (1R,4R)-4-(methoxymethyl)cyclohexylcarbamate.

Sodium hydride (by 0.055 g, to 2.29 mmol, 60% wt. suspension in mineral oil) was washed three times with hexane (10 ml portions) and suspended in anhydrous tetrahydrofuran (8 ml). The mixture was cooled to 0°C in nitrogen atmosphere. Added tert-butyl (1R,4R)-4-(hydroxymethyl)cyclohexylcarbamate (see PR the measures 126.B) (0.35 g, 1.53 mmol) and 15-crown-5 (0,354 g, 1.6 mmol) and the mixture was left for stirring for 30 minutes at 0°C. was Added dropwise methyliodide (0,227 g, 1.6 mmol) and stirred at 0°C for 30 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The excess hydride was suppressed by slow addition of water and the mixture was extracted with ethyl acetate. The organic layers were combined and concentrated. The resulting material was purified using chromatography on silica gel (25-70% ethyl acetate in hexane) to obtain the specified title compound (0.31 g, 83% yield). MS (ESI) m/z to 244.1 [M+1]+.

B. Hydrochloride (1R,4R)-4-(methoxymethyl)cyclohexanamine.

tert-Butyl (1R,4R)-4-(methoxymethyl)cyclohexylcarbamate (0.31 g, of 1.27 mmol) was treated with 1 n HCl solution in 1,4-dioxane (4 ml) and stirred at room temperature overnight. The solvent was removed and the residue was dried in high vacuum to obtain specified in the title compound as a white solid (0.21 g, 92% yield). MS (ESI) m/z 144,3 [M+1]+.

C. 6-Bromo-N2-((1R,4R)-4-(methoxymethyl)cyclohexyl)pyrazin-2,3-diamine.

2-Amino-3,5-dibromopyrazine (MX 0.317 g, 1.25 mmol), hydrochloride, (1R,4R)-4-(methoxymethyl)cyclohexanamine (0.21 g, of 1.16 mmol) and diisopropylethylamine (0.45 g, 3.5 mmol) was subjected to interaction in accordance with the General Procedure AI was purified using chromatography on silica gel (30-100% ethyl acetate in hexane) to obtain the specified title compound (0.15 g, 41% yield). MS (ESI) m/z 315 [M+1]+.

D. 4-(5-Amino-6-((1R,4R)-4-(methoxymethyl)-cyclohexylamino)pyrazin-2-yl)phenol

6-Bromo-N2-((1R,4R)-4-(methoxymethyl)cyclohexyl)pyrazin-2,3-diamine (0.15 g, 0.47 mmol), 4-hydroxybenzophenone acid (0,065 g, 0.47 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0.04 g, 0,047 mmol) and sodium carbonate (0.25 g of 2.38 mmol) were combined in 1,4-dioxane (3 ml) and water (2 ml) and heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 20 minutes. The resulting material was purified using chromatography on silica gel (10% hexane in ethyl acetate) to obtain the specified title compound (0.15 g, 96% yield). MS (ESI) m/z 329 [M+1]+.

E. 6-(4-Hydroxyphenyl)-1-((1R,4R)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 4-(5-amino-6-((1R,4R)-4-(methoxymethyl)cyclo-hexylamino)pyrazin-2-yl)phenol (0.15 g, 0.45 mmol) and urea (to 0.055 g of 0.91 mmol) in dimethylformamide (2 ml) was subjected to interaction in accordance with the General Procedure D2. The solvent was removed and the residue was purified using chromatography on silica gel (30% hexane in ethyl acetate)and then by reversed-phase prepreparation HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and washed with water to obtain specified in the connection header (0,033 g, 20% of you who ar). 1H NMR (400 MHz, DMSO-d6) δ 11,90 (s, 1H), RS 9.69 (s, 1H), 8,35 (s, 1H),a 7.85 (d, J=8,4, 2H), 6.87 in (d, J=8,4, 2H), 4,21 (m, 1H), 3,26 (s, 3H), 3,2 (d, J=6, 2H), is 2.37 (m, 2H), of 1.84 (m, 4H), of 1.65 (m, 1H), 1,13 (m, 2H); MS (ESI)m/z355,3 [M+1]+; TPL 300-303°C.

5.1.129 EXAMPLE 129: SYNTHESIS of 6-(1-METHYL-1H-PYRAZOLE-4-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(1-Methyl-1H-pyrazole-4-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (0.2 g, was 0.63 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.16 g, from 0.76 mmol), dichloro[1,1'-bis(diphenyl-phosphino)ferrocene]palladium(II) in the form adduct with dichloromethane (0.05 g, 0,063 mmol) and potassium phosphate (of 0.53 g, 2.5 mmol) were combined in dimethylformamide (5 ml) and water (1 ml) in a sealed tube and subjected to interaction in accordance with the General Procedure B. the Reaction solution was concentrated and purified by chromatography on silica gel (ethyl acetate)and then by reversed-phase prepreparation HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min) to obtain specified in the connection header (0,018 g, 9% yield).1H NMR (400 MHz, DMSO-d6) δ 11,89 (s, 1H), they were 8.22 (s, 2H), of 7.96 (s, 1H), with 3.89 (s, 3H), 3,82 (d, 2H), of 3.73 (d, J=7,2H), 3,25 (t, J=8, 2H), 2,12 (m, 1H), 1.55V (d, 2H), 1,3 (m, 2H); MS (ESI)m/z315,3 [M+1]+; TPL 224-226°C.

5.1.130 EXAMPLE 130: SYNTHESIS of 1-(((1R,4R)-4-HYDROXYCYCLOHEXYL)METHYL)-6-(4-HYDRO IS SETENIL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (1R,4R)-4-Hydroxycyclohexanecarboxylate.

(1R,4R)-4-Hydroxycyclohexanecarboxylate acid (5.4 g, 38 mmol), ammonium chloride (2.2 g, 41 mmol), hexaflurophosphate O-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (15.6 g, 41 mmol), triethylamine (16 ml, 113 mmol) and acetonitrile (80 ml) was stirred together at room temperature for 16 hours. The reaction mixture was filtered and washed with acetonitrile. The filtrate was concentrated and triturated to powder with ethyl acetate to obtain a white solid (3.7 g, 69% yield). MS (ESI) m/z 144,1 [M+1]+.

B. Hydrochloride (1R,4R)-4-(aminomethyl)cyclohexanol.

(1R,4R)-4-Hydroxycyclohexanecarboxylate (1.4 g, 10 mmol) was dissolved in tetrahydrofuran (15 ml). Added complex harbored·metilsulfate (2.1 ml, 20 mmol) and the reaction mixture was heated to boiling point under reflux in nitrogen atmosphere for 16 hours. The reaction was suppressed by slow addition of methanol. To the reaction mixture was added a 4 n solution of hydrogen chloride in dioxane (5 ml) and the solution was concentrated. The residue was ground into powder with 10% methanol in ethyl acetate to obtain, after filtration of the white solid (1.2 g, 75% yield). MS (ESI) m/z 303,3 [M+1]+.

C. (1R,4R)-4-((3-Amino-6-bromopyrazine-2-ylamino)methyl)cyclohexanol

3,5-dibromo-pyrazin-2-amine (253 mg, 1 mmol), hydrochloride, (1R,4R)-4-(aminomethyl)cyclohexanol (200 mg, 1.2 m is ol), diisopropylethylamine (1 ml) and n-butanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 2 hours. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (138 mg, 46% yield). MS (ESI) m/z 303,3 [M+1]+.

D. 6-Bromo-1-(((1R,4R)-4-hydroxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he

(1R,4R)-4-((3-Amino-6-bromopyrazine-2-ylamino)methyl)cyclohexanol (138 mg, 0.45 mmol), 1,1'-carbonyldiimidazole (223 mg, 1.4 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 1 hour. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (125 mg, 83% yield). MS (ESI) m/z 311,3 [M+1]+.

E. 1-(((1R,4R)-4-Hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(((1R,4R)-4-hydroxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (125 mg, 0.4 mmol), 4-hydroxyphenylarsonic acid (61 mg, 0.44 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (15 mg, 0.02 mmol), 1M sodium carbonate (1 ml, 0.8 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. the content of inorganic fillers layer was concentrated and the resulting material was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (53 mg, 35% yield).1H NMR (400 MHz, DMSO-d6) δ 11,91 (s, 1H), RS 9.69 (s, 1H), 8,35 (s, 1H), 7,82-7,86 (m, 2H), 6,85-6,89 (m, 2H), 4,49 (d, J=4,3, 1H), 3,70 (d, J=7,0,2H), 1,80 (s, 3H), of 1.66 (s, 2H), with 1.07 (t, J=10,3, 4H); MS (ESI)m/z341,5 [M+1]+; TPL 332-334°C.

EXAMPLE 131: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((TETRAHYDROFURAN-3-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. Hydrochloride (tetrahydrofuran-3-yl)methanamine.

A solution of tetrahydrofuran-3-carboxaldehyde (50% wt. in water, 5 ml, 25 mmol), ammonium chloride (13 g, 25 mmol), Raney Nickel (slurry 2 ml) in methanol was subjected to interaction in the Parr apparatus for shaking under hydrogen pressure of 40 psi (2,812 kg/cm2) for 16 hours at room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain oil. To the obtained oil was added dioxane (50 ml), 1M sodium hydroxide solution (50 ml) and di-tert-BUTYLCARBAMATE (5.5 g, 25 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain oil. The resulting oil was purified on a column of silica gel (0-20% ethyl acetate in hexane) Poluchenie transparent oil. The obtained oil was treated with 4 N. a solution of hydrogen chloride in dioxane. The solution was concentrated and triturated to powder with simple ether to obtain a white solid (0.33 g, 10% yield). MS (ESI) m/z 101,9 [M+1]+.

B. 6-Bromo-N2-((tetrahydrofuran-3-yl)methyl)pyrazin-2,3-diamine.

3,5-Dibromopyridin-2-amine (253 mg, 1 mmol), hydrochloride (tetrahydrofuran-3-yl)methanamine (0.33 g, 2.4 mmol), diisopropylethylamine (0.5 ml) and n-butanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 2 hours. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (140 mg, 51% yield). MS (ESI) m/z 303,3 [M+1]+.

C. 6-Bromo-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-N2-((tetrahydrofuran-3-yl)methyl)pyrazin-2,3-diamine (140 mg, 0.5 mmol), 1,1'-carbonyldiimidazole (250 mg, 1.5 mmol) and dioxane (5 ml) was heated to boiling point under reflux for 3 hours. The reaction mixture was purified on a column of silica gel (0-100% ethyl acetate in hexane) to give white solid (90 mg, 60% yield). MS (ESI) m/z 299,0 [M+1]+.

D. 6-(4-Hydroxyphenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (90 mg, 0.3 mmol), 4-hydroxyphenylarsonic acid (50 mg, 0,mol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (11 mg, of 0.017 mmol), 1M sodium carbonate (1 ml, 0.8 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (60 mg, 64% yield).1H NMR (400 MHz, DMSO-d6) δ 11,96 (s, 1H), to 9.70 (s, 1H), of 8.37 (s, 1H), a 7.85 (d, J=9,0, 2H), 6.87 in (d, J=8,6, 2H), 3,86 (d, J=7,4, 2H), 3,80 (TD, J=8,1, 5,7, 1H), 3,65-3,71 (m, 1H), 3,57-to 3.64 (m, 2H), 2.77-to of 2.86 (m, 1H), 1,92 is 2.01 (m, 1H), 1,66-of 1.74 (m, 1H); MS (ESI)m/z313,5 [M+1]+; TPL 256-258°C.

5.1.132 EXAMPLE 132: SYNTHESIS of 1-(((1S,4S)4-HYDROXYCYCLOHEXYL)METHYL)-6-(4-HYDROXYPHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (1S,4S)-4-Hydroxycyclohexanecarboxylate.

(1S,4S)-4-Hydroxycyclohexanecarboxylate acid (5.4 g, 38 mmol), ammonium chloride (2.2 g, 41 mmol), O-(benzotriazol-1-yl)-N) hexaphosphate N,N,N',N'-tetramethylurea (15.6 g, 41 mmol), triethylamine (16 ml, 113 mmol) and acetonitrile (80 ml) was stirred together at room temperature for 16 hours. Reactionary see the camping was filtered and washed with acetonitrile. The filtrate was concentrated and then triturated to powder with ethyl acetate to obtain a white solid (2.1 g, 39% yield). MS (ESI) m/z 144,1 [M+1]+.

B. Hydrochloride (1S,4S)-4-(aminomethyl)cyclohexanol.

(1S,4S)-4-Hydroxycyclohexanecarboxylate (1.4 g, 10 mmol) was dissolved in tetrahydrofuran (15 ml). Added complex harbored·metilsulfate (2.1 ml, 20 mmol) and the reaction mixture was heated to boiling point under reflux in nitrogen atmosphere for 16 hours. The reaction was suppressed by slow addition of methanol. To the reaction mixture was added a 4 n solution of hydrogen chloride in dioxane (5 ml) and the solution was concentrated. The residue was ground into powder with 10% methanol in ethyl acetate to obtain, after filtration of the white solid (0.2 g, 10% yield). MS (ESI) m/z to 130.1 [M+1]+.

C. (1S,4S)-4-((3-Amino-6-bromopyrazine-2-ylamino)methyl)cyclohexanol

3,5-Dibromopyridin-2-amine (253 mg, 1 mmol), hydrochloride, (1S,4S)-4-(aminomethyl)cyclohexanol (200 mg, 1.2 mmol), diisopropylethylamine (1 ml) and n-butanol (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 2 hours. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (135 mg, 45% yield). MS (ESI) m/z 303,3 [M+1]+.

D. 6-Bromo-1-(((1S,4S)-4-hydroxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

(1S,4S-4-((3-Amino-6-bromopyrazine-2-ylamino)methyl) cyclohexanol (135 mg, 0.45 mmol), 1,1'-carbonyldiimidazole (218 mg, 1.3 mmol) and dioxane (3 ml) was heated in a microwave reactor Biotage Emrys Optimizer) at 200°C for 1 hour. The reaction mixture was purified on a column of silica gel (0-10% methanol in ethyl acetate) to give a reddish brown solid (80 mg, 44% yield). MS (ESI) m/z 311,3 [M+1]+.

E. 1-(((1S,4S)-4-Hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he.

6-Bromo-1-(((1S,4S)-4-hydroxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (80 mg, 0.2 mmol), 4-hydroxyphenylarsonic acid (33 mg, 0.24 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (7 mg, 0.02 mmol), 1M sodium carbonate (0.6 ml, 0.8 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (25 mg, 37% yield).1H NMR (400 MHz, DMSO-d6) δ 11,92 (s, 1H), to 9.70 (s, 1H), 8,35 (s, 1H), a 7.85 (d, J=8,6,2H), 6.87 in (d, J=8,6,2H), 4,34 (d, J=3,5, 1H, in), 3.75 (d, J=7,0,214), 3,71 (s, 1H), 1,95 (s, 1H),1.56 to of 1.66 (m, 2H), 1,34 of 1.46 (m, 6H); MS (ESI)m/z341,8 [M+1]+; TPL 314-316°C.

5.1.133 EXAMPLE 133: SYNTHESIS of 6-(1H-BENZO[D]IMIDAZOL-5-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 5-bromo-1H-benzo[d]imidazol-2-carboxylate.

A solution of 5-bromo-1H-benzimidazole (1.06 g, 5,38 mmol), di-tert-BUTYLCARBAMATE (1.3 g, 5,91 mmol), triethylamine (0.9 ml, of 6.45 mmol) and dimethylaminopyridine (few crystals) in anhydrous tetrahydrofuran (15 ml) was left to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified using Biotage chromatography (0-55% ethyl acetate in hexane) to give the desired product (0,85 g, 54%) as a white solid. MS (ESI) m/z 297,3 [M+1]+.

B. tert-Butyl 5-(tributylstannyl)-1H-benzo[d]imidazol-2-carboxylate.

A solution of tert-butyl 5-bromo-1H-benzo[d]imidazol-2-carboxylate (500 mg, by 1.68 mmol), hexamethyldisilane (0.45 ml, 2.02 mmol), tetrakis(triphenylphosphine)palladium(0) (195 mg, 0,17 mmol) in toluene (10 ml) was heated at 100°C for 2 hours. After the reaction was completed, toluene was removed under reduced pressure and the obtained residue was purified using Biotage chromatography (0-50% ethyl acetate in hexane) to obtain the specified title compound (640 mg, 100%). MS (ESI) m/z 383,2 [M+1]+.

C. the Hydrochloride of 6-(1H-benzo[d]imidazol-5-yl)-1-((then it is carbonated the ro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

tert-Butyl 5-(tributylstannyl)-1H-benzo[d]imidazol-2-carboxylate (640 mg, 1.7 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 101. B) (420 mg, 1.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (90 mg, 0.13 mmol) in DMF (25 ml) was subjected to interaction for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops) and subjected to ultrasonic treatment. This procedure was repeated two more times to obtain 6-(1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (48 mg, 10% yield) in the form of cleaners containing hydrochloride salt.1H NMR (400 MHz, DMSO-d6) δ 12,07 (s, 1H), 8,55 (s, 1H), charged 8.52 (s, 1H), 8,33 (with,1H), of 8.06 (DD, J=8.0 a, 1,6, 1H), 7,80 (d, J=8,8, 1H), 3,81 (m, 2H), 3,80 (d, J=7,2, 2H), 3.27 to (d, J=11,6, 2H), and 2.14 (m, 1H), 1,59 (m, 2H), 1,33 (m, 2H); MS (ESI)m/z351,2 [M+1]+.

5.1.134 EXAMPLE 134: SYNTHESIS of 6-(4-(5-(MORPHOLINOMETHYL)-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 4-[2-Oxo-3-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)-4-imidazoline[4,5-e]pyrazin-5-yl]benzoporphyrin.

6-Bromo-1-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)-4-imidazoline[4,5-b]pyrazin-2-he (0,700 g, 2,24 mmol), 4-cyanoaniline acid (0,395 g, 2,69 m is ol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0,183 g, 0,224 mmol), potassium carbonate (1.90 g, 8,96 mmol), dimethylformamide (15 ml) and water (5 ml) were combined in a sealed tube and heated to 100°C for 3 hours. The solution are condensed under reduced pressure and the resulting material was distributed between water and ethyl acetate. The organic layers were collected, dried over magnesium sulfate, filtered and concentrated. The resulting residue was taken for absorption in methanol and subjected to ultrasonic treatment for 10 minutes. Was the precipitation of the product, and it was filtered to obtain specified in the connection header (0,497 g, 66%). MS (ESI) m/z 336,4 [M+1]+.

B. Ethyl 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate.

A solution of 4-[2-oxo-3-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)-3-gydromanipulator-5-yl]benzonorbornadiene (0,497 g, 1.48 mmol) in ethanol (100 ml) was cooled to 0°C and was barbotirovany through a solution of gaseous hydrogen chloride for 10 minutes. The resulting solution was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the obtained solid was used directly in the next stage in the form of cleaners containing hydrochloride salt (0,637 g, 95%,). MS (ESI) m/z 382 [M+1]+.

C.6-(4-(5-(Morpholinomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of ethyl 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (0.20 g, 0,525 mmol), 2-morpholinobutyrophenone (0,334 g, 2.1 mmol) and triethylamine (of 1.46 ml, 10.5 mmol) and methanol (4 ml) was subjected to interaction, as described in General Procedure F. the Reaction mixture was concentrated under reduced pressure and the resulting residue was taken for absorption in methylene chloride. Purification using Biotage column chromatography (0-80% ethyl acetate in hexane) gave pure product with a purity of 95.9 per cent (0.11 g, 44%).1H NMR (400 MHz, CD3OD) δ and 8.50 (s, 1H), 8,13 (m, 4H), of 3.96 (m, 4H), of 3.75 (m, 7H), of 3.43 (m, 2H), 2,58 (s, 4H), of 2.50 (m, 1H), 2,30 (m, 1H), 1,67 (m, 2H), of 1.52 (m, 2H); MS (ESI)m/z477,5 [M+1]+; TPL 281-283°C.

5.1.135 EXAMPLE 135: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(3-(2-OXOPYRROLIDIN-1-YL)PROPYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(3-(3-Amino-6-bromopyrazine-2-ylamino)propyl)pyrrolidin-2-it.

3,5-Dibromo-pyrazin-2-amine (253 mg, 1 mmol), 1-(3-aminopropyl)pyrrolidin-2-he (426 mg, 1 mmol) and n-butanol (2 ml) was stirred at 100°C in nitrogen atmosphere for 3 days. The reaction mixture was purified on a column of silica gel (0-100% ethyl acetate in hexane) to obtain the specified title compound (250 mg, 80% yield) as a white solid. MS (ESI) m/z 315,9 [M+1]+.

B. 6-Bromo-1-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(3-(3-Amino-6-bromopyrazine-2-ylamino)propyl)pyrrole the Jn-2 Oh (250 mg, 0.8 mmol), 1,1'-carbonyldiimidazole (387 mg, 2.4 mmol) and dioxane (5 ml) was heated to boiling point under reflux for 3 hours. The reaction mixture was purified on a column of silica gel (0-100% ethyl acetate in hexane) to give a clear oil. MS (ESI) m/z 342,1 [M+1]+.

C. 6-(4-Hydroxyphenyl)-1-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (119 mg, 0.35 mmol), 4-hydroxyphenylarsonic acid (53 mg, 0,39 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (13 mg, of 0.017 mmol), 1M sodium carbonate (1 ml, 0.8 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layer was concentrated and the resulting material was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and the residue was ground into powder with simple ether to obtain a white solid (69 mg, 24% yield).1H NMR (400 MHz, DMSO-d6) δ 11,93 (s, 1H), to 9.70 (s, 1H), at 8.36 (s, 1H), 7,86 (d, J=8,6, 2H), 6,86 (d, J=8,6, 2H), 3,84 (t, J=7,2, 2H), 3,35-3,39 (m, 2H), 3,25 (t, J=7,0, 2H), 2,16 (t, J=8,0, 2H), 1,94-2,02 (m, 2H), 1,86-1,3 (m, 2H); MS (ESI)m/z354,4 [M+1]+; TPL 305-306°C.

5.1.136 EXAMPLE 136: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(2-MORPHOLINOETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-N2-(2-morpholinoethyl)pyrazin-2,3-diamine.

In a sealed tube a solution of 5-bromopyrazine-2,3-diamine (5.0 g, of 19.7 mmol), 2-morpholinoethyl (5,14 g of 39.5 mmol), diisopropylethylamine (6.9 ml, to 39.5 mmol) in n-butanol (100 ml) was heated at 120°C for 17 hours. Volatiles were removed under reduced pressure. The residue was taken for absorption in hexane and diethyl ether and subjected to ultrasonic treatment. The precipitate was collected by filtration to obtain specified in the connection header (5,23 g, 88%). MS (ESI) m/z 304,2 [M+1]+.

B. 6-Bromo-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

In a sealed tube a solution of 6-bromo-N2-(2-morpholinoethyl)pyrazin-2,3-diamine (5,23 g, and 17.2 mmol), 1,1'-carbonyldiimidazole (4,2 g, 25,89 mmol) in tetrahydrofuran (50 ml) was heated at 110°C. Volatiles were removed under reduced pressure. The resulting residue was taken for absorption in hexane and diethyl ether, subjected to ultrasound treatment and the precipitate was collected by filtration, washed with hexane and dried in a vacuum oven to obtain the product (4,65 g, 82% yield) as a reddish brown solid. MS (ESI) m/z 328,2[M+1]+.

C. the Hydrochloride of 6-(4-hydroxyphenyl)-1-(2-morpholinoethyl-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

6-Bromo-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (300 mg, 0.95 mmol), [4-(N-methylaminomethyl)phenyl]Bronevoy acid (205 mg, 1.15 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (80 mg, 0.09 mmol) and potassium phosphate (805 mg, 3.8 mmol) in DMF (30 ml) and water (8 ml) was subjected to interaction in accordance with the General Procedure C. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, treated with a 4 n solution of hydrochloric acid in diethyl ether (few drops) and subjected to ultrasonic treatment. This procedure was repeated two more times to obtain 6-(4-hydroxyphenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she (67 mg, 16%) as a colourless solid cleaners containing hydrochloride salt.1H NMR (400 MHz, CD3OD-d6) δ scored 8.38 (s, 1H), 8,84 (d, J=8,4, 2H), 7,44 (s, 1H), 7,39 (d, J=8,4, 2H), 4,45 (t, J=5,6, 2H); 4,07 (d, J=12,4, 2H), 3,82 (d, J=12,4, 2H), 3,69-to 3.64 (m, 4H); MS (ESI)m/z342,15 [M+1]+.

5.1.137 EXAMPLE 137: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(4-(OXAZOL-5-YL)PHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 5-(4-Bromophenyl)oxazol.

A solution of 2,4'-dibromoacetone (2.5 g, 9.0 mmol) in formamide (40 ml) was heated in a sealed tube at 110°C for 2.5 hours. After cooling, the reaction mixture was poured into ice water, extracted with methylene chloride (2 is), was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using Biotage chromatography (0-50% ethyl acetate in hexane) to obtain the specified title compound (380 mg, 19%). MS (ESI) m/z 226,1 [M+1]+.

B. 5-(4-(Tributylstannyl)phenyl)oxazol.

A solution of 5-(4-bromophenyl)oxazole (380 mg, 1.70 mmol), hexamethyldisilane (0.45 ml, 2.02 mmol), tetrakis(triphenylphosphine)palladium(0) (195 mg, 0,17 mmol) in toluene (10 ml) was heated at 100°C for 2 hours. After the reaction was completed, toluene was removed under reduced pressure and the residue was purified using Biotage chromatography (0-50% EtOAc in hexane) to give the desired product (250 mg, 47%). MS (ESI) m/z 305,8[M+1]+.

C. 1-(Cyclohexylmethyl)-6-(4-(oxazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

5-(4-(Tributylstannyl)phenyl)oxazole (250 mg, 0.8 mmol), 6-bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (208 mg, 0.66 mmol), dichlorobis-(triphenylphosphine)palladium(II) (42 mg, 0.06 mmol) in DMF (10 ml) was subjected to interact for 2 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (10-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and treated with the help of 6 N. aqueous ammonium hydroxide solution (a few drops). Volatiles were removed under reduced pressure, the NII and the residue was taken for absorption in water (2 ml) and the solid was filtered and washed with water. The resulting solid was dried in vacuum to obtain specified in the title compound (20 mg, 8% yield).1H NMR (400 MHz, DMSO-d6) δ 12,06 (s, 1H), 8,71 (s, 1H), 8,55 (s, 1H), 8,51 (s, 1H), 8,11 (d, J=8,4, 2H), to $ 7.91 (d, J=8,4,2H), 3,74 (d, J=7,2, 2H), 1,92 (m, 1H), 1,68 (m, 3H), 1,60 (m, 2H), 1,18 (m, 3H), of 1.03 (m, 2H); MS (ESI)m/z376,2[M+1]+.

5.1.138 EXAMPLE 138: SYNTHESIS of 6-(2-METHYL-1H-BENZO[D]IMIDAZOL-5-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 6-bromo-2-methyl-1H-benzo[d]imidazol-1-carboxylate.

A solution of 6-bromo-2-methyl-1H-benzo[d]imidazole (1 g, to 4.73 mmol), di-tert-BUTYLCARBAMATE (1,09 g, to 5.21 mmol), triethylamine (0,72 ml, 5,67 mmol) and N,N-dimethylpyridin-4-amine (few crystals) in anhydrous tetrahydrofuran (15 ml) was left to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified using Biotage chromatography (0-55% ethyl acetate in hexane) to give the desired product (0,22 g, 15%) as a white solid. MS (ESI) m/z 313,2 [M+1]+.

B. tert-Butyl 2-methyl-6-(tributylstannyl)-1H-benzo[d]imidazol-1-carboxylate.

A solution of tert-butyl 6-bromo-2-methyl-1H-benzo[d]imidazol-1-carboxylate (0,22 g, 0.70 mmol), hexamethyldisilane (0,19 ml, 0.84 mmol), tetrakis(triphenylphosphine)palladium(0) (of 0.081 g, 0.07 mmol) in toluene (10 ml) was heated at 100°C for 2 hours. After Rea the tion was completed, the toluene was removed under reduced pressure and the residue was purified using Biotage chromatography (0-50% ethyl acetate in hexane) to obtain the specified title compound (120 mg, 44%). MS (ESI) m/z 397,3[M+1]+.

C. the Hydrochloride of 6-(2-methyl-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

tert-Butyl 2-methyl-6-(tributylstannyl)-1H-benzo[d]imidazol-1-carboxylate (120 mg, 0.30 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 101. B) (96 mg, 0.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.03 mmol) in DMF (5 ml) was subjected to interaction for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (10-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and treated with a 4 n solution of hydrochloric acid in diethyl ether (few drops)was subjected to ultrasonic processing, and concentrated. This procedure was repeated two more times to obtain specified in the title compound (8 mg, 6.5% of the output).1H NMR (400 MHz, DMSO-d6) ∆ 12,12 (s, 1H), to 8.62 (s, 1H), 8,31 (s, 1H), 8,15 (d, J=8,4, 1H), 7,82 (d, J=8,4, 1H), 3,85 (m, 2H), 3,81 (d, J=8,0, 2H), 3,26 (t, J=11,2, 2H), 1,90 (m, 1H), 1,61 (m, 2H), 1,35 is 1.23 (m, 3H), 0,89-0,86 (m, 2H); MS (ESI)m/z365,1 [M+1]+.

5.1.139 EXAMPLE 139: SYNTHESIS of 6-(4-(5-(METHOXYMETHYL)-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METH IS L)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(5-(Methoxymethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of ethyl 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (see Example 134.B) (0,205 g, 0,538 mmol), 2-methoxyacetophenone (0,224 g of 2.15 mmol), triethylamine (1.5 ml, about 10.8 mmol) and methanol (4 ml) was subjected to interaction, as described in General Procedure F. the Reaction mixture was concentrated under reduced pressure and the obtained residue took for acquisitions in methylene chloride. Purification using Biotage column chromatography (0-20% methanol in dichloromethane) gave pure product to 98.6% purity (0,076 g, 34%).1H NMR (400 MHz, CD3OD) δ 8,49 (s, 1H), 8,16 (m, 4H), 4,63 (s, 2H), 3.96 points (m, 5H), 3,47 (s, 3H), 3,42 (m, 3H), 2,32 (m, 1H), 1,67 (m, 2H), of 1.52 (m, 2H); MS (ESI)m/z422,5 [M+1]+.; TPL 273-276°C.

5.1.140 EXAMPLE 140: SYNTHESIS of 1-((1S,4S)-4-(HYDROXYMETHYL)CYCLOHEXYL)-6-(4-HYDROXYPHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (1S,4S)-4-(tert-Butoxycarbonylamino)cyclohexanecarbonyl acid.

(1S,4S)-4-Amino-cyclohexanecarbonyl acid (2 g, 14 mmol) was dissolved in 1,4-dioxane (40 ml) was added di-tert-BUTYLCARBAMATE (6,1 g, 28 mmol) and sodium bicarbonate (4,06 g, 48 mmol)dissolved in water (25 ml). The mixture was stirred at room temperature overnight. Was added dropwise a saturated solution of potassium hydrosulfate to stop shedding hazaratbal was removed and the residue was taken for absorption in ethyl acetate and washed with water. The organic fractions were combined, dried over magnesium sulfate and concentrated in high vacuum to obtain specified in the title compound (3.4 g, 100% yield). MS (ESI)m/z244,4 [M+1]+.

B. tert-Butyl (1S,4S)-4-(hydroxymethyl)cyclohexylcarbamate

(1S,4S)-4-(tert-Butoxycarbonylamino)cyclohexanecarbonyl acid (3.4 g, 14 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and the solution was cooled to -10°C (ice bath/methanol). Was added N-methylmorpholine (1,41 g, 14 mmol) and isobutylparaben (1,91 g, 14 mmol) and the reaction mixture was stirred for 10 minutes. Added borohydride sodium (1,59 g, 42 mmol) in one portion, the reaction mixture was heated to 0°C and added dropwise methanol (5 ml). The reaction mixture was stirred for 30 minutes at 0°C and extinguished a saturated solution of potassium hydrosulfate (5 ml), extracted with ethyl acetate, dried over magnesium sulfate and concentrated to obtain specified in the connection header in the form of oil, which was aterials during maturation (3.2 g, 100% yield). MS (ESI) m/z 230,6 [M+1]+.

C. Hydrochloride ((1S,4S)-4-aminocyclohexane)methanol

tert-Butyl (1S,4S)-4-(hydroxymethyl)cyclohexylcarbamate (1.0 g, 4,36 mmol) were placed in 1,4-dioxane (4 ml) at room temperature was added 4 n hydrochloric acid in 1,4-dioxane (3.5 ml, of 13.1 mmol) and the resulting solution was stirred over night. R is storytell removed, the residue was treated with simple ether, subjected to ultrasound treatment and filtered. The resulting solid was dried in high vacuum to obtain specified in the title compounds as white solids (0,61 g, 84.7% of output). MS (ESI) m/z to 130.1 [M+1]+.

D. ((1S,4S)-4-(3-Amino-6-bromopyrazine-2-ylamino)cyclohexyl)methanol

2-Amino-3,5-dibromopyrazine (1,53 g, 6 mmol), hydrochloride ((1S,4S)-4-aminocyclohexane)methanol (1.0 g, 6 mmol) and diisopropylethylamine (2,32 g, 18 mmol) was dissolved in n-butanol (3 ml) and subjected to interaction in accordance with the General Procedure A. the Mixture was purified using chromatography on silica gel (30-100% ethyl acetate in hexane) to obtain specified in the connection header (0,42 g, 23% yield). MS (ESI) m/z 301,3 [M]+, 303,3 [M+2]+.

E. 4-(5-Amino-6-((1S,4S)-4-(hydroxymethyl)cyclohexylamine)pyrazin-2-yl)phenol

((1S,4S)-4-(3-Amino-6-bromopyrazine-2-ylamino)cyclohexyl)methanol (0,42 g of 1.39 mmol), 4-hydroxybenzophenone acid (0,192 g of 1.39 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0,113 g, 0,139 mmol) and sodium carbonate (0.74 g, 6,97 mmol) was subjected to interaction in 1,4-dioxane (4 ml) according to General Procedure B2 and purified using chromatography on silica gel (50-100% ethyl acetate in hexane) to obtain specified in the connection header (0,175 g, 40% yield). MS (ES) m/z 315,5 [M+1] +.

F. 1-((1S,4S)-4-(Hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he

4-(5-Amino-6-((1S,4S)-4-(hydroxymethyl)cyclohexylamine)pyrazin-2-yl)phenol (0,175 g, 0,557 mmol), 1,1'-carbonyldiimidazole (0.27 g, 1,67 mmol) and tetrahydrofuran (3 ml) were combined in a sealed tube and heated to 120°C for 3 hours. The mixture was cooled, was added potassium carbonate (1 g, 7.2 mmol) in methanol (3 ml) and stirred at room temperature overnight. The product was purified using reverse-phase prepreparation HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated to obtain not quite white solid (17,0 mg, 9% yield).1H NMR (400 MHz, DMSO-d6) δ 11,9 (s, 1H), 9,71 (s, 1H), 8,35 (s, 1H), a 7.85 (d, J=8,8,2H), 6,86 (d, J=8,8,2H), 4,58 (t, J=5,6,1H), 4,23 (m, 1H), 3,64 (t, J=5,6,2H), to 1.86 (m, 2H), 1,79 (m, 2H), 1.55V (m, 4H); MS (ESI)m/z341,3[M+1]+; TPL 208-210°C.

5.1.141 EXAMPLE 141: SYNTHESIS of 6-(3-METHYL-1H-PYRAZOLE-4-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 4-bromo-3-methyl-1H-pyrazole-1-carboxylate.

4-Bromo-3-methyl-1H-pyrazole (0.3 g, of 1.86 mmol), di-tert-BUTYLCARBAMATE(0.65 g, 2,98 mmol) and sodium hydroxide (0,082 g, 2.05 mmol) were placed in 1,4-dioxane (10 ml) and stirred at room temperature overnight. The solvent was removed and the residue was treated with ethyl acetate and Phil is travali. The filtrate was concentrated to obtain specified in the connection header (0,48 g, 100% yield). MS (ESI) m/z 261,3 [M]+, 263,3 [M+2]+.

B. 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

tert-Butyl 4-bromo-3-methyl-1H-pyrazole-1-carboxylate (0,48 g of 1.84 mmol), bis(pinacolato)LIBOR (0,535 g, 2.1 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0.156 g, 0,19 mmol) and potassium acetate (0.56 g, 5.7 mmol) were placed in a tightly closed tube in DMSO (5 ml). The system was purged with nitrogen, tightly closed and heated to 90°C for 18 hours. The solvent was removed and the desired product was isolated using chromatography on silica gel (50% ethyl acetate in hexane) to obtain the specified title compound (0.2 g, 50% yield). MS (ESI) m/z 209,1 [M+1]+.

C. tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.

3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.2 g, 0.96 mmol), di-tert-BUTYLCARBAMATE (0.4 g, 1.8 mmol) and triethylamine (0.18 g, to 1.79 mmol) were placed in 1,4-dioxane (5 ml) and stirred under nitrogen atmosphere at room temperature for two days. The solvent was removed and the desired product was isolated using chromatography on silica gel (25% ethyl acetate in hexane) to obtain specified in the connection header (0,175 g, 59% yield). MS (ESI) m/z 309,4 [M+1]+.

D. 6(3-Methyl-1H-pyrazole-4-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 101. B) (0.16 g, 0.51 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0,175 g of 0.56 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0.04 g, 0.05 mmol) and potassium phosphate (0,43 g, 2.05 mmol) were combined in DMF (3 ml) and water (0.2 ml), the mixture was purged with nitrogen and heated in a sealed tube at 100°C during the night. The solvent was removed and the crude product was purified by chromatography on silica gel (100% ethyl acetate) to obtain the specified title compound as a white solid (0.036 g, 22% yield).1H NMR (400 MHz, DMSO-d6) δ 12,77 (s, 1H), 11.87 per (s, 1H), 8,17 (s, 1H), 7,92 (s, 1H), 3,82 (d, J=12, 2H), and 3.72 (d, J=7,2,2H), 3,23 (t, J= 10,2H), 2,54 (s, 3H), 2.13 in (m, 1H), and 1.54 (d, J=12,2H), 1.26 in(m, 2H); MS (ESI)m/z315,1 [M+1]+; TPL 222-224°C.

5.1.142 EXAMPLE 142: SYNTHESIS of 6-(1H-PYRAZOLE-4-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(1H-Pyrazole-4-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (0.25 g, 0.8 mmol), pyrazole-4-Bronevoy acid (0.1 g, 0.89 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0,065 g, 0.08 mmol) and potassium phosphate (0.68 g, 3.2 mmol) were combined in DMF (3 ml) and water 0.2 ml), the mixture was purged with nitrogen and heated in a sealed tube at 100°C during the night. The solvent was removed and the crude product was purified by chromatography on silica gel (100% ethyl acetate) to obtain specified in the connection header in the form of not-quite-white solid (0.075 g, 31% yield).1H NMR (400 MHz, DMSO-d6) δ 13,06 (s, 1H), 11,88 (s, 1H), compared to 8.26 (s, 1H), 8,02 (s, 1H), 3,82 (d, J=11,6,2H), 3,74 (d, J=7,2,2H)at 3.25 (t, J=11,2,2H), 2,12 (m, 1H), 1,54(d,J=10,8, 2H), 1,30 (m, 2H); MS (ESI)m/z301,3 [M+1]+; TPL 238-240°C.

5.1.143 EXAMPLE 143: SYNTHESIS of 6-(2-AMINO-1H-BENZO[D]IMIDAZOL-5-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 2-(bis(tert-butoxycarbonyl)amino)-5-bromo-1H-benzo[d]imidazol-1-carboxylate.

A solution of 5-bromo-1H-benzimidazole-2-amine (1 g, 4,71 mmol), di-tert-BUTYLCARBAMATE (3,81 g, 17,45 mmol), triethylamine (of 1.44 ml, 10,36 mmol) and 4-dimethylaminopyridine (few crystals) in anhydrous tetrahydrofuran (15 ml) was left to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified using Biotage chromatography (0-40% EtOAc in hexane) to give the desired product (1,690 g, 70%) as a white solid. MS (ESI) w/z 514,2 [M+1]+.

B. tert-Butyl 2-(bis(tert-butoxycarbonyl)amino)-5-(tributylstannyl)-1H-benzo[d]imidazol-1-carboxylate./p>

A solution of tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-bromo-1H-benzo[d]imidazol-1-carboxylate (0,30 g of 0.58 mmol), hexamethyldisilane (0.15 ml, 0.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,067 g, 0.06 mmol) in toluene (10 ml) was heated at 100°C for 2 hours. After the reaction was completed, toluene was removed under reduced pressure and the residue was purified using Biotage chromatography (0-40% EtOAc in hexane) to obtain the specified title compound (120 mg, 34%). MS (ESI) m/z 598,4 [M+1]+.

C. the Dihydrochloride 6-(2-amino-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

A solution of tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-(tributylstannyl)-1H-benzo[d]imidazol-1-carboxylate (120 mg, 0.20 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (see Example 101.B) (63 mg, 0.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol) in DMF (5 ml) was subjected to interaction for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops)was subjected to ultrasonic processing, and concentrated. This procedure was repeated two more times to obtain specified in sialometaplasia (10,2 mg, 12,7% yield).1H NMR (400 MHz, DMSO-d6) δ 12,54 (d, J=11,2, 2H), 12,09 (s, 1H), 8,53 (s, 1H), 8,49 (s, 1H), of 7.97 (s, 1H), of 7.90 (d, J=8,4, 1H), 7,44 (d, J=8,4, 1H), 3,84 (d, J=10,8, 2H), 3,79 (d, J=10,8, 2H), 3,26 (t, J=10,8, 2H), 2,13 (m, 1H), 1,58 (m, 2H), 1,35 is 1.23 (m, 3H); MS (ESI)m/z366,1 [M+1]+.

5.1.144 EXAMPLE 144: SYNTHESIS of 6-(4-(5-(2-HYDROXYPROPAN-2-YL)-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(5-(2-Hydroxypropan-2-yl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of ethyl 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (see Example 134.B) (0.20 g, 0,525 mmol), 1-hydroxypiperidine (0,248 g, 2.10 mmol), triethylamine (of 1.46 ml, 10.5 mmol) and methanol (4 ml) was subjected to interaction, as described in General Procedure F. the Solution are condensed under reduced pressure and the product was purified with using reverse-phase preparative HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions were combined, neutralized with ammonium hydroxide and then extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting substance was dried in vacuum overnight to obtain specified in the connection header in the form of not-quite-white solid with a purity of 99.9% (15 mg, 7%).1H NMR (400 MHz, CD3/sub> OD) δ 8,49 (s, 1H), 8,12 (s, 4H), of 3.96 (m, 4H), 3.43 points (m, 4H), to 2.29 (m, 1H), 1,67 (m, 8H), of 1.52 (m, 2H); MS (ESI)m/z436,5 [M+1]+; TPL 249-253°C.

5.1.145 EXAMPLE 145: SYNTHESIS of 6-(4-(5-ISOPROPYL-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(5-Isopropyl-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of ethyl 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (see Example 134.B) (0.20 g, 0,525 mmol), 2-methylpiperazine (0,214 g, 2.1 mmol), triethylamine (of 1.46 ml, 10.5 mmol) and methanol (4 ml) was subjected to interaction, as described in General Procedure F. the Reaction mixture was concentrated under reduced pressure and was purified the use of reversed-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions were combined, neutralized with ammonium hydroxide and then extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting substance was dried in vacuum overnight to obtain specified in the connection header in the form of not-quite-white solid with a purity of 99.9% (27 mg, 12%).1H NMR (400 MHz, CD3OD) δ 8,49 (s, 1H), 8,14 (m, 4H), of 3.96 (m, 4H), 3.43 points (m, 3H), 2,28 (m, 1H), 1,67 (m, 2H), 1,41 (d, J=6,4, 6H); MS (ESI)m/z420,5 [M+1]+; TPL 305-308°C.

5.1.146 EXAMPLE 146 SYNTHESIS of the HYDROCHLORIDE of 4-(2-METHOXY-1-(2-MORPHOLINOETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-6-YL)BENZAMIDE

A. 4-(3-(2-Morpholinoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

6-Bromo-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 136.B) (500 mg, of 1.52 mmol), (4-aminosulphonylphenyl)baronova acid (302 mg, 1.82 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (124 mg, 0.09 mmol) and potassium phosphate (1280 mg, between 6.08 mmol) in DMF (30 ml) and water (8 ml) was subjected to interaction in accordance with the General Procedure C. the Product was purified using reverse-phase prepreparation HPLC (10-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the resulting material was used in the next stage as TFA salt. MS (ESI) m/z 369,1 [M+1]+.

B. Hydrochloride 4-(2-methoxy-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzamide.

In a tightly closed tube TFA salt of 4-(3-(2-morpholinoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide (200 mg, 0.41 mmol) were processed using dineopentyl N,N-dimethylformamide at 96°C for 2 hours. The product was purified using reverse-phase prepreparation HPLC (10-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops)was subjected to ultrasonic processing, and concentrated. This procedure is carried and twice with obtaining specified in the title compound (19 mg, 11%).1H NMR (400 MHz, DMSO-d6) δ 8,71 (s, 1H), 8,16 (d, J=8,4, 2H), 8,03 (Sirs, 1H), to 7.99 (d, J=8,4, 2H), to 4.38 (t, J=5,6, 2H), 3,98-3,88 (m, 2H), 3.75 to of 3.60 (m, 6H), 3,39 (s, 3H); MS (ESI)m/z383,1 [M+1]+.

5.1.147 EXAMPLE 147: SYNTHESIS of 4-(1-((1S,4S)-4-HYDROXYCYCLOHEXYL)-2-METHOXY-1H-IMIDAZO[4,5-B]PYRAZIN-6-YL)BENZAMIDE

A. 4-(3-((1S,4S)-4-Hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide.

6-Bromo-1-((1S,4S)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (250 mg, 0.79, which mmol), (4-aminosulphonylphenyl)baronova acid (160 mg, 1.2 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (65 mg, 0.08 mmol) and potassium phosphate (676 mg, 3,19 mmol) in DMF (20 ml) and water (4 ml) was subjected to interaction in accordance with the General Procedure C. the Product was purified using reverse-phase prepreparation HPLC (10-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the product was used in the next stage as TFA salt. MS (ESI) m/z 354,2[M+1]+.

B. 4-(1-((1S,4S)-4-Hydroxycyclohexyl)-2-methoxy-1H-imidazo[4,5-b]pyrazin-6-yl) benzamide.

In a tightly closed tube TFA salt of 4-(3-((1S,4S)-4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide (172 mg, 0.41 mmol) were processed using dineopentyl N,N-dimethylformamide at 96°C for 2 hours. The product was purified using reverse-phase prepreparation HPLC (10-100% acetoni the Rila + 0,1% TFA in H 2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops) and concentrated. This procedure was repeated two more times to obtain specified in the title compound (21 mg, 15%).1H NMR (400 MHz, DMSO-d6) δ 8,66 (s, 1H), 8,15 (d, J=8,4, 2H), 8,05 (Sirs, 1H), of 7.97 (d, J=8,4, 2H), or 4.31 (m, 1H), 3,91 (s, 1H), 2,79 (sq, J=12,4, 2H), 1.85 to is 1.81 (m, 1H), 1,62-of 1.52 (m, 3H), 1,28-of 1.23 (m, 2H), 0,89 is 0.86 (m, 1H); MS (ESI)m/z368,1 [M+1]+.

5.1.148 EXAMPLE 148: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((1S,4S)-4-(METHOXYMETHYL)CYCLOHEXYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl (1S,4S)-4-(methoxymethyl)cyclohexylcarbamate

Sodium hydride (0,204 g, 8.5 mmol, 60% wt. suspension in mineral oil) was washed three times with hexane (10 ml portions), suspended in anhydrous tetrahydrofuran (10 ml) and cooled to 0°C in nitrogen atmosphere. To the resulting suspension was added tert-butyl (1S,4S)-4-(hydroxymethyl)cyclohexylcarbamate (see Example 140.B) (1.5 g, 6,55 mmol) and 15-crown-5 (1.52 g, 6,9 mmol). The reaction mixture was stirred at 0°C for 30 minutes. Was added dropwise methyliodide (0,98 g, 6,9 mmol) and continued stirring at 0°C for 30 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The excess hydride was suppressed by slow addition of water and the product was extracted with ethyl acetate. Org the organic layers were combined and concentrated. The resulting material was purified using chromatography on silica gel (25-70% ethyl acetate in hexane) to obtain specified in the connection header (0,70 g, 44% yield). MS (ESI) m/z to 244.1 [M+1]+.

B. Hydrochloride (1S,4S)-4-(Methoxymethyl)cyclohexanamine

tert-Butyl (1S,4S)-4-(methoxymethyl)cyclohexylcarbamate (0,70 g, 2,63 mmol) were placed in 1,4-dioxane (2 ml) at room temperature was added 4 n hydrochloric acid in 1,4-dioxane (2.5 ml, 10.5 mmol) and the resulting mixture was stirred over night. The solvent was removed, the resulting residue was treated with simple ether and methanol, subjected to ultrasound treatment, concentrated and dried in high vacuum to obtain specified in the title compound as a white solid (0.51 g, 98.6% of the output). MS (ESI) m/z to 130.1 [M+1]+.

C. 6-Bromo-N2-((1S,4S)-4-(methoxymethyl)cyclohexyl)pyrazin-2,3-diamine.

2-Amino-3,5-dibromopyrazine (0,845 g, to 3.34 mmol), hydrochloride, (1S,4S)-4-(methoxymethyl)cyclohexanamine (0.5 g, 2,78 mmol) and diisopropylethylamine (0,72 g, to 5.57 mmol) was dissolved in n-butanol (3 ml) and subjected to interaction in accordance with the General Procedure A. the Mixture was purified using chromatography on silica gel (50% ethyl acetate in hexane) to obtain specified in the connection header (0,348 g, 40% yield). MS (ESI) m/z 315,5 [M]+, 317,5 [M+2]+.

D. 4-(5-Amino-6-((1S,4S)-4-(methoxymethyl is)cyclohexylamino)pyrazin-2-yl)phenol.

(3-6-Bromo-N2-((1S,4S)-4-(methoxymethyl)cyclohexyl)pyrazin-2,3-diamine (0,348 g, 1.1 mmol), 4-hydroxybenzophenone acid (has 0.168 g, 1.2 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0.09 g, 0.1 to 1 mmol) and potassium phosphate (0,93 g, 4.3 mmol) were combined in DMF (3 ml) and water (0.2 ml) and heated together in a sealed tube at 150°C for 2 hours. The product was purified using chromatography on silica gel (1:9 hexane in ethyl acetate) to obtain the specified title compound (0.34 g, 94% yield). MS (ESI) m/z 329,5 [M+1]+.

E. 6-(4-Hydroxyphenyl)-1-((1S,4S)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he.

4-(5-Amino-6-((1S,4S)-4-(methoxymethyl)-cyclohexylamino)pyrazin-2-yl)phenol (0.34 g, 1.0 mmol), 1,1'-carbonyldiimidazole (of 0.67 g, 4 mmol) and tetrahydrofuran (5 ml) were combined in a sealed tube and heated up to 80°C for 48 hours. The mixture was cooled to room temperature, was added potassium carbonate (0.15 g, 1.1 mmol) and methanol (3 ml) and the mixture was stirred at room temperature overnight. The product was purified by chromatography on silica gel (1:2 hexane in ethyl acetate) to obtain specified in the title compounds as a pale yellow solid (0.12 g, 34% yield).1H NMR (400 MHz, DMSO-d6) δ 11,9 (s, 1H), 9,71 (s, 1H) of 8.37 (s, 1H), 7,88 (d, J=8,8,2H), 6,85 (d, J=8,8,2H), 4,25 (m, 1H), 3,6 (d, J=7,6,2H), the 3.35 (s,3H), the 2.46 (m, 2H), 1,99 (m, 1H), of 1.85 (m, 1H), is 1.81 (m, 1H), 1,58 (m,4H); MS (ESI)m/z355,3 [M+1]+; TPL 236-238°C.

5.1.149 EXAMPLE 149: SYNTHESIS of 6-(3H-IMIDAZO[4,5-B]PYRIDINE-6-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 6-bromo-3H-imidazo[4,5-b]pyridine-3-carboxylate.

A solution of 6-bromo-3H-imidazo[4,5-b]pyridine (0,700 g of 3.53 mmol), di-tert-BUTYLCARBAMATE (0,847 g, 3.88 mmol) and triethylamine (0,984 ml, 7.1 mmol) in tetrahydrofuran (10 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain product as a solid (of 1.03 g, 98%). The resulting material was used directly in the next stage without further purification or analysis. MS (ESI) m/z 299 [M+1]+.

B. tert-Butyl 6-(tributylstannyl)-3H-imidazo[4,5-b]pyridine-3-carboxylate.

A solution of tert-butyl 6-bromo-3H-imidazo[4,5-b]pyridine-3-carboxylate (0.167 g, 0,560 mmol), hexamethylditin (0,220 g, 0,672 mmol) and tetrakis (triphenylphosphine)palladium(0) (0,0647 g, 0.07 mmol) in toluene (4 ml) was heated in a sealed tube at 115°C for 90 minutes. The reaction mixture was concentrated under reduced pressure. Purification using Biotage column chromatography (0-20% methanol in dichloromethane) gave pure product (0,165 g, 64%). MS (ESI) m/z 382,9 [M+1]+.

C. 6-(3H-imidazo[4,5-b]pyridine-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5b]pyrazin-2(3H)-he.

A solution of 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (see Example 101.B) (is 0.135 g, 0,432 mmol), tert-butyl 6-(tributylstannyl)-3H-imidazo[4,5-b]pyridine-3-carboxylate (0,165 g, 0,432 mmol), dichlorobis(triphenylphosphine)palladium(II) (0,028 g, 0.04 mmol) in dimethylformamide (2 ml) was heated in a sealed tube at 115°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and purification using Biotage column chromatography (0-20% methanol in dichloromethane) gave pure product (0,053 g, 44%).1H NMR (400 MHz, CD3OD) δ 9,05 (s, 1H), 8,61 (s, 1H), charged 8.52 (s, 1H), 8,45 (s, 1H), 3.96 points (m, 4H), 3,42 (m, 2H), 2,31 (m, 1H), 1,68 (m, 2H), of 1.52 (m, 2H); MS (ESI)m/z352,4 [M+1]+; TPL 367-370°C.

5.1.150 EXAMPLE 150: SYNTHESIS of 1-(2-(2,2-DIMETHYLETHER-2H-PIRAN-4-YL)ETHYL)-6-(4-HYDROXYPHENYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-1-(2-(2,2-dimethylether-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

3,5-Dibromopyridin-2-amine (161 mg, 0.6 mmol), hydrochloride of 2-(2,2-dimethyl-tetrahydropyran-4-yl) - ethylamine (100 mg, 0.5 mmol), diisopropylethylamine (0.5 ml) and dimethylsulfoxide (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer to 150°C for 2 hours to obtain crude 6-bromo-N2-(2-(2,2-dimethylether-2H-Piran-4-yl)ethyl)pyrazin-2,3-diamine. MS (ESI) m/z 329,5, 331,5 [M+1]+. To the reaction mixture was added 1,1'-carbonyldiimidazole (194 mg, 1.2 mmol) and then heated again in the microwave reactor Biotage Emrys Optimizer to 150°C for 10 minutes. The product was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (90 mg, 42% yield from the two stages). MS (ESI) m/z 355,4 [M]+, 357,4 [M+2]+.

B. 1-(2-(2,2-Dimethylether-2H-Piran-4-yl)ethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(2-(2,2-dimethylether-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (90 mg, 0.25 mmol), 4-hydroxyphenylarsonic acid (46 mg, 0.33 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (9 mg, 0.012 mmol), 1 M sodium carbonate (0.75 ml, 0,0,75 mmol) and dioxane (1.5 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layer was concentrated and the resulting residue was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (45 mg, 48% yield).1H NMR (400 MHz, DMSO-d6) δ 11,90 (s, 1H), RS 9.69 (s, 1H), 8,35 (s, 1H), to 7.84 (d, J=8.6 Hz, 2H),6,83 (d, J=9,0, 2H), 3,82-of 3.94 (m, 2H), 3,50 of 3.56 (m, 1H), 3,39-of 3.48 (m, 2H), 1,64-of 1.73 (m, 2H), 1,51-to 1.63 (m, 3H), 0,99-1,08 (m, 4H), 0,91-0,98 (m, 4H); MS (ESI)m/z354,4 [M+1]+; TPL 232-234°C.

5.1.151 EXAMPLE 151: SYNTHESIS of 6-(4-(1H-PYRAZOLE-1-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(4-(Tributylstannyl)phenyl)-1H-pyrazole.

A solution of 1-(4-bromophenyl)-1H-pyrazole (1.0 g, 4,48 mmol), hexamethyldisilane (1.08 ml, is 4.93 mmol), tetrakis(triphenylphosphine)palladium(0) (0,508 g, 0.06 mmol) in toluene (15 ml) was heated at 100°C for 2 hours. After the reaction was completed, toluene was removed under reduced pressure and the residue was purified using Biotage chromatography (0-40% ethyl acetate in hexane) to give the desired product (1.20 g, 87%). MS (ESI) m/z 309,3[M+1]+.

B. 6-(4-(1H-Pyrazole-1-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(4-(Tributylstannyl)phenyl)-1H-pyrazole (300 mg, 0.97 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 101. B) (304 mg, 0.97 mmol), dichlorobis(triphenylphosphine)palladium(II) (68 mg, 0,097 mmol) in DMF (15 ml) was subjected to interaction for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (10-60% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and treated with the help of 6 N. aqueous ammonium hydroxide solution (a few drops). Volatiles were removed is under reduced pressure, the residue was taken for absorption in water (2 ml) and the solid was filtered and washed with water to obtain specified in the connection header (14,5 mg, 4% yield).1H NMR (400 MHz, DMSO-d6) δ to 8.57 (s,1H), 8,32 (d, J=8,8, 2H), 8,01 (d, J=8,8, 2H), 7,68 (s, 2H), 2,27 is 2.33 (m, 2H), 1,66-to 1.63 (m, 2H), 1,51-1,49 (m, 2H), 1.27mm (m, 2H), 0,88-0,84 (m, 2H); MS (ESI)m/z377,3 [M+1]+; TPL 294-296°C.

EXAMPLE 152: SYNTHESIS of 6-(4-(4H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-MORPHOLINOETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 4-(3-(2-Morpholinoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile.

6-Bromo-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 136.B) (700 mg, 2,13 mmol), (4-cyanophenyl)baronova acid (376 mg, 2.56 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (171 mg, 0.21 mmol) and potassium phosphate (1,80 mg of 6.52 mmol) in DMF (30 ml) and water (8 ml) was subjected to interaction in accordance with the General Procedure C. the Product was purified using reverse-phase prepreparation HPLC (10-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and the desired product (410 mg, 41%) was used in the next stage as TFA salt. MS (ESI) m/z 351,4[M+1]+.

B. Ethyl 4-(3-(2-morpholinoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate.

Gaseous HCl was barbotirovany in suspension of 4-(3-(2-morpholinoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile (410 mg, 0.88 mmol) in izvozna ethanol (30 ml) at 0°C. The flask was closed and the reaction mixture was stirred over night at room temperature. After complete conversion to the product (tracked using IHMS) volatile substances were removed under reduced pressure and the resulting solid was dried in a vacuum oven to give the desired product (460 mg, of 1.16 mmol). The obtained substance was used in the next stage without additional purification. MS (ESI) m/z 397,3 [M+1]+.

C. 6-(4-(4H-1,2,4-Triazole-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Ethyl 4-(3-(2-morpholinoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (460 mg, of 1.16 mmol) in methanol (15 ml) was treated with formic hydrazide (278 mg, with 4.64 mmol) and triethylamine (3,23 ml, 2.32 mmol) and the resulting reaction mixture was stirred at 110°C for 3 hours. Volatiles were removed under reduced pressure and the crude product was purified using reverse-phase prepreparation HPLC (10-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated and treated with the help of 6 N. aqueous ammonium hydroxide solution (a few drops). Volatiles were removed under reduced pressure and the residue was taken for absorption in water (2 ml), the solid was filtered and washed with water to obtain specified in the title compound (71 mg, 15.5 per cent).1H NMR (400 MHz, LCA is-d 6) δ 12,09 (s, 1H), 8,65 (s, 1H), to 8.57 (d, J=8,4, 2H), 8,12 (d, J=8,4, 2H), Android 4.04 (t, J=6,4, 2H), 3.45 points (t, J=4,0, 4H), to 3.34 (s, 4H), 2,70 (t, J=6,4, 2H); MS (ESI)m/z393,1 [M+1]+; TPL 295-297°C.

5.1.153 EXAMPLE 153: SYNTHESIS of 6-(4-(l H-BENZO[D]IMIDAZOL-2-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 2-(4-Bromophenyl)-1H-benzo[d]imidazole.

1,2-Phenyldiamine (2.16 g,20 mmol) and iodine (0.1 g, 0.4 mmol) was placed in tetrahydrofuran (4 ml) and water (4 ml) was added 4-bromobenzaldehyde (3.7 g, 20 mmol). The mixture was stirred at room temperature for 2 hours, extracted with ethyl acetate and concentrated. The resulting solid was treated with ethyl acetate (30 ml) and subjected to ultrasonic treatment. The resulting suspension was filtered to give the desired product (1 g, 18% yield). MS (ESI) m/z 273,3 [M]+, 275,3 [M+2]+.

B. 2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-benzo[d]imidazole.

2-(4-Bromophenyl)-1H-benzo[d]imidazole (0.3 g, 1.1 mmol), bis(pinacolato)LIBOR (0.31 g, 1.2 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0.09 g, 0.11 mmol) and potassium acetate (0.32 g, 3.2 mmol) were placed in a tightly closed tube in DMSO (4 ml). The system was purged with nitrogen, tightly closed and heated to 90°C for 2 hours. The solvent was removed and the desired product was purified using chromatography on silica gel (50% ethyl acetate in hexane) with receipt of the m specified in the title compound (0.2 g, 57% yield). MS (ESI) m/z 321 [M+1]+.

C. 6-(4-(1H-Benzo[d]imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-benzo[d]imidazole (0.2 g, 0.6 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (0.20 g, 0.6 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II in the form of an adduct with dichloromethane (0,052 g, 0.06 mmol) and potassium phosphate (0.54 g, 2.5 mmol) were combined in DMF (3 ml) and water (0.5 ml), the mixture was purged with nitrogen and heated in a sealed tube at 100°C during the night. The solvent was removed and the crude substance was purified using chromatography on silica gel (100% ethyl acetate) to obtain the specified title compound as a white solid (0.04 g, 16% yield).1H NMR (400 MHz, DMSO-d6) δ 12,98 (s, 1H), 12,13 (s, 1H), 8,63 (s, 1H), 8,29 (d, J=8,8, 2H), 8,23 (d, J=8,2H), 7,69 (d, J=1,6, 1H), 7,56 (d, J=8, 1H), 7,22 (m, 2H), 3,83 (m, 4H), of 3.27 (t, J=11,6, 2H), 2,16 (m, 1H), 1,59 (d, J=12, 2H), 1,33 (m, 2H); MS (ESI) m/z 427,2 [M+1]+; TPL >300°C.

5.1.154 EXAMPLE 154: SYNTHESIS of the HYDROCHLORIDE of 6-(4-(1H-IMIDAZOL-2-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)MUTIL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 2-(4-(Tributylstannyl)phenyl)-1H-imidazole.

A solution of 2-(4-bromophenyl)-1H-imidazole (1.0 g, 4,48 mmol), hexamethyldisilane (1.08 ml, is 4.93 mmol), tetrakis(triphenylphosphine)palladium(0) (0,508 g, 0.06 mmol) in toluene (15 ml) was heated at 100°C in t the value of 2 hours. After the reaction was completed, toluene was removed under reduced pressure and the residue was purified using Biotage chromatography (0-40% EtOAc in hexane) to give the desired stannane (635 mg, 46%). MS (ESI) m/z 309,2[M+1]+.

B. Hydrochloride 6-(4-(1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

2-(4-(Tributylstannyl)phenyl)-1H-imidazole (400 mg, 1,29 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (406 mg, 1,29 mmol), dichlorobis(triphenylphosphine)palladium(II) (90 mg, 0.13 mmol) in DMF (15 ml) was subjected to interaction for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (10-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops) and concentrated. This procedure was repeated two more times to obtain specified in the title compound (4.0 mg, about 0.75% yield).1H NMR (400 MHz, DMSO-d6) δ to 8.57 (s, 1H), 8,32 (d, J=8,8, 2H), 8,01 (d, J=8,8, 2H), 7,68 (s, 2H), 2,27 is 2.33 (m, 2H), 1,66-to 1.63 (m, 2H), 1,51-1,49 (m, 2H), 1.27mm (m, 2H), 0,88-0,84 (m, 2H); MS (ESI)m/z377,3 [M+1]+.

5.1.155 EXAMPLE 155: SYNTHESIS of 6-(4-(5-(HYDROXYMETHYL)-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 2-Hydroxyacetophenone.

A solution of ethyl 2-hydroxyacetate (1.0 g, a 9.60 mmol), hydrazine (0,324 mg, 10.1 mmol) and ethanol (20 ml) were combined and heated to 85°C for 3 hours. The reaction mixture was concentrated to obtain specified in the connection header (0,702 g, 81%). MS (ESI) m/z to 91.1 [M+1]+.

B. 6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of ethyl 4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (see Example 134.B) (0,280 g, 0,367 mmol), 2-hydroxyethylhydrazine (0,265 g of 1.47 mmol), triethylamine (2,04 ml, 7,34 mmol) and methanol (4 ml) was subjected to interaction, as described in General Procedure F. the Reaction mixture was concentrated under reduced pressure and was purified the use of reversed-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions were combined, neutralized with ammonium hydroxide, extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting substance was dried in vacuum overnight to obtain specified in the connection header in the form of not-quite-white solid with a purity of 99.9% (211 mg, 71%).1H NMR (400 MHz, DMSO-d6) δ 12,1 (Sirs, 1H), 8,56 (s, 1H), 8,13 (Sirs, 2H), 3,85 (m, 4H), 3,23 (m, 3H), of 2.15 (m, 1H), 1,59 (m, 2H), 1,36 (m, 2H); MS (ESI)m/z408,5 [M+1]+; TPL 258-260°C.

5.1.156 P IS EMER 156: SYNTHESIS of the HYDROCHLORIDE of 6-(4-(1H-IMIDAZOL-5-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 2-(4-Bromophenyl)-4-tosyloxy.

4-Bromobenzaldehyde (700 mg, of 3.78 mmol) in ethanol (20 ml) were processed using tosyl-methyl-isocyanate (722 mg, 3,70 mmol) and sodium cyanide (181 mg, 3,70 mmol). The resulting suspension was left to stir over night at room temperature. Volatiles were removed under reduced pressure. The residue was taken for absorption in diethyl ether, subjected to ultrasonic treatment was filtered and washed with diethyl ether to obtain the product (820 mg, 57%) as a yellow solid. MS (ESI) m/z 380,2 [M+1]+.

B. 5-(4-Bromophenyl)-1H-imidazole.

2-(4-Bromophenyl)-4-tosyloxy (820 mg, 2,17 mmol) was treated with 7 n ammonia solution in methanol. The resulting reaction mixture was left to stir over night at room temperature. Volatiles were removed under reduced pressure. The residue was taken for absorption in diethyl ether, subjected to ultrasonic treatment was filtered and washed with diethyl ether to obtain the product (100 mg, 21%) as a white solid. MS (ESI) m/z 225,1 [M+1]+.

C. 5-(4-(Tributylstannyl)phenyl)-1H-imidazole.

A solution of 5-(4-bromophenyl)-1H-imidazole (100 mg, 0.44 mmol), hexamethyldisilane (of 0.11 ml, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (0,050 g 0,006 mmol) in toluene (5 ml) was heated at 100°C for 2 hours. After the reaction end is stayed, the toluene was removed under reduced pressure and the residue was purified using Biotage chromatography (0-40% ethyl acetate in hexane) to obtain the specified title compound (50 mg, 36%). MS (ESI) m/z 309,3 [M+1]+.

D. 6-(4-(1H-imidazol-5-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he hydrochloride.

5-(4-(Tributylstannyl)phenyl)-1H-imidazole (50 mg, 0.16 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (51 mg, 0.16 mmol), dichlorobis(triphenylphosphine)palladium(II) (11 mg, to 0.016 mmol) in DMF (5 ml) was subjected to interaction for 1.5 hours at 115°C. the Product was purified using reverse-phase prepreparation HPLC (10-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops) and concentrated. This procedure was repeated two more times to obtain specified in the connection header (or 24.2 mg, 37% yield).1H NMR (400 MHz, CD3OD-d6) δ 8,46 (s, 1H), 8,12 (d, J=8,8, 2H), to 7.84 (d, J=8,8, 2H), to 7.59 (s, 2H), 3,97-3,91 (m, 2H), 1,67-to 1.63 (m, 2H), 1,50-of 1.42 (m, 2H), 1.27mm (m, 2H), 0,97-0,84 (m, 2H); MS (ESI)m/z378,1 [M+1]+.

5.1.157 EXAMPLE 157: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((5-OXOPYRROLIDIN-2-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

3,5-Dibromopyridin-2-amine (253 mg, 1 m is ol), hydrochloride 5-(aminomethyl)pyrrolidin-2-she (150 mg, 1 mmol), diisopropylethylamine (0.5 ml) and dimethylsulfoxide (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 2 hours to obtain crude 5-((3-amino-6-bromopyrazine-2-ylamino)methyl)pyrrolidin-2-it-MS (ESI) m/z 286,0 [M]+, 288,0 [M+2]+. To the reaction mixture was added 1,1'-carbonyldiimidazole (243 mg, 1.5 mmol) and the solution was heated again in the microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The product was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain white solids. MS (ESI) m/z 312,0 [M]+, 314,0 [M+2]+.

B. 6-(4-Hydroxyphenyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (312 mg, 1 mmol), 4-hydroxyphenylarsonic acid (152 mg, 1.1 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (37 mg, 0.05 mmol), 1 M sodium carbonate (3 ml, 3 mmol) and dioxane (6 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 20 minutes. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate, the m The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and the resulting material was ground into powder with simple ether to obtain a white solid (42 mg, 13% yield from 2 stages).1H NMR (400 MHz, DMSO-d6) δ 11,92 (s, 1H), RS 9.69 (s, 1H), at 8.36 (s, 1H), 7,86 (d, J=8,6, 2H), 7,82 (s, 1H), 6,85 (d, J=8,6, 2H), 4,11 (m, 1H), 3,92 (DD, J=13,7, 6, 1H), 3,82 (DD, J=13,7, 6,2, 1H), 2,24 (m, 1H), 2,11 (m, 2H), 1.85 to (DD, J=13,7, 6,2, 1H); MS (ESI)m/zto 326.1 [M+1]+; TPL 338-340°C.

5.1.158 EXAMPLE 158: SYNTHESIS of 6-(4-(4,5-DIMETHYL-1H-IMIDAZOL-2-YL)PHENYL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 2-(4-Bromophenyl)-4,5-dimethyl-1H-imidazol

4-Bromobenzaldehyde (1.39 g, 7.5 mmol), 2,3-butandione (0,43 g, 5 mmol) and ammonium acetate (3,85 g, 50 mmol) were combined in glacial acetic acid (10 ml) and was heated to 60°C over night. The solvent was removed and the residue was treated with saturated sodium bicarbonate solution and was extracted into ethyl acetate. The organic layer is then washed with water, dried over magnesium sulfate, filtered and concentrated. The resulting solid was purified by chromatography on silica gel (100% ethyl acetate) to obtain specified in the title compounds as a pale yellow solid (0.8 g, 64% yield).1H NMR (400 MHz, CDCl3) δ7,63 (d, J=8,4, 2H), 7,49 (d, J=8,8,2H), 2,2 (s, 6H); MS (ESI)m/z251,1 [M]+, 253,1 [M+2]+.

B. 4,5-Dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol

A solution of 2-(4-bromophenyl)-4,5-dimethyl-1H-imidazole (0.4 g, of 1.59 mmol), bis(pinacolato)Debora (0,44 g of 1.75 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0,13 g, strength of 0.159 mmol) and potassium acetate (0,47 g, 4.77 mmol) in DMSO (5 ml) was heated in a sealed tube at 90°C for 2 hours. After cooling to room temperature the reaction mixture was filtered through celite and washed with methanol and ethyl acetate. The filtrate and washing liquid were combined and concentrated under reduced pressure. The resulting material was treated with water and extracted into ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to obtain a solid residue. The product was isolated by filtration to obtain specified in the title compound (0.16 g, 34% yield). MS (ESI) m/z 299,5 [M+1]+.

C. 6-(4-(4,5-Dimethyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he

4,5-Dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole (0.16 g, of 0.53 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (has 0.168 g of 0.53 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II in VI is e adduct with dichloromethane (0,044 g, 0,053 mmol) and potassium phosphate (0.45 g, 2.14 mmol) was subjected to interaction in DMF (2 ml) according to General Procedure B2, except that the reaction mixture was heated for 2 hours. Purification by chromatography on silica gel (10% methanol in ethyl acetate) gave specified in the title compound in the form of not-quite-white solid (40,0 mg, 19% yield).1H NMR (400 MHz, DMSO-d6) δ 12,1 (s, 1H), charged 8.52 (s, 1H), of 8.06 (d, J=8,6, 2H), to 7.93 (d, J=8,20, 2H), 4,0 at 3.69 (m, 4H), 3,26 (t, J=11,1, 2H), 2,2 (s, 3H), of 2.15 (m, 1H), 2.05 is (s, 3H), 1,7 (m, 2H), 1,13 (m, 2H); MS (ESI)m/z405,4 [M+1]+; TPL 250-254°C.

5.1.159 EXAMPLE 159: SYNTHESIS of 6-(4-(1H-1,2,4-TRIAZOLE-5-YL)PHENYL)-1-(((1S,4S)-4-METHOXYCYCLOHEXYL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl ((1S,4S)-hydroxycyclohexyl)methylcarbamate.

To (1S,4S)-4-hydroxycyclohexanecarboxylate (see Example 132.A) (3.5 g) was added tetrahydrofuran (60 ml) and monochloroborane·dimethyl sulfide (5,1 ml, 48 mmol). The reaction mixture was heated to 60°C for 16 hours. The reaction was suppressed by slow addition of methanol and then concentrated to obtain a thick oil. To the obtained oil was added triethylamine (10 ml, 72 mmol), 2-propanol (40 ml) and di-tert-BUTYLCARBAMATE (10.5 g, 48 mmol). The reaction mixture was heated to 60°C for 2 hours. The reaction mixture was concentrated and then purified on a column of silica gel (0-80% ethyl acetate in hexane) to give white solids is (1.2 g, 15% yield for 2 stages). MS (ESI) m/z 230,4 [M+1]+.

B. Hydrochloride ((1S,4S)-4-Methoxycyclohexyl)methanamine.

Sodium hydride (326 mg, 14 mmol) was added to a solution of tert-butyl ((1S,4S)-4-hydroxycyclohexyl)methylcarbamate (1.2 g, 4.5 mmol) in tetrahydrofuran (40 ml), followed by the addition of iodomethane (283 μl, 4.5 mmol). The reaction mixture was stirred at room temperature for 16 hours. Added an additional amount of sodium hydride and continued stirring the mixture. The reaction was suppressed by the slow addition of water and then was extracted with ethyl acetate (3×). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated to obtain a colorless oil. The resulting oil was purified on a column of silica gel (0-50% ethyl acetate in hexane) to give colorless oil. The obtained oil was treated with 4 N. a solution of hydrogen chloride in dioxane for 30 minutes. The reaction mixture was concentrated and then triturated to powder with 10% methanol in diethyl ether to obtain white solids (0,38 g, 47% yield). MS (ESI) m/z 144,4 [M+1]+.

C. 6-Bromo-1-(((1S,4S)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

3,5-Dibromopyridin-2-amine (537 mg, 2.1 mmol), hydrochloride ((1S,4S)-4-methoxycyclohexyl)methanamine (380 mg, 2.1 mmol), diisopropylethylamine (1 ml) and dimethylsulfoxide (2 ml) was heated in the microwave the first reactor Biotage Emrys Optimizer at 150°C for 2 hours to obtain crude 6-bromo-N 2-(((1S,4S)-4-methoxycyclohexyl)methyl)pyrazin-2,3-diamine. MS (ESI) m/z 315,0, 317,0 [M+1]+. Added 1,1'-carbonyldiimidazole (680 mg, 4.2 mmol) and the reaction mixture was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 minutes. The reaction mixture was concentrated and the product was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (450 mg, 63% yield from the two stages). MS (ESI) m/z 341,0, 343,0 [M+1]+.

D. Hydrochloride 4-(1H-1,2,4-Triazole-5-yl)phenylboronic acid.

A solution of 4-cyanophenylacetic acid (5.5 g, 37 mmol) in ethanol (200 ml) was cooled in an ice bath. Was carried out by bubbling the reaction mixture with gaseous hydrogen chloride for 15 minutes and the resulting solution was left to stir at room temperature for 3 days. The solution was concentrated under reduced pressure to obtain cleaners containing hydrochloride salt of imidate in the form of a white solid. Imidate was combined with 2-propanol (15 ml), triethylamine (16 ml, 112 mmol) and formic hydration (6.7 g, 112 mmol). The mixture was heated to 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting material was purified on a column of silica compound is elem (0-100% (5% methanol in ethyl acetate in hexane) to give a thick oil. The obtained oil was treated with 4 N. a solution of hydrogen chloride in dioxane. The solution was concentrated under reduced pressure to obtain the product in the form of cleaners containing hydrochloride salt. Salt was rubbed into powder with 10% methanol in diethyl ether, filtered and dried to obtain white solid (7.2 g, 86% yield).1H NMR (400 MHz, DMSO-d6) δ 11,24 (Sirs, 2H), 8,69 (s, 1H), 8,23 (s, 2H), 8,02 (d, J=8,0, 2H), to $ 7.91 (d, J=8,6, 2H); MS (ESI)m/z190,1 [M+1]+.

E. 6-(4-(1H-1,2,4-Triazole-5-yl)phenyl)-1-(((1S,4S)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(((1S,4S)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (450 mg, 1.3 mmol), hydrochloride of 4-(1H-1,2,4-triazole-5-yl)phenylboronic acid (356 mg, 1.6 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (48 mg, 0.06 mmol), 1 M carbonate sodium (4 ml, 4 mmol) and dioxane (8 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 1 hour. The reaction mixture was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fraction was passed through ion-exchange column Strata-XC and then was isolated from the column using 2m ammonia in methanol. The solution was concentrated and then triturated to powder with diethyl ether to obtain white solid (31 mg, 6% yield).1H NMR (400 MG IS, DMSO-d6) δ 12,10 (s, 1H), to 8.57 (s, 1H), 8,13 (m, 4H), 3,76 (d, J=7,0, 2H), 3,20 (s, 3H), 1,99 (width, s, 1H), 1,81 (d, J=4,3, 1H), to 1.37 (m, 6H); MS (ESI)m/zis 406.5 [M+1]+; TPL 294-296°C.

5.1.160 EXAMPLE 160: SYNTHESIS of 6-(4-(1H-1,2,4-TRIAZOLE-5-YL)PHENYL)-1-(((1R,4R)-4-METHOXYCYCLOHEXYL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl ((1R,4R)-4-hydroxycyclohexyl)methylcarbamate.

(1R,4R)-4-Hydroxycyclohexanecarboxylate (see Example 130.A) (5 g) was dissolved in tetrahydrofuran (60 ml), was added monochloroborane·dimethyl sulfide (7.3 ml, 70 mmol) and the reaction mixture was heated to 60°C for 16 hours. The reaction was suppressed by slow addition of methanol and concentrated to obtain a thick oil. The resulting oil was combined with triethylamine (16 ml, 105 mmol), 2-propanol (50 ml) and di-tert-BUTYLCARBAMATE (15 g, 70 mmol). The reaction mixture was heated to 60°C for 2 hours. The reaction mixture was concentrated and the resulting material was purified on a column of silica gel (0-80% ethyl acetate in hexane) to give white solid (3 g, 52% yield for 2 stages). MS (ESI) m/z 230,3 [M+1]+.

B. Hydrochloride ((1R,4R)-4-methoxycyclohexyl)methanamine.

To a solution of tert-butyl ((1R,4R)-4-hydroxycyclohexyl)methylcarbamate (3 g, 11 mmol) in tetrahydrofuran (40 ml) were added successively sodium hydride (815 mg, 34 mmol) and jodean (707 μl, 11 mmol). The reaction mixture was stirred at room temperature for 16 cha is impressive. Added an additional amount of sodium hydride to complete the reaction. After completion (monitored by using TLC) the reaction was suppressed by the slow addition of water and then was extracted with ethyl acetate (3×). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to obtain a colorless oil. The resulting oil was purified on a column of silica gel (0-50% ethyl acetate in hexane) to give colorless oil. The obtained oil was treated with 4 N. a solution of hydrogen chloride in dioxane for 30 minutes. The reaction mixture was concentrated and the resulting material was ground into powder with 10% methanol in diethyl ether to obtain white solid (1 g, 20% yield). MS (ESI) m/z 144,4 [M+1]+.

C. 6-Bromo-1-(((1R,4R)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

3,5-Dibromopyridin-2-amine (537 mg, 2.1 mmol), hydrochloride ((1R,4R)-4-methoxycyclohexyl)methanamine (380 mg, 2.1 mmol), diisopropylethylamine (1 ml) and dimethylsulfoxide (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 2 hours to obtain crude 6-bromo-N2-(((1R,4R)-4-methoxycyclohexyl)methyl)pyrazin-2,3-diamine. MS (ESI) m/z 315,0 [M]+, 317,0 [M+2]+. To the reaction mixture were added 1,l'-carbonyldiimidazole (680 mg, 4.2 mmol) and the solution was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 10 mi the ut. The reaction mixture are condensed and the product was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and triturated to powder with simple ether to obtain a white solid (400 mg, 56% yield from the two stages). MS (ESI) m/z 341,0 [M]+, 343,0 [M+2]+.

D. 6-(4-(1H-1,2,4-Triazole-5-yl)phenyl)-1-(((1R,4R)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(((1R,4R)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (400 mg, 1.2 mmol), hydrochloride of 4-(1H-1,2,4-triazole-5-yl)phenylboronic acid (see Example 159.D) (395 mg, 1.7 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (48 mg, 0.06 mmol), 1 M sodium carbonate (4 ml, 4 mmol) and dioxane (8 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 1 hour. The reaction mixture was concentrated and the resulting material was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fraction was passed through ion-exchange column Strata-XC and then was isolated from the column using 2m ammonia in methanol. The solution was concentrated and the resulting material was ground into powder with simple ether to obtain a white solid (36 mg, 8% yield).1H NMR (400 MHz, DM what About the-d 6) δ 12,09 (s, 1H), to 8.57 (s, 1H), 8,13 (width, s, 4H), 3,76 (d, J=6,6, 2H), 3,21 (s, 3H), 3,09 (width, s, 1H), 1,99 (d, J=8,6, 2H), 1,87 (width, s, 1H), 1,73 (d, J=11,7, 2H), 1,08 (m, 4H), MS (ESI)m/zto 406.4 [M+1]+, TPL 286-288°C.

5.1.161 EXAMPLE 161: SYNTHESIS of 6-(6-(1H-1,2,4-TRIAZOLE-3-YL)PYRIDINE-3-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

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

A solution of 5-bromopicolinic (0,500 g, 2.49 mmol) and dimethylformamidine (20 ml) was heated to 85°C for 3 hours. The reaction mixture was concentrated and the obtained product was used directly in the next stage (0,604 g, 95%). 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)picolinamides (0,604 mg, 2.36 mmol) and hydrazine (2,12 g of 66.1 mmol) was stirred at 25°C for 3 hours. The reaction mixture was concentrated and diluted with water. The precipitate was collected by filtration and dried in vacuum to obtain specified in the connection header (0,442 g, 83%). 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-Piran (0,256 g, 3.04 from mmol) and 4-methylbenzenesulfonic acid (0,058 g, 0.30 mmol) in tetrahydrofuran was heated to 75°C for 6 hours. The reaction mixture was concentrated and purified using Biotage column chrome is adopted (0-20% methanol in dichloromethane) to give procedendo product in the form of oil (0,614 g, >100%). MS (ESI) m/z 310,2 [M+1]+.

D. 2-(1-(Tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)-5-(tributylstannyl)pyridine.

A solution of 5-bromo-2-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine (0,200 g, 0,647 mmol), hexamethyldisilane (0,254 g, 0,776 mmol), tetrakis(triphenylphosphine)palladium(0) (0,069 g, 0.06 mmol) in toluene (3 ml) was heated in a sealed tube at 115°C for 90 minutes. The reaction mixture was concentrated under reduced pressure. Purification using Biotage column chromatography (0-20% methanol in dichloromethane) gave pure product (0,153 g, 60%). MS (ESI) m/z 382,9 [M+1]+.

E. 6-(6-(1-(Tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (see Example 101. B) (0,122 g, 0,389 mmol), 2-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)-5-(tributylstannyl)pyridine (0,153 g, 0,389 mmol), dichlorobis(triphenylphosphine)palladium(II) (0,027 g, 0.04 mmol) in dimethylformamide (3 ml) was heated to 115°C in a sealed tube and within 2 hours. The reaction mixture was concentrated under reduced pressure. Purification using Biotage column chromatography (0-20% methanol in dichloromethane) gave pure product (0,098 g, 55%); MS (ESI) m/z 463,5 [M+1]+.

F. 6-(6-(1H-1,2,4-Triazole-3-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5b]pyrazin-2(3H)-he.

A solution of 6-(6-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she (0,098 g, 0,212 mmol) and 4.0 M hydrochloric acid in dioxane (4.0 ml) was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting material was purified using reverse-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions were combined, neutralized with ammonium hydroxide and then extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting substance was dried in vacuum overnight to obtain specified in the connection header in the form of not-quite-white solid with a purity of 99.9% or 30.4 mg, 38%).1H NMR (400 MHz, DMSO-d6) δ 9,29 (d, J=1,6, 1H), charged 8.52 (m, 2H), of 8.25 (s, 1H), 8,14 (d, J=8,4, 1H), 3,85 (m, W, 2H, in), 3.75 (d, J=7,2, 1H), 3,3 (m, 2H), and 2.14 (m, 1H), and 1.56 (m, W, 2H), 1,36 (m, 2H); MS (ESI)m/z379,4 [M+1]+; TPL 353-356°C.

5.1.162 EXAMPLE 162: SYNTHESIS of 6-(4-(1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-(2-OXOPYRROLIDIN-1-yl)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(1H-1,2,4-Triazole-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he

6-Bromo-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 157.A) (290 mg, 0.8 mmol), hydrochloride of 4-(1H-1,2,4-triaz is l-5-yl)phenylboronic acid (see Example 159.D) (224 mg, 0,99 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (30 mg, 0.04 mmol), 1 M sodium carbonate (2.5 ml, 2.5 mmol) and dioxane (5 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 1 hour. The reaction mixture was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fraction was passed through ion-exchange column Strata-XC and the product was isolated from the column using 2m ammonia in methanol. The solution was concentrated and the resulting material was ground into powder with simple ether to obtain a white solid (23 mg, 7% yield).1H NMR (400 MHz, DMSO-d6) δ 8,58 (s, 1H), 8,48 (width, 1H), to 8.20 (d, J=10,0, 2H), 8,13 (d, J=10,0, 2H), 4,06 (m, 2H), to 3.58 (m, 2H), 3,52 (t, J=6,8, 2H), 1,85 (d, J=7,8, 2H), 1,74 (m, 2H); MS (ESI)m/z391,5 [M+1]+; TPL 300-301°C.

5.1.163 EXAMPLE 163: SYNTHESIS of 3-(1-PHENYLETHYL)-5-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRIDINE-2(3H)-It

A. 6-Chloro-3-nitro-N-(1-phenylethyl)pyridine-2-amine.

To a solution of 2,6-dichloro-3-nitropyridine (2.0 g, 10.4 mmol) in tetrahydrofuran (18 ml) at -78°C was added diisopropylethylamine (2,17 ml, 12.4 mmol) and 1-fenilatilamin (1.51 g, 12.4 mmol). The reaction mixture was maintained at -78°C for 2 hours and then gave to slowly warm to room temperature over night. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel with obtaining specified in the title compound (2.24 g, 78% yield).1H NMR (400 MHz, DMSO-d6) δ 8,68 (d, J=7,5, 1H), 8,42 (d, J=8,5, 1H), 7,45 (d, J=7,5, 2H), 7,34 (t, J=7,5, 2H), 7,25 (t, J=7,5, 1H), 6,80 (d, J=8,5, 1H), are 5.36 (Quint., J=7, 1H), 1,57 (d, J=7, 3H).

B. 3-Nitro-N-(1-phenylethyl)-6-(quinoline-5-yl)pyridin-2-amine.

To a solution of 6-chloro-3-nitro-N-(1-phenylethyl)pyridine-2-amine (2.24 g, 8,07 mmol) and quinoline-5-Voronovo acid (1,81 g, 10.5 mmol) in DMF (150 ml) was added potassium carbonate (4,46 g, and 32.3 mmol) in water (25 ml). The reaction solution was purged by a stream of nitrogen, followed by addition of tetrakis(triphenylphosphine)palladium(0) (932 mg, 0.81 mmol). After heating at 85°C for 2 hours the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with obtaining specified in the connection header (2,36 g, 79% yield). MS (ESI) m/z 371,3 [M+1]+.

C. N2-(1-Phenylethyl)-6-(quinoline-5-yl)pyridine-2,3-diamine.

A solution of 3-nitro-N-(1-phenylethyl)-6-(quinoline-5-yl)pyridin-2-amine (2,36 g, 6,37 mmol) in ethanol (175 ml) was purged with nitrogen for several minutes. After addition of palladium on carbon (245 mg, to 2.29 mmol) in a flask was created by the vacuum and set on top of a balloon filled with hydrogen. After stirring at room temperature for 18 hours the reaction mixture was filtered and the solvent was removed under reduced pressure to obtain specified in the title compound (1.89 g, 87% yield). MS (ESI) m/z 341,3 [M+1]+.

D. 3-(1-FeNi is ethyl)-5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he

A solution of N2-(1-phenylethyl)-6-(quinoline-5-yl)pyridine-2,3-diamine (0,500 g of 1.47 mmol) and urea (0,265 g, to 4.41 mmol) in 1-methylpyrrolidine-2-Ohe (2 ml) was heated at 185°C for 1 hour. The solvent was removed under reduced pressure and the crude substance was dissolved in DMSO. Purification using reversed-phase HPLC (10-100% acetonitrile in water, within 18 min) gave specified in the title compound (110 mg, 21% yield).1H NMR (300 MHz, DMSO-d6) δ 11,40 (s, 1H), 8,90-of 8.92 (m, 1H), of 8.37 (d, J=8, 1H), with 8.05 (d, J=8, 1H), 7,80 (t, J=7, 1H), of 7.70 (d, J=7, 1H), 7,49 (d, J=8, 1H), 7,28-7,42 (m, 7H), 5,73 (sq, J=7,5, 1H), 1,95 (d, J=7,5, 3H); MS (ESI)m/z366,8 [M+1]+.

5.1.164 EXAMPLE 164: SYNTHESIS of (R)-3-(1-PHENYLETHYL)-5-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRIDINE-2(3H)-It

A. (R)-6-Chloro-3-nitro-N-(1-phenylethyl)pyridine-2-amine.

To a solution of 2,6-dichloro-3-nitropyridine (1.0 g, 5.18 mmol) in tetrahydrofuran (8 ml) at -78°C was added diisopropylethylamine (1.08 ml, from 6.22 mmol) followed by addition of (R)-1-fenilalanina (0.75 g, from 6.22 mmol) in tetrahydrofuran (2 ml). The reaction mixture was stirred at -78°C for 2 hours and then gave to slowly warm to room temperature over night. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel with obtaining specified in the title compound (1.12 g, 78% yield).1H NMR (400 MHz, DMSO-d6) δ 8,67 (d, J=7,5, 1H), 8,43 (d, J=8,5, 1H), 7,46 (d, J=7,5, 2H), 7,35 (t, J=7,5, 2H, of 7.25 (t, J=7,5, 1H), 6,80 (d, J=8,5, 1H), 5,38 (Quint., J=7, 1H), 1,59 (d, J=7, 3H).

B. (R)-3-Nitro-N-(1-phenylethyl)-6-(quinoline-5-yl)pyridin-2-amine.

To a solution of (R)-6-chloro-3-nitro-N-(1-phenylethyl)pyridine-2-amine (1.12 g, a 4.03 mmol) and quinoline-5-Voronovo acid (0,91 g of 5.24 mmol) in DMF (75 ml) was added potassium carbonate (2,23 g, 16,1 mmol) in water (25 ml). The reaction solution was purged by a stream of nitrogen, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0,466 g, 0,403 mmol). After heating at 85°C for 2 hours the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with obtaining specified in the title compound (1.1 g, 74% yield). MS (ESI) m/z 371,3 [M+1]+.

C. (R)-N2-(1-Phenylethyl)-6-(quinoline-5-yl)pyridine-2,3-diamine.

A solution of (R)-3-nitro-N-(1-phenylethyl)-6-(quinoline-5-yl)pyridin-2-amine (1.10 g, of 2.97 mmol) in ethanol (95 ml) was purged with nitrogen for several minutes. After addition of palladium on carbon (0.125 g, 1.18 mmol) in a flask was created by the vacuum and set on top of a balloon filled with hydrogen. After stirring at room temperature for 18 hours the reaction mixture was filtered and the solvent was removed under reduced pressure to obtain specified in the connection header (0,77 g, 76% yield). MS (ESI) m/z 341,3 [M+1]+.

D. (R)-3-(1-Phenylethyl)-5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he.

A solution of (R)-N2-(1 peneliti is)-6-(quinoline-5-yl)pyridine-2,3-diamine (0,30 g, 0,881 mmol) and urea (0.16 g, of 2.64 mmol) in 1-methylpyrrolidine-2-Ohe (1.2 ml) was heated at 185°C for 1 hour. Purification of the crude substances by using reversed-phase HPLC (10-100% acetonitrile in water, within 18 min) gave specified in the title compound (55 mg, 17% yield).1H NMR (400 MHz, DMSO-d6) δ 11,42 (s, 1H), of 8.92 (DD, J=2,4, 1H), scored 8.38 (d, J=8,1H), 8,07 (d, J=8,1H), 7,82 (t, J=7, 1H), of 7.70 (DD, J=1, 7,1H), 7,51 (d, J=8, 1H), 7,29-7,44 (m, 7H), 5,75 (sq, J=7,5, 1H), 1,96 (d, J=7,5, 3H); MS (ESI) m/z 366,8 [M+1]+.

5.1.165 EXAMPLE 165: SYNTHESIS of (S)-3-(1-HYDROXY-3-METHYLBUTANE-2-YL)-5-(5-ISOPROPYL-2-METHOXYPHENYL)-1H-IMIDAZO[4,5-B]PYRIDINE-2(3H)-It

A. (S)-2-(6-Chloro-3-nitropyridine-2-ylamino)-3-methylbutane-1-ol.

To a solution of 2,6-dichloro-3-nitropyridine (1.0 g, 5.18 mmol) in tetrahydrofuran (8 ml) at -78°C was added diisopropylethylamine (1.08 ml, from 6.22 mmol) followed by addition of (S)-2-amino-3-methylbutane-1-ol (0,641 g, from 6.22 mmol) in tetrahydrofuran (2 ml). The reaction mixture was stirred at -78°C for 2 hours and then gave to slowly warm to room temperature over night. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel with obtaining specified in the connection header (0.810 g, 60% yield). MS (ESI) m/z of 260.2 [M+1]+.

B. (S)-2-(6-(5-isopropyl-2-methoxyphenyl)-3-nitropyridine-2-ylamino)-3-methylbutane-1-ol.

To a solution of (S)-2-(6-chloro-3-nitropyridine-2-ylamino)-3-methylbutane-1-ol (0,80 g, 3.8 mmol) and 5-isopropyl-2-methoxyphenylacetic acid (0,78 g, 4.00 mmol) in DMF (50 ml) was added potassium carbonate (1.7 g, 12.3 mmol) in water (8 ml). The reaction solution was purged by a stream of nitrogen, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0,358 g, 0,308 mmol). After heating at 85°C for 2 hours the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with obtaining specified in the connection header (1,11 g, 96% yield). MS (ESI) m/z 374,3 [M+1]+.

C. (S)-2-(3-Amino-6-(5-isopropyl-2-methoxyphenyl)pyridine-2-ylamino)-3-methylbutane-1-ol.

A solution of (S)-2-(6-(5-isopropyl-2-methoxyphenyl)-3-nitropyridine-2-ylamino)-3-methylbutane-1-ol (0.33 g, 0.88 mmol) in ethanol (30 ml) was purged with nitrogen for several minutes. After addition of palladium on carbon (0,038 g, 0.35 mmol) in a flask was created by the vacuum and set on top of a balloon filled with hydrogen. After stirring at room temperature for 18 hours the reaction mixture was filtered and the solvent was removed under reduced pressure to obtain specified in the connection header (0,30 g, 99% yield). MS (ESI) m/z 344,3 [M+1]+.

D. (S)-3-(1-Hydroxy-3-methylbutane-2-yl)-5-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-2(3H)-he.

In the vessel of borosilicate glass with thick walls was added (S)-2-(3-Amino-6-(5-isopropyl-2-methoxyphenyl)pyridine-2-ylamino)-3-methylbutane-1-ol (0,70 g, 2.04 mmol), urea (0,245 g, 4,08 mmol) is DMF (14 ml). The reaction vessel was tightly closed and placed in a microwave reactor Biotage Emrys Optimizer and irradiated at 220°C for 2700 (sec). After cooling to ambient temperature the solution are condensed and the crude substance was purified using reverse-phase HPLC (10-100% acetonitrile in water, within 18 min). The fractions containing the product were combined and concentrated under reduced pressure. The resulting material was then purified by chromatography on silica gel with obtaining specified in the title compound (0.04 g, 5% yield).1H NMR (300 MHz, DMSO-d6) δ 11,05 (s, 1H), to 7.61 (s, 1H), 7,55 (d, J=8, 1H), was 7.36 (d, J=8, 1H), 7,21 (d, J=7,5, 1H),? 7.04 baby mortality (d, J=7,5, 1H), 4,87 (t, J=5, 1H), 4,21-4,32 (m, 1H), 4.04 the-to 4.15 (m, 1H), 3,80-3,86 (m, 1H), 3,80 (s, 3H), 2,81-is 2.88 (m, 1H), 2,42-of 2.50 (m, 1H), 1,21 (d, J=7, 6H), of 1.05 (d, J=7, 3H), of 0.75 (d, J=7, 3H); MS (ESI)m/z370,3 [M+1]+.

5.1.166 EXAMPLE 166: SYNTHESIS of (R)-1-(1-PHENYLETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRIDINE-2(3H)-It

A. Ethylpyridine-2-ylcarbamate.

To a mixture of 2-hydroxypyridine (2.0 g, 21,0 mmol) and potassium carbonate (7,3 g, for 52.6 mmol) in acetone (40 ml) was added ethylchloride (5.7 g, for 52.6 mmol). After heating at 40°C overnight, the reaction mixture was passed through a layer of celite and the solvent was removed under reduced pressure. The crude substance was dissolved in ethyl acetate, washed with water (4×), dried over sodium sulfate, filtered and are condensed with obtaining specified in the header is connected to the I (2.8 g, 80%). MS (ESI) m/z 168,2 [M+1]+.

B. Ethyl 6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxylate.

A solution of 6-bromo-1H-imidazo[4,5-b]pyridine-2(3H)-she (2 g, 9.3 mmol), ethylpyridine-2-ylcarbamate (2.1 g, 12.5 mmol) and potassium carbonate (1.8 g, 12.5 mmol) in acetonitrile (20 ml) and DMF (20 ml) was heated at 75°C during the night. After concentration under reduced pressure was added water, followed by addition of 1 n HCl solution to obtain a mixture with a pH of 1. The precipitate was filtered, washed with water and dried in a vacuum oven to obtain specified in the title compound (2.3 g, 85%).1H NMR (400 MHz, DMSO-d6) δ 12,17 (Sirs, 1H), 8,18 (d, J=2, 1H), 7,98(d, J=2, 1H), 4,42 (sq, J=7, 2H), 1,35 (t, J=7, 3H); MS (ESI)m/z286,0 [M+1]+.

C. tert-Butyl 6-bromo-2-oxo-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate.

To a solution of ethyl 6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxylate (1.6 g, 5,59 mmol) and di-tert-BUTYLCARBAMATE (1.47 g, of 6.71 mmol) in tetrahydrofuran (20 ml) was added 4-dimethylaminopyridine (is 0.102 g, 0,839 mmol). The reaction mixture was stirred for 90 minutes at room temperature and was added Isopropylamine (0.40 g, of 6.71 mmol). After stirring for 30 minutes the solvent was removed under reduced pressure and the crude product was ground into powder with diethyl ether (3×2 ml) to obtain the specified title compound (1.6 g, 91%). MS (ESI) m/z 314,0 [M+1]+ .

D. (R)-tert-Butyl 6-bromo-2-oxo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate.

To a solution of tert-butyl 6-bromo-2-oxo-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate (1.6 g, 5,09 mmol), (S)-1-phenylethanol (0.75 g, 6,11 mmol) and triphenylphosphine (1.6 g, 6,11 mmol) in tetrahydrofuran (45 ml) was added diisopropylcarbodiimide (1,19 ml, 6,11 mmol). After stirring at room temperature for 1 hour the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with obtaining specified in the connection header (0,60 g, 28% yield). MS (ESI) m/z 418,2 [M+1]+.

E. Hydrochloride (R)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-2(3H)-it.

(R)-tert-Butyl 6-bromo-2-oxo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate (0,60 g of 1.43 mmol) were processed using 4.0m hydrochloric acid in dioxane (30 ml) at room temperature over night. The solvent was removed under reduced pressure to obtain specified in the title compound (0.50 g, 98% yield). MS (ESI) m/z 318,1 [M+1]+.

F. (R)-1-(1-Phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he.

In the vessel of borosilicate glass with thick walls, containing a solution of hydrochloride of (R)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-2(3H)-she (0.25 g, 0,705 mmol) and quinoline-5-Voronovo acid (0.16 g, 0,916 mmol) in DMF (18 ml), was added potassium carbonate (0.39 g, 2.82 mmol) in the de (2 ml). The reaction solution was purged by a stream of nitrogen, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0,090 g 0,078 mmol). The reaction vessel was tightly closed and placed in a microwave reactor Biotage Emrys Optimizer at 150°C for 15 minutes. After cooling to ambient temperature the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel and washed with methanol to obtain specified in the title compound (0.09 g, 35% yield).1H NMR (400 MHz, DMSO-d6) δ 11,34 (s, 1H), to 8.94 (DD, J=1,5, 4, 1H), 8,24 (d, J=8, 1H), 8,08 (d, J=8,5, 1H), 8,03 (d, J=2, 1H), 7,83 (DD, J=7, and 8.5, 1H), 7,60 (DD, J=1,7, 1H), of 7.48-rate of 7.54 (m, 3H), 7,40 (d, J=2, 1H), of 7.36 (t, 7=to 7.5, 2H), 7,28 (t, J=7,5, 1H), 5,78 (sq, J=7, 1H), 2,02 (d, J=7, 3H); MS (ESI)m/z367,2 [M+1]+.

5.1.167 EXAMPLE 167: SYNTHESIS of 1-(1-PHENYLETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-B]PYRIDINE-2(3H)-It

A. tert-Butyl 6-bromo-2-oxo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate.

To a solution of tert-butyl 6-bromo-2-oxo-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate (see Example 166.C) (0,60 g, 1.97 mmol), 1-phenylethanol (0,289 g, is 2.37 mmol) and triphenylphosphine (0,62 g, is 2.37 mmol) in tetrahydrofuran (15 ml) was added diisopropylcarbodiimide ones (0.46 ml, is 2.37 mmol). After stirring at room temperature for 1 hour the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with obtaining specified in the title is information connection (0,30 g, 36% yield). MS (ESI) m/z 418,2 [M+1]+.

B. Hydrochloride of 6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-2(3H)-it.

tert-Butyl 6-bromo-2-oxo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate (0,30 g to 0.72 mmol) were processed using 4.0m hydrochloric acid in dioxane (20 ml) at room temperature over night. The solvent was removed under reduced pressure to obtain specified in the connection header (0,23 g, 90% yield). MS (ESI) m/z 318,1 [M+1]+.

C. 1-(1-Phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he.

In the vessel of borosilicate glass with thick walls containing solution of the hydrochloride of 6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-2(3H)-she (0.125 g, 0,352 mmol) and quinoline-5-Voronovo acid (0,080 g, 0,458 mmol) in DMF (9 ml), was added potassium carbonate (of € 0.195 g of 1.41 mmol) in water (1 ml). The reaction solution was purged by a stream of nitrogen, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0,045 g, 0,039 mmol). The reaction vessel was tightly closed and placed in a microwave reactor Biotage Emrys Optimizer at 150°C for 15 minutes. After cooling to ambient temperature the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel and washed with methanol to obtain specified in the title compound (0.02 g, 16% yield).1H NMR (400 MHz, DMSO-d6) δ 11,34 (s, 1H), to 8.94 (DD, J=1,7, 4, 1H), 8,24 (who, J=8, 1H), 8,08 (d, J=8,5, 1H), 8,03 (d, J=2, 1H), 7,83 (DD, J=7, and 8.5, 1H), 7,60 (DD, J=1,7, 1H), of 7.48-rate of 7.54 (m, 3H), 7,40 (d, J=2, 1H), was 7.36 (t, J=7,5, 2H), 7,28 (t, J=7,5, 1H), 5,78 (sq, J=7, 1H), 2,02 (d, J=7, 3H); MS (ESI) m/z 367,2 [M+1]+.

5.1.168 EXAMPLE 168: SYNTHESIS of (R)-1-(1-PHENYLETHYL)-6-(QUINOLINE-5-yl)-1H-imidazo[4,5-C]PYRIDINE-2(3H)-It

A. ((1R)-1-Phenylethyl)(2-bromo-5-nitro(4-pyridyl))amine.

To a solution containing 2,4-dibromo-5-nitropyridine (500 mg, about 1.75 mmol) and diisopropylethylamine (314 μl, of 1.80 mmol) in tetrahydrofuran (8 ml), at 0°C was added (R)-(+)-1-phenylethylamine (225 mg, of 1.86 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. After starting material was completely consumed (monitored by using IHMS), the solution are condensed under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with water and dried over sodium sulfate, filtered and are condensed to obtain (5.6 g, 99%) of product. MS (ESI) m/z 322 [M+1]+.

B. ((1R)-1-Phenylethyl)(5-nitro-2-(5-chinolin)(4-pyridyl))amine.

((1R)-1-Phenylethyl)(2-bromo-5-nitro(4-pyridyl))amine (5.6 g, a 1.75 mmol) and 5-hinolinovogo acid (393 mg, of 2.27 mmol) was dissolved in DMF (25 ml). The solution was barbotirovany nitrogen gas for 2 minutes. Then was added potassium carbonate (970 mg, 7,00 mmol) in water (5 ml) followed by addition of tetrakis(triphenylphosphine)palladium(0) (0,175 mmol). The solution is then heated to 85°C in nitrogen atmosphere for the of 1 hour. The solution are condensed under reduced pressure and the crude product was diluted with ethyl acetate and filtered through a layer of silica gel. The obtained filtrate are condensed under reduced pressure to obtain specified in the title compound (502 mg, 77%). MS (ESI) m/z 371 [M+1]+.

C. ((1R)-1-phenylethyl)(3-amino-6-(5-chinolin)(4-pyridyl))amine

((1R)-1-Phenylethyl)(5-nitro-2-(5-chinolin)(4-pyridyl))amine (500 mg, 1.35 mmol) was dissolved in ethanol (100 ml). Added palladium on carbon (70 mg) followed by the addition of hydrogen. The reaction mixture was stirred at room temperature for 18 hours, then filtered through celite. The filtrate are condensed under reduced pressure to give the desired product (450 mg, 97,9%). MS (ESI) m/z 341 [M+1]+.

D. 1-((1R)-1-phenylethyl)-6-(5-chinolin)-4-imidazoline[4,5-c]pyridine-2-it.

((1R)-1-Phenylethyl)(3-amino-6-(5-chinolin)(4-pyridyl))amine (150 mg, 0.44 mmol) and urea (52,8 mg, 0.88 mmol) were combined in 1 methylpyrrolidine-2-Ohe (4 ml) and heated at 185°C for 2 hours. Was added water (10 ml) and the crude product collected by filtration. The product was purified using reverse-phase preparative HPLC (20-95% acetonitrile in water over 30 min) to obtain specified in the connection header (52,3 mg, 32.4 percent) as not quite white solid.1H NMR (400 MHz, DMSO-d6) δ of 11.45 (s, 1H), 8,91 (DD, J=4,10, 1,56, 1H), 8,39 (d, J=0,78, 1H), 8,33 (DDD,J=a total of 8.74, 1,71, 0,88, 1H), with 8.05 (d, J=8,49, 1H), 7,80 (DD, J=8,49, 7,13, 1H), to 7.59 (DD, J=7,22, 1,37, 1H), 7,41-7,46 (m, 3H), 7,30-7,40 (m, 3H), of 5.75 (d, J=7,22, 1H), 4.16 the (d, J=0,98, 1H), 1,87 (d, J=7,22, 3 H); MS (ESI)m/z367,0 [M+1]+.

5.1.169 EXAMPLE 169: SYNTHESIS of (S)-1-(1-PHENYLETHYL)-6-(QUINOLINE-5-YL)-1H-IMIDAZO[4,5-C]PYRIDINE-2(3H)-It

A. ((1S)-1-phenylethyl)(2-bromo-5-nitro(4-pyridyl))amine.

To a solution containing 2,4-dibromo-5-nitropyridine (500 mg, about 1.75 mmol) and diisopropylethylamine (314 μl, of 1.80 mmol) in tetrahydrofuran (8 ml), at 0°C was added (S)-(-)-1-phenylethylamine (225 mg, of 1.86 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The reaction was completed, according to GHMC, and solution are condensed under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated to give the desired product (5.6 g, 99%). MS (ESI) m/z 322 [M+1]+.

B. ((1S)-1-Phenylethyl)(5-nitro-2-(5-chinolin)(4-pyridyl))amine.

((1S)-1-Phenylethyl)(2-bromo-5-nitro(4-pyridyl))amine (5.6 g, a 1.75 mmol) and 5-hinolinovogo acid (393 mg, of 2.27 mmol) was dissolved in DMF (25 ml). The solution was barbotirovany nitrogen gas for 2 minutes. Then was added potassium carbonate (970 mg, 7,00 mmol) in water (5 ml) followed by addition of tetrakis(triphenylphosphine)palladium(0) (0,175 mmol). The solution is then heated to 85°C in nitrogen atmosphere for 1 hour. The solution are condensed at ponie nom pressure and the crude product was diluted with ethyl acetate and filtered through a layer of silica gel. The obtained filtrate are condensed under reduced pressure to obtain specified in the header of the compound (500 mg, 77%). MS (ESI) m/z 371 [M+1]+.

C. ((1S)-1-Phenylethyl)(3-amino-6-(5-chinolin)(4-pyridyl))amine.

((1S)-1-Phenylethyl)(5-nitro-2-(5-chinolin)(4-pyridyl))amine (500 mg, 1.35 mmol) was dissolved in ethanol (100 ml). Added palladium on carbon (80 mg) followed by a balloon of hydrogen. The reaction mixture was stirred at room temperature for 18 hours, then filtered through celite. The filtrate are condensed under reduced pressure to get crude product (450 mg, 97,9%). MS (ESI) m/z 341 [M+1]+.

D. (S)-1-(1-Phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-c]pyridine-2(3H)-he

((1S)-1-Phenylethyl)(3-amino-6-(5-chinolin)(4-pyridyl))amine (450 mg, 1,32 mmol) and urea (158 mg, of 2.64 mmol) were combined in 1 methylpyrrolidine-2-Ohe (4 ml) and heated at 185°C for 2 hours. Was added water (10 ml) and the crude product collected by filtration. The product was purified using reverse-phase preparative HPLC (20-95% acetonitrile in water over 30 min) to give the product (of 92.9 mg, 19%) as not quite white solid.1H NMR (400 MHz, DMSO-d6) δ of 11.45 (s, 1H), 8,91 (DD, J=4,10, 1,76, 1H), 8,39 (d, J=0,78, 1H), 8,33 (DDD, J=8,00, 1,27, 1,07, 1H), with 8.05 (d, J=8,40, 1H), 7,80 (DD, J=8,49, 7,13, 1H), to 7.59 (DD, J=7,13, 1,27, 1H), 7,41-7,47 (m, 3H), 7,29-7,41 (m, 3H), of 5.75 (d, J=7,22, 1H), 4.16 the (d, J=0,78, 1H), 1,87 (d, J=7,22, 3 H); MS (ESI) m/z 367,0 [M+1]+.

51.170 EXAMPLE 170: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(2-(METHYLAMINO)PYRIMIDINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(2-methylthio)pyrimidine-5-yl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (of 0.53 g, 1.7 mmol), 2-(methylthio)pyrimidine-5-Voronovo acid (0.35 g, 2.04 mmol), potassium phosphate (1.44 g, for 6.81 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (0.14 g, 0,17 mmol) were combined together in DMF/water (9:1 V/V, 6 ml) and subjected to interaction in accordance with the General Procedure B2. The cooled reaction mixture was diluted with ethyl acetate (50 ml) and 5% HCl (aq., 50 ml). The mixture was shaken and separated. The organic layer was washed with saturated saline (50 ml), dried over sodium sulfate, filtered and concentrated to about 5 ml volume. Was the precipitation of the product from the solution, and the product was filtered (0,46 g, 76%). MS (ESI) m/z 357,4 [M+1]+.

B. 1-(Cyclohexylmethyl)-6-(2-(methylsulphonyl)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(Cyclohexylmethyl)-6-(2-(methylthio)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-ones (0.46 g, 1,29 mmol) was dissolved in chloroform (10 ml). To the resulting solution was added m-haloperoxidase acid (0.6 g, 2.6 mmol). The mixture was stirred for 2 hours at room temperature. The reaction mixture is washed with 5% sodium bicarbonate solution (aq., 2×50 ml), water (50 ml) and then saturated saline solution. The organic layer was dried over su is hatom sodium, was filtered and concentrated to obtain the product (0,48 g, 96%). MS (ESI) m/z 389,0 [M+1]+.

C. 1-(Cyclohexylmethyl)-6-(2-(methylamino)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(Cyclohexylmethyl)-6-(2-(methylsulphonyl)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0.05 g, 0,129 mmol) was dissolved in 2 M methylamine in tetrahydrofuran (3 ml). The mixture was stirred at 70°C for 24 hours. The reaction mixture was concentrated and the residue was purified prepreparation HPLC (20-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 45 min). In the concentration of the desired fractions were obtained product (10 mg, 23%, a purity of 99.7% according to HPLC).1H NMR (400 MHz, DMSO-d6) δ of $ 11.97 (s, 1H), 8,90 (s, 2H), 8,39 (s, 1H), 7,41 (d, J=4,4, 1H), 3,71 (l,J=6,8,2H), 2,86 (d, J=4,8,2H), 1,89 (m, 1H), 1,62 (m, 5H), of 1.16 (m, 3H), of 1.03 (m, 2H); MS (ESI)m/z340,4 [M+1]+.

5.1.171 EXAMPLE 171: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(2-(2-METHOXYETHYLAMINE)PYRIMIDINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(2-(2-methoxyethylamine)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(Cyclohexylmethyl)-6-(2-(methylsulphonyl)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 170.B) (0.05 g, 0,129 mmol) was dissolved in tetrahydrofuran (3 ml). To the resulting solution were added 2-methoxyethylamine (0,097 g, 1,287 mmol). The mixture was stirred at 70°C for 24 hours. The reaction mixture was concentrated and the residue was purified using propre arational HPLC (20-80% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 45 min). In the concentration of the desired fractions were obtained product (15 mg, 30%, purity 100% according to HPLC).1H NMR (400 MHz, DMSO-d6) δ 12,00 (s, 1H), 8,89 (s, 2H), 8,39 (s, 1H), 7,47 (t, J=5,6, 1H), 3,70 (d, J=7,2,2H), 3,48 (d, J=5,2,4H), of 3.27 (s, 3H), 1,89 (m, 1H), 1,62 (m, 5H), 1,17 (m, 3H), 1.04 million (m, 2H); MS (ESI)m/z384,3 [M+1]+; TPL >250°C.

5.1.172 EXAMPLE 172: SYNTHESIS of (1R,4R)-4-(6-(4-HYDROXYPHENYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-1-YL)CYCLOHEXANECARBOXYLATE

A. tert-Butyl (1R,4R)-4-carbamoylaspartate.

(1R,4R)-4-(tert-Butoxycarbonyl-amino)cyclohexylcarbonyl acid (1.7 g, of 6.99 mmol), ammonium chloride (560 mg, 10.5 mmol), hexaflurophosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (2.66 g, of 6.99 mmol), triethylamine (2,92 ml, 20,96 mmol) and acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered and washed with fresh acetonitrile. The solid was dried in vacuum to obtain the product (1,57 g, 93% yield) as a white solid. MS (ESI) m/z 242,9 [M+1]+.

B. (1R,4R)-4-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic.

tert-Butyl (1R,4R)-4-carbamoylaspartate (0.5 g, 2,063 mmol) was treated with a 4 n solution of hydrochloric acid in dioxane for 2 hours at room temperature. The reaction mixture was concentrated to obtain a white solid ve is esta. Solid (1R,4R)-4-aminocyclohexanecarboxylic was combined with 3,5-dibromopyridin-2-amine (0,522 g 2,063 mmol), diisopropylethylamine (0,721 ml of 4.13 mmol) and methylsulfoxide (4 ml) and heated in a microwave reactor Biotage Emrys Optimizer for 2 hours at 150°C. the Product was purified using chromatography on silica gel (0-100% (5% methanol in ethyl acetate in hexane) to highlight diamine, (1R,4R)-4-(3-amino-6-bromopyrazine-2-ylamino)cyclohexanecarboxylic. The resulting diamine was combined with 1,1'-carbonyl diimidazol (0,669 g of 4.13 mmol) and dioxane (4 ml) and heated in a microwave reactor Biotage Emrys Optimizer for 10 minutes at 100°C. the resulting material was purified by chromatography on silica gel (0-100% (5% methanol in ethyl acetate in hexane). Selected fractions were concentrated and then triturated to powder with simple ether to obtain a white solid (85 mg, 12% yield from 3 stages). MS (ESI) m/z 340,0 [M]+, 342,0 [M+2]+.

C. (1R,4R)-4-(6-(4-Hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic.

(1R,4R)-4-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic (85 mg, 0.25 mmol), 4-hydroxyphenylarsonic acid (41 mg, 0.3 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (10 mg, 0.012 mmol), 1 M sodium carbonate (0.75 ml, 0.75 mmol) and dioxane (3 ml) was heated in a Biotage microwave reactor Emrys Otimizer at 150°C for 1 hour. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layer was concentrated and then purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and the resulting material was ground into powder with 10% methanol in diethyl ether to obtain white solid (37 mg, 42% yield).1H NMR (400 MHz, DMSO-d6) δ 11,92 (s, 1H), 9,71 (s, 1H), at 8.36 (s, 1H), 7,86 (d, J=8,6, 2H), 7,31 (s, 1H), 6.87 in (d, J=8,6, 2H), 6,77 (s, 1H), 4,23 (m, 1H), of 2.38 (m, 2H), 2,22 (m, 1H), of 1.88 (m, 4H), of 1.52 (m, 2H); MS (ESI)m/z354,3 [M+1]+; TPL 324-326°C.

5.1.173 EXAMPLE 173: SYNTHESIS of (1S,4S)-4-(6-(4-HYDROXYPHENYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-1-YL)CYCLOHEXANECARBOXYLATE

A. tert-Butyl (1S,4S)-4-carbamoylaspartate.

(1S,4S)-4-(tert-Butoxycarbonylamino)cyclohexanecarbonyl acid (1.7 g, of 6.99 mmol), ammonium chloride (560 mg, 10.5 mmol), hexaflurophosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (2.66 g, of 6.99 mmol), triethylamine (2,92 ml, 20,96 mmol) and acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered and then washed with fresh acetonitrile. The solid was dried in vacuum to obtain specified in the title compound (1.5 g, 89% yield) as a white solid prophetic the STV. MS (ESI) m/z 243,3 [M+1]+.

B. (1S,4S)-4-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic.

tert-Butyl (1S,4S)-4-carbamoylaspartate (1.5 g, 6.2 mmol) was treated with a 4 n solution of hydrochloric acid in dioxane (5 ml) for 2 hours at room temperature. The reaction mixture was concentrated to obtain a white solid. The solid was combined with 3,5-dibromopyridin-2-amine (1.7 g, 7 mmol), diisopropylethylamine (3.6 ml, 21 mmol) and methylsulfoxide (4 ml) and heated in a microwave reactor Biotage Emrys Optimizer for 2 hours at 150°C. the resulting material was purified on silica gel (0-100% (5% methanol in ethyl acetate in hexane) to highlight diamine, (1S,4S)-4-(3-amino-6-bromopyrazine-2-ylamino)cyclohexanecarboxylic. The resulting diamine was combined with 1,1'-carbonyl diimidazol (0,669 g of 4.13 mmol) and dioxane (4 ml) and heated in a microwave reactor Biotage Emrys Optimizer for 10 minutes at 100°C. the Product was purified using chromatography on silica gel (0-100% (5% methanol in ethyl acetate in hexane). Selected fractions were concentrated to obtain the product. MS (ESI) m/z 340,0 [M]+, 342,0 [M+2]+.

C. (1S,4S)-4-(6-(4-Hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b] pyrazin-1-yl)cyclohexanecarboxylic.

(1S,4S)-4-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic (200 mg, 0.59 mmol), hydroxyphenylarsonic acid (97 mg, 0.71 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (24 mg, 0,029 mmol), 1 M sodium carbonate (1.7 ml, 1.7 mmol) and dioxane (3 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 1 hour. The reaction mixture is brought to pH 7 using 1 n hydrochloric acid solution and then was extracted with water and ethyl acetate. The organic layer was concentrated and purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were concentrated and the resulting material was ground into powder with 10% methanol in diethyl ether to obtain white solid (90 mg, 43% yield).1H NMR (400 MHz, DMSO-d6) up 11,86 δ (s, 1H), 9,67 (s, 1H), at 8.36 (s, 1H), to $ 7.91 (d, J=9,0, 2H), 7,27 (s, 1H), 6,92 (s, 1H), 6.87 in (d, J=8,6, 2H), 4,22 (m, 1H), 2,61 (m, 3H), 2,45 (width, s, 1H), 2,21 (d, J=13,7, 2H), 1.57 in (m, 4H); MS (ESI)m/z354,3 [M+1]+; TPL 310-312°C.

5.1.174 EXAMPLE 174: SYNTHESIS of 6-(5-(HYDROXYMETHYL)THIOPHENE-2-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(5-(Hydroxymethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

To a solution of 5-formylthiophene-2-Voronovo acid (100 mg, 0,639 mmol) in methanol (2 ml) was added borohydride sodium (242 mg, to 6.39 mmol). The mixture was stirred at 25°C for 10 minutes. Added 6-bromo-1-((tetrahydro-2H-Piran-4-yl)METI is)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 101.B) (100 mg, 0,319 mmol), dichloro[1,1'-bis(diphenyl-phosphino)ferrocene]palladium(II)· dichloromethane (0.05 g, 0.06 mmol), water (2 ml) and dioxane (2 ml) and the reaction mixture was heated in a microwave reactor Biotage Emrys Optimizer at 140°C for 30 minutes. The reaction mixture was then extracted with ethyl acetate (3×25 ml) and washed with an aqueous solution of sodium bicarbonate (3×25 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was subjected to purification using chromatography on silica gel (100% ethyl acetate). In the concentration of the desired fractions were obtained is indicated in the title compound in the form of not-quite-white solid (0,g, 77%).1H NMR (400 MHz, DMSO-d6) δ a 12.03 (s, 1H), to 8.41 (s, 1H), 7,56 (d, J=3,6, 1H), 7,56 (d, J=3,6, 1H), of 6.96 (d, J=3,6, 1H), of 5.53 (t, J=5,6, 1H), with 4.64 (d, J=5,6, 2H), 3,84-3,82 (m, 2H), of 3.73 (d, J=6,8, 2H), 3,28-up 3.22 (m, 2H), 2,11 (m, 1H), 1,57-and 1.54 (m, 2H), 1,35-1,25 (m, 2H); MS (ESI)m/z347,1 [M+1]+.

5.1.175 EXAMPLE 175: SYNTHESIS of 6-(3-(HYDROXYMETHYL)THIOPHENE-2-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(3-(Hydroxymethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

To a solution of 3-formylthiophene-2-Voronovo acid (0.156 g, 1 mmol) in methanol (2 ml) was added tetrahydroborate sodium (0,378 g, 10,00 mmol). The mixture was stirred at 25°C for 10 minutes. Then was added 6-bromo-1-((tetrahydro-2H-Piran-4 and is)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 101.B) (of) 0.157 g, 0,500 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (0,041 g 0,050 mmol), potassium carbonate (was 0.138 g, 1.000 mmol), 1,4-dioxane (2 ml) and water (6,00 ml). The reaction mixture was heated in a microwave reactor Biotage Emrys Optimizer at 140°C for 30 minutes. The reaction mixture was then extracted with ethyl acetate (3×25 ml) and washed with an aqueous solution of sodium bicarbonate (3×25 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was subjected to purification using chromatography on silica gel (100% ethyl acetate). In the concentration of the desired fractions were obtained is indicated in the title compound (0,070 g, 40.4 percent) as not quite white solid.1H NMR (400 MHz, DMSO-d6) δ 12,09 (s, 1H), to 8.20 (s, 1H), 7,54 (d, J=5,2, 1H), 7,21 (d, J=5,2, 1H), and 5.30 (t, J=5,4, 1H), 4,67 (d, J=5,6, 2H), 3,85-3,82 (m, 2H), of 3.73 (d, J=7,2, 2H), 3.27 to up 3.22 (m, 2H), 2,15-2,07 (m, 1H), 1,57-and 1.54 (m, 2H), 1,34 is 1.23 (m, 2H); MS (ESI)m/z347,1 [M+1]+.

5.1.176 EXAMPLE 176: SYNTHESIS of 6-(5-(2-HYDROXYETHYL)THIOPHENE-2-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(5-(2-Hydroxyethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

To a solution of 2-(5-bromothiophene-2-yl)ethanol (0,207 g, 1 mmol) [JACS 2001, p1 1600] in DMSO (3 ml) was added potassium acetate (0,294 g, 3 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (0,041 g, mmol 0,050), 4,4,4,4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0,381 g, 1.5 mmol). The mixture was stirred at 80°C for 16 hours. To the reaction mixture were added 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (of) 0.157 g, 0,500 mmol), potassium carbonate (was 0.138 g, 1.000 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (0,041 g 0,050 mmol), water (2 ml) and 1,4-dioxane (8 ml). The reaction mixture was heated in a microwave reactor Biotage Emrys Optimizer at 140°C for 30 minutes. The reaction mixture was then extracted with ethyl acetate (3×25 ml) and washed with an aqueous solution of sodium bicarbonate (3×25 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was subjected to purification using chromatography on silica gel (5% methanol in ethyl acetate). In the concentration of the desired fractions were obtained is indicated in the title compound in the form of not-quite-white solid (0,047 g, 26%).1H NMR (400 MHz, DMSO-d6) δ 12,02 (s, 1H), scored 8.38 (s, 1H), 7,54 (d, J=3,6, 1H), to 6.88 (d, J=3,6, 1H), 4,85 (t, J=5,2, 1H), 3,84-3,82 (m, 2H), and 3.72 (d, J=7,2, 2H), 3,67-3,62 (m, 2H), 3.27 to up 3.22 (m, 2H), 2,96 of 2.92 (m, 2H), 2,15-2,07 (m, 1H), 1.56 to 1,53 (m, 2H), 1,34 is 1.23 (m, 2H); MS (ESI)m/z361,0 [M+1]+.

5.1.177 EXAMPLE 177: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(PYRROLIDIN-2-YLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 2-((3-amino-6-bromopyrazine-2-ylamino)methyl)pyrrolidin-1-carboxylate

3,5-Dibromopyridin-2-amine (2.24 g cent to 8.85 mmol), tert-butyl 2-(amine is methyl)pyrrolidin-1-carboxylate (1,95 g, 9,54 mmol) and diisopropylethylamine (1,74 g, 17 mmol) was dissolved in n-butanol (3 ml) and heated in a sealed tube to 110°C for 48 hours. The mixture was purified using chromatography on silica gel (20% ethanol in ethyl acetate) to obtain the specified title compound (2 g, 62.5% of output). MS (ESI) m/z 372,2 [M]+, 374,2 [M+2]+.

B. tert-Butyl 2-((6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl) pyrrolidin-1-carboxylate

tert-Butyl 2-((3-amino-6-bromopyrazine-2-ylamino)methyl) pyrrolidin-1-carboxylate (2.0 g, 5.4 mmol), 1,1'-carbonyldiimidazole (1.75 g, 10,80 mmol) and tetrahydrofuran (7 ml) were combined in a sealed tube and heated to 120°C during the night. The solvent was removed and the crude product was purified using chromatography on silica gel (20% hexane in ethyl acetate) to obtain the specified title compound (1.73 g, 80% yield). MS (ESI) m/z 398 [M]+, 400 [M+2]+.

C. tert-Butyl 2-((6-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)pyrrolidin-1-carboxylate.

tert-Butyl 2-((6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)pyrrolidin-1-carboxylate (0.5 g, 1.25 mmol), 4-hydroxyphenylarsonic acid (0.17 g, 1.25 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0,103 g, 0,126 mmol) and sodium carbonate (0,665 g, 6,28 mmol) was subjected to interaction in tip is of 40 minutes in 1,4-dioxane (4 ml) according to General Procedure B2 and purified using chromatography on silica gel (60% ethyl acetate in hexane) to obtain the specified title compound (0.21 g, 41,4% yield). MS (ESI) m/z 412,4 [M+1]+.

D. Hydrochloride 6-(4-hydroxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

tert-Butyl 2-((6-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)pyrrolidin-1-carboxylate (0.2 to 1 g, 0.52 mmol) was dissolved in 1,4-dioxane (3 ml)was added 1 M hydrochloric acid in 1,4-dioxane (1 ml) and the mixture was stirred at room temperature for 48 hours. The solvent was removed, the resulting residue was ground into powder with methanol and filtered to obtain specified in the title compound (0.11 g, 61% yield).1H NMR (400 MHz, DMSO-d6) δ 12,09 (s, 1H), 9,768 (s, 1H), 9,4 (Sirs, 1H), 8,68 (Sirs, 1H), 8,415 (s, 1H), 7,906 (d, J=8,8, 2H), 6,873 (d, J=8,8, 2H), 4,19 (d, J=6,8, 2H), with 3.89 (m, 1H), 3,30 (m, 1H), 3,13 (m, 1H), and 2.14 (m, 1H), 1,97 (m, 2H), 1,79 (m, 1H); MS (ESI)m/z312,1 [M+1]+; TPL 178-180°C.

5.1.178 EXAMPLE 178: SYNTHESIS of 6-(4-(4H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-(PIPERIDINE-1-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-N2-(2-(piperidine-1-yl)ethyl)pyrazin-2,3-diamine.

3,5-Dibromopyridin-2-amine (1.54 g, 5,91 mmol), 2-(piperidine-1-yl)ethanamine and diisopropylethylamine (1,74 g, 17 mmol) was dissolved in n-butanol (5 ml) and heated in a sealed tube at 110°C over night. The mixture was purified using chromatography on silica gel (20% ethanol in ethyl acetate) to obtain the specified title compound (1.3 g, 73,3% yield). MS (ESI) m/z 300 [M]+, 302 [M+2]+.

. 6-Bromo-1-(2-(piperidine-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he

6-Bromo-N2-(2-(piperidine-1-yl)ethyl)pyrazin-2,3-diamine (1.27 g, to 4.23 mmol), 1,1'-carbonyldiimidazole (1,37 g, 8,46 mmol) and tetrahydrofuran (5 ml) were combined in a sealed tube and heated to 110°C over night. The solvent was removed and the residue was treated with water and extracted into ethyl acetate, dried over magnesium sulfate, filtered and concentrated. After the mixture was allowed to settle, there was precipitation of the desired product, and it was collected by filtration to obtain specified in the connection header in the form of a reddish-brown solid (1.2 g, 87% yield). MS (ESI) m/z 326,2 [M]+, 328,2 [M+2]+.

C. 4-(2-Oxo-3-(2-(piperidine-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile.

6-Bromo-1-(2-(piperidine-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (1.2 g, 3,68 mmol), 4-cyanoaniline acid (0,595 g of 4.05 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (0.3 g, 0,368 mmol) and potassium phosphate (3.12 g, 14.7 mmol) were combined in DMF (9 ml) and was heated in a sealed tube to 100°C during the night. The flask was cooled to room temperature and the reaction mixture was filtered through celite, washed with methanol and ethyl acetate. The filtrate and wash liquid were combined, concentrated and treated with water. The product of the extras who were garofali in ethyl acetate, the organic layer was concentrated and the resulting material was subjected to purification using chromatography on silica gel (60-100% ethyl acetate in hexane) to obtain the specified title compound (0.5 g, 39% yield). MS (ESI) m/z 349,3 [M+1]+.

D. Hydrochloride ethyl 4-(2-oxo-3-(2-(piperidine-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate.

4-(2-Oxo-3-(2-(piperidine-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile (0.5 g, was 1.43 mmol) was placed in anhydrous ethanol (5 ml) and cooled in an ice bath. In containing a mixture of the vessel was loaded with gaseous hydrogen chloride for 15 minutes, covered with a lid and left to stir overnight, warming up to room temperature. The solvent was removed and the residue was treated with simple ether, filtered and dried in high vacuum to obtain specified in the title compound (0.4 g, 64,6% yield). MS (ESI) m/z 395,6 [M+1]+.

E. Hydrochloride 6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-(piperidine-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

Hydrochloride ethyl 4-(2-oxo-3-(2-(piperidine-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (0.4 g, 1.01 mmol), formic hydrazide (0,183 g, 3.04 from mmol) and triethylamine (0,42 ml, 3.04 from mmol) were combined in methanol (4 ml) and heated in a sealed tube at 100°C for 3 hours. The reaction mixture was cooled to room temperature and purified the ri using reversed-phase prepreparation HPLC (5-100% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). Pure fractions were collected and concentrated and the obtained solid substance was processed using hydrochloric acid in a simple ether, filtered and dried in high vacuum to obtain specified in the title compound (0.035 g, 8.1% yield).1H NMR (400 MHz, DMSO-d6) δ 8,64 (s, 1H), and 8.50 (s, 1H), to 8.20 (d, J=8,4, 2H), 8,15 (d, J=8,4, 2H), 4,34 (m, 2H), 3,76 (d, J=10,8, 2H), 3,53 (m, 2H), 2,98 (t, J=10,8, 2H), to 1.86 (m, 2H), 1.70 to (m, 2H), 1,5 (m, 2H); MS (ESI)m/z391,5[M+1]+; TPL 194-197°C.

5.1.179 EXAMPLE 179: SYNTHESIS of 6-(2-AMINOBENZIMIDAZOLE-5-YL)-1-(CYCLOHEXYLMETHYL)-4-IMIDAZOLINE[4,5-b]PYRAZIN-2-It

A. Dihydrochloride 6-(2-aminobenzimidazole-5-yl)-1-(cyclohexylmethyl)-4-imidazoline[4,5-b]pyrazin-2-it.

tert-Butyl 2-(bis(tert-butoxycarbonyl)amino)-5-(tributylstannyl)-1H-benzo[d]imidazol-1-carboxylate (480 mg, 0.80 mmol), 6-bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (250 mg, 0.80 mmol), dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0,008 mmol) in DMF (5 ml) subjected interaction for 1.5 hours at 90°C. the Product was purified using reverse-phase prepreparation HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops)was subjected to ultrasonic processing, and concentrated. This procedure was repeated for the two more times to obtain specified in the title compound (11.4 mg, 3% yield).1H NMR (400 MHz, DMSO-d6) to 12.52 δ (Sirs, 1H), 12,05 (s, 1H), 8,48 (Sirs, 2H), 7,95 (s, 1H), 7,88 (d, J=8,4, 1H), 7,43 (d, J=8,4, 1H), of 3.73 (d, J=7,6, 2H), 1.93 and (m, 1H), 1,68 (m, 2H), 1,28-of 1.23 (m, 2H), 1.18 to to 1.16 (m, 2H), 1,02 (m, 1H), 0,89-0,85 (m, 2H); MS (ESI)m/z364,2 [M+1]+.

5.1.180 EXAMPLE 180: SYNTHESIS of 6-(2-(DIMETHYLAMINO)-1H-BENZO[D]IMIDAZOL-5-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-N,N-dimethyl-1H-benzo[d]imidazol-2-amine.

A solution of 6-bromo-2-chloro-1H-benzo[d]imidazole (0.5 g, of 2.16 mmol), dimethylamine (2.0 M in methanol, 4.3 ml, 8.6 mmol), diisopropylethylamine (1.50 ml, 8.60 mmol) in n-butanol (5 ml) was heated at 105°C for 2.5 days. The reaction mixture was concentrated under reduced pressure and the crude product was purified using Biotage chromatography (0-80% ethyl acetate in hexane) to give the desired product (0.5 g, 100%) as a white solid. MS (ESI) m/z 241,3 [M+1]+.

B. tert-Butyl 6-bromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-carboxylate.

A solution of 6-bromo-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (0.5 g, of 2.08 mmol), di-tert-BUTYLCARBAMATE (0.54 g, 2.5 mmol), triethylamine (0.35 ml, 2.55 mmol) and dimethylaminopyridine (few crystals) in anhydrous tetrahydrofuran (10 ml) was left to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified using Biotage chromatography (0-55% etelaat is and in hexane) to give the desired product (0.32 g, 54%) as a white solid. MS (ESI) m/z 341,3 [M+1]+.

C. tert-Butyl 2-(dimethylamino)-6-(tributylstannyl)-1H-benzo[d]imidazol-1-carboxylate

A solution of tert-butyl 6-bromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-carboxylate (320 mg, of 0.93 mmol), hexamethyldisilane (0,22 ml of 1.03 mmol), tetrakis(triphenylphosphine)palladium(0) (107 mg, 0.09 mmol) in toluene (10 ml) was heated at 100°C for 2 hours. After the reaction was completed, toluene was removed under reduced pressure and the obtained residue was purified using Biotage chromatography (0-50% ethyl acetate in hexane) to obtain the specified title compound (230 mg, 58%). MS (ESI) m/z 425,2 [M+1]+.

D. 6-(2-(Dimethylamino)-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

tert-Butyl 2-(dimethylamino)-6-(trimethyl-stannyl)-1H-benzo[d]imidazol-1-carboxylate (230 mg, 0.54 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (170 mg, 0.54 mmol), dichlorobis(triphenylphosphine)palladium(II) (38 mg, 0.05 mmol) in DMF (5 ml) was subjected to interaction for 1.5 hours at 105°C. the Product was purified using reverse-phase prepreparation HPLC (30-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops) and subjected to ultras okoboi processing. This procedure was repeated two more times to obtain specified in the title compound (5.5 mg, 2.3% of output) in the form of cleaners containing hydrochloride salt.1H NMR (400 MHz, DMSO-d6) δ 8,44 (s, 1H), 8,03 (s, 1H), with 8.33 (s, 1H), 7,95 (DD, J=8,4, 1,6, 1H), 7,46 (d, J=8,4 1H) 3,95 (m, 2H), 3,92 (s, 3H), 3,90 (s, 3H), of 2.25 (m, 1H), 1,65 (m, 2H), 1,49-of 1.41 (m, 2H), 1.27mm (m, 2H), 0,95-0,88 (m, 2H), MS (ESI)m/z394,2 [M+1]+.

5.1.181 EXAMPLE 181: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-(PIPERIDINE-3-YLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. tert-Butyl 3-((3-amino-6-bromopyrazine-2-ylamino)methyl)piperidine-1-carboxylate.

In a sealed tube a solution of 5-bromopyrazine-2,3-diamine (1.88 g, 7,46 mmol), tert-butyl 3-(aminomethyl)piperidinecarboxylate (2.0 g, was 9.33 mmol), diisopropylethylamine (1,95 ml, 11,19 mmol) in n-butanol (200 ml) was heated at 120°C for 17 hours. Volatiles were removed under reduced pressure. The residue was taken for absorption in hexane and subjected to ultrasonic treatment. The precipitate was collected by filtration to obtain specified in the title compound (1.7 g, 61%). MS (ESI) m/z 387,3 [M+1]+.

B. tert-Butyl 3-((6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate.

In a sealed tube a solution of tert-butyl 3-((3-amino-6-bromopyrazine-2-ylamino)methyl)piperidine-1-carboxylate (1.7 g, to 4.41 mmol), 1,1'-carbonyldiimidazole (0.9 g, 5.51 mmol) in tetrahydrofuran (10 ml) was heated at 110°C. Volatile substances is tion was removed under reduced pressure. The resulting residue was taken for absorption in hexane and diethyl ether, subjected to ultrasound treatment and the precipitate was collected by filtration, washed with hexane and dried in a vacuum oven to obtain the product (0,59 g, 26% yield) as a reddish brown solid. MS (ESI) m/z 413,3,2 [M+1]+.

C. 6-(4-Hydroxyphenyl)-1-(piperidine-3-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

tert-Butyl 3-((6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (0.5 g, to 1.21 mmol), 4-hydroxyphenylarsonic acid (0.16 g, to 1.21 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (0.1 g, 0.12 mmol) were combined in DMF (30 ml). Was added potassium phosphate (1,02 g, 4,84 mmol) in water (10 ml) and the reaction mixture was stirred at 100°C for 2 hours. The cooled reaction solution was filtered through celite and the filter cake was washed with ethyl acetate. The an ethyl acetate filtrate and washing were combined and the solvent was removed under reduced pressure. The compound was purified using reverse-phase prepreparation HPLC (20-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops) and subjected to ultrasonic treatment. This procedure was repeated twice. The resulting substance was dried in the Aquum during the night with obtaining specified in the connection header as not quite white solids, to 99.2% purity (10.1 mg, 2.2 per cent).1H NMR (400 MHz, DMSO-d6) δ with 8.33 (s, 1H), a 7.85 (d, J=8,4,2H), 6,86 (d, J=8,4,2H), 3,99 (m, 2H), 3.43 points is 3.40 (m, 1H), 2,92-of 2.86 (m, 2H), 2,01 is 1.96 (m, 2H), 1,47-of 1.27 (m, 3H), 0.95 to-0,88 (m, 1H); MS (ESI)m/zto 326.1 [M+1]+.

5.1.182 EXAMPLE 182: SYNTHESIS of 6-(4-(5-OXOPYRROLIDIN-2-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 7a-(4-Bromophenyl)-3-vinyltetrahydrofuran[2,l-b]oxazol-5(6H)-he.

Racemic phenylglycinol (6,40 g, to 46.7 mmol), 4-(4-bromophenyl)-4-oxobutanoic acid (12.0 g, to 46.7 mmol) and toluene (50 ml) were combined in a 100 ml round bottom flask with a rod stirrer, was intensively stirred and heated at 120°C using traps Dean-stark and back of the refrigerator under nitrogen atmosphere for 16 hours. Flash chromatography (15-30-50% ethyl acetate in hexane) gave the desired product as a white solid (12,77 g, 76%). Rf= 0,23 (30% ethyl acetate in hexane);1H NMR (400 MHz, DMSO-d6) δ 7,51-7,56 (m, 2H), 7,42-7,47 (m, 2H), 7,15-7,26 (m, 3H), 7,05-7,10 (m, 2H), is 5.06 (t, J=8,20, 1H), 4,78-4,84 (m, 1H), 3,63 (t, J=8,79, 1H), 2,98-3,10 (m, 1H), of 2.51 at 2.59 (m, 2H), 2,17-of 2.27 (m, 1H); MS (ESI)m/z359[M+1]+.

B. 5-(4-Bromophenyl)pyrrolidin-2-it.

7a-(4-Bromophenyl)-3-vinyltetrahydrofuran[2,1-b]oxazol-5(6H)-he (8,61 g of 24.0 mmol) was dissolved in dichloromethane (120 ml) under stirring in nitrogen atmosphere and cooled to -75°C. was Added titanium tetrachloride (3,95 ml, at 36.1 mmol) and the resulting mixture was stirred for 5 minutes at 75°C. Added triethylsilane (USD 5.76 ml, at 36.1 mmol) and the resulting mixture was stirred for 3 hours while slowly warming to 10°C. was Added a saturated solution of ammonium chloride to extinguish the reaction. The resulting mixture was diluted with dichloromethane and was intensively stirred for 10 minutes. The mixture was filtered through celite to remove the white salts and the filter cake washed with dichloromethane. The layers of the filtrate were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and dried in vacuum to obtain a yellow oil, which was used in the next stage without purification. The obtained yellow oil was dissolved in tetrahydrofuran (120 ml) and cooled to 0°C under stirring in nitrogen atmosphere. Added thionyl chloride (3,50 ml, 48.1 mmol). The cooling bath was removed and the reaction mixture was stirred for 15 minutes while slowly warming to room temperature. Added additional amount of thionyl chloride (1 ml, 13.7 mmol) and the resulting mixture was stirred for 1 hour. All volatiles were removed on a rotary evaporator. The obtained residue was dissolved in ethanol (80 ml) at room temperature under stirring in nitrogen atmosphere. Added ethoxide sodium (45 ml 21% wt. solution in ethanol, 120 mmol) poluchennuyu turbid mixture was stirred for 40 hours at room temperature. All volatiles were removed on a rotary evaporator. The residue was processed using dichloromethane (100 ml) and 1 M sodium bisulfate in water (200 ml). The resulting mixture was shaken in a separating funnel with the receipt of two transparent layers. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated on a rotary evaporator. The obtained residue was dissolved in tetrahydrofuran (175 ml) under stirring at 70°C. was Added 1 M hydrochloric acid in water (48 ml) and the resulting mixture was heated at 70°C boiling under reflux in nitrogen atmosphere for about 1.75 hours. The tetrahydrofuran was removed on a rotary evaporator. Added solid sodium bicarbonate (6,10 g) followed by the addition of additional quantities of water and dichloromethane. After all the acid has been neutralized, the mixture was shaken in a separating funnel and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator almost dry (particulate matter was deposited). The resulting mixture was diluted with hexane and the solids were collected by means of filtration under vacuum. The solids were washed three times with hexane and dried in vacuum to give the desired product (4,74 g, 82%) as not much is m white solid. 1H NMR (400 MHz, DMSO-d6) δ 8,11 (s, 1H), 7,52-7,58 (m, 2H), 7.23 percent-7,30 (m, 2H)and 4.65 (t, J=7.03, YOU, 1H), 2,39-2,49 (m, 1H), 2,22 (t, J=8,00, 2H), 1,71 (m, 1H); MS (ESI)m/z241 [M+1]+.

C. 6-Bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

3,5-Dibromopyridin-2-amine (9,79 g of 38.7 mmol) was dissolved in dimethyl sulfoxide (12 ml) with stirring in 150 ml hermetically closed vessel. Added diisopropylethylamine (13,5 ml, 77.4 mmol) followed by addition of 2-(tetrahydro-2H-Piran-4-yl)ethanamine (5,00 g of 38.7 mmol). The vessel was purged with nitrogen to displace the air and hermetically closed. The reaction mixture was intensively stirred and heated at 100°C for 16 hours and then cooled to room temperature. Added 1,1'-carbonyldiimidazole (9,41 g, 58,0 mmol) and the resulting mixture was heated at 70°C. the Vessel was purged with nitrogen to displace the air and hermetically closed. The reaction mixture was intensively stirred and heated at 70°C for 3 hours and then cooled to room temperature. Added additional amount of 1,1'-carbonyldiimidazole (3,14 g, and 19.4 mmol) and the resulting mixture was heated at 70°C for 3.5 hours and then cooled to room temperature. The resulting mixture was diluted with ethyl acetate and poured into a separating funnel containing water and 50% ethyl acetate in hexane. There was a formation of solid particles, with d the long funnel was shaken. The solids were collected by means of filtration under vacuum, washed three times with water and twice as easy with ethyl ether and dried in vacuum at 45°C to give the desired product (5,57 g, 44%) as a brownish-gray solid. The second batch of solid particles collected from the filtrate to give the desired product (1,74 g, 14%) as a brownish-gray solid.1H NMR (400 MHz, DMSO-d6) δ 12,20 (width, s, 1H), 8,03 (s, 1H), 3,82 (t, J=7.03 is, 4H), 3,23 (TD, J=1,62, 1,76, 2H), 1,58 is 1.70 (m, 4H), 1,42-of 1.55 (m, 1H), 1,10-of 1.23 (m, 2H); MS (ESI)m/z327 [M+1]+.

D. 1-(2-(Tetrahydro-2H-Piran-4-yl)ethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (1,00 g, a 3.06 mmol), hexamethylditin (1.20 g, to 3.67 mmol), tetrakis(triphenylphosphine)palladium(0) (0.71 g, 0.61 mmol) and 1,4-dioxane (10 ml) were combined in 150 ml hermetically closed vessel with a rod stirrer. The vessel was purged with nitrogen to displace the air and hermetically closed. The reaction mixture was intensively stirred and heated at 100°C for 5 hours and then cooled to room temperature. The resulting mixture was diluted with ethyl acetate and filtered through celite. The filter cake was thoroughly washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator. Flash chromatography (30-60% ethyl acetate in hexane) gave gelomyrtol (783 mg, 62%) as a yellow waxy solid. Rf=0,20 (50% ethyl acetate/hexane);1H NMR (400 MHz, DMSO-d6) δ 11,84 (s, 1H), 7,88 (s, 1H), a 3.87 (t, J=6,64, 2H), 3,80 (DD, J=11,32, 3,12, 2H), 3,18 (t, J=of 10.93, 2H), 1.60-to of 1.73 (m, 4H), 1,33 of 1.46 (m, 1H), 1,08 is 1.23 (m, 2H), 0.31 in (s, 9H); MS (ESI)m/z413[M+1]+.

E. 6-(4-(5-Oxopyrrolidin-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

5-(4-Bromophenyl)pyrrolidin-2-he (220 mg, 0,916 mmol), 1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (396 mg, 0,962 mmol), Tris(dibenzylideneacetone)dipalladium(0) (84 mg, 0,092 mmol), tri-o-tolylphosphino (56 mg, 0,183 mmol), triethylamine (of 0.38 ml of 2.75 mmol) and N,N-dimethylformamide (2.5 ml) were combined in a scintillation vessel with rod stirrer. The air from the vessel was removed and was replaced three times with nitrogen. The resulting mixture was intensively stirred and heated at 100°C in nitrogen atmosphere for 2.5 hours and then cooled to room temperature. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase prepreparation HPLC (50% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, Socrat.). The fractions containing the desired product were combined and the acetonitrile was removed on a rotary evaporator. Was added a saturated aqueous sodium bicarbonate solution to neutralize the mixture and then was extracted with dichloromethane (5×20 ml). United on the organic layers were dried over magnesium sulfate, was filtered and concentrated on a rotary evaporator almost dry (particulate matter was deposited). Residual solvent was removed with a pipette. The remaining solids were washed two times simple with ethyl ether and dried in vacuum at 5°C to give the desired product (68 mg, 18%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12,05 (width, s, 1H), 8,49 (s, 1H), 8,15 (s, 1H), 8,00 (d, J=8,20, 2H), 7,41 (d, J=8,20, 2H), 4.72 in (t, J=7.03, you, 1H), 3,93 (t, J=6,83, 2H), 3,82 (DD, J=of 10.93, 3,12, 2H), 3,21 (t, J=11,13, 2H), 2,44 is 2.55 (m, 1H), and 2.26 (t, J=8,00, 2H), 1,65-of 1.84 (m, 5H), 1,44-of 1.57 (m, 1H), 1,20 (CVD, J=12,10, 4,30, 2H); MS (ESI)m/z408 [M+1]+.

5.1.183 EXAMPLE 183: SYNTHESIS of 6-(4-(4H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-METHYL-2-MORPHOLINOPROPAN)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-N2-(2-methyl-2-morpholinopropan)pyrazin-2,3-diamine.

In the vessel of borosilicate glass with thick walls (5 ml) was added 2-amino-3,5-dibromopyrazine (559 mg, 2.21 mmol), 2-methyl-2-morpholinopropan-1-amine (350 mg, 2,212 mmol) and diisopropylethylamine (0,773 ml, was 4.42 mmol), in ethanol. The solution is then heated in a microwave reactor Biotage Emrys Optimizer at 140°C for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified using Biotage chromatography (0-15% methanol in dichloromethane) to give the desired product (555 mg, 76%) as a pale yellow oil.1H NMR (400 MHz, CD3OD) δ 7,16 (s, 1H), 3.72 points-3,63 (m, 4H), 3,39 (s, 2H), 2,2 (Shir. s, 4H), of 1.12 (s, 6H); MS (ESI)m/z330,1 [M+1]+.

B. 6-Bromo-1-(2-methyl-2-morpholinopropan)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of phosgene in toluene (20%, 2.35 ml of 4.45 mmol) was added to 6-bromo-N2-(2-methyl-2-morpholinopropan)pyrazin-2,3-diamine (550 mg, 1,67 mmol) in tetrahydrofuran (16,7 ml) at room temperature and was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and the crude product was recrystallized from hot methanol to obtain a reddish brown solid (244 mg, 41%).1H NMR (400 MHz, DMSO-d6) δ 12,20 (s, 1H), 8,03 (s, 1H), 3,76 (s, 2H), 3,51 (t, J=4,30, 4H), 2,64 of $ 2.53 (m, 4H), 1,01 (s, 6H); MS (ESI)m/z356,0 [M+1]+.

C. 6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-methyl-2-morpholinopropan)-Ls-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(2-methyl-2-morpholinopropan)-Ls-imidazo[4,5-b]pyrazin-2(3H)-he (235 mg, 0,660 mmol), hydrochloride of 4-(1H-1,2,4-triazole-5-yl)phenylboronic acid (see Example 159.D) (178 mg, 0,792 mmol), sodium carbonate (210 mg, to 1.98 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (26.9 mg, 0,033 mmol) were added to dioxane (5.5 ml) and water (0.5 ml) in a vessel of borosilicate glass with thick walls (20 ml). The solution is then heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 90 minutes. The reaction mixture was filtered and purified using reverse-phase prepreparation HPLC (5-0% acetonitrile + 0.1% of TFA in H 2O + 0.1% of TFA, over 30 min). The fractions containing pure product was passed through ion-exchange column Phenomenex Strata-X-C. the Product was isolated from the column using 2m ammonia in methanol. The solution was concentrated under reduced pressure and dried in vacuum to obtain the product as a white solid (6.8 mg, 2.5 per cent).1H NMR (400 MHz, DMSO-d6) δ 12,08 (Shir. s, 1H), 8,59 (s, 1H), 8.17-a 8,10 (m, 4H), to 3.89 (s, 2H), 3.46 in (lat. s, 4H), 2,66 (Shir. s, 4H), 1,10 (s, 6H); MS (ESI)m/z421,5 [M+1]+.

5.1.184 EXAMPLE 184: SYNTHESIS of 6-(4-(4H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(1-MORPHOLINOPROPAN-2-YL)-Ls-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-N2-(1-morpholinopropan-2-yl)pyrazin-2,3-diamine.

In the vessel of borosilicate glass with thick walls (5 ml) was added 2-amino-3,5-dibromopyrazine (789 mg, of 3.12 mmol), 1-morpholinopropan-2-amine (450 mg, of 3.12 mmol) and diisopropylethylamine (1,09 ml, 6,24 mmol), in ethanol. The solution is then heated in a microwave reactor Biotage Emrys Optimizer at 140°C for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified using Biotage chromatography (0-15% methanol in dichloromethane) to give the desired product (601 mg, 61%) as a pale yellow oil.1H NMR (400 MHz, CD3OD) δ 7,17 (s, 1H), 4,35 (Shir. s, 1H), 3,71 (Shir. s, 4H), 2,67 (Shir. s, 6H), of 1.26 (d, J=6,64, 3H); MS (ESI)m/z316,0 [M+1]+.

B. 6-Bromo-1-(1-morpholinopropan-2-yl)-Ls-imidazo[4,5-b]pyrazin-2(3H)-is called

A solution of phosgene in toluene (20%, of 1.64 ml, 3.10 mmol) was added to 6-bromo-N2-(1-morpholinopropan-2-yl)pyrazin-2,3-diamine (600 mg, 1,90 mmol) in THF (19 ml) at room temperature and was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and the crude product was recrystallized from hot methanol to obtain a reddish brown solid (324 mg, 50%).1H NMR (400 MHz, DMSO-d6) δ to 12.35 (s, 1H), 8,08 (s, 1H), 4,99-4,82 (m, 1H), 4,11-of 3.32 (m, 8H), 3.25 to a 3.01 (m, 2H), 1,53 (d, J=7.03, you, 3H); MS (ESI) m/z 342,0 [M+1]+.

C. 6-(4-(4H-1,2,4-Triazole-3-yl)phenyl)-1-(1-morpholinopropan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(1-morpholinopropan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (315 mg, 0,921 mmol), hydrochloride of 4-(1H-1,2,4-triazole-5-yl)phenylboronic acid (see Example 159.D) (249 mg, 1,105 mmol), sodium carbonate (293 mg, was 2.76 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (37,6 mg, 0.046 mmol) were added to dioxane (7,6 ml) and water (0.5 ml) in a vessel of borosilicate glass with thick walls (20 ml). The solution is then heated in a microwave reactor Biotage Emrys Optimizer at 150°C for 60 minutes. The reaction mixture was filtered and purified using reverse-phase prepreparation HPLC (5-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product was passed through ion-exchange column henomenex Strata-X-C. The product was isolated from the column using 2m ammonia in methanol. The solution was concentrated under reduced pressure and dried in vacuum to obtain the product as a white solid (32 mg, 9%).1H NMR (400 MHz, DMSO-d6) δ 12,06 (Shir. s, 1H), to 8.57 (s, 1H), 8,46 (Shir. s, 1H), 8,20-with 8.05 (m, 4H), 4,79-and 4.68 (m, 1H), 3,43-3,30 (m, 4H), 3,21-3,14 (m, 1H), 2,60-of 2.50 (m, 2H), 2.26 and-of 2.21 (m, 2H), 1,57 (d, J=7.03, you, 3H); MS (ESI)m/z407,0 [M+1]+.

5.1.185 EXAMPLE 185: SYNTHESIS of 6-(4-(PYRROLIDIN-2-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(Pyrrolidin-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

To sociallyengaged (332 mg, is 8.75 mmol) in a round bottom flask with a rod stirrer was added tetrahydrofuran (13 ml). Received the gray mixture was stirred at room temperature under nitrogen atmosphere for 5 minutes. Was added 5-(4-bromophenyl)pyrrolidin-2-he (700 mg, of 2.92 mmol) and the resulting mixture was heated at 70°C boiling under reflux in nitrogen atmosphere for 2 hours. The resulting mixture was cooled to 0°C and was suppressed by adding a saturated aqueous solution of sodium sulfate, slowly dropwise. Added a simple ethyl ester for better mixing and slaked the reaction mixture was stirred for 20 minutes at room temperature. Was added di-tert-BUTYLCARBAMATE (1.18 g, 5.41 mmol) and the resulting mixture paramesh the Wali for 1.5 hours at room temperature in a nitrogen atmosphere. The resulting mixture was filtered through celite and the filter cake was thoroughly washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator. Flash chromatography (10-30-50% ethyl acetate in hexane) to give 658 mg of colorless oil which was a mixture of products. This mixture was used in the next stage without additional purification. 323 mg viseporodicnog mixture, 1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 182.D) (407 mg, 0,990 mmol), Tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0,099 mmol), tri-o-tolylphosphino (60 mg, 0,198 mmol), triethylamine (0,41 ml of 2.97 mmol) and N,N-dimethylformamide (2.0 ml) were combined in a scintillation vessel with rod stirrer. The air from the vessel was removed and was replaced three times with nitrogen. The resulting mixture was intensively stirred and heated at 100°C in nitrogen atmosphere for 1.5 hours and then cooled to room temperature. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparative HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the desired product were combined and the entire quantity of the solvent was removed on a rotary evaporator. The obtained residue was dissolved in ethanol (4 ml) at 80°C under stirring. Added 6 n hydrochloric acid (0.35 ml, 2,10 mm is l) and the resulting clear solution was heated at 80°C boiling under reflux in nitrogen atmosphere for 30 minutes. The reaction mixture was filtered and purified using reverse-phase preparative HPLC (10-60% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The contents of the vessels with the product were combined and almost the entire quantity of the solvent was removed on a rotary evaporator. Added acetonitrile and the resulting mixture was loaded on an ion exchange column Strata from Phenomenex. The column was washed successively with water, acetonitrile, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated with the help of a 5% solution of ammonium hydroxide in methanol as eluent, concentrated on a rotary evaporator and dried in vacuum at 50°C to give the desired product (64 mg, 16%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ to 8.45 (s, 1H), to 7.93 (d, J=8,20, 2H), 7,46 (d, J=8,20, 2H), 4.09 to (t, J=to 7.61, 1H), 3,92 (t, J=6,83, 2H), 3,82 (DD, J=to 11.52, 2,93, 2H), 3,51 (width, s, 2H), 3,21 (TD, J=11,71, 1,95, 2H), 3,05 (DDD, J=9,96, to 7.61, 5,47,1H), 2,87-2,95 (m, 1H), 2,08-of 2.20 (m, 1H), 1,64-to 1.87 (m, 6H), 1,42 is 1.58 (m, 2H), 1,12-of 1.27 (m, 2H); MS (ESI)m/z394 [M+1]+.

5.1.186 EXAMPLE 186: SYNTHESIS of 6-(4-(5-OXOPYRROLIDIN-3-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. Ethyl 3-(4-bromophenyl)-4-nitrobutane.

(E)ethyl 3-(4-bromophenyl)acrylate (12.0 g, and 47.0 mmol), 1,1,3,3-tetramethylguanidine (1.0 ml) and nitromethane (100 ml) were combined in a 250 ml round bottom flask with a rod stirrer, was intensively stirred and heated at 50°C for Kip the treatment under reflux in nitrogen atmosphere for 36 hours. Microeconomy the solvent was removed on a rotary evaporator. Flash chromatography (10-30% ethyl acetate/hexane) gave the desired product (13,62 g, 92%) as a colourless oil. Rf=0,36 (30% ethyl acetate/hexane);1H NMR (400 MHz, DMSO-d6) δ 7,49-rate of 7.54 (m, 2H), 7,28-7,33 (m, 2H), 4,93-5,00 (m, 1H), 4,82-of 4.90 (m, 1H), 3,97 (CVD, J=7,09, 2,15, 2H), 3,79 (TT, J=9,18, 6,05, 1H), 2,78-to 2.85 (m, 1H), 2,65-to 2.74 (m, 1H), of 1.07 (t, J=7.03, you, 3H); MS (ESI)m/z317[M+1]+.

B. 4-(4-Bromophenyl)pyrrolidin-2-it.

Ethyl 3-(4-bromophenyl)-4-nitrobutane (2,02 g, to 6.39 mmol) was dissolved in ethanol (80 ml) and 4 M hydrochloric acid in 1,4-dioxane (16 ml), and 63.9 mmol) with stirring and cooled to 0°C in nitrogen atmosphere. Was added zinc dust (4,18 g, and 63.9 mmol) slowly in portions over 10 minutes. It was possible to observe the evolution of gas. After 30 minutes the cooling bath was removed and the grey reaction mixture was stirred for 1 hour at room temperature. The resulting mixture was filtered through celite and the filter cake was thoroughly washed with methanol. The filtrate was concentrated on a rotary evaporator. The obtained residue was dissolved in ethanol (50 ml) under stirring at room temperature. Added ethoxide sodium (24 ml of a solution of 2.68 M in ethanol, and 63.9 mmol) and the resulting cloudy mixture (alkaline pH) was stirred at room temperature overnight. The obtained turbid mixture was poured into a separating funnel containing di is Loretan (300 ml) and 1 M sodium bisulfate (80 ml). The mixture was shaken and the layers were separated. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The obtained residue was dissolved in acetonitrile and added water to cause precipitation of the solid particles. The solids were collected by means of filtration under vacuum, washed twice with water and twice with a simple ether and dried in vacuum at 45°C to give the desired product (929 mg, 61%) as orange solid.1H NMR (400 MHz, DMSO-d6) δ 7,73 (width, s, 1H), 7,49-rate of 7.54 (m, 2H), 7,25-7,31 (m, 2H), 3,55-the 3.65 (m, 2H), 3,12-3,20 (m, 1H), 2,46 is 2.55 (m, 1H), 2,23 of-2.32 (m, 1H); MS (ESI)m/z241 [M+1]+.

C. 6-(4-(5-Oxopyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

4-(4-Bromophenyl)pyrrolidin-2-he (215 mg, 0,894 mmol), 1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 182.D) (386 mg, 0,939 mmol), Tris(dibenzylidene-acetone)dipalladium(0) (82 mg, 0,089 mmol), tri-o-tolylphosphino (54 mg, 0,179 mmol), triethylamine (0,37 ml, 2.68 mmol) and N,N-dimethylformamide (2.5 ml) were combined in a scintillation vessel with rod stirrer. The air from the vessel was removed and was replaced three times with nitrogen. The resulting mixture was intensively stirred and heated at 100°C in nitrogen atmosphere for 2.5 hours and then cooled to room is temperature. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparative HPLC (20-60% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the desired product were combined and the acetonitrile was removed on a rotary evaporator. Was added a saturated aqueous sodium bicarbonate solution to neutralize the mixture and then was extracted with dichloromethane (4×20 ml). The combined organic layers were concentrated on a rotary evaporator. The obtained residue was dissolved in hot dimethyl sulfoxide was added in methanol to cause precipitation of the solid particles. The solids were collected by means of filtration under vacuum and washed sequentially with methanol, acetonitrile and ethyl ether. This procedure was repeated and the solids were dried in vacuum at 45°C to give the desired product (60 mg, 16%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ a 12.03 (width, s, 1H), 8,48 (s, 1H), of 7.97 (d, J=8,59, 2H), of 7.75 (s, 1H), 7,43 (d, J=8,59, 2H), 3,92 (t, J=6,83, 2H), 3,82 (DD, J=11,32, 2,73, 2H), 3,61-and 3.72 (m, 2H), 3,16-of 3.27 (m, 3H), 2,52-of 2.58 (m, 1H), 2,29-to 2.40 (m, 1H), from 1.66 to 1.76 (m, 4H), 1,44-of 1.57 (m, 1H), 1,14-of 1.26 (m, 2H); MS (ESI)m/z408 [M+1]+.

5.1.187 EXAMPLE 187: SYNTHESIS of 6-(4-(PYRROLIDIN-3-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(Pyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

p> To sociallyengaged (190 mg, 5.00 mmol) in a round bottom flask with a rod stirrer was added tetrahydrofuran (7 ml). Received the gray mixture was stirred at room temperature under nitrogen atmosphere for 5 minutes. Was added 4-(4-bromophenyl)pyrrolidin-2-he (400 mg, to 1.67 mmol) and the resulting mixture was heated at 65°C boiling under reflux in nitrogen atmosphere for 1.25 hours. The resulting mixture was cooled to 0°C and extinguished by slowly adding dropwise a saturated aqueous solution of sodium sulfate. Added a simple ethyl ester for better mixing and the resulting hydrated reaction mixture was stirred for 20 minutes at room temperature. Was added di-tert-BUTYLCARBAMATE (727 mg, of 3.33 mmol) and the resulting mixture was stirred for 35 minutes at room temperature in a nitrogen atmosphere. The resulting mixture was filtered through celite and the filter cake was thoroughly washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator. Flash chromatography (5-10-30% ethyl acetate in hexane) to give 204 mg of colorless oil which was a mixture of products. This mixture was combined with 1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 182.D) (205 mg, 0,499 mmol), Tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0,050 mmol), tri-o-tolylphosphino (30 mg, 0,mol), by triethylamine (of 0.21 ml, 1.50 mmol) and N,N-dimethylformamide (1.5 ml)in a scintillation vessel with rod stirrer. The air from the vessel was removed and was replaced three times with nitrogen. The resulting mixture was intensively stirred and heated at 100°C in nitrogen atmosphere for 1 hour and then cooled to room temperature. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparative HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the desired product were combined and the entire quantity of the solvent was removed on a rotary evaporator. The obtained residue was dissolved in ethanol (4 ml) at 80°C under stirring. Added 6 n hydrochloric acid (0,42 ml, 2.49 mmol) and the resulting clear solution was heated at 80°C boiling under reflux in nitrogen atmosphere for 70 minutes. The reaction mixture was filtered and purified using reverse-phase preparative HPLC (10-60% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The contents of the vessels with the product were combined and almost the entire quantity of the solvent was removed on a rotary evaporator. Added acetonitrile and the resulting mixture was loaded on an ion exchange column Strata from Phenomenex. The column was washed successively with water, acetonitrile, methanol, and then 5% hydroxide solution is of ammonia in methanol. The product was isolated with the help of a 5% solution of ammonium hydroxide in methanol as eluent and was concentrated on a rotary evaporator. The residue was ground into powder with ethyl ether to obtain a fine powder and dried in vacuum at 50°C to give the desired product (41 mg, 6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ to 8.41 (s, 1H), 7,92 (d, J=8,20, 2H), 7,37 (d, J=8,20, 2H), 3,90 (t, J=6,83, 2H), 3,82 (DD, J=1,32, 2,73, 2H), 3,59 (width, s, 1H), 3,15-of 3.31 (m, 5H), 3,02-3,10 (m, 1H), 2,96 (DDD, J=a 10.74, 7,81, to 7.61, 1H), 2,72 (DD, J=10,15, 8,20, 1H), 2,13-of 2.24 (m, 1H), 1,65-of 1.81 (m, 5H), 1,42-of 1.55 (m, 1H), 1,13-of 1.26 (m, 2H); MS (ESI)m/z394 [M+1]+.

5.1.188 EXAMPLE 188: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(PYRIMIDINE-5-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 1-(Cyclohexylmethyl)-6-(pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0,324 g 1,041 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (of 0.085 g, in 0.104 mmol), potassium phosphate (0,884 g of 4.16 mmol) and pyrimidine-5-Voronovo acid (0,181 g 1,458 mmol) were combined together in DMF:water (9:1 V/V, 5 ml) and subjected to interaction in accordance with the General Procedure B2. The reaction mixture was cooled, diluted with ethyl acetate (50 ml) and washed with 5% hydrochloric acid (aq., 50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The obtained OST is OK purified using Biotage chromatography (50% hexane in ethyl acetate). In the concentration of the desired fractions were obtained product (0,014 g, 4%) with a purity 95,1% according to HPLC.1H NMR (400 MHz, DMSO-d6) δ 12,23 (s, 1H), 9,41 (s, 2H), which 9.22 (s, 1H), 8,67 (s, 1H), 3,74 (d, J=7,2, 2H), 1.91 a (m, 1H), of 1.66 (m, 5H), of 1.18 (m, 3H), of 1.09 (m, 2H); MS (ESI)m/z311,3 [M+1]+; TPL >260°C.

5.1.189 EXAMPLE 189: SYNTHESIS of 6-(6-HERPERIDIN-3-yl)-1-((TETRAHYDRO-2H-PIRAN-4-yl)METHYL)-1H-imidazo[4,5-B]PYRAZIN-2(3H)-he

A. 6-(6-Herperidin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (0,324 g 1,041 mmol), 6-triptorelin-3-Voronovo acid (0,204 g 1,449 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (of 0.085 g, 0.104 g mmol) and potassium phosphate (of 0.878 g, 4.14 mmol) were combined together in DMF:water (9:1 V/V, 6 ml) and subjected to interaction in accordance with the General Procedure B2. The reaction mixture was cooled, diluted with ethyl acetate (60 ml) and washed with 5% hydrochloric acid (aq., 50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was ground into powder with methanol and diethyl ether (5 ml), was filtered and dried to obtain specified in the title compound (0.26 g, 76%) with a purity of 91.7% according to HPLC.1H NMR (400 MHz, DMSO-d6) δ 12,16 (s, 1H), 8,90 (l,J=2,4, 1H), 8,59 (m, 2H), 7,33 (DD, J=8,4,the 2.8,1H), a-3.84 (m, 1), of 3.78 (d, J=7,6, 2H), 3,26 (d, J=9,2, 1H), 2,13 (m, 1H), and 1.56 (d, J=10,8,2H), 1,33 (m, 2H); MS (ESI)m/z330,3 [M+1]+; TPL 220-222°C.

5.1.190 EXAMPLE 190: SYNTHESIS of 6-(6-AMINOPYRIDINE-3-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(6-Aminopyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

In the pressure vessel Parra6-(6-herperidin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 189.A) (to 0.108 g, 0,328 mmol) suspended in 7 N. solution of ammonia in methanol (10 ml). The vessel was tightly closed and heated to 160°C within 24 hours. The mixture was concentrated and the residue was subjected to prepreparation reversed-phase HPLC (5-40% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were combined and subjected to the procedure of ion exchange to separate the product as the free base (50 mg, 47%) with a purity of 99.3% according to HPLC.1H NMR (400 MHz, DMSO-d6) δ 11,85 (Shir. s, 1H), 8,59 (d, J=3,2, 1H), with 8.33 (s, 1H), 8,00 (DD, J=12,0, 3,2,1H), is 6.54 (d, J=11,6, 1H), 6,23 (s, 2H), 3,84 (DD, J=12,4, 3,2,2H), 3,76 (d, J=9,6,2H), 2,11 (m, 1H), 1.55V (d, J=14,0,2H), 1,31 (DQC., J=15,6, 5,6,2H); MS (ESI)m/z327,1 [M+1]+; TPL >260°C.

5.1.191 EXAMPLE 191: SYNTHESIS of 6-(6-(METHYLAMINO)PYRIDINE-3-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(6-(Methylamino)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

In the vessel in the high pressure Parra 6-(6-herperidin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 189.A) (is 0.102 g, 0,310 mmol), methanimidamide (0,627 g, 9,29 mmol) and triethylamine (1,254 g, KZT 12.39 mmol) were combined in tetrahydrofuran (10 ml). The vessel was tightly closed and heated to 160°C for 3 days. The reaction mixture was cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified using preparative reverse-phase HPLC (0-50% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min) and then prepreparation reversed-phase HPLC (5-45% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were subjected to the procedure of ion exchange for allocation specified in the title compound as free base (8 mg, 8%) with a purity of 97.7% according to HPLC.1H NMR (400 MHz, DMSO-d6) δ 8,67 (d, J=2,8, 1H), with 8.33 (s, 1H), 8,00 (DD, J=8,8, 2,8, 1H), 6,79 (DD, J=9,6, 4,8, 1H), is 6.54 (DD, J=9,2, 0,8, 1H), 3,83 (d, J=12,0,2H, in), 3.75 (d, J=7,2, 2H), 3,25 (t, J=10,8, 2H), 2,82 (d, J=4,8, 3H), 2.13 in (m, 1H), 1.55V (d, J=10,8, 2H), 1,31 (DCV, J=11,2, 4,4,2H); MS (ESI)m/z341,5 [M+d]+; TPL >260°C.

5.1.192 EXAMPLE 192: SYNTHESIS of N-(4-(2-OXO-3-(1-PHENYLETHYL)-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-5-YL)PHENYL)METHANESULFONAMIDE

A. N-(4-(2-Oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide.

A solution of 6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it (see Example 31.B) (0.125 g, 0,393 mmol), 4-(meth is sulphonamido)phenylboronic acid (0,084 g, 0,471 mmol), potassium phosphate (of 0.333 g, 1.57 mmol) and complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) methylene chloride (0,032 g, 0,0393 mmol) in dimethylformamide (2 ml) and water (0.6 ml) was heated at 100°C using an orbital heating plate. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude substance was purified using preparative HPLC (20-100% acetonitrile in water) to produce specified in the title compound with a purity of 96,3% (40 mg, 25%).1H NMR (400 MHz, DMSO-d6) δ 12,09 (s, 1H), to 9.91 (s, 1H), 8,46 (s, 1H), of 7.97 (d, J=8,6, 2H), 7,50 (d, J=7,0, 2H), 7.23 percent-7,38 (m, 5H), 5,72 (sq, J=7,3, 1H), 3.04 from (s, 3H), 2,01 (d, J=7,0, 3H); MS (ESI)m/z410,1 [M+1]+.

5.1.193 EXAMPLE 193: SYNTHESIS 99-PHENYL-2-(QUINOLINE-5-YL)-7H-PURINE-8(9H)-It

A. 2-Bromo-N4-phenylpyrimidine-4,5-diamine.

Aniline (0,566 g, 5,97 mmol) was added to 2-amino-3,5-dibromopyrazine (1.0 g, 3,98 mmol) in n-butanol (10 ml) and the resulting mixture was heated at 220°C for 4500 seconds in a microwave reactor Emrys Optimizer. The reaction mixture are condensed to obtain a brown oil. Purification using Biotage chromatography (10-60% ethyl acetate in hexane) gave (0,599 g, 5,62 mmol, 56%) of 2-bromo-N4-phenylpyrimidine-4,5-diamine. MS (ESI) m/z 265 [M]+, 267 [M+2]+.

B. N4-Phenyl-2-(quinoline-5-yl)pyrimidine-4,5-diamine.

2-Bromo-N4-phenylpyrimidine-4,5-diamine (0,599 g of 2.26 mmol), quinoline-5-Bo is about acid (0,469 g, a 2.71 mmol), tetrakis(triphenylphosphine)palladium (0,261 g, 0,183 mmol), potassium carbonate (1.24 g, 9,04 mmol), water (6 ml) and dimethylformamide (25 ml) was subjected to interaction in accordance with the General Procedure B. the Crude product was subjected to purification by means of chromatography on the Biotage silica gel (0-8% methanol in dichloromethane) to obtain specified in the connection header (0,140 g, 19.8% of output). MS (ESI) m/z 314.4 M. [M+1]+.

C. 9-Phenyl-2-(quinoline-5-yl)-7H-purine-8(9H)-he.

N4-Phenyl-2-(quinoline-5-yl)pyrimidine-4,5-diamine (0,140 g, 0,447 mmol) and urea (0.66 g, 1.11 mmol) was subjected to interaction in accordance with the General Procedure D2. The solution are condensed under reduced pressure and was purified using preparative HPLC (10-60% acetonitrile in water) to produce specified in the connection header (0,41 g, 15% yield). 1 N. NMR (300 MHz, CD3OD) δ 8,89 (m, J=7,8, 1H), 8,44 (d, J=7,8, 1H), to 8.20 (s, 1H), 8,13 (d, J=7,8, 1H), 7,87 (t, J=8,4, 1H), to 7.77 (d, J=6,9, 2H), 7,55 (d, J=6,3, 1H), 7,45 (m, 5H); MS (ESI)m/z340,0 [M+1]+.

5.1.194 EXAMPLE 194: SYNTHESIS of 6-(4-(5-METHYL-1H-

1,2,4-TRIAZOLE-3-yl)PHENYL)-1-(2-(2-OXOPYRROLIDIN-1-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. the Hydrochloride of 4-(5-methyl-4H-1,2,4-triazole-3-yl)phenylboronic acid.

4-Cyanoaniline acid (0,91 g, 6.2 mmol) was dissolved in absolute ethanol (100 ml) and cooled in an ice bath. Was carried out by bubbling the reaction mixture with gaseous hydrogen chloride in the Techa is their 15 minutes and left to stir for 3 days. The solution was concentrated and then washed with methanol. This procedure was repeated four times to remove all traces of hydrogen chloride to obtain white solids. The solid substance was added 2-propanol (10 ml), triethylamine (0.5 ml) and acetohydrazide (0,69 g, 9.3 mmol). The mixture was heated in a microwave reactor Biotage Emrys Optimizer to 100°C for 10 minutes. The reaction mixture was concentrated under reduced pressure and then purified on a column of silica gel (0-100% ethyl acetate in hexane, followed by addition of 0-40% methanol in ethyl acetate) to give a clear oil. The obtained oil was treated with 4 N. a solution of hydrogen chloride in dioxane. The solution was concentrated in vacuum to obtain specified in the connection header. Salt was rubbed into powder with 10% solution of methanol in diethyl ether to obtain white solid (0.8 g, 54% yield). MS (ESI) m/z to 204.1 [M+1]+.

B. 6-(4-(5-Methyl-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 162.A) (203 mg, of 0.62 mmol), hydrochloride of 4-(5-methyl-4H-1,2,4-triazole-3-yl)phenylboronic acid (152 mg, 0.75 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of an adduct with dichloromethane (25 mg, 0.03 mmol), 1 M sodium carbonate (1.9 ml, 1.9 mmol) and dioxane (3 ml) was heated in the microwave the first reactor Biotage Emrys Optimizer at 150°C for 1 hour. The reaction mixture was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were purified by extraction column solid phase Phenomenex Strata-X-C to remove TFA and then was isolated from the column using a solution of 2 M ammonia in methanol. The solution was concentrated and then triturated to powder with simple ether to obtain a white solid (16 mg, 6% yield).1H NMR (400 MHz, DMSO-d6) δ 8,56 (s, 1H), 8,16 (m, 2H), 8,08 (m, 2H), of 4.05 (m, 2H), only 3.57 (m, 2H), 3,51 (t, J=6,8, 2H), 2,41 (width, s, 3H), of 1.86 (m, 2H), 1,75 (t, J=7,4, 2H); MS (ESI)m/z391,5 [M+1]+; TPL 315-316°C.

5.1.195 EXAMPLE 195: SYNTHESIS of 6-(3-METHYL-4-(1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 4-Bromo-2-methylbenzamide.

A solution of 4-bromo-2-methylbenzonitrile (1.0 g, 5.1 mmol), triperoxonane acid (4.0 ml) and sulfuric acid (1.0 ml) were combined and heated to 65°C for 18 hours. The reaction mixture was poured into ice water, and precipitation of the product, which was collected by filtration. The resulting substance was dried in vacuum overnight to obtain specified in the title compound as a white solid (0.96 g, 88%). MS (ESI) m/z 420,5 [M+1]+.

B. (Z)-4-Bromo-N-((dimethylamino)methylene)-2-methylbenzamide.

A solution of 4-bromo-2-methylbenzamide (0,961 g of 4.49 mmol), 1,1-dimethoxy-N,N-dimethylethanol is on (10.0 ml) were combined and heated to 85°C for 3 hours. The reaction mixture was concentrated under reduced pressure and used in the next stage without additional purification (0,500 g). MS (ESI) m/z 270 [M+1]+.

C. 3-(4-Bromo-2-were)-1H-1,2,4-triazole.

(Z)-4-Bromo-N-((dimethylamino)methylene)-2-methylbenzamide (0,500 g of 1.86 mmol) was added to acetic acid (20,0 ml) and cooled to 0°C. was Added dropwise hydrazine (2.0 ml, 0.64 mmol) and the reaction mixture was allowed to warm to room temperature with stirring for 2 hours. The reaction mixture was concentrated and diluted with water (20 ml). The precipitate was collected by filtration and dried in high vacuum. The product was used in the next stage without additional purification (0,338 g). MS (ESI) m/z 239 [M+1]+.

D. 3-(4-Bromo-2-Were)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole.

3-(4-Bromo-2-were)-1H-1,2,4-triazole (0,338 g of 1.42 mmol) was added to tetrahydrofuran (15.0 ml) followed by the addition of 3,4-dihydro-2H-Piran (0,239 g, 2,84 mmol) and 4-methylbenzenesulfonic acid (0,054 g, 0.28 mmol). The solution was heated to 75°C for 2 hours. The reaction mixture was concentrated under reduced pressure and was purified using Biotage column chromatography (0-80% hexane in ethyl acetate) to give the pure product (0,239 g, 17%). MS (ESI) m/z 322,2 [M+1]+.

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

3(4-Bromo-2-were)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (0,239 g, 0,742 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0,816 g, 0,816 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,054 g, 0.07 mmol), potassium acetate (0,218 g of 2.23 mmol) and dimethylsulfoxide (2.0 ml) were combined in a sealed tube and heated at 90°C for 2 hours. The solution are condensed under reduced pressure and was purified using Biotage column chromatography (0-80% hexane in ethyl acetate) to obtain procedendo product (0,267 g)which was used directly in the next stage. MS (ESI) m/z 370,3 [M+1]+.

F. 6-(3-Methyl-4-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-he.

3-(2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (0,267 g, 0,723 mmol), 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (0,226 g, mmol 0,722), the complex [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) with dichloromethane (1:1) (0,059 g, 0.07 mmol), potassium phosphate (0,153 g, 0,722 mmol), dimethylformamide (5.0 ml) and water (2.0 ml) were combined in a sealed tube and heated at 90°C for 2 hours. The solution are condensed under reduced pressure and was purified using reverse-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 minutes is with getting procedendo product (0,134 g), which was used directly in the next stage. MS (ESI) m/z 476,5 [M+1]+.

G. 6-(3-Methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-he.

6-(3-Methyl-4-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-he (0,134 g, 0,281 mmol) was added to a solution of 6.0 M hydrogen chloride in dioxane (4.0 ml) and stirred at 25°C for 2 hours. The solution are condensed under reduced pressure and was purified using reverse-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions were combined, neutralized with ammonium hydroxide, concentrated, diluted with water (20,0 ml) and the desired product was collected by filtration to obtain specified in the connection header in the form of not-quite-white solid with a purity of 99.9% (0,040 g, 36%). 1 N. NMR (400 MHz, CD3OD) δ of 8.47 (s, 1H), 8,40 (s, 1H), to 7.99 (s, 1H), 7,92-of 7.97 (m, 1H), to 7.77 (d, J=8,20, 1H), br4.61 (width, s, 2H), 3,88-a 4.03 (m, 4H), 3,40 (TD, J=are 11.62, 2,15, 2H), 2,60 (s, 3H), 2,19-of 2.36 (m, 1H), 1,66 (DD, J=12,49, 1,95, 2H), 1,39-of 1.55 (m, 2H); MS (ESI)m/z408,5 [M+1]+; TPL 271-274°C.

5.1.196 Example 196: SYNTHESIS of 6-(4-(1H-IMIDAZOL-2-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(1H-imidazol-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-PIR is n-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (see Example 195.B) (0,300 g, from 0.76 mmol), 2,2-diethoxyethane (100 mg, from 0.76 mmol) and glacial acetic acid (0,114 ml, 1.9 mmol) were thoroughly mixed in a sealed tube and the resulting reaction mixture was stirred at 120°C for 16 hours. The resulting substance was dissolved in methanol (10 ml) and a black insoluble residue was filtered. The filtrate was purified using reverse-phase prepreparation HPLC (15-40% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated using a 5% solution of ammonium hydroxide in methanol as eluent and was concentrated on a rotary evaporator. The residue was ground into powder with ethyl ether in hexane to obtain a fine powder and dried in vacuum at 50°C to give the desired product (0,093 g, 30%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12,61 (width, s, 1H), to 8.57 (s, 1H), 8.07-a 8,18 (m, 2H), 7,94-8,08 (m, 2H), 7,29 (width, s, 1H), 7,07 (width, s, 1H), 3,95 (t, J=6,64, 2H), 3,83 (DD, J=11,13, 3,32, 2H), up 3.22 (t, J=of 10.93, 3H), 1,63-of 1.84 (m, 4H), 1.41 to of 1.62 (m, 1H), 1,09 is 1.35 (m,2H); MS (ESI)m/z391,2 [M+1]+; TPL 293-295°C.

5.1.197 EXAMPLE 197: SYNTHESIS of 6-(4-(5-(AMINOMETHYL)-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (see Example 195.B) (0,250 g to 0.63 mmol) in ethanol (20 ml) was treated with 2-hydroxyethylhydrazine (0.17 g, 1.9 mmol) and triethylamine (of 0.26 ml, 1.9 mmol) and the resulting reaction mixture was stirred in a sealed tube at 110°C for 16 hours. The cooled reaction solvent was removed under reduced pressure. The resulting material was purified using reverse-phase prepreparation HPLC (15-50% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated using a 5% solution of ammonium hydroxide in methanol as eluent and was concentrated on a rotary evaporator. The residue was ground into powder with ethyl ether in hexane to obtain a fine powder and dried in vacuum at 50°C to give the desired product (0,130 g, 49%) as a white solid. MS (ESI) m/z 422,3 [M+1]+.

B. 6-(4-(5-(Chloromethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-it is dazo[4,5-b]pyrazin-2(3H)-he.

6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0,130 g, 0.31 mmol) in thionyl chloride (2 ml) was stirred in a sealed tube at 80°C for 1 hour. The cooled reaction solvent was removed under reduced pressure. The resulting substance was dried in vacuum at 50°C to give the desired product (0,110 g, 81%) as a white solid. MS (ESI) m/z 440,0 [M+1]+.

C. 6-(4-(5-(Aminomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-(4-(5-(Chloromethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0,110 g of 0.250 mmol) in ethanol (20 ml) was treated with ammonium hydroxide (10 ml, 250 mmol) and the resulting reaction mixture was stirred in a sealed tube at 25°C for 16 hours. The reaction solvent was removed under reduced pressure. The resulting material was purified using reverse-phase prepreparation HPLC (15-50% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated using 5% ammonium hydroxide solution in meta the OLE as eluent and was concentrated on a rotary evaporator. The residue was ground into powder with ethyl ether in hexane to obtain a fine powder and dried in vacuum at 50°C to give the desired product (0,074 g, 70,4%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8,56 (s, 1H), 7,93 is 8.25 (m, 4H), a 3.87-Android 4.04 (m, 4H), 3,83 (DD, J=11,32, 2,73, 2H), up 3.22 (t, J=a 10.74, 2H), 1,63-of 1.81 (m, 4H), of 1.52 (DDD, 1H), 1.04 million to 1.34 (m, 2H); MS (ESI)m/zUAH 421,2 [M+1]+; TPL 258-260°C.

5.1.198 EXAMPLE 198: SYNTHESIS of 6-(1H-BENZO[D]IMIDAZOL-5-YL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(1H-Benzo[d]imidazol-5-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

5-Bromo-1H-benzo[d]imidazole (0,100 g, 0,487 mmol), 1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-6-(tributylstannyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 182.D) (0,200 g, 0,487 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,045 g, 0,049 mmol), tri-o-tolylphosphino (30 mg, mmol 0,100), triethylamine (0,200 ml, 1.5 mmol) and N,N-dimethylformamide (6 ml) were combined in a scintillation vessel with rod stirrer. The air from the vessel was removed and was replaced three times with nitrogen. The resulting mixture was intensively stirred and heated at 100°C in nitrogen atmosphere for 3 hours and then cooled to room temperature. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparative HPLC (20-60% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Fractions provided the desired product, was passed through the ion exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated using a 5% solution of ammonium hydroxide in methanol as eluent and was concentrated on a rotary evaporator. The residue was ground into powder with ethyl acetate in hexane to obtain fine powder and solids were dried in vacuum at 45°C to give the desired product (20 mg, 15%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8,53 (s, 1H), 8,53 (s, 1H), 8,28 (s, 1H), 8,17 (width, s, 1H), 7,88 (width, s, 1H), 7,70 (width, s, 1H), 3.96 points (t, J=6,83, 2H), 3,84 (DD, J=11,32, 2,73, 2H), 3,12 of 3.28 (m, 3H), 1,74 (sq, J=7,16, 4H), of 1.52 (m, 1H), 1,09 is 1.35 (m, 3H); MS (ESI)m/z365,1 [M+1]+; TPL 264-265°C.

5.1.199 EXAMPLE 199: SYNTHESIS of 6-(2-AMINOPYRIMIDINE-5-YL)-1-(CYCLOHEXYLMETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(2-Aminopyrimidine-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

1-(Cyclohexylmethyl)-6-(2-(methylsulphonyl)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 170.B) (0.5 g, 1,29 mmol) was dissolved in tetrahydrofuran (3 ml). The solution was cooled in an ice bath and then blew ammonia (gas) for 1 minute. The mixture was stirred at 70°C for 3 hours. The reaction mixture was concentrated and the residue was purified using preparative HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, who for 30 minutes). The fractions containing the desired product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then 7 N. solution of ammonia in methanol (10 ml). The product was suirable using a solution of ammonia in methanol. In the concentration of the eluate received the product (30 mg, 7%, purity of 94.6% according to HPLC).1H NMR (400 MHz, DMSO-d6) δ 11,96 (Sirs, 1H), cent to 8.85 (s, 2H), scored 8.38 (s, 1H), 6,95 (s, 2H), 3,71 (d, J=6,5, 2H), 1,89 (m, 1H), and 1.63 (m, 5H), 1,17 (m, 3H), of 1.02 (m, 2H); MS (ESI)m/zto 326.1 [M+1]+; TPL >250°C.

305.1.200 EXAMPLE 200: SYNTHESIS of 6-(4-HYDROXYPHENYL)-1-((1-METHYLPIPERIDIN-2-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-Bromo-N2-((1-methylpiperidin-2-yl)methyl)pyrazin-2,3-diamine.

In a tightly closed flask (1 methylpiperidin-2-yl)methanamine (1 g, 7,80 mmol), 3,5-dibromopyridin-2-amine (1,578 g, 6,24 mmol) and diisopropylethylamine (1,635 ml, 9,36 mmol) were mixed in n-butanol (30 ml) and the resulting reaction mixture was heated overnight at 115°C. After cooling, the volatiles were removed under reduced pressure. The crude product was purified using Biotage column chromatography (0-65% ethyl acetate in hexane) to obtain specified in the connection header (0,g, 1,616 mmol, 25.9% of output). MS (ESI) m/z 301,1 [M+1]+.

B. 6-Bromo-1-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A solution of 6-bromo-N2-((1-methylpiperidin-2-yl)met the l)pyrazin-2,3-diamine (0,48 g, 1,599 mmol) and 1,1'-carbonyldiimidazole (0,324 g 1,999 mmol) in anhydrous tetrahydrofuran (15 ml) was heated overnight at 115°C. Volatiles were removed under reduced pressure and the crude product was purified using Biotage column chromatography (0-15% methanol in dichloromethane) to obtain specified in the connection header (0,48 g, 1,472 mmol, 92% yield). MS (ESI) m/z 327,2 [M+1]+.

C. the Hydrochloride of 6-(4-hydroxyphenyl)-1-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-it.

6-Bromo-1-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (0.25 g, 0,766 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (0,063 g 0,077 mmol) were combined in DMF (30,0 ml). Was added potassium phosphate (0.65 g, of 3.07 mmol) in water (8.0 ml) and the reaction mixture was stirred at 100°C for 2 hours. The cooled reaction solution was filtered through celite and the filter cake was washed with ethyl acetate. The an ethyl acetate filtrate and washing were combined and the solvent was removed under reduced pressure. The resulting material was purified using reverse-phase prepreparation HPLC (10-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were concentrated, treated with 4 N. a solution of hydrochloric acid in diethyl ether (few drops) and subjected to ultrasonic treatment. This procedure was repeated another DV the times to give the desired product (0,045 g, 0.133 mmol, 17,30% yield) in the form of cleaners containing hydrochloride salt.1H NMR (400 MHz, DMSO-d6) δ 12,13 (s, 1H), 9,76 (s, 1H), charged 8.52 (s, 1H), 8,42 (s, 1H), 7,87 (d, J=8,4, 2H), 6.87 in (d, J=8,4, 2H), 4,23 (DD, J=8.4 and 5,6, 2H), 4,15-4,12 (m, 1H), 2,07 (m, 1H), of 1.84 (m, 1H), 1,76-of 1.73 (m, 2H), 1,64-1,57 (m, 2H), 1.28 (in m, 3H), 0,89-0,85 (m, 2H); MS (ESI)m/z340,1 [M+1]+.

5.1.201 EXAMPLE 201: SYNTHESIS of 6-(2-METHYL-4-(1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 4-Bromo-3-methylbenzamide.

A solution of 4-bromo-3-methylbenzonitrile (2.0 g, 5.1 mmol), triperoxonane acid (4.0 ml) and sulfuric acid (1.0 ml) were combined and heated to 65°C for 18 hours. The reaction mixture was poured into ice water, and precipitation of the product, which was filtered. The resulting substance was dried in vacuum overnight to obtain specified in the title compounds as white solids (2,12 g, 97%). MS (ESI) m/z 215,1 [M+1]+.

B. (Z)-4-Bromo-N-((dimethylamino)methylene)-3-methylbenzamide.

A solution of 4-bromo-3-methylbenzamide (2,12 g, 9,88 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (10.0 ml) was heated to 85°C for 3 hours. The reaction mixture was concentrated under reduced pressure and used in the next stage without additional purification (1,93 g). MS (ESI) m/z 270 [M+1]+.

C. 3-(4-Bromo-3-were)-1H-1,2,4-triazole.

(Z)-4-Bromo-N-((dimethylamino)methylene)-3-methylbenzamide (1,93 g, 7,17 mmol) was added to acetic acid (20,0 ml) and cooled d is 0°C. Was added dropwise hydrazine (6.0 ml, 201 mmol) and the reaction mixture was allowed to warm to room temperature with stirring for 2 hours. The reaction mixture was concentrated and diluted with water (20 ml). Was the precipitation of the product, which was filtered, dried under high vacuum and used in the next stage without additional purification (1.88 g). MS (ESI) m/z 239 [M+1]+.

D. 3-(4-Bromo-3-were)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole.

3-(4-Bromo-3-were)-1H-1,2,4-triazole (1.88 g, of 7.90 mmol) was added to tetrahydrofuran (15.0 ml) followed by the addition of 3,4-dihydro-2H-Piran (1,33 g, 15.8 mmol) and 4-methylbenzenesulfonic acid (0,300 g to 1.60 mmol). The reaction mixture was heated to 75°C for 2 hours. The reaction mixture was concentrated under reduced pressure and was purified using Biotage column chromatography (0-80% hexane in ethyl acetate) to give the pure product (0,377 g, 15%). MS (ESI) m/z 322,2 [M+1]+.

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

3-(4-Bromo-3-were)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (0,377 g at 1.17 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0,327 g, 1,29 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,086 g, 0.12 mmol), potassium acetate (0,345 g, 3,51 mmol) and dimethylsulfoxide (2.0 ml) were combined in ger is etechno a sealed tube and heated at 90°C for 2 hours. The solution are condensed under reduced pressure and was purified using Biotage column chromatography (0-80% hexane in ethyl acetate) to obtain procedendo product (0,232 g)which was used in the next stage without additional purification. MS (ESI) m/z 370,3 [M+1]+.

F. 6-(3-Methyl-4-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-he.

3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (0,232 g, 0,628 mmol), 6-bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 108.B) (0,171 g, 0,523 mmol), the complex [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,043 g, 0.05 mmol), potassium phosphate (0,444 g of 2.09 mmol), dimethylformamide (5.0 ml) and water (2.0 ml) were combined in a sealed tube and heated at 90°C for 2 hours. The solution are condensed under reduced pressure and was purified using reverse-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min) to obtain procedendo product (0,283 g)which was used in the next stage without additional purification. MS (ESI) m/z 476,5 [M+1]+.

G. 6-(3-Methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-he.

6-(3-Methyl-4-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazo the-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-he (0,283 g, 0,578 mmol) was added to 6.0 M hydrogen chloride in dioxane (4.0 ml) and stirred at 25°C for 2 hours. The solution are condensed under reduced pressure and was purified using reverse-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions were combined, neutralized with ammonium hydroxide, concentrated, diluted with water (20 ml). The desired product was collected by filtration to obtain specified in the connection header in the form of not-quite-white solid with a purity of 99.5% (0,061 g, 26%). 1 N. NMR (400 MHz, CD3OD-d4) δ 8,40 (width, s, 1H), 8,07 (s, 1H), 8,00 (s, 1H), 7,94 (d, J=8,20, 1H), 7,55 (d, J=8,20, 1H), Android 4.04 (t, J=7,22, 2H), 3,90 (DD, J=1,32, 3,51, 2H), 3,34-of 3.42 (m, 3H), 2.49 USD (s, 3H), 1.70 to to 1.87 (m, 4H), 1,58 (dddd, J=of 10.93, 7,32, 4,10, 3,81, 1H), 1,50-of 1.66 (m, 1H), 1,22-of 1.40 (m, 2 H); MS (ESI)m/z408,5 [M+1]+; TPL 258-260°C.

5.1.202 EXAMPLE 202: SYNTHESIS of 1-(CYCLOHEXYLMETHYL)-6-(6-(2-HYDROXYPROPAN-2-YL)PYRIDINE-3-YL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 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 mixture was cooled to -78°C. was Added dropwise n-utility (3,02 ml of 4.83 mmol). The mixture was stirred for 30 minutes followed by the addition of acetone (2 ml). The mixture was stirred for 40 minutes and then allowed it to warm to room temperature. The mixture is washed with 5% solution of ammonium chloride(aq., 50 ml), water (50 ml) and then saturated brine (50 ml). Organics were dried over sodium sulfate, filtered and concentrated. The residue was purified using Biotage chromatography (5:1 hexane:ethyl acetate). In the concentration of the desired fractions were obtained product (0,82 g, 86%).1H NMR (300 MHz, CDCl3) δ to 8.57 (DD, J=5,4, 0,6, 1H), 7,81 (DD, J=8,4, 2,4, 1H), 7,30 (DD, J=8,4, 0,6,1H), 4,43 (s, 1H), and 1.54 (s, 6H).

B. 2-(5-(Tributylstannyl)pyridine-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) (of 0.182 g, of) 0.157 mmol) were combined in toluene (5 ml) in a 50 ml sealed flask. The reaction mixture was stirred at 115°C for 1.5 hours. The mixture was then concentrated to about 2 ml volume. The residue was purified using Biotage chromatography (5:1 hexane:ethyl acetate). In the concentration of the desired fractions were obtained is indicated in the title compound (0.33 g, 70%).1H NMR (300 MHz, CDCl3) δ to 8.57 (DD, J=5,4, 0,6,1H), 7,81 (DD, J=8,4, 2,4, 1H), 7,30 (DD, J=5,4 0,6, 1H), 5,18 (Sirs, 1H), and 1.54 (s, 6H), of 0.35 (s, 9H).

C. 1-(Cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A 20-ml flask for microwave heating was added 6-bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 55.B) (0.17 g, 0,546 mmol), 2-(5-(tributylstannyl)pyridine-2-yl)propane-2-on the (0,164 g, 0,546 mmol) and the complex [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,089 g, 0,109 mmol) in DMF (3 ml). The mixture was then purged with nitrogen gas for 1 minute and then stirred in a microwave reactor at 140°C for 15 minutes. The mixture was concentrated and the residue was subjected to prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the desired product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then 7 N. solution of ammonia in methanol (10 ml). The product was suirable using ammonia in methanol. In the concentration of the eluate received the product (11 mg, 5%, purity 96,9% according to HPLC).1H NMR (400 MHz, DMSO-d6) δ 9,10 (DD, J=2,4, 0,8, 1H), charged 8.52 (s, 1H), 8,32 (DD, J=7,6, 2,4, 1H), of 7.75 (DD, J=8.0 a, 0,4, 1H), from 5.29 (s, 1H), of 3.73 (d, J=7,2, 2H), 1.91 a (m, 1H), 1,64 (m, 5H), of 1.47 (s, 6H), of 1.16 (m, 3H), of 1.02 (m, 2H); MS (ESI)m/z368,4 [M+1]+; TPL >250°C.

5.1.203 EXAMPLE 203: SYNTHESIS of 6-(6-(2-HYDROXYPROPAN-2-yl)PYRIDINE-3-YL)-1-((TETRAHYDRO-2H-PIRAN-4-YL)METHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(6-(2-Hydroxypropan-2-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A 20-ml flask for microwave heating was added 6-bromo-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (see Example 101.B) (0.33 g, 1,054 mmol), 2-(5-(tributylstannyl)pyridine-yl)propan-2-ol (see Example 202. B) (0,316 g 1,054 mmol) and the complex [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0.172 g, 0,211 mmol) in DMF (4 ml). The mixture was stirred in a microwave reactor at 140°C for 15 minutes. The mixture was concentrated and the residue was subjected to prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the desired product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then 7 N. solution of ammonia in methanol (10 ml). The product was suirable using ammonia in methanol. In the concentration of the eluate obtained product (84 mg, 21%, a purity of 99.3% according to HPLC).1H NMR (400 MHz, CD3OD) δ remaining 9.08 (DD, J=2,4, 0,8, 1H), 8,44 (s, 1H), at 8.36 (DD, J=10,8, 2,8, 1H), 7,79 (DD, J=10,4, 1,6, 1H), 3,98 (s, 1H), 3,93 (d, J=9,6, 2H), 3,37 (m, 3H), and 2.26 (m, 1H), 1,67 (m, 2H), 1,60 (s, 6H), of 1.46 (m, 2H,); MS (ESI)m/z370,1 [M+1]+; TPL 207-209°C.

5.1.204 EXAMPLE 204: SYNTHESIS of 6-(6-(2-HYDROXYPROPAN-2-yl)PYRIDINE-3-YL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 6-(6-(2-Hydroxypropan-2-yl)pyridine-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

A 20-ml flask for microwave heating was added 6-bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 108.B) (0.17 g, 0,520 mmol), 2-(5-(tributylstannyl)pyridine-2-yl)propan-2-ol (see Example 202.B) (0.156 g, 0,520 the mol) and the complex [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (of 0.085 g, in 0.104 mmol) in DMF (3 ml). The mixture was stirred in a microwave reactor at 140°C for 15 minutes. The mixture was concentrated and the residue was subjected to prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing the desired product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then 7 N. solution of ammonia in methanol (10 ml). The product was suirable using ammonia in methanol. In the concentration of the eluate received the product (40 mg, 20%, 95.9% of purity according to HPLC).1H NMR (400 MHz, CD3OD) δ 9,03 (d, J=2,0, 1H), 8,39 (s, 1H), 8,30 (d, J=2.4 to,1H), 7,74 (d, J=8,1, 1H), 3,99 (t, J=7,2, 2H), a 3.87(DD, J=11,2, 3,2, 2H), and 3.31 (m, 1H), 1,76 (m,4H), of 1.55 (s, 6H), of 1.53 (m, 2H), 1.27mm (m, 2H); MS (ESI)m/z384,3 [M+1]+; TPL 132-133°C.

5.1.205 EXAMPLE 205: SYNTHESIS of 6-(4-(4H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-MORPHOLINO-2-OXOETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. Ethyl 2-(3-(3,5-dibromopyridin-2-yl)ureido)acetate.

3,5-Dibromopyridin-2-amine (5,00 g of 19.8 mmol), 1,1'-carbonyldiimidazole (3,37 g of 20.8 mmol), diisopropylethylamine (10.3 ml, to 7.67 mmol), 1,4-dioxane (7.5 ml) and N,N-dimethylformamide (15 ml) were combined in a 100 ml round bottom flask with a rod stirrer, stirred and heated at 50°C boiling under reflux in nitrogen atmosphere for 4.5 hours. Added additional amount of 1,l'-carbonyldiimidazole (0.34 g, 2.0 mmol) and the reaction mixture was heated at 50°C for 3.5 hours. The resulting reaction mixture was cooled to room temperature and was added the hydrochloride of the ethyl ester of glycine (2,90 g of 20.8 mmol). The resulting reaction mixture was stirred at room temperature for 13 hours, was added to water with vigorous stirring, to cause the precipitation of the solid particles. The solids were collected by means of filtration under vacuum, washed twice with water and twice with hexane and dried in vacuum at 45°C to give the desired product (of 5.17 g, 68%) as a pale orange solid, which contained a small amount of impurities ethyl 2-(3-(5-bromo-3-(1H-imidazol-1-yl)pyrazin-2-yl)ureido)acetate.1H NMR (400 MHz, DMSO-d6) δ 8,89 (s, 1H), 8,53 (s, 1H), 8,08 (t, J=5,66, 1H), 4,12 (sq, J=7,29, 2H), 3.96 points (d, J=5,86, 2H), 1,21 (t, J=7.03, you, 3H); MS(ESI)m/z383 [M+1]+.

B. Ethyl 2-(6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)acetate and isopropyl 2-(6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)acetate.

Ethyl 2-(3-(3,5-dibromopyridin-2-yl)ureido)acetate (1,00 g, 2,62 mmol), palladium(II) acetate (0,059 g, 0.26 mmol), Xantphos (0,454 g of 0.79 mmol), sodium bicarbonate (0,660 g, 7.85 mmol) and wet isopropanol (15 ml) were combined in a tightly closed vessel with a rod stirrer. The mixture was purged with nitrogen for 1 minute and then hermetically closed, intensively stirred and heated at 120°C for 26 hours. The resulting mixture ohla is given to room temperature, was diluted with ethyl acetate and filtered through celite. The filter cake was thoroughly washed with ethyl acetate and the filtrate was concentrated on a rotary evaporator with the use of silica gel. Flash chromatography on a short column of silica gel (20-60% ethyl acetate in hexane) provided partial purification. After concentration of the elution solvent on a rotary evaporator, the resulting residue was purified using reverse-phase preparative HPLC (20-60% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 minutes, and then 60-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, 30 to 35 minutes). The contents of the vessels with the product were combined and the entire quantity of the solvent was removed on a rotary evaporator. The residue was dried in vacuum to obtain a mixture of the desired product (188 mg, 24%) as a pale yellow solid. MS (ESI) m/z 301 and 315 [M+1]+.

C. 2-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)acetic acid.

A mixture of ethyl 2-(6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)acetate and isopropyl 2-(6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)acetate (170 mg, of 0.565 mmol), lithium hydroxide (41 mg, was 1.69 mmol), water (3 ml) and tetrahydrofuran (15 ml) were combined in a round bottom flask with stirrer rod intensively stirred and heated at 65°C boiling under reflux in nitrogen atmosphere for 45 minutes. The whole amount will dissolve the La was removed on a rotary evaporator. The obtained residue was dissolved in a mixture of methanol (4 ml) and 6 N. hydrochloric acid in water (0,38 ml, 2.28 mmol), filtered and purified using reverse-phase preparative HPLC (5-50% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The contents of the vessels with the product were combined and the entire quantity of the solvent was removed on a rotary evaporator. The residue was dried in vacuum at 45°C to give the desired product (140 mg, 91%) as a yellowish foamy solid.1H NMR (400 MHz, DMSO-d6) δ 13,40 (width, s, 1H), 12,42 (s, 1H), 8,11 (s, 1H), of 4.54 (s, 2H); MS (ESI)m/z273 [M+1]+.

D. 6-Bromo-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-2,2,2-triptorelin.

2-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)acetic acid (141 mg, 0,516 mmol) and 1,1'-carbonyldiimidazole (256 mg, was 1.58 mmol) were combined in a round bottom flask with a rod stirrer. Added methylene chloride (6 ml) and the resulting mixture was stirred at room temperature under nitrogen atmosphere. Was added DMF (2 ml). All solids were dissolved. The obtained transparent reaction mixture was stirred at room temperature under nitrogen atmosphere for 2.5 hours, during which time was added morpholine (0,34 ml, 3.90 mmol). The resulting mixture was stirred at room temperature for 1 hour. The methylene chloride was removed on a rotary evaporator. Obtained from the ect was diluted with methanol, was filtered and purified using reverse-phase preparative HPLC (5-50% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The contents of the vessels with the product were combined and the entire quantity of the solvent was removed on a rotary evaporator. The residue was dried in vacuum to give the desired product (209 mg, 89%) as a yellowish foamy solid.1H NMR (400 MHz, DMSO-d6) δ 12,36 (s, 1H), of 8.09 (s, 1H), 4,78 (s, 2H), 3,63 at 3.69 (m, 2H), 3,55-3,62 (m, 4H), 3.43 points (t, J=4,88, 2H); MS (ESI)m/z342 [M+1]+.

E. 6-(4-(4H-1,2,4-Triazole-3-yl)phenyl)-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

6-Bromo-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-2,2,2-triptorelin (205 mg, 0,449 mmol), hydrochloride of 4-(1H-1,2,4-triazole-5-yl)phenylboronic acid (see Example 159.D) (152 mg, 0,674 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (33 mg, 0.045 mmol), 1 M carbonate sodium in water (2.25 ml, 2.25 mmol), 1,4-dioxane (1.5 ml) and isopropanol (0.5 ml) were combined in a tightly closed tube with a rod stirrer. The mixture was purged with nitrogen for 1 minute to remove air. The resulting mixture was hermetically closed, intensively stirred and heated at 120°C during the night. The resulting mixture was cooled to room temperature, diluted with methanol and the solvents were completely removed on a rotary evaporator. To the residue was added methanol and poluchenno the mixture was filtered. The filtrate was purified using reverse-phase preparative HPLC (5-60% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The contents of the vessels with the product were combined and almost the entire quantity of the solvent was removed on a rotary evaporator. Added acetonitrile and the resulting mixture was loaded on an ion exchange column Strata-XC from Phenomenex. The column was washed successively with water, acetonitrile, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated using a 5% solution of ammonium hydroxide in methanol as eluent and was concentrated on a rotary evaporator. The obtained residue was dissolved in 20% methanol in dichloromethane and then concentrated on a rotary evaporator with the use of silica gel. Flash chromatography (5-12-15% methanol in dichloromethane) gave the desired product (43 mg, 24%) as a white solid. Rf= 0,16 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-d6) δ 12,21 (width, s, 1H), at 8.60 (s, 1H), 8,09-8,17 (m, 4H), a 4.86 (s, 2H), 3,63-,72 (m, 4H), of 3.60 (t, J=4,88, 2H), 3.45 points (t, J=4,69, 2H); MS (ESI)m/z407 [M+1]+.

5.1.206 EXAMPLE 206: SYNTHESIS of (R)-6-(4-(4H-1,2,4-TRIAZOLE-3-YL)PHENYL)-3-(CYCLOHEXYLMETHYL)-3,4-DIHYDROPYRIDO[2,3-B]PYRAZIN-2(1H)-It

A. (R)-tert-Butyl 3-cyclohexyl-1-(3,5-dibromopyridin-2-ylamino)-1-oxoprop-2-ylcarbamate.

(R)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropionic acid (1,00 g of 3.69 mmol), 1,1'-carbonyl is imidazol (896 mg, of 5.53 mmol), dichloromethane (3 ml) and DMF (1 ml) were combined in a scintillation vessel and was stirred for a 3.75 hours at room temperature in a nitrogen atmosphere. Added 3,5-dibromopyridin-2-amine (1.86 g, 7,37 mmol) and the resulting mixture was tightly closed and heated for 21 hours at 40°C, then for 22.5 hours at 50°C. was Added diisopropylethylamine (1.3 ml, 7,37 mmol) and the resulting mixture was tightly closed and heated at 45°C with stirring overnight. Dichloromethane was removed on a rotary evaporator. The resulting mixture was diluted with ethyl acetate and water and were shaken in a separating funnel. The resulting suspension was filtered through celite and the filter cake was thoroughly washed with ethyl acetate. To the filtrate was added a saturated saline solution and the resulting two layers were separated in a separating funnel. The organic layers were washed with water, then with saturated saline and concentrated on a rotary evaporator. The obtained residue was dissolved in methanol, filtered and purified using reverse-phase preparative HPLC (20-100% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The contents of the vessels with the product were combined and neutralized using a saturated aqueous solution of sodium bicarbonate. The acetonitrile was removed on a rotary evaporator and the resulting aqueous mixture was extracted with utilize the atom. The organic layers were washed with saturated salt solution, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and dried in vacuum to give the desired product (616 mg, 33%) as not quite white solid.1H NMR (400 MHz, DMSO-d6) δ 10,54 (s, 1H), 8,77 (s, 1H), 7,14 (d, J=8,20, 1H), 4.26 deaths (sq, J=7,81, 1H), 1.77 in (d, J=12,49, 1H), 1,58-1,72 (m, 5H), 1,51-of 1.57 (m, 2H), to 1.38 (s, 9H), 1,07-1,25 (m, 3H), 0,80-0,98 (m, 2H); MS (ESI)m/z507 [M+1]+.

B. (R)-6-Bromo-3-(cyclohexylmethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he.

(R)-tert-Butyl 3-cyclohexyl-1-(3,5-dibromopyridin-2-ylamino)-1-oxoprop-2-ylcarbamate (726 mg, 1,43 mmol) was dissolved in dichloromethane (20 ml) under stirring in nitrogen atmosphere. Added triperoxonane acid (2 ml) and the resulting clear yellow solution was stirred for 50 minutes at room temperature. Added additional amount triperoxonane acid (1 ml) and the resulting mixture was stirred for 5.5 hours at room temperature. The solvents were completely removed on a rotary evaporator and the resulting residue was dried in vacuum over night. Was added sodium bicarbonate (to 1.21 g, 14.4 mmol), Xantphos (249 mg, 0.43 mmol), palladium(II) acetate (32 mg, 0,143 mmol) and wet isopropanol (21 ml) and the resulting mixture was purged with nitrogen for 1 minute to remove air. The resulting mixture was intensively stirred and heated PR is 80°C boiling under reflux in nitrogen atmosphere for 8 hours and 20 minutes and then cooled to room temperature over night. The resulting mixture was diluted with ethyl acetate and filtered through celite. The filter cake was thoroughly washed with ethyl acetate and the filtrate was concentrated on a rotary evaporator. Added methanol and tardie substance was collected by means of filtration under vacuum. The solids were washed twice with methanol, twice as easy with ethyl ether and dried in vacuum to give the desired product (241 mg, 53%) as a yellowish brown solid.1H NMR (400 MHz, DMSO-d6) δ 11,21 (s, 1H), with 8.05 (d, J=2,34, 1H), 7,50 (s, 1H), 4,16 (TD, J=6,15, 2,15, 1H), 1,73 (d, J=11,32, 1H), 1,50 by 1.68 (m, 8H), 1,07-of 1.27 (m, 3H), 0.77-a of 0.94 (m, 1H); MS (ESI)m/z325 [M+1]+.

C. (R)-di-tert-Butyl 6-bromo-3-(cyclohexylmethyl)-2-oxo-2,3-dihydropyrido[2,3-b]pyrazin-l,4, in primary forms

(R)-6-Bromo-3-(cyclohexylmethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he (167 mg, 0,514 mmol), di-tert-BUTYLCARBAMATE (280 mg, 1.28 mmol), 4-(dimethylamino)pyridine (6 mg, 0,051 mmol) and acetonitrile (4 ml) were combined in a scintillation vessel, stirred and heated at 60°C in nitrogen atmosphere for 1 hour. The resulting mixture was cooled to room temperature. Added to water with vigorous stirring and the solid substance was collected by means of filtration under vacuum. The solids were washed with water and dried in vacuum at 45°C to give the desired product (241 mg, 89%) as a pale orange powder.1H NMR (400 MG IS, DMSO-d6) δ to 8.45 (s, 1H), 4,94 (DD, J=9,18, 6,44, 1H), 1,84 (d, J=12,49, 1H), 1,57 is 1.70 (m, 4H), of 1.53 (s, 9H), for 1.49 (s, 9H), 1,34-of 1.42 (m, 2H), 1,23-of 1.30 (m, 1H), 1,09-of 1.18 (m, 3H), 0,82-0,94 (m, 2H); MS (ESI)m/z525 [M+1]+.

D. (R)-6-(4-(4H-1,2,4-Triazole-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-he

(R)-di-tert-Butyl 6-bromo-3-(cyclohexylmethyl)-2-oxo-2,3-dihydropyrido[2,3-b]pyrazin-l,4, in primary forms (237 mg, 0,451 mmol), hydrochloride of 4-(1H-1,2,4-triazole-5-yl)phenylboronic acid (see Example 159.D) (153 mg, 0,677 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (33 mg, 0.045 mmol), 1 M sodium carbonate in water (1.80 ml of 1.80 mmol), 1,4-dioxane (1.5 ml) and isopropanol (0.5 ml) were combined in a tightly closed tube with a rod stirrer. The mixture was purged with nitrogen for 1 minute to remove air. The resulting mixture was hermetically closed, intensively stirred and heated at 120°C during the night. The resulting mixture was cooled to room temperature, diluted with methanol and the solvents were completely removed on a rotary evaporator. To the residue was added methanol (5 ml) and 6 n hydrochloric acid solution in water (0.35 ml, 2.1 mmol). The resulting mixture was rapidly heated by using the apparatus for drying a stream of warm air and then filtered. The filtrate was purified using reverse-phase preparative HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). With the hold of the vessel with the product were combined and almost the entire quantity of the solvent was removed on a rotary evaporator. Added acetonitrile and the resulting mixture was loaded on an ion exchange column Strata from Phenomenex. The column was washed successively with water, acetonitrile, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated using a 5% solution of ammonium hydroxide in methanol as eluent, concentrated on a rotary evaporator and then dried in vacuum at 45°C to give the desired product (7 mg, 4%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11,21 (width, s, 1H), 8,46 (width, s, 1H,) 8,03-to 8.14 (m, 5H), to 7.68 (d, J=1,56, 1H), 4,14-4,20 (m, 1H), 1.77 in (d, J=12,10, 1H), 1,53-1,71 (m, 7H), 1,07-of 1.30 (m, 3H), of 0.79 to 0.97 (m, 2H); MS (ESI)m/z390[M+1]+.

5.1.207 EXAMPLE 207: SYNTHESIS of (R)-6-(4-(1H-1,2,4-TRIAZOLE-3-YLPHENYL)-1-(1-PHENYLETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. ((1R)-1-Phenylethyl)(3-amino-6-bromopyrazine-2-yl)amine.

A solution of (R)-α-methylbenzylamine (2,28 ml, 17,93 mmol) and 2-amino-3,5-dibromopyrazine (3.00 g, 1 a 1.96 mmol) in n-butanol (30 ml)as described in General Procedure A. the Crude molecule was purified using chromatography on silica gel (20-30% ethyl acetate in hexane). Pure fractions were combined and are condensed with further kneading the powder from methanol with water, while processing the ultrasound, obtaining (1.92 g, is 6.54 mmol, 55%) ((1R)-1-phenylethyl)(3-amino-6-bromopyrazine-2-yl)amine. MS (ESI) m/z 294,0 [M+1]+.

B. 1-((1R)-1-Phenylethyl)-6-bromo-4-imidazoline[4,5-b]pyrazin-2-it.

At asanee in the title compound was obtained using ((1R)-1-phenylethyl)(3-amino-6-bromopyrazine-2-yl)amine (0.50 g, 1,71 mmol, 1.0 EQ.), 1,1'-carbonyldiimidazole (0.35 g, 2,13 mmol, 1.25 EQ.) and tetrahydrofuran (7 ml)as described in General Procedure D1. The crude substance was dissolved in methanol (5 ml) and the product was ground into powder with water, while processing the ultrasound. The precipitate was filtered and dried in a vacuum oven overnight to obtain 0.27 g (0.83 mmol, 49%) of 1-((1S)-1-phenylethyl)-6-bromo-4-imidazoline[4,5-b]pyrazin-2-it. MS (ESI) m/z 319,3 [M+1]+.

C. (R)-4-(2-Oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile.

1-((1R)-1-Phenylethyl)-6-bromo-4-imidazoline[4,5-b]pyrazin-2-he (0,500 g, 1.57 mmol), 4-cyanoaniline acid (0,276 g, 1.88 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)complex with dichloromethane (1:1) (0,128 g, 0.10 mmol), potassium phosphate (1,33 g, 6,27 mmol), dimethylformamide (5.0 ml) and water (2.0 ml) were combined in a sealed tube and heated together at 90°C for 2 hours. The solution are condensed under reduced pressure and was purified using reverse-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min) to give the pure product (0,462 g, 86%). MS (ESI) m/z 476,5 [M+1]+.

D. (R) - Ethyl 4-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate.

A solution of (R)-4-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile (0,462 g, 1.35 mmol) and ethanol (100 ml) was cooled to 0°C and who was arbitrable through a solution of gaseous hydrogen chloride for 10 minutes. The reaction mixture was left for stirring and warming to 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure and used in the next stage without additional purification in the form of cleaners containing hydrochloride salt (0,281 g, 57%). MS (ESI) m/z of 388.4 [M+1]+.

E. (R)-6-(4-(1H-1,2,4-Triazole-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-he.

(R) - ethyl 4-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (0,281 g, 0,725 mmol), thermohydrogen (0,174 g, 2,90 mmol), triethylamine (0,734 g of 7.25 mmol) and methanol (4.0 ml) were combined in a sealed tube and heated to 100°C for 4 hours. The solution are condensed under reduced pressure and was purified using reverse-phase prepreparation HPLC (20-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Pure fractions were combined, neutralized with ammonium hydroxide, concentrated, diluted with water (20 ml) and the desired product was collected by filtration to obtain specified in the connection header in the form of not-quite-white solid with a purity of 96.7% of (0,039 g, 14%).1H NMR (400 MHz, CD3OD) δ 8,48-8,51 (m, 1H), 8,49 (s, 2H), to 8.41 (width, s, 1H), 8,12 (s, 4H), 7,60 (d, J=7.03, you, 2H), 7,31-7,39 (m, 2H), 7.23 percent-7,30 (m, 1H), 5,85 (sq, J=7,29, 1H), 2,12 (d, J=7,42, 3H); MS (ESI)m/z384,4 [M+1]+; TPL 258-260°C.

5.1.208 EXAMPLE 208: SYNTHESIS of (S)-6-(4-(4H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(1-PHENYLETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. (S)-6-(4-(4H-1,2,4-Triazole-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

In a sealed tube, to a solution of the hydrochloride of 4-(1H-1,2,4-triazole-5-yl)phenylboronic acid (see Example 159.D) (0,239 g, the 1.265 mmol), (S)-6-(4-bromophenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she (0.5 g, the 1.265 mmol), [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) dichloromethane (1:1) (1,033 g, the 1.265 mmol) in DMF (30 ml) was added potassium phosphate (0,281 g, the 1.265 mmol) in water (10 ml). The resulting reaction mixture was degirolami and brought up to 120°C for 2 hours. Volatiles were removed under reduced pressure, the crude product was filtered through celite, washed with methanol. After concentration the crude product was purified using reverse-phase prepreparation HPLC (10-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The desired fractions were combined, concentrated to minimum content of the solvent and neutralized with ammonium hydroxide. The obtained free base was filtered, washed with water and dried in a vacuum oven to obtain specified in the title compound (0.008 g, 0,021 mmol, 1,649% yield).1H NMR (400 MHz, DMSO-d6) δ 9,24 (s, 1H), 8,53 (s, 1H), they were 8.22 (d, J=8,8, 2H), 8,10 (d, J=8,8, 2H), 7,58 (d, J=7,6, 2H), 7,32 (d, J=7,6, 2H), 7,26 (d, J=8,8, 1H), of 5.84 (q, J=7,2, 1H), 2,10 (d, J=7,2, 2H); MS (ESI)m/z384,1[M+1]+.

5.1.209 EXAMPLE 209: SYNTHESIS of (1R,4R)-4-(6-(4-(2-HYDROXYP IS OPAN-2-YL)PHENYL)-2-OXO-2,3-DIHYDRO-1H-IMIDAZO[4,5-B]PYRAZIN-1-YL)CYCLOHEXANECARBOXYLATE

A. tert-Butyl (1R,4R)-4-carbamoylaspartate.

(1R,4R)-4-(tert-Butoxycarbonyl-amino)cyclohexylcarbonyl acid (1.7 g, of 6.99 mmol), ammonium chloride (560 mg, 10.5 mmol), O-(benzotriazol-1-yl)-hexaphosphate N,N,N',N'-tetramethylurea (2.66 g, of 6.99 mmol), triethylamine (2,92 ml, 20,96 mmol) and acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered and washed with fresh acetonitrile. The solid was dried in vacuum to give the desired product (1,57 g, 93% yield) as a white solid. MS (ESI) m/z 242,9 [M+1]+.

B. (1R,4R)-4-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic.

tert-Butyl (1R,4R)-4-carbamoylaspartate (0.5 g, 2,063 mmol) was treated with 4 N. a solution of hydrochloric acid in dioxane for 2 hours at room temperature. The reaction mixture was concentrated to obtain a white solid. To the obtained solid substance was added 3,5-dibromopyridin-2-amine (0,522 g 2,063 mmol), diisopropylethylamine (0,721 ml of 4.13 mmol) and methylsulfoxide (4 ml) and heated in a microwave reactor Biotage Emrys Optimizer for 2 hours at 150°C. the Reaction mixture was subjected to purification using chromatography on silica gel (0-100% (5% methanol in ethyl acetate in hexane) to highlight diamine. To the resulting diamine was added 1,1'-carbonyldiimidazole (0,669 g, 413 mmol) and dioxane (4 ml) and the mixture was heated in a microwave reactor Biotage Emrys Optimizer for 10 minutes at 100°C. The reaction mixture was purified on silica gel (0-100% (5% methanol in ethyl acetate in hexane). Selected fractions were concentrated and triturated to powder with simple ether to obtain a white solid (85 mg, 12% yield from 3 stages). MS (ESI) m/z 340,0 [M]+, 342,0 [M+2]+.

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

1-(4-Bromophenyl)alanon (9,25 g, 46.5 mmol) was dissolved in tetrahydrofuran (200 ml). The solution was cooled to -50°C bath. Added methylmagnesium (3 M in a simple ester, a 46.5 ml, 139 mmol) for 15 minutes. The reaction mixture was allowed to warm to room temperature and then was stirred for 20 hours. The reaction was suppressed by using a saturated solution of ammonium chloride and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain oil. The resulting oil was purified on a column of silica gel (0-20% ethyl acetate in hexane) to give the product as a colourless oil (9.1 g, 91% yield). MS (ESI) m/z 197,1 [M]+, 199,1 [M+2]+.

D. 2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol.

2-(4-Bromophenyl)propan-2-ol (4.7 g, 21,85 mmol), bis(pinacolato)LIBOR (6,66 g, to 26.2 mmol), potassium acetate (to 6.43 g, 65,6 mmol) and dimethylsulfoxide (50 ml) were mixed together and were degirolami in vacuum for 10 minutes. Added complex [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0,892 is, 1,093 mmol) and the reaction mixture was degirolami for another 5 minutes. The reaction mixture then was heated up to 80°C in nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and then was extracted with a mixture of 1:1 simple ether:ethyl acetate and water. Black emulsion was filtered through a layer of celite. The organic layer was dried over magnesium sulfate, filtered and then purified on a column of silica gel (0-25% ethyl acetate in hexane). Containing the product fractions were concentrated and then triturated to powder in hexane to obtain a white solid (4 g, 70% yield). MS (ESI) m/z 263,3 [M+1]+.

E. (1R,4R)-4-(6-(4-(2-Hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic.

(1R,4R)-4-(6-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylate (100 mg, 0.29 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (53 mg, 0.29 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane adduct (12 mg, 0.015 mmol), 1 M sodium carbonate (from 0.88 ml, 0.88 mmol) and dioxane (2 ml) was heated in a microwave reactor Biotage Emrys Optimizer at 130°C for 20 minutes. The reaction mixture was purified using reverse-phase prepreparation HPLC (10-70% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). Containing the product fractions were neutralized by adding carbonate ka the Oia. The solution was concentrated and dried. The solid was purified on a column of silica gel (0-100% (5% methanol in ethyl acetate in hexane) to give white solid (50 mg, 43% yield).1H NMR (400 MHz, DMSO-d6) δ 12,01 (s, 1H), 8,44 (s, 1H), to 7.93 (d, J=8,6, 2H), EUR 7.57 (d, J=8,2, 2H), 7,30 (s, 1H), 6,77 (s, 1H), 5,08 (s, 1H), 4,24 (t, J=12,5, 1H), 2.40 a (m, 2H), 2,22 (t, J=12,3, 1H), 1,92 (d, J=10,9, 2H), 1.85 to (d, J=9,0, 2H), 1,53 (m, 2H), 1,46 (s, 6H); MS (ESI)m/z396,0 [M+1]+; TPL 280-282°C.

5.1.210 EXAMPLE 210: SYNTHESIS of 6-(4-(5-METHYL-1H-1,2,4-TRIAZOLE-3-YL)PHENYL)-1-(2-(TETRAHYDRO-2H-PIRAN-4-YL)ETHYL)-1H-IMIDAZO[4,5-B]PYRAZIN-2(3H)-It

A. 4-(2-Oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile.

6-Bromo-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he (see Example 108.B) (2.5 g, 7,60 mmol), 4-cyanoaniline acid (1,69 g, 1 1.5 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane (0,62 g, 0.70 mmol) were combined in dioxane (10 ml). Was added sodium carbonate (0,91 g of 15.2 mmol) in water (10 ml) and the reaction mixture was stirred at 100°C during the night. The cooled reaction solution was filtered through celite and the filter cake was washed with ethyl acetate. The an ethyl acetate filtrate and washing were combined and the solvent was removed under reduced pressure. The resulting material was purified using reverse-phase preparative HPLC (20-80% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 of the minutes). The fractions containing pure product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated with the help of a 5% solution of ammonium hydroxide in methanol as eluent and was concentrated on a rotary evaporator. The residue was ground into powder with ethyl ether in hexane to obtain fine powder and dried in vacuum at 50°C to give the desired product (1.2 g, 46%) as a white solid. MS (ESI) m/z 350,0 [M+1]+.

B. Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate.

Gaseous HCl was barbotirovany in suspension of 4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile (1.2 g, of 3.43 mmol) in anhydrous ethanol (30 ml) at 0°C. the Flask was closed and the reaction mixture was stirred over night at room temperature. After complete conversion to the product (tracked using IHMS), volatiles were removed under reduced pressure and the resulting white solid was dried in a vacuum oven to give the desired product (1.2 g, 88%). The obtained substance was used in the next stage without additional purification. MS (ESI) m/z 396,0 [M+1]+.

C. 6-(4-(5-Methyl-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahedron-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (0,250 g to 0.63 mmol) in ethanol (20 ml) was treated with acetohydrazide (0,23 g, and 3.16 mmol) and triethylamine (3,23 ml, 2.32 mmol) and the resulting reaction mixture was stirred at 110°C for 3 hours. The cooled reaction solvent was removed under reduced pressure. The resulting material was purified using reverse-phase prepreparation HPLC (20-50% acetonitrile + 0.1% of TFA in H2O + 0.1% of TFA, over 30 min). The fractions containing pure product was passed through ion-exchange column Phenomenex Strata-X-C to remove TFA. The column was washed successively with water, methanol and then with 5% ammonium hydroxide solution in methanol. The product was isolated using a 5% solution of ammonium hydroxide in methanol as eluent and was concentrated on a rotary evaporator. The residue was ground into powder with ethyl ether in hexane to obtain a fine powder and dried in vacuum at 50°C to give the desired product (0,185 g, 72%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13,73 (width, s, 1H), 12,07 (width, s, 1H), 8,56 (s, 1H), 8,09 (m, 4H), 3,93 (d, 2H), 3,83 (d, J=14,1, 2H), up 3.22 (m, 2H), 2,42 (width, s, 3H), at 1.73 (m, 4H), of 1.52 (m, 1H), 1,21 (m, 2H); MS (ESI)m/z406,2 [M+1]+; TPL 290-292°C.

5.2 BIOLOGICAL EXAMPLES

5.2.1 Analysis of MG63 pS6 SScale

Below are examples from the analysis, which can be used to determine the anticancer activity of the test compounds.

For this analysis used cells MG63 human osteosarcoma (ATCC: CRL-1427) (arcade 7-15). Cells were maintained using DMEM (high glucose with 1-glutamine), 10% FBS and Pen/Strep. Used the following buffers: Full Tris Litany Buffer (for use in the amount of 10 ml: 100 ál phosphatase inhibitor I (100X the original solution), 100 μl of phosphatase inhibitor II (100X the original solution), 1 tablet Complete Mini (without EDTA), 40 ál PMSF, all carefully mixed for 5 minutes at room temperature); 1X Tris wash Buffer (for use in the amount of 250 ml: 25 ml 10X Tris wash buffer, 225 ml of deionized water, kept at room temperature); MSD blocking solution A (for use 20 ml: 20 ml 1X Tris wash buffer and 600 mg MSD blocker A, kept on ice); Buffer for dilution of antibodies (for use in the amount of 3 ml: 1 ml blocking solution-A, 1,82 ml 1X Tris wash buffer, 150 μl of 2% MSD blocker D-M, 30 ál of 10% MSD blocker D-R, and kept on ice).

Day one in the morning, the cells were sown in 96-well flat-bottomed culture tablets at a density of 5000 cells/well in 100 µl volume. Day 2 in the morning of the test compounds were diluted to the desired concentration and added to the cells. Cells clicks sativali connection for 16-24 hours at 37°C, 0,5% CO2.

The plates were blocked for about 5 minutes before completing a connection by adding 150 μl of MSD blocking solution-a tablet and incubation at strong shaking at room temperature for 1 hour.

The cells were collected and received lysates by removing the medium by means of a multichannel device for pipetting, washing 1X cooled on ice PBS (containing Ca and not containing Mg), add 50 μl/well Complete Tris Lisanova Buffer and incubation with shaking at 4°C for 1 hour.

Samples of the lysates were added to the tablet with plenty of spots MSD by pipetting the cell lysate up and down about 4-5 times, transfer 25 ál/well in your tablet, with many spots MSD (RAfor negative control, and RBfor positive control) (litany buffer was added only to the control wells) and incubation at strong shaking at room temperature for 2 hours.

Antibody for the detection added by breeding anti-pS6 antibody (labeled with SULFO-TAG, photosensitive) in 3 ml of chilled buffer for dilution of antibodies to a final concentration of 10 nm, add 25 ál/well of 10 nm antibody for detection in MSD tablet incubation at strong shaking at room temperature in the dark for 1 hour and washing tablet 4 times with 1X Tris wash b is from.

The tablet reads by adding 1X in the amount of 150 μl/well of buffer to read T (surface-active agent) and using, for example, MSD SECTOR tablet reader and appropriate software for data analysis.

5.2.2 HTR-FRET analysis of mTOR

Below is an example of analysis that can be used to determine the inhibitory activity of test compounds against mTOR. The reagents were prepared as follows.

"Simple TOR buffer (used for cultivation 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 (1 M source solution, frozen at -20°C immediately before use). For convenience, a large number of "Simple TOR buffer w/o DTT can be stored at 4°C. It can bring to room temperature and add DTT immediately before breeding TOR faction.

5XKB/5XMn/5XATP solution (used for cultivation substrate GST-p70S6kin 81 A.A.. immediately prior to use) (shown certain amount to 40 ml):

0.075 mm ATP30 μl of 0.1 M ATP (from their powder)
12.5 mm MnCl2500 μl of 1M MnCl2
50 mm Hepes, pH 7,4ml of 1 M Hepes, pH7,4
50 mm β-GOP2 ml of 1M β-GOP
250 nm Microcystin LR500 μl of 20 μm Microcystin LR (DMSO)
0.25 mm EDTA20 μl of 0,5M EDTA
5 mm DTT200 μl of 1M DTT
ddH2About34,752 ml

Enzyme solution: Dilute TOR faction 1:14 in the "Simple TOR Buffer". This lot is 640 μg/ml TOR faction, diluted with 14X receipt of 45.7 µg/ml TOR in the buffer (i.e. a 7.85 ml combined fractions TOR + 102,1 ml Simple TOR buffer =110 ml 14X diluted TOR faction). It is necessary to control the quality of each batch of enzyme prior to analysis.

Substrate solution: you can get It directly before analysis, if this is preferred.

Dilute the original solution of 5.3 mg/ml GST-p70S6 fragment to 3.5 μg/ml (97 nm) working source solution in 5XKB/5XMn/5XATP solution (i.e. 26,41 μl (5.3 mg/ml) GST-p70S6 + 40 ml 5XKB/5XMn/5XATP = 40 ml of 3.5 mcg/ml (97 nm)).

Buffer for analysis (used for cultivation of antibodies in the reagent for detection of antibodies):

50 mm Hepes, pH 7,412.5 ml 1M Hepes, pH 7,4
1mm DTT250 μl of 1M DTT
0,01% Triton X-100250 μl of 10% Triton X-100
0.01% of BSA25 mg BSA
0.1 mm EDTA50 μl of 0,5M EDTA
ddH2O236,5 ml

Reagent for the detection of antibodies (this reagent should be obtained immediately before adding to the analytical tablets):

3,056 ml1000 ág/ml Cy5-αGST Amersham Cat#PA92002V
0,07661 ml1000 µg/ml α-p70S6(Thr389) cell signaling mouse monoclonal #9206L
0,223 ml690 µg/ml α-mouse Lance Eu Perkin Elmer Cat#AD0077
236,64 mlbuffer for analysis

Using PlateTrak program (Screen) or Matrix Pipettor (SAR), a 19.5 ál of diluted TOR faction was added to the analytical tablet all wells with the test compound, control or positive control. a 19.5 ál of "Simple TOR buffer was added to all wells of negative control. If you handle more than one tablet in the same connection, the mod is but to increase the amount of the enzyme to the values multiples of 19.5 μl, high 384-well polypropylene plate.

Using EP3, and 0.5 μl of test compound, control or DMSO control were added to each well with mixing. The plates were incubated for 30 minutes at room temperature.

Using PlateTrak program (Screen) or Matrix Pipettor (SAR), 5 μl 5XKB/5XMn/5XATP/5X substrate solution was added to each well of analytical tablet to start the reaction. The solutions were thoroughly mixed and incubated for 2 hours at room temperature.

Using PlateTrak program (Screen) or Matrix Pipettor (SAR), was added 5 μl of 60 mm EDTA to stop the reaction. The solutions were thoroughly mixed and allowed to stand for 15-20 minutes before the next stage.

Using PlateTrak program (Screen) or Matrix Pipettor (SAR), was added 10 μl of the reagent for detection of antibodies. The solutions were thoroughly mixed and incubated for 5 hours to O/N, allowing the formation of complexes between antibodies to phosphorylated substrate.

Tablets read on AnalystHT using Protocol Multi-Method.

5.2.3 IMAP analysis of PKCθ

Below is an example of analysis that can be used to determine the activity of the test compounds aimed at the inhibition of PKCθ. The reagents were prepared as follows.

Buffer for analysis: 50 mm HEPES (pH 7,6), 10 mm MgCl, 0, mm EDTA, 5 mm MBP, 0,01% Triton, 1 mm DTT, 0.05 mg/ml phosphatidylserine, 0.05 mg/ml diacylglycerol.

The final concentration of PKCθ (Invitrogen) was 0.5 nm. The final concentration of substrate (FAM-AKRRRLSSLRA) (Molecular Devices) was 100 nm. The final concentration of ATP in the reaction mixture was 35 μm. The final concentration of DMSO in the reaction mixture was 2.5%.

The enzyme was kept in a 5 µl aliquot was stored at -80°C until use. The test compound was left with enzyme pre-incubation for 45 minutes before the start of the reaction.

The reaction mixture consisted of: 5 μl of test compound in 10% DMSO, 5 μl of 400 nm substrate (FAM-AKRRRLSSLRA), 5 μl of 40 nm PKCθ and 5 µl of 140 μm ATP (ATP was added to the reaction mixture last to initiate the reaction) to the hole.

The reaction was carried out for 60 minutes and stopped by adding 30 μl per well of 90% buffer A Progressive/10% buffer B Progressive and 1:400 dilution of granules for binding (Molecular Devices).

For incubation and binding of the reaction mixture gave the time at least 30 minutes before reading the signal polarization fluorescence using a reader Analyst (the detector was set at excitation of fluorescein - 485 nm, emission of fluorescein - 530 nm, the dichroism fluorescein - 505 nm).

5.2.4 Protocol HTRF analysis Tyk2 (shift ATF)

Below is an example of analysis that can be used in the t to determine the activity of the test compound, aimed at the inhibition of Tyk2.

25 μl/well DMSO was added to Columns 2 and 14 (except that of 28.5 µl was added into the hole P14 384-well polypropylene tablet Greiner). 20 μl/well DMSO was added to all remaining wells.

Added 5 mm solutions of compounds by adding 5 μl of 30 mm connection to 25 µl of DMSO in Columns 2 and 14 of the tablet. 1.5 mm comparative control was obtained by addition of 1.5 μl of 30 mm JAK3 inhibitor VI of 28.5 ál of DMSO in the well P14.

Then was carried out by serial dilution by carrying out the following stages: (i) Compounds in column 2 were mixed by pipetting when moving up and down 20 ál of 6X; (ii) 10 μl/well of compounds in DMSO was transferred from one column to the next column, Columns 2-11; (iii) the contents of the wells were mixed by pipetting when moving up and down 20 ál of 6X; (iv) the upper layers were washed using 3X 25 μl DMSO, 25 µl of 2X another DMSO; (v) stage i-iv were repeated for Columns 14-23.

Received the following buffers.

Buffer for analysis: 50 mm HEPES pH of 7.6; 1 mm DTT; 10 mm MgCl2; 0,01% Triton X100; 0,01% BSA and 0.1 mm EDTA.

Kinase buffer for analysis: 450 ng/ml TYK2 kDa (Carna Biosciences 08-147 Lot 06CBS-3022D).

The substrate/air mixture for the detection (1X ATP) in the buffer for analysis: 188 nm DyLight 647-Streptavidin (Pierce 21824); 5 μm Biotin-EQEDEPEGDYFEWLE (Lyn Substrate Peptide); 750 ng/ml Eu-anti-phospho-Tyrosine (PerkinElmer AD0069); 62.5 μm ATP; 80 nm peptide substrate (American Peptide Company 332722).

The substrate/air mixture for the detection (20X ATP) in the buffer for analysis: 188 nm DyLight 647-Streptavidin; 5 μm Biotin-EQEDEPEGDYFEWLE; 750 ng/ml Eu-anti-phospho-Tyrosine; 1250 μm ATP; 80 nm of the peptide substrate.

of 14.5 μl/well enzyme mixture or dilution buffer (Control) was added to 384-well black tablets Costar.

The connection and the mixture was added by carrying out the following stages: (i) 0,5 μl/well DMSO/compounds in DMSO was transferred from 384-well polypropylene tablet Greiner in the tablet containing the 14.5 μl/well of a mixture of enzyme and buffer for cultivation; (ii) were mixed by pipetting 10 µl of movement up and down 4X; (iii) the upper layers were washed 4X 10 μl in DMSO, 20 µl of 2X in another DMSO; (iv) stage i-iii were repeated until the processing is finished all the tablets.

Added 10 μl/well of substrate/mixtures for detection and incubated at room temperature for 2 hours (by shaking the device for the first 2+ minutes).

Added 10 μl/well of 50 mm EDTA/0.01% of Triton X100 and incubated >15 minutes at room temperature on a shaking device for the first 2+ minutes).

Tablets read at 665 nm and 620 nm emission using Analyst GT Protocol HTRF_SP_A (the Number of pulses = 665/620 X 10000).

5.2.5 Protocol HTRF analysis of Syk

5 μl/well DMSO was added in column 2, the wells A-O, and 29.5 μl into the hole P2 384-well polypropylene tablet Greiner. 20 μl/well DMSO doba who ranged in columns 1 and 3-12.

25 mm solutions of compounds were obtained by adding 25 μl of 30 mm connection in column 2 and 0.5 μl of 30 mm comparative control in well P2.

Then got a serial dilution by carrying out the following stages: (i) compounds in column 2 were mixed by pipetting 20 μl of movement up and down 6X; (ii) 10 μl/well of compounds in DMSO was transferred from one column to the next column, columns 2-11; (iii) the contents of the wells were mixed by pipetting 20 μl of movement up and down 6X; (iv) the upper layers were washed using 3X 25 μl DMSO, 25 µl of 2X another DMSO.

EP-3 scheme (Annex)

Received the following buffers.

The dilution buffer: 50 mm HEPES pH of 7.6; 1 mm DTT; 10 mm MgCl2; 0,01% Triton X100; 0,01% BSA; 0.1 mm EDTA.

The mixture of the enzyme in the buffer for cultivation: 8,621 ng/ml Syk (Carna Biosciences 08-176).

The initial mixture in the buffer for cultivation: of 87.5 μm ATP; 80 nm peptide substrate (American Peptide Company 332722).

of 14.5 μl/well enzyme mixture or dilution buffer (Control) was added to 384-well black tablets Costar.

The connection and the mixture was added by carrying out the following stages: (i) 0,5 μl/well DMSO/compound in DMSO was transferred from 384-well polypropylene tablet Greiner in the left half of the analytical tablet containing a 14.5 μl/well of a mixture of enzyme and buffer for cultivation; (ii) were mixed by pipetting 10 µl while moving upward and downward the 4X; (iii) the upper layers were washed using 4X 10 μl in DMSO, 20 µl of 2X in another DMSO; (iv) stage i-iii were repeated with the transfer of the right side of the analytical tablet; (v) stage i-iv was repeated with each connection/analytical tablet to complete processing of all tablets.

EP-3 scheme

Added 10 μl/well of the original mixture and incubated at room temperature on a shaking device for 2 minutes (total reaction time of 1 hour).

Received the following buffers.

Stop solution buffer for cultivation: 120 mm EDTA.

The mixture of antibodies in a buffer for cultivation: a 4.86 µg/ml DyLight 647 Streptavidin (Pierce 21824); 1 µg/ml Lance Eu-Anti-Phosphotyrosine (PerkinElmer AD0069).

Added 5 µl/hole/in the buffer for dilution and incubated at room temperature on a shaking device within 2 minutes.

Added 10 ml/well of a mixture of antibodies, and incubated at room temperature on a shaking device for 2 minutes (the total time from 4 hours to overnight).

Tablets read at 665 nm and 620 nm emission using Analyst GT Protocol HTRF_SP_A or EnVision Protocol Steve's TR-FRET.

5.2.6 Protocol functional analysis of Syk (expression of CD69 in anti-IgM-stimulated primary B-cells)

Cells: Primary B-cells were purified from cell Buffy coat preparations, which were obtained from healthy donors in the Blood Bank San Diego (SDBB). Cells under arrival in RPIM/10%FBS.

Reagents: AffiniPure F(ab') fragment goat anti-human IgM (Jackson, cat. 109-006-129, 1.3 mg/ml); PE-labeled anti-human CD69 (BD Pharmingen, cat. 555531,2 mls); 7AAD (BD Pharmingen, cat. 559925, 2 mls); RosetteSep B-cell enriched reagent (Stem Cell Technologies, cat. 15064, 10 mls); Ficoll-Paque Plus (Amersham, cat. 17-440-02); a coloring FBS buffer (BD Pharmingen).

Protocol: (i) cellular preparation of Buffy coat were ordered in advance from the firm SDBB (usually order two in case you have any difficulties with one of them); (ii) B-cells were purified using the method of negative selection RosetteSep as follows:

a) 2.0 ml of reagent RosetteSep was added to 40 ml of Buffy coat. The volume of each Buffy coat typically 80-100 ml of the Mixture was gently mixed and allowed to stand at room temperature for 20 minutes; there may be some condensation);

b) in a flask with tissue culture 40 ml buffy coat was mixed with an equal volume of sterile filtered 2% FBS in PBS (without calcium/magnesium);

c) 35 ml of this diluted buffy coat was added to each of the five 50-ml polypropylene conical tubes. Was slowly added 14 ml of Ficoll Paque under buffy coat and the bottom of each tube (be careful not to mix with buffy coat);

d) the tubes were centrifuged at 2200 rpm for 20 minutes in a tabletop centrifuge Sorvall with braking;

e) after centrifugation of the cells should be visually distinguishable on the surface of the partition serum/Ficoll. Siva otcu carefully aspirated to a point near the surface of the partition. Using a Pasteur pipette, the cell layer was removed from the surface of the section, taking precautions to remove the amount of Ficoll was as minimal as possible;

f) the selected cells were diluted (approx. 10 ml) in 100 ml of 2% FBS in PBS, centrifuged at 1200 rpm for a period of time from 5 minutes and the cell precipitate after centrifugation resuspendable in 5-10 ml of nutrient medium RPMI, depending on the expected number of selected cells.

Cells were counted and the density of cells is brought up to 1 million/ml in culture medium RPMI. Preparing a tablet for pre-treatment compound in 96-well round-bottom format with enough cells to cover the desired number of holes, assuming that the number in the tablet to handle 50 μl of cells/well. In a separate 96-well tablet compounds were diluted 1:50 in a nutrient medium RPMI. 22 μl of the diluted compounds were added to 200 μl of cells in the tablet for pre-treatment compound. The mixture was placed in an incubator for tissue culture for 30-60 minutes.

Received 20 µg/ml anti-IgM solution in culture medium RPMI. Added 50 μl of anti-IgM solution per well to a new 96-well round-bottom tablet (tablet for stimulation of the cells). Included only the used culture medium as controls. 50 μl tentative is but processed by the connection of cells were added to the tablet, contains anti-IgM, using a multi-channel device for pipetting. The mixture was again placed in the incubator for tissue culture for 12-14 hours.

The tablet was centrifuged at 1200 rpm for 5 minutes. Wednesday was unloaded and the plate is gently dried through blotting paper. Prepare a sufficient quantity of the solution of antibodies to cover the tablet, taking into account that 100 μl of buffer for staining contain 5 μl of CD69 antibody/well. Added 100 μl of antibody solution per well, the tablet gently tapped to mix, the tablet was covered with aluminum foil and placed under a hood at room temperature for 30 minutes.

The tablet was centrifuged, unloaded and dried by soaking. The tablet was washed once with 250 μl of buffer for staining, centrifuged, unloaded and dried by soaking. End-cellular precipitate after centrifugation resuspendable in 100 μl of buffer for staining and read on the cytometer.

5.2.7 Functional Analysis of Syk S.O.P. (IgE-dependent secretion of beta-hexosaminidase of fat cells a person's line LAD2)

Overview: LAD2 cells were planted in 96-well plate, were senzibilizirani through FcepsilonR using NP-IgE and degranulate by cross-linking with NP16-BSA. Supernatant collected and secretory components of the granules, including beta-hexosaminidase measured in different colorimetric assays.

Cells: LAD2 cells were obtained from Metcalf lab at the NIH. Detailed description of the selection, performance and growth/retention of these cells, see the original publication (Kirshenbaum et al. Leukemia Research 27:677-682, 2003). Cells grow relatively slowly, doubled every 10-14 days, and thus, they need to recharge when poluistoschennoe every week and occasional cleavage. Nutrient medium: StemPro-34 plus whey Supplement (Invitrogen) with 100 ng/ml recombinant human SCF (BioSource). Cells can be maintained in culture for approximately 15 passages to morphological and Funktsionalnyi changes.

Reagents: recombinant human nitrophenyl-IgE (Serotec, MCA333S, 20 μg/ml of the original solution); NP16-BSA (Biosearch Technologies, N5050-10 mg, 10 mg/ml initial solution); PNAG substrate (p-Nitrophenyl N-acetyl-β-D-Glucosaminide; Sigma N-9376) 0,004 M=1,37 mg/ml; prepare to 1.37 mg/ml in citrate/phosphate buffer, 150 μl/sample (it takes 30-60 minutes at 37°C with frequent vortex mixing)); citrate/phosphate buffer (0,04 M anhydrous citric acid (FW 192 g/mol); 2 ml 1 M citric acid (Hampton Research); of 0.02 M Na2HPO4; 2 ml of 0.5 M Na2HPO4(SIGMA), 5 n NaOH to bring the pH to 4.6 (approximately 1 ml) to 50 ml of solution); a modified Tyrode buffer (Tyrode buffer powder (SIGMA, T2145) one vial in 1 l of distilled water; allow the powder to dissolve and then add the ü the following: 1 M HEPES buffer pH 7.8 to a final concentration of 20 mm (1:50), of 0.5 M NA2HPO4to a final concentration of 0.5 mm (1:1000), 0,04% BSA (400 mg/l), pH should be 7,4); glycine stop-solution (0,32 mg glycine, 2.4 g/100 ml of 0.2 M sodium carbonate (FW 106 g/mol), 2.5 g/100 ml).

Protocol: LAD2 was carefully unloaded from a flask for culturing were collected and centrifuged at 1200 rpm for 5 minutes. Used culture medium was removed and preserved. Cells resuspendable at 0.8-1 million/ml in the culture medium. 100 μl of 0.5 μg/ml NP-IgE were sown in the used culture medium in round-bottom 96-well plate. Note: IgE solution should be made transparent with the removal of aggregates by centrifugation at > 10000 rpm for 10 minutes at 4°C. 100 μl of cells were added to the tablet and again placed in the incubator for tissue culture for 12-14 hours for sensitization of cells and load FcepsilonR receptors. Chilled modified Tyrode buffer was allowed to warm to room temperature overnight.

The next morning the tablet was centrifuged at 1200 rpm for 5 minutes. The medium was removed using a multichannel device for pipetting. The cell precipitates after centrifugation resuspendable in 100 μl of modified Tyrode buffer with gentle rubbing (5 strokes). Cells were left for 3.5 hours in the incubator for tissue culture. Note: this lie is necessary to heat citrate/phosphate buffer to 37°C and then resuspending PNAG substrate to 1.3 mg/ml with periodic wireman mixing. Was carried out by serial dilution of compound 1:50 in a modified Tyrode's buffer and then 11 ál connection, without further mixing, was added to each well (getting a final DMSO concentration of 0.2%). The connection preincubated for 30-60 minutes in the incubator for tissue culture.

Added 12 μl of 1.0 μg/ml NP16-BSA diluted in modified Tyrode buffer. The total amount now was 123 μl. You can add ionomycin at a final concentration of 100 nm instead of NP-BSA as a Syk-independent control for stimulation. Cells were then incubated in the incubator for tissue culture for 90 minutes.

The tablet was centrifuged at 1200 rpm for 5 minutes, 75 μl of the supernatant (SN) was transferred into an empty 96-well plate for storage. The remaining SN was removed from the containing cell of the tablet and is discarded. 125 μl of 0.1% Triton X-100 in a modified Tyrode buffer was added to the cell precipitate after centrifugation, pietravalle up/down for lysis of the cells and the mixture incubated on ice for 15 minutes.

30 μl of the supernatant from the tablet storage or 5 ál of cell lysate sediment plus 25 μl of 0.1% solution of Triton was added to new 96-well flat-bottomed plates in proper order for the end-reader tablets. 150 μl of PNAG substrate was added to all wells. Tablet incubated at 37°C in a bacterial incubator for 1 hour.

<> 50 μl of stop solution was added to each well. The wells with the most activity should be bright yellow. The tablet immediately read at 405 nm.

Expected % allocation per well (by subtracting background values from all wells) = 100×(SN/(SN + 6×cell lysate)). Net% allocation=100×(SN trims.-SN PBS)/(SN trims. + cell lysate steam.-SN PBS).

Control criteria the quality of the analysis: 3 primary parameter analysis:

1) the percentage allocation should be within 10-20% in IgE-and DMSO-treated wells (40% allocation to 100 nm ionomycin); 2) the value IR50for compounds with Syk should be in the range of 50-200 nm; 3) Z' for analysis must be >0,55.

5.2.8 Protocol analysis of biomarker Syk (measurement BLNK using PhosFlow in anti-IgM stimulated Ramos)

Cells: cell B-cell lymphoma Ramos (clone RA1, CRL1596) from ATCC grow quickly and need splitting 1:20 every 3-4 days to maintain. Cells were grown in RPMI/10% FBS.

Reagents: AffiniPure F(ab')fragment goat anti-human IgM (Jackson, cat, 109-006-129, 1.3 mg/ml); PE mouse anti-BLNK (pY84, BD Pharmingen, cat. 558442); reagent CytoFix (BD Pharmingen, cat. 554655); Perm/wash buffer I (BD Pharmingen, cat. 557885, 10X solution); BSA buffer for staining (BD Pharmingen, cat. 554657).

Protocol: Ramos cells were split 1:1 with fresh nutrient medium the day before the experiment. On the day of experiment, cells were centrifuged at 1200 rpm at t the value of 5 minutes. The used culture medium was maintained. Cells resuspendable at 1 million/ml in the culture medium. Prepared pre-processed by the connection plate in a 96-well format with enough cells to cover the desired number of holes, whereas that in the tablet to handle the number of cells in 50 μl of cells/well, for example, 4 holes were added to 200 μl of cells. In a separate 96-well tablet compounds were diluted 1:50 in the used culture medium. 22 μl of the diluted compounds were added to 200 μl of cells in the tablet is pre-processed by the connection. The tablet was again placed in the incubator for tissue culture for 30-60 minutes. CytoFix reagent was pre-heated to 37°C water bath before stimulation of the cells.

Prepared 40 µg/ml anti-IgM solution used in the culture medium. 50 μl of anti-IgM solution per well was added to a new 96-well round-bottom tablet (tablet for stimulation of the cells). Included only the used culture medium as controls. 50 μl of pre-processed by the connection of the cells was rapidly added to a tablet containing anti-IgM, using a multi-channel device for pipetting, and the plate was again placed in the incubator for tissue culture for 10 minutes.

Equal volume (100 is CL) preheated CytoFix reagent was added to all wells for stimulation of the cells. The tablet was again placed in the incubator for tissue culture for 10 minutes, centrifuged at 1200 rpm for 5 minutes, the medium was carefully unloaded and the plate was dried through blotting paper.

100 μl of Perm/wash buffer I was added to all wells. The tablet was left at room temperature for 10 minutes, centrifuged at 1200 rpm for 5 minutes, the medium was carefully unloaded and the plate was dried through blotting paper. Cells were washed three times using 200 μl BSA buffer for staining. The tablet was centrifuged, unloaded and got wet.

Prepare a sufficient quantity of the solution of antibodies to cover the tablet, taking into account that 100 μl of buffer for staining contain 5 μl pBLNK antibody/well. Added 100 μl of antibody solution per well, the tablet gently tapped to mix, the tablet was covered with aluminum foil and placed under a hood at room temperature for 30 minutes.

The tablet was centrifuged, unloaded and dried by soaking. The tablet was washed once using 200 ál of buffer for staining, centrifuged, unloaded and dried by soaking. End-cellular precipitate after centrifugation resuspendable in 100 μl of buffer for staining and read on the cytometer.

Compounds in table 2 have the following values, defined in Ana is the izam PKCθ, mTOR and Syk.

Table 2
ConnectionmTOR (µm)PKCθ IR50(µm)Syk IR50(µm)
1ND**
2******ND
3ND*ND
4******ND
5*****ND
6*****NDND
7ND*ND
8ND**********
9ND *ND
10********ND
11****
12ND*ND
13ND*******
14******ND
15******ND
16ND*ND
17ND*ND
18ND****ND
19ND*ND
20NDND
21ND*ND
22ND*ND
23ND*ND
24**ND
25**ND
26*****ND
27*****ND
28ND**********
29ND*ND
30ND*******
31ND *ND
32ND***ND
33ND*ND
34ND*ND
35ND*ND
36ND*ND
37ND*ND
38ND*ND
39ND*ND
40******ND
41*********ND
42ND *****ND
43ND*ND
44ND*ND
45******ND
46ND***ND
47******ND
48ND*ND
49ND*ND
50********ND
51********ND
52*********ND
53**** *ND
54*********ND
55*********ND
56******ND
57**ND
58****ND
59******ND
60***ND
61*******ND
62ND*ND
63ND*ND
64**** **ND
65*********ND
66ND*ND
61ND**ND
68**ND
69*****ND
70NDNDND
71NDNDND
72NDNDND
73*****ND
74ND*ND
75ND ***ND
76ND****ND
77ND**ND
78ND*ND
79NDNDND
80****NDND
81*NDND
82NDNDND
83ND*ND
84********ND
85*****ND
86*ND
87*****NDND
88*****NDND
89*****NDND
90*****NDND
91*****NDND

In table 2 above used the following system: ***** = 0,1-5 μm, **** = 5,1-10 μm, *** = 10,1-20 μm, ** = 20,1-30 µm, * = >30 μm. "ND" means that the connection has not been tested specifically against the specified enzyme.

The volume variations of the embodiment of the invention disclosed in this application should not be limited to specific variants of the embodiment disclosed in the examples, which are intended to illustrate certain aspects of the disclosed variants of embodiment of the invention, and any variants of embodiment of the invention, which are functionally equivalent are covered by the present disclosure. Indeed, various modifications of the variants of embodiment of izopet the tion, disclosed in the present application, which is in addition to those shown and described in this application, should be obvious to specialists in this field and included in the scope of the attached claims.

Have been listed in various references, the disclosure of which is incorporated into the present application by reference in their entirety.

1. The compound having the following formula:

or its pharmaceutically acceptable salt,
where R1represents or aryl, unsubstituted or substituted one of the groups: halogen, hydroxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkyls1-6alkoxy, C1-6alkylperoxy, -C(O)NH2, -S(O)OS1-6alkyl, -C(O)NHC1-6alkyl, cyano, carboxy, heteroaryl and heteroseksualci; or heteroaryl, unsubstituted or substituted one of the groups:1-6alkoxy, hydroxy, C1-6alkyl, NH2and NHC1-6alkyl; heteroseksualci, unsubstituted or substituted with one group =O; and
R2represents H; unsubstituted With3-4alkyl; C1-4alkyl, substituted C5-6cycloalkyl, unsubstituted or substituted with one group selected from amino, hydroxyl, C1-6alkoxy, or heterocyclization, unsubstituted or substituted by 1-2 groups selected from =O1-6 of alkyl; or
With5-6cycloalkyl substituted by one group selected from hydroxyl, C1-6alkoxyl,1-6alkyls1-6alkoxy, C1-6alkylperoxy, CONH2; or
substituted or unsubstituted heteroseksualci;
where aryl represents an aromatic structure, consisting of 6-10 carbon atoms, containing one ring or two condensed rings;
where heteroaryl is a 5-10-membered aryl ring system containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur;
where heteroseksualci is a 5-9-membered nonaromatic cycloalkyl, in which 1-2 heteroatoms, selected from nitrogen and oxygen;
provided that the compound is not a 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-it.

2. The compound according to claim 1, where R1represents a substituted or unsubstituted heteroaryl.

3. The compound according to claim 2, where R1represents a substituted or an unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole or substituted or unsubstituted thiophene.

4. The compound according to claim 1, where R1represents a substituted or unsubstituted aryl.

5. The compound according to claim 4, where R1represents a substituted or unsubstituted phenyl.

6. The compound according to claim 1, where R represents unsubstituted With3-4alkyl or C1-4alkyl, substituted substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclization.

7. The connection according to claim 6, where R1represents a substituted or unsubstituted phenyl.

8. The compound according to claim 1, where R1represents a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and R2represents a C1-4alkyl, substituted substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclization.

9. The compound or its pharmaceutically acceptable salt, where the connection is:
(1-((tetrahydro-2H-Piran-4-yl)methyl)-6-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(3-methoxybenzyl)-6-(4-methylsulphonyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-1-(1-hydroxy-3-methylbutane-2-yl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(R)-1-(1-hydroxy-3-methylbutane-2-yl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(R)-1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-1-(1-hydroxy-3-methylbutane-2-yl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he;
(R)-1-(1-hydroxy-3-methylbutane-2-yl)-6-(quinoline-5-yl)-1H-they are the azo[4,5-b] pyrazin-2(3H)-he;
(R)-1-(1-hydroxy-3-methylbutane-2-yl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-benzyl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(4-methoxybenzyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(R)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-isopropyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-cyclohexyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
5-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-isobutyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(2-hydroxyethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he;
6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(R)-6-(5-isopropyl-2-methoxyphenyl)-1(3-methylbutane-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-6-(5-isopropyl-2-methoxyphenyl)-1-(3-methylbutane-2-yl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he;
1-cyclopentyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(R)-6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclopropylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclopentylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohex is methyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(5-isopropyl-2-methoxyphenyl)-1-neopentyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-isopropyl-6-(3-isopropylphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-isopropyl-6-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(R)-1-(2-hydroxy-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-1-(2-hydroxy-1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-phenylethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-benzhydryl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-1-(1-phenylpropyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(R)-1-(1-phenylpropyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-Piran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(3-methoxybenzyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclopentylmethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(2-forfinal)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(4-forfinal)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-cyclopentyl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(3-forfinal)ethyl)-6-quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(3-methoxyphenyl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(4-methoxyphenyl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(quinoline-5-yl)-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(quinoline-5-yl)-1-(tetrahydro-2H-Piran-3-yl)-1H-what imidazo[4,5-b]pyrazin-2(3H)-he;
1-((1S,4S)-4-hydroxycyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-((1R,4R)-4-hydroxycyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(isoquinoline-5-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-isopropyl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(4-chlorophenyl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(4-methylsulphonyl)phenyl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(pyridin-4-yl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-phenylethyl)-6-(quinoline-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(2-forfinal)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-phenylethyl)-6-(quinoline-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(piperidine-4-ylmethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(pyridin-2-yl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-(pyridin-3-yl)ethyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-((1S,4S)-4-hydroxymethyl)cyclohexyl)-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
N-(4-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide;
6-(3-(methylsulphonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(3-AMINOPHENYL)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(3-(dimethylamino)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-phenyl-6-(quinoline-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(1-phenylethyl)-6-(4-(triptime the l)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
N-(3-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide;
6-(4-(methylsulphonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclopentylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-isopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-isobutyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((tetrahydro-2H-Piran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-cyclopentyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-cyclohexyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;
methyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate;
1-(cyclohexylmethyl)-6-(pyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-methylbenzamide;
1-(cyclohexylmethyl)-6-(4-(hydroxymethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile;
1-(cyclohexylmethyl)-6-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-isopropylbenzene;
1-(2-hydroxyethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(1H-indol-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
3-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;
6-(4-(aminomethyl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile;
1-((1S,4S)-4-hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(pyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-ethylbenzamide;
1-(cyclohexylmethyl)-6-(4-(2-hydroxypropan-2-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(4-hydroxy-2-were)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic acid;
6-(4-hydroxyphenyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-phenylethyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-((1R,4R)-4-hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(cyclohexyl the Teal)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(1H-pyrazole-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(3-(1H-tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(2-oxindol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(1H-indazol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(6-methoxypyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-(piperidine-4-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(((1R,4R)-4-aminocyclohexane)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(6-hydroxypyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(2-methoxypyridine-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(3-((1R,4R)-4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyrazin-5-yl)benzamide;
2-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetic acid;
2-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)ndimethylacetamide;
1-(cyclohexylmethyl)-6-(2-oxoindole-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-3-methylbenzoic acid;
N-methyl-4-(2-oxo-3-(((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-is)benzamide;
4-(2-oxo-3-((tetrahydro-2H-Piran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;
6-(4-(2-hydroxypropan-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(1H-indol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(1H-benzo[d]imidazol-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
4-(2-oxo-3-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;
6-(3-(2H-1,2,3-triazole-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-imidazol-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(2H-1,2,4-triazole-3-yl)phenyl)-1-((1R,4R)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(2H-tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(2-hydroxypyridine-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(2H-1,2,4-triazole-3-yl)phenyl)-1-(2-tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-imidazol-2-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-1,2,3-triazole-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)FeNi is)-1H-imidazo[4,5-b] pyrazin-2(3H)-he;
6-(4-(1H-pyrazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-pyrazole-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(4-(5-(aminomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b] pyrazin-2(3H)-she;
1-(cyclohexylmethyl)-6-(4-(5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((1R,4R)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(3-(1H-1,2,4-triazole-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-((1R,4R)-4-(hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((1S,4S)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((1R,4R)-4-methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(1-methyl-1H-pyrazole-4-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(((1R,4R)-4-hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(((1S,4S)-4-hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
6-(4-(5-(morpholinomethyl)-1H-1,2,4-triaz the l-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(4-hydroxyphenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
1-(cyclohexylmethyl)-6-(4-(oxazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(2-methyl-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
6-(4-(5-(methoxymethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-((1S,4S)-4-(hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(3-methyl-1H-pyrazole-4-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(1H-pyrazole-4-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the dihydrochloride 6-(2-amino-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
6-(4-(5-(2-hydroxypropan-2-yl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(5-isopropyl-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-((1S,4S)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(3H-imidazo[4,5-b]pyridine-6-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(2-(2,2-dimethylether-2H-Piran-4-yl)ethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-feast of the evils-1-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(4-(1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
6-(4-(5-hydroxymethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(4-(1H-imidazol-5-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
6-(4-hydroxyphenyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(4,5-dimethyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-1,2,4-triazole-5-yl)phenyl)-1-((1S,4S)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-1,2,4-triazole-5-yl)phenyl)-1-((1R,4R)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(6-(1H-1,2,4-triazole-3-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b] pyrazin-2(3H)-he;
6-(4-(5-((dimethylamino)methyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(4-hydroxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
the dihydrochloride 6-(2-aminobenzimidazole-5-yl)-1-(cyclohexylmethyl)-4-imidazole is but[4,5-b]pyrazin-2-it;
6-(2-dimethylamino)-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-hydroxyphenyl)-1-(piperidine-3-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-piperidine-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
1-(cyclohexylmethyl)-6-(2-(methylamino)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(2-(2-methoxyethylamine)pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(5-oxopyrrolidin-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-methyl-2-morpholinopropan)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(1-morpholinopropan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(pyrrolidin-2-yl)phenyl)-1-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(5-(hydroxymethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(1R,4R)-4-(6-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic;
(1S,4S)-4-(6-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic;
6-(4-(5-oxopyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(pyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(3-(hydroxymethyl)thiophene-2-yl)-1-((tetrahydro-2H-PYRAN-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(5-(2-hydroxyethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(pyrimidine-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(6-herperidin-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(6-aminopyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(6-(methylamino)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(2-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
1-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(hydroxymethyl)thiophene-2-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(1H-benzo[d]imidazol-6-yl)-1-(1R,4R)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(4,5-dimethyl-1H-imidazol-2-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1-((tetrahydro-2H-Piran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(4H-1,2,4-triazole-3-yl)phenyl)-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(3-methyl-4-(1H-1,2,4-triazole-3-yl)phenyl)-1-((tetrahydro-2H-p the RAS-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(1H-imidazol-2-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(4-(5-(aminomethyl)-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(1H-benzo[d]imidazol-5-yl)-1-(2-tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
6-(2-aminopyrimidine-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
the hydrochloride of 6-(4-hydroxyphenyl)-1-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-she;
(R)-6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(S)-6-(4-(1H-1,2,4-triazole-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he;
(1R,4R)-4-(6-(4-(2-hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxylic or
6-(4-(5-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1-(2-(tetrahydro-2H-Piran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-he.

10. Pharmaceutical composition for use in treating or preventing cancer, inflammatory conditions, immunological, or metabolic condition, comprising an effective amount of a compound having the formula:

or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier, excipient or filler
where R1represents or aryl, unsubstituted or substituted one of the groups: halogen, hydroxyl, C1-6and the keel, With1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkyls1-6alkoxy, C1-6alkylperoxy, -C(O)NH2, -S(O)OS1-6alkyl, -C(O)NHC1-6alkyl, cyano, carboxy, heteroaryl and heteroseksualci; or heteroaryl, unsubstituted or substituted one of the groups:1-6alkoxy, hydroxy, C1-6alkyl, NH2and NHC1-6alkyl; heteroseksualci, unsubstituted or substituted with one group =O; and
R2represents H; unsubstituted With3-4alkyl; C1-4alkyl, substituted C5-6cycloalkyl, unsubstituted or substituted with one group selected from amino (NH2), hydroxyl, C1-6alkoxy, or heterocyclization, unsubstituted or substituted by 1-2 groups selected from =O,1-6of alkyl; or
With5-6cycloalkyl substituted by one group selected from hydroxyl, C1-6alkoxyl,1-6alkyls1-6alkoxy, C1-6alkylperoxy, CONH2; or
the unsubstituted heteroseksualci;
where aryl represents an aromatic structure, consisting of 6-10 carbon atoms, containing one ring or two condensed rings;
where heteroaryl is a 5-10-membered aryl ring system containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur;
where heteroseksualci is a 5-9-membered, neuromate the definition of cycloalkyl, in which 1-2 heteroatoms, selected from nitrogen and oxygen;
provided that the compound is not a 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-it.

11. The pharmaceutical composition of claim 10, which is suitable for oral, parenteral, injection through the mucous membrane, percutaneous or topical administration.

12. A method of treating or preventing cancer, inflammatory conditions, immunological, or metabolic condition, comprising administration to a patient in need, an effective amount of a compound according to claim 1.

13. The method according to item 12, where the cancer is a cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or Central nervous system.

14. The method according to item 12, where the inflammatory condition is a psoriasis, asthma, allergic rhinitis, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative which of Olite, diabetes or obesity.

15. The method according to item 12, where immunological status represents rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiple sclerosis, ordinary erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Grave's disease or diabetes.

16. The method according to item 12, where the metabolic state is an obesity or diabetes.

17. Method of inhibiting kinase activity in a cell expressing the indicated kinase, comprising contacting the specified cell with an effective amount of a compound according to claim 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

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

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

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel intermediate epoxy compound of general formula (2), where R1 represents hydrogen or a lower alkyl group; and R2 represents a piperidinyl group of general formula (A1), where R3 represents a phenoxy group, having a halogen-substituted lower alkoxy group, substituted with a phenyl group, and other similar groups; and n is an integer from 1 to 6, to obtain 2,3-dihydroimidazo[2,1-b]oxazole. The invention also relates to specific epoxy compounds, a method of producing epoxy compounds of formula (2) and a method of producing 2,3-dihydroimidazo[2,1-b]-oxazole using a novel intermediate epoxy compound.

EFFECT: obtaining 2,3-dihydroimidazo[2,1-b]oxazole with high output and high purity.

4 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1, or their pharmaceutically acceptable salts showing the properties of incretin secretagogues, preferentially the properties of a bile acid receptor TGR5 agonist. The compounds are applicable for treating metabolic diseases associated with glucose metabolism, such as diabetes, obesity, metabolic syndrome, etc. In formula 1 R1, R2 and R3 independently represent a cyclic system substitute specified in: hydrogen, C1-C3alkyl, halogen, a trifluoromethyl group, C1-C3alkoxy, a cyano group, a trifluoromethoxy group; an amino group substituted by C1-C3alkyl; or two radicals R3, found at carbon neighbours in a benzene ring, together with the benzene ring bound therewith form 3,4-methylene dioxyphenyl; R4 represents hydrogen, C1-C5alkyl, a carboxyl group, C1-C3alkoxycarbonyl or an amide group CONHR5; R5 is an optionally substituted by C1-C3alkyl, C5-C6cycloalkyl optionally substituted by phenyl, benzyl, pyridyl; X and Y represent two hydrogen atoms or an oxygen atom, provided Y=O, then X=2H, provided Y=2H, then X=O or X=Y=2H; the sign (N) shows the possibility of bioisosteric substitution of the benzene ring by the pyridine, pyrimidine, pyridazine, triazine or pyrazine ones.

EFFECT: preparing the pharmaceutical composition and the combined drugs with the use of the compounds of formula 1 or the based pharmaceutical composition and a protein kinase DPP-IV inhibitor specified in Vildagliptin or Sitagliptin, and/or an endogenous bile acid or mied bile acid secretagogues.

53 cl, 7 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (R)-N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide substantially free from (S)-N-(3-amino-propyl)-N[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methypropyl]-4-methyl-benzamide, or its pharmaceutically acceptable salt which shows the properties of Eg5 inhibitor.

EFFECT: invention also refers to a pharmaceutical composition containing said compound and its pharmaceutically acceptable salt.

4 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), and a salt or hydrate thereof:

,

in which R1 denotes a hydrogen atom; R2 denotes a hydrogen atom; R3 and R4 independently denote a hydrogen atom; R5 denotes a hydrogen atom or a fluorine atom; R6 and R7, together with carbon atoms to which they are bonded, form a 5- or 6-member cyclic structure, where the cyclic structure is a partial structure which, together with a pyrrolidine ring, forms a condensed cyclic (bicyclic) structure, the 5- or 6-member cyclic structure can contain an oxygen atom as a ring atom, R5 can be a methylene group which, together with R6, forms a 3-member condensed cyclic structure; and Q is a partial structure of formula (II):

,

in which R8 denotes a 1,2-cis-2-halogencyclopropyl group, a cyclopropyl group or a 6-amino-3,5-difluoropyridin-2-yl group; R9 denotes a hydrogen atom; R10 denotes a hydrogen atom; R11 denotes a hydrogen atom; XI denotes a fluorine or hydrogen atom; A1 denotes a nitrogen or partial structure of formula (III):

,

in which X2 is a methyl group, an ethyl group, a methoxy group or a chlorine atom, or X2 and R8, together with their coupling part of the parent skeleton, form a cyclic structure, such that Q denotes a partial structure of formula , in which Y0 denotes a methyl group or a pre-methyl group, and X1, R9, R10, R11 assume values given above. The invention also describes a medicinal agent based on said compound, having antibacterial activity, an antibacterial agent and a therapeutic agent for treating infections.

EFFECT: novel compounds are obtained and described, which have strong antibacterial activity not only on gram-negative bacteria, but gram-positive cocci as well, which have low sensitivity to quinolone antibacterial agents, and which demonstrate high safety and excellent pharmacokinetic properties.

18 cl, 61 ex

FIELD: pharmachology.

SUBSTANCE: invention describes new compounds with general formula (I-c) Where R1 is a radical (d-1) or (d-2) (radical values are given in the invention formula) and pharmaceutical composition containing them. The described compounds are the hepatitis C inhibitors and can be used in medicine.

EFFECT: enhanced hepatitis C inhibition.

5 cl, 1 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them.

EFFECT: invention also refers to a method for preparing the compounds of formula (I), the based pharmaceutical compounds, to the use of said compounds for preparing said drug preparation for treating or preventing anxiety, epilepsy, sleep disorders, including insomnia, as well as for inducing a sedative-hypnotic effect, anaesthesia and muscular relaxation.

23 cl, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (VIII):

X represents NR7; Y represents O or N-(CH2)nR19; n is equal to 1 or 2; m is equal to 1 or 2; R1 represents H or C1-6alkyl; R2 independently represents H, C1-6alkyl or C5-6cycloalkyl; each of R4 and R4 independently represents H or C1-6alkyl; or R4 and R4 together form spiro-C3-6cycloalkyl group; R19 represents H, C1-6alkyl, C6aryl or C3cycloalkyl group; R6 represents OR8 ; and each of R7 and R8 independently represents H or C1-6alkyl. The invention also refers to compounds of formula VI, VII, a pharmaceutical composition containing said compounds, and a method of treating a proliferative disease, such as cancer.

EFFECT: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a PLK1 kinase inhibitor.

24 cl, 8 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, to a based composition, the use of said crystalline form 1, methods for preparing it.

EFFECT: what is prepared is the new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide effective for treating cancer.

10 cl, 9 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

,

where X1 denotes a bond, NR8 or S; Y1 denotes O or NR ; R1 denotes C1-10alkyl, C6-10aryl or a 5-10-member heteroaryl containing 1-3 heteroatoms which are independently selected from N or S; where said R1 is optionally substituted with 0-2 J1; R2 denotes H or C1-10alkyl; each of R3, R4, R5 and R6 independently denotes H or C1-10alkyl; and R7 denotes C1-10alkyl, C3-10cycloalkyl, phenyl, 5-6-member heterocyclyl containing 1-3 heteroatoms independently selected from O and N, - (C1-6alkyl) -(C3-10cycloalkyl), - (C1-6alkyl) - (phenyl) or -(C1-6alkyl)-(6-member heterocyclyl containing 2 heteroatoms selected from O and N); where said R7 is optionally substituted with 0-5 J7; or R3 and R4, together with a carbon atom with which they are bonded, optionally form a 3-4-member saturated or partially unsaturated monocyclic fragment; R3 and R5, together with carbon atoms with which they are bonded, optionally form a 5-member monocyclic fragment; R8 denotes H; R9 denotes H or unsubstituted C1-6alkyl; or R2 and R9, together with atoms with which they are bonded, optionally form a 5-member aromatic monocyclic fragment containing 3 nitrogen atoms; each J1 independently denotes C1-6halogenalkyl, halogen, NO2, CN, Q or -Z-Q; or two J1 together can optionally form =O; Z denotes C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -NR-, -O-, -C(O)- or -SO2-; wherein each Z is optionally substituted with 0-2 J2; Q denotes H; C1-6alkyl; 3-8-member aromatic or non-aromatic monocyclic fragment containing 0-3 heteroatoms independently selected from O, N and S; or an 8-10-member aromatic bicyclic system; each Q is optionally substituted with 0-2 JQ; each J7 independently denotes C1-6alkyl or halogen(C1-4alkyl); each of JQ and J7 independently denotes M or -Y-M; each Y independently denotes an unsubstituted C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -O-, -C(O)- or -SO2-; each M independently denotes H, C1-6alkyl, C3-6cycloalkyl; halogen (C1-6alkyl), phenyl, halogen, CN, OH, OR1; or two M together can optionally form =O; R denotes H or an unsubstituted C1-6alkyl; R' denotes an unsubstituted C1-6alkyl. The invention also relates to methods of producing said compounds and a pharmaceutical composition for inhibiting PLK based on said compounds.

EFFECT: novel compounds which can be used in medicine as inhibitors of protein kinase are obtained.

34 cl, 1 tbl, 279 ex

FIELD: chemistry.

SUBSTANCE: method involves heating cyclic thiourea at temperature from higher than 200°C to 250°C in a solvent which is selected from ethers, alcohols or mixtures thereof, to form bicyclic guanidines.

EFFECT: method enables to obtain a product with high output.

13 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heterocyclic amide compound of formula I: or a pharmaceutically acceptable salt thereof. Described also is a pharmaceutical composition containing said compound, having protein kinase inhibitor, regulator or modulator properties, which is acceptable in treating or preventing a proliferative disease, an anti-proliferative disorder, inflammation, arthritis, neurologic or neurodegenerative disease, cardiovascular disease, hair loss, neural disease, ischemic disorder, viral disease or fungal disease.

EFFECT: high efficiency of using the compounds.

2 cl, 20 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of formula (I) and pharmaceutically acceptable salts and solvates thereof, having IGF-IR and IR inhibiting properties, which can be used to treat proliferative cancerous diseases such as breast cancer, sarcoma, lung cancer and prostate cancer. In the compound of formula (I): R1 is selected from H and C1-C3alkyl; R2 is selected from H, C1-C3alkyl and halogen; R3 is selected from H, OH, C1-C6alkyl, groups -C1-C6alkylene-OH, -C1-C6alkylene-phenyl (optionally substituted with a halogen) and -C1-C6alkylene-C(O)NH2; R4 is selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl; or R3 and R4, together with atoms with which they are bonded, form a 5- or 6-member lactam; each of R5 and R6 is independently selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl, or R5 and R6 together with an aryl with which they are bonded form naphthalene; R7 is selected from C1-C6alkyl, -O-C1-C6alkyl, halogen, -N-R19R19 and -O-C1-C6alkylene-halogen; R8 is selected from H, halogen and C1-C6alkyl; one of R9 and R10 is selected from -C1-C6alkylene-SO2-C1-C6alkyl, -NR19-C(O)-C0-C6alkylene-NR22R23, -O- C0-C6alkylene(optionally substituted with -OH)-NR22R23, and etc, given in the claim and the other of R9 and R10 is selected from H, C1-C6alkyl, -O- C1-C6alkyl and halogen.

EFFECT: improved method.

41 cl, 12 dwg, 263 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

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