Aminotriazolopyridines and using them as kinase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I), their pharmaceutically acceptable salts, tautomers or stereoisomers. In formula R1 represents benzimidazolyl optionally substituted by C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, dimethylaminoC1-4alkyl or oxo group; benzioxazolyl optionally substituted by C1-4alkyl or amino group; benzotriazolyl optionally substituted by C1-4alkyl; dihydrobenzisothiazol-1,1-dionyl; pyrimidyl; dihydroisoquinolinonyl optionally substituted by oxo group; imidazopyridyl; indazolyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, tetrahydropyranylamino, piperidinylamino, halogen, trifluoromethyl or amino group; indolinyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, carboxylate or oxo group; isoindolinyl optionally substituted by C1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or oxo group; phenyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, trifluoromethyl, carbamoyl, methylcarbamoyl, piperidinylcarbamoyl, methylpiperidinylcarbamoyl, aminoC1-4alkyl, carboxyl, amino, dialkylamino, imidazolyl, pyrrolidin-2-one, triazolyl, morpholinyl, C1-4alkylcarbonylamino, C1-4alkoxyC1-4alkoxy or hydroxyC1-4alkyl; pyrazolopyridyl optionally substituted by C1-4alkyl; pyridyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, hydroxy, amino, morpholinyl, carbamoyl, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkoxy, aminoC1-4alkylamino, hydroxypiperidinyl, hydroxyC1-4alkyl, hydroxyC1-4alkoxy, pyrrolidinylC1-4alkylamino, pyrrolidinylC1-4alkoxy; pyrrolopyridinyl optionally substituted by oxo group; quinolinyl optionally substituted by amino or hydroxy group; or triazolopyridyl substituted by C1-4alkyl. The other radical values are presented in the patent claim. The invention also refers to individual compounds, to a pharmaceutical composition, possessing kinase inhibitory activity and containing an effective amount of the compound of the invention, to a method for kinase inhibition in a cell, to a method of treating or preventing inflammatory conditions, immunological conditions, allergic conditions, rheumatic conditions, cancer, and neuroinflammatory diseases.

EFFECT: there are prepared new compounds possessing Syk, FLT3, JAK1, JAK2 inhibitory activity.

21 cl, 1 tbl, 133 ex

 

The present application claims the benefit of Provisional Application U.S. No. 61/095217, filed September 8, 2008, and Provisional Application U.S. No. 61/230479, filed July 31, 2009, the complete contents of which are incorporated in this application by reference.

1. Field of the invention

In the present application presents certain 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 treatable or preventable by inhibition of a kinase or kinase path, comprising administering an effective amount of the heteroaryl compound to a subject in need of it.

2. Background of the invention

The link between abnormal protein phosphorylation and the cause or consequence of diseases has been known for over 20 years. Accordingly, protein kinases represent a very important group of objects which are targets for drugs. Cm. Cohen, Nature, 1: 309-315 (2002). Various protein kinase inhibitors clinically used to treat 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 �annualrate family of enzymes that catalyze protein phosphorylation and play a critical role in cellular signal transmission. Protein kinases can be positive or negative regulatory effects, depending on their protein target. Protein kinase involved in specific signaling pathways that regulate cellular functions, such as, but not limited to, metabolism, development, cell cycle, cell adhesion, function of blood vessels, apoptosis, inflammation and angiogenesis. Violation of cellular signal transmission is associated with many diseases, the most typical of which include inflammation, cancer, and diabetes. Regulation of signal transduction by cytokines and communication signaling molecules with protooncogenes and tumor-suppressor genes is described in detail in various documents. In this way, we demonstrated the Association between diabetes and related conditions, and impaired regulation of the levels of protein kinases. See, for example, Sridhar et al. Pharmaceutical Research, 17(11):1345-1353 (2000). Viral infections and conditions associated with them, 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 amino acid identity(amino acids) to which they are aimed (serine/threonine, tyrosine, lysine and histidine). For example, tyrosine kinases include tyrosine Kina�s receptors (RTKs), such as growth factors and receptor tyrosine kinases, such as src family kinases. There are also protein kinases with dual specificity, which are aimed at both tyrosine and serine/threonine, such as cyclin-dependent kinases (CDKs) and mitogen-activated protein kinases (MAPKs).

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 disease conditions. For example, cell cycle control and angiogenesis, in which protein kinases play an essential role, represent cellular processes razlichnye painful conditions, such as, but not limited to, cancer, inflammatory diseases, abnormal angiogenesis and diseases related to them, atherosclerosis, macular degeneration, diabetes, obesity and pain.

One of the key events in signaling pathways following activation of mast cells is the activation tyrosinemia kinase Syk. Mast cells play a critical role in asthma and allergic disorders by releasing Pro-inflammatory mediators and cytokines. Antigen-mediated aggregation of FcεRI, the high affinity receptor for IgE results in activation of the clouds�'s cells. This triggers a series of signaling events leading to release of mediators, including histamine, proteases, leukotrienes, and cytokines. These mediators cause increased vascular permeability, mucus production, bronchostenosis, tissue destruction and inflammation, thus, they play a key role in the etiology and symptoms of asthma and allergic disorders. Syk kinase acts as a Central initiator of all subsequent signaling events leading to mediator release. Critical role of Syk kinase in signaling pathways was demonstrated by the complete inhibition of the release of the mediator protein containing SH2 domains of Syk kinase, which functioned as an inhibitor of Syk kinase (J. A. Taylor et al, Molec. and Cell Biol, 15: 4149-4157 (1995). In addition, it was discovered that direct the formation of clusters Syk, entered into a line of fat cells as part of a chimeric transmembrane protein, is sufficient to stimulate events leading to the release of a mediator, usually induced the formation of clusters of FcεRI (V. M. Rivera, et al, Molec. and Cell Biol, 15: 1582-1590 (1995).

Activation and activity of Syk kinase is required for FcεRI-mediated release of mediators from mast cells. Therefore, agents that block the activity of Syk kinase, have an effect of blocking the release of allergic and Pro-inflammatory mediators and �of Fokino. These agents have a potential application in the treatment of inflammatory and allergic disorders, including asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, adult or acute respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, conjunctivitis, psoriasis, scleroderma, urticaria, dermatitis and allergic rhinitis.

In addition to mast cells, Syk is expressed in other hematopoietic cells, including B cells, where, as believe it plays a significant role in transduction of signals necessary for the transition of immature B-cells into Mature recirculating B cells (M. Turner et al, Immunology Today, 21: 148 (2000). There are reports that B-cells play an important role in some inflammatory conditions such as lupus (O. T. Chan et al. Immunological Rev, 169: 107-121 (1999) and rheumatoid arthritis (A. Gause et al, Biodrugs, 15(2): 73-79 (2001).

It was also reported that Syk is an element of the signaling cascade in beta-amyloid and the prion fibrils, leading to the production of neurotoxic products (C. K. Combs et al, J. Neurosci, 19: 928-939 (1999). Furthermore, the Syk inhibitor blocked the production of these neurotoxic products. Thus, the heteroaryl compound is potentially useful for the treatment of Alzheimer's disease and related neuro-inflammatory diseases. Another message (Y. Kuno et al., Blood, 97, 1050-1055 (2001)demonstrates that Syk plays an important role in the progression of malignant disease. It was found that the TEL-Syk fusion protein transforms hematopoietic cells, suggesting its role in the pathogenesis of hematopoietic malignancies. Therefore, heteroaryl compound can be useful for treating some types of cancer.

Other tyrosine protein kinases that are involved in hematological malignancies, include ABL (ABLl), ARG (ABL2), PDGFβR, PDGFaR, JAK2, TRKC, FGFRl, FGFR3, FLT3 and FRK. Janus kinases (JAK) are a family of tyrosine kinases, including JAK1, JAK2, JAK3 and TYK2. JAKs play a critical role in signaling activity of cytokines. Further on this way, the substrates of the JAK family of kinases include protein, which is the signal transducers and activators of transcription (STAT). Signal transmission JAK/STAT is involved in mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection(allograft), rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematologic malignancies such as leukemia and lymphoma (review of pharmaceutical intervention in respect of the JAK/STAT path, see Frank, Mol. Med. 5, 432:456 (1999) and Seidel et al, Oncogene 19, 2645-2656 (2000). JAK2 is a recognized target with great p�market potential for the treatment of myeloproliferative disorders (MPDs), which include true polycythemia Vera (PV), essential thrombocytosis, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic mielomonocitarnyi leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systemic mastocytosis.

Fms-like tyrosinekinase 3 (FLT3), also known as FLK-2 (fetal liver kinase 2) and STK-I (kinase 1 stem cells), plays an important role in the proliferation and differentiation of hematopoietic stem cells. FLT3 receptor kinase highly expressed in normal hematopoietic cells, placenta, gonads and the brain. However, this enzyme is expressed at very high levels on cells more than 80% of myelogenous patients and in a certain proportion of cells of acute lymphoblastic leukemia. In addition, this enzyme also can be detected on cells from patients with chronic myelogenous leukemia in lymphoid blast crisis. It was reported that FLT3 kinase is mutated in 30% of cases of acute myeloid leukemia (AML), and also in certain percentage of cases of acute lymphoblastic leukemia (ALL) (Gilliland et al, Blood 100, 1532-1542 (2002); Stirewalt et al, Nat. Rev. Cancer, 3, 650-665 (2003). The most common activating mutations in FLT3 are internal tandem duplications in kolomanbrunnen area, then ka� point mutations insertions or deletions in the kinase domain is less typical. Some of these mutant FLT3 kinases are constitutive active. FLT3 mutations are associated with poor prognosis (Malempati et al., Blood, 104, 11 (2004). More than a dozen known FLT3 inhibitors have been developed and some have shown promising clinical effects against AML (Levis et al Int. J. Hematol, 52, 100- 107 (2005). It was reported that some small molecule FLT3 inhibitors are effective in inducing apoptosis in cell lines with FLT3-activating mutations and extend the survival period of mice that Express mutant FLT3 in their bone marrow cells (Levis et al, Blood, 99, 3885-3891 (2002); Kelly et al, Cancer Cell, 1, 421-432 (2002); Weisberg et al, Cancer Cell, 1, 433-443 (2002); Yee et al, Blood, 100, 2941-2949 (2002).

The elucidation of the complexity proteinkinase ways and the complexity of the relationships and interactions among and between the various protein kinases and kinase pathways emphasizes the importance of developing pharmaceutical agents that can act as modulators, regulators or inhibitors of protein kinases, which has a favorable effect on multiple kinases or multiple kinase pathways. Accordingly, there remains a need for new modulators of kinases.

Citation or indication of any of the reference document in section 2 of the present application should be construed as the assumption that this reference document is famous�m from the prior art analogue of the present invention.

3. Brief description of the invention

In the present application presents heteroaryl compounds having the following formula (I):

and their pharmaceutically acceptable salts, tautomers, stereoisomers, solvates or a prodrug, where R1and R2have the meaning defined below.

In one aspect, the present application presents heteroaryl compounds presented in Table 1 of this disclosure and their pharmaceutically acceptable salts, tautomers, stereoisomers, solvates and prodrug.

In one aspect, the present application includes pharmaceutical compositions comprising an effective amount heteroaryl compounds described in this application, or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug and a pharmaceutically acceptable carrier, excipient or filler. In some embodiments embodiment the pharmaceutical composition is suitable for administration orally, parenterally, through the mucous membrane, or percutaneous local path.

In one aspect, the present application presents methods for the treatment or prophylaxis of inflammatory conditions of immunological conditions, autoimmune conditions, allergic conditions, rheumatic conditions, thrombotic conditions, �aka, infections, neurodegenerative diseases, neuro-inflammatory diseases, cardiovascular diseases and metabolic conditions, comprising administering to a subject in need, an effective amount of the heteroaryl compounds described in this application, or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug; and a pharmaceutically acceptable carrier, excipient or filler. In some embodiments embodiment, the methods further comprise the introduction of additional therapeutic ingredients described in the present application.

In one aspect, the present application presents methods for inhibiting kinase in a cell expressing the indicated kinase, comprising contacting the specified cell with an effective amount of the heteroaryl compounds described in this application, or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug.

In one aspect, the present application presents methods for the treatment or prophylaxis of cancer, comprising administering to a subject suffering from cancer, a certain number heteroaryl compounds described in this application, or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug.

The options presented waples�tion will be better understood with reference to the detailed description and examples which are intended to illustrate and not to limit embodiments.

4. Detailed description of the invention

4.1 Definition

"Alkyl" group is a saturated, partially saturated or unsaturated linear or branched non-cyclic hydrocarbon containing from 1 to 10 carbon atoms, typically from 1 to 8 carbon atoms or, in some embodiments embodiment, from 1 to 6, 1 to 4 or from 2 to 6 carbon atoms. Representative alkyl groups include-methyl, -ethyl, -n-propyl, n-butyl, n-pentyl and-n-hexyl; while saturated branched alkali include-isopropyl, -sec-butyl, -isobutyl, tert-butyl, - isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -OC(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3and-CH2C≡C(CH7CH3), among others. The alkyl group can be substituted or unsubstituted.

"Cycloalkyl" group is a saturated, partially saturated or unsaturated cyclic alkyl group containing 3 to 10 carbon atoms, containing one cyclic ring �whether multiple condensed or linked by bridging communication rings which optionally may be substituted with 1-3 alkyl groups. In some embodiments of the incarnation, cycloalkyl group contains from 3 to 8 ring members, whereas in other embodiments, embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6 or 3 to 7. Such cycloalkyl groups include, as an example, structures with a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentene, 2-methylcyclohexyl and the like, or a structure that includes multiple bridged or connected by connection rings, such as adamantyl and the like. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. Cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, as an example, cyclohexanone and the like.

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

"Heteroaryl" group is an aryl ring system containing one to four heteroatoms as ring atoms in a heteroaromatic ring system, where the remaining atoms are carbon atoms. In some embodiments, embodiments, heteroaryl groups contain from 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of such groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In some embodiments embodiment, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolidine, pyrazolidine, imidazolidine, triazoline, tetrataenia, oxazolidine, isoxazolidine, benzisoxazole (e.g., benzo[d]isoxazolyl), thiazolidine, pyrrolidine, pyridinoline, piramidalnaya, piratininga, teofilina, benzothiazoline, furazilina, benzofuranyl, indlela (n�example, indole-2-o'neill or isoindoline-1-o'neill), isoindoline (pyrrolopyridine or 1H-imidazo[2,3-b]pyridyl), indazolinone, benzimidazolyl (for example, 1H-benzo[d]imidazolyl), imidazopyridine (e.g. asianshemales or 1H-imidazo[4,5-b]pyridyl), pyrazolopyrimidine, triazolopyrimidine, benzotriazolyl (for example, 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazoline, benzothiadiazole, isoxazolidine, teenattila, Puringla, cantinella, adreniline, huarinilla, hyalinella, sochineniia (for example, 3,4-dihydroisoquinoline-1(2H)-o'neill), tetrahydropyrimidine, khinoksalinona and chinazoline group.

"Heterocyclyl" is an aromatic (also listed as heteroaryl) or a non-aromatic cycloalkyl in which one to four of the ring carbon atoms independently substituted heteroatom selected from the group comprising O, S and N. In some embodiments of the incarnation, heterocyclyl groups include from 3 to 10 ring members, whereas other such groups contain from 3 to 5, 3 to 6 or 3 to 8 ring members. Heterocyclyl can also be linked to other groups via any ring atom (i.e., any carbon atom or heteroatom of the heterocyclic ring). Geteroseksualnoe group can be samisen�th or unsubstituted. Heterocyclyl cover unsaturated, partially saturated or saturated ring system, such as, for example, imidazolidine, imidazolidinone and imidazolidinethione (e.g. imidazolidin-4-he or imidazolidin-2,4-dionyl) group. Heterocyclyl includes condensed ring types, including types, including condensed aromatic and non-aromatic groups, such as, for example, benzotriazolyl (for example, 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (for example, 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxines and benzo[1,3]dioxole. This term also includes the associated bridging communication polycyclic ring systems containing a heteroatom such as, but not limited to, Hinkley. Representative examples heterocyclyl groups include, but are not limited to, aziridinyl, azetidinone, sepanlou, pyrrolidino, imidazolidinyl (e.g. imidazolidin-4-o'neill or imidazolidin-2,4-dionyl), pyrazolidinone, diazolidinylurea, tetrahydrothiophene, tetrahydrofuranyl, DIOXOLANYL, fornillo, Teofilo, pyrrolidino, pyrrolidinyl, imidazolidinyl, imidazolylalkyl, parasailing, pyrazolidine, triazoline, tetrazolyl, oxazolidinyl, isoxazolidine, benzisoxazole (e.g., benzo[d]isoxazolyl), thiazolidine, tiaso�enelow, isothiazolinone, thiadiazolidine, oxadiazolidine, piperidino, piperazinilnom (e.g., piperazine-2-o'neill), morpholinyl, thiomorpholine, tetrahydropyranyloxy (for example, tetrahydro-2H-pyranyl), tetrahydropyranyloxy, occationally, dioxidine, ditionally, pyranyloxy, pyridyloxy, pyramidalnou, pyridazinyl, personilnya, triazinyl, dihydropyridine, dihydropyrimidine, dihydropyrimidine, homopiperazine, genocidally, indolenine (for example, indole-2-o'neill or isoindoline-1-o'neill), indolinyl, isoindolyl, isoindolyl, isoindolyl (pyrrolopyridine or 1H-imidazo[2,3-b]pyridyl), indazolinone, indolizinyl, benzothiazolyl (for example, 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (for example, 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-o'neill), benzofuranyl, benzothiophene, benzothiazolyl, benzoxazolyl, benzoxazolyl, benzodithiol, benzoxadiazole, benzothiazinone, benzoxazolyl (i.e. benzo[d]oxazolyl), benzothiazolyl, benzothiadiazole, benzo[1,3]DIOXOLANYL, pyrazolopyrimidine (for example, 1H-pyrazolo[3,4-b]pyridyloxy, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridine (e.g. asianshemales or 1H-imidazo[4,5-b]pyridyl), triazolopyridine, isoxazolidine, parinello, santinello, hell�kinilow, guanidino, hyalinella, athinodorou (for example, 3,4-dihydroisoquinoline-1(2H)-o'neill), hyalinella, chinoxalin, chinazoline, indolinyl, talinolol, naphthyridinone, pteridinyl, tianeptine, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydroindole, dihydroergotoxine, tetrahydroindole, tetrahydroindazole, tetrahydroaminoacridine, tetrahydrobenzothieno, tetrahydroprotoberberine, tetrahydroprotoberberine, tetrahydroaminoacridine, tetrahydroprotoberberine, tetrahydropyrimidin-2(1H)-he tetrahydropyranyloxy group. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, for example, but not limited to, peredelnye or morpholinyl groups that are 2-, 3-, 4-, 5- or 6-substituted, or disubstituted with various substituents such as those listed below.

"Kalkilya" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted kalkilya groups may be substituted by alkyl, aryl, or both the alkyl and aryl portions of the group. Representative kalkilya groups include, but are not limited to, benzyl and fenetylline group and condensed�s (cycloalkenyl)alkyl group, such as 4-ethyl-indanyl.

"Geterotsiklicheskie" group is a radical of the formula: -alkyl-heterocyclyl, where the alkyl and heterocyclyl defined above. Substituted geterotsiklicheskikh groups may be substituted by alkyl, heterocyclyl or both the alkyl and heterocyclyl fragments of the group. Representative geterotsiklicheskikh groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylbiphenyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-retil and indole-2-ylpropyl.

"Halogen" represents fluorine, chlorine, bromine or iodine.

"Hydroxyalkyl" group represents an alkyl group described above substituted by one or more hydroxy groups.

"Alkoxy" group is an-O-(alkyl), where alkyl is defined above.

"Alkoxyalkyl group" represents -(alkyl)-O-(alkyl), where alkyl is defined above.

"Amino" group is a radical of the formula: -NH2.

"Alkylamino" group is a radical of the formula: -NH-alkyl or-N(alkyl)2where each alkyl independently defined above.

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

"Aminocarbonyl group is a radical of the formula: -C(O)N(R#)2, -C(O)NH(R#) or-C(O)NH2where each R#independent PR�dstanley a substituted or unsubstituted alkyl, cycloalkyl, aryl, Uralkaliy, heterocyclyl or heterocyclyl group, as defined in this application.

"Acylamino" group is a radical of the formula: -NHC(O)(R#) or-N(alkyl)C(O)(R#), where each alkyl, and R#independently have the values defined above.

"Sulfonylamino" group is a radical of the formula: -NHSO2(R#) or-N(alkyl)SO2(R#), where each alkyl, and R#defined above.

Group "urea" represents a radical of the formula: -N(alkyl)C(O)N(R#)2, -N(alkyl)C(O)NH(R#), -N(alkyl)C(O)NH2, -NHC(O)N(R#)2, -NHC(O)NH(R#) or-NH(CO)NHR#where each alkyl, and R#independently have the values defined above.

In one embodiment, when the groups described in the present application, is listed as "replaced", they can be replaced by any suitable Deputy or deputies. Illustrative examples of the substituents are the substituents that can be found in the illustrative compounds and variations of the embodiment disclosed in the present application, as well as halogen (chlorine, iodine, bromine or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; Yiming; imide; amidine; guanidine; ionamin; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; su�honami; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamino; arelaxing; N-oxide; hydrazine; hydrazide; hydrazon; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or condensed or neskondensirovannyh polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclyl, which may be monocyclic or condensed or neskondensirovannyh polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl or triazinyl); monocyclic or condensed or neskondensirovannyh polycyclic aryl or heteroaryl (for example, phenyl, naphthyl, pyrrolyl, indole, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, chinoline, ethenolysis, acridines, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophene or benzofuranyl) aryloxy; aralkylated; heterocyclics; and heterocyclyl alkoxy.

As used in the present invention, the term "heteroaryl compound" refers to compounds of formula (I) and the following embodiments of the embodiments presented in this application. In one embodiment, "heteroaryl compound" is a�connected, presented in Table 1. The term "heteroaryl compound" includes pharmaceutically acceptable salts, tautomers, stereoisomers, solvates and prodrugs of the compounds presented in this application.

As used in the present invention, the term "pharmaceutically acceptable salt(salt)" refers to salts derived from pharmaceutically acceptable non-toxic acids or bases including inorganic acid and base and organic acid and base. Suitable pharmaceutically acceptable basic additive salts heteroaryl compounds include, but are not limited to, metal salts of 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, alginic, Anthranilic, mixture of Benzenesulfonic, benzoic, camphorsulfonic, lemon, Tinsulanonda, formic, fumaric, Turaeva, galacturonic, gluconic, glucuronic, glutamic, glycolic, Hydrobromic, hydrochloric, setinova, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, Panov�I, Pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, Sultanova, sulfuric, tartaric acid and p-toluensulfonate acid.

Specific non-toxic acids include hydrochloric, Hydrobromic, maleic, phosphoric, sulfuric and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesilate salt. Other examples are well known in the art, see, for example, in Remington's Pharmaceutical Sciences, 18theds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19theds., Mack Publishing, Easton PA (1995).

As used in the present invention, and unless otherwise indicated, the term "solvate" means a heteroaryl compound or its salt, which further includes a stoichiometric or non-stoichiometric amount of solvent bound non-covalent intermolecular forces. In some embodiments embodiment, the solvate is a hydrate. As used in the present invention, and unless otherwise indicated, the term "hydrate" means a heteroaryl compound or its salt, which further includes a stoichiometric or non-stoichiometric amount of water bound non-covalent intermolecular forces.

As used in the present invention, and unless otherwise indicated, the term "prodrug" oz�ACHAT derived heteroaryl compounds which can be hydrolyzed, oxidized or otherwise react in biological conditions (in vitro or in vivo) to provide an active compound, in particular, the heteroaryl compounds. Examples of the prodrug include, but are not limited to, derivatives and metabolites heteroaryl compounds that include biohydrology fragments, such as biokerosene amides, biohydrology esters, biohydrology carbamates, biohydrology carbonates, biohydrology ureide and biokerosene phosphate analogues. In some embodiments embodiment, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of carboxylic acids. Carboxylate esters are conveniently obtained by esterification of any carbonation fragments, prisutstvuyushih in the molecule. Prodrugs can typically be obtained using well known methods such as described in Burger's Medicinal Chemistry and Drug Discovery 6thed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

As used in the present invention, and unless otherwise indicated, the term "stereoisomer" or "stereomono pure" means one stereoisomer heteroaryl compounds, which essentially does not contain other stereoisomers of that soy�of inane. For example, stereomono pure compound containing one chiral centre, essentially, does not contain the opposite enantiomer of the compound. Stereomono pure compound containing two chiral center, essentially does not contain other diastereomers of the compound. Typical stereomono pure compound comprises greater than about 80% of the mass. of one stereoisomer of the compound and less than about 20% of the mass. other stereoisomers of the compound, greater than about 90% of the mass. of one stereoisomer of the compound and less than about 10 wt%. other stereoisomers of the compound, greater than about 95% of the mass. of one stereoisomer of the compound and less than about 5 wt%. other stereoisomers of the compound, or greater than about 97% of the mass. of one stereoisomer of the compound and less than about 3 wt%. other stereoisomers of the compound. Heteroaryl compounds may contain chiral centers and may exist in the form of racemates, individual enantiomers or diastereomers and their mixtures. All such isomeric forms are included in variants of the embodiment disclosed in the present application, including mixtures thereof.

Use stereomono pure forms of such Heteroaryl Compounds, and the use of mixtures of these forms is covered by embodiments of the embodiment disclosed in the present application. For example, mixtures comprising equal or unequal amounts Enan�of Omarov specific heteroaryl compounds can be used in the methods and compositions disclosed in the present application. These isomers may be asymmetrically synthesized or separated using standard techniques such as chiral columns or chiral separation agents. See, for example, Jacques, J., et al, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., 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 noted 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 embodiment, the heteroaryl compounds are isolated in the form of either E or Z isomer. In other embodiments embodiment, the heteroaryl compounds are a mixture of E and Z isomers.

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

As will be easily understandable specia�leaves in the field, many different functional groups and other structures may exhibit tautomere, and all tautomers of compounds of formula (I) are included in the scope of the present invention.

It should also be noted that heteroaryl compounds can contain non-natural proportions of atomic isotopes at one or more atoms. For example, the compounds can be labeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), sulfur-35 (35S) or carbon-14 (14C), or may be isotopically enriched, such as deuterium (2H), carbon-13 (13C) or nitrogen-15 (15N). As used in the present invention, the term "isotopolog" means isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of that atom. "Isotopically enriched" may also refer to the compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each present for a given isotope of an atom. Labeled with a radioactive isotope and isotope-enriched compounds are useful as therapeutic agents, for example, terapeuticas funds for cancer treatment and �asplenia, research reagents, e.g., reagents for analysis of binding and diagnostic agents, for example, imaging agents in vivo. All isotopic variants Heteroaryl Compounds described in the present application, regardless of whether they are radioactive or not, are assumed as included in the scope of the embodiments presented in this application. In some embodiments embodiment, provided isotopolog Heteroaryl Compounds, for example, isotopologues are deuterium, carbon-13 or nitrogen-15-enriched heteroaryl compounds.

"Treatment" as that term is used in the present invention, means an alleviation, in whole or in part, symptoms associated with the disorder or disease, or slowing or stopping further progression or worsening of those symptoms, or preventing or providing prophylaxis of a disease or disorder in a subject having a risk of developing such disease or condition.

The term "effective quantity" in connection with an Heteroaryl Compound can mean an amount capable of facilitating, in whole or in part, symptoms associated with the disorder or disease, or to slow or halt of further progression or worsening of those symptoms, or preventing or providing�and develop prevention of a disease or disorder in a subject with the risk of developing the disease, as disclosed in the present application, such as inflammatory conditions, immunological conditions, cancer, metabolic state or condition that can be treated or prevented by inhibition of a kinase or a kinase pathway, in one embodiment, Syk, FLT-3, JAKl and/or JAK2 way. In one embodiment, an effective amount heteroaryl compounds represents an amount that inhibits a kinase in a cell, e.g., in vitro or in vivo. In some embodiments embodiment, the effective amount of the heteroaryl compound inhibits a kinase in a cell on 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the kinase activity in untreated cells. An effective amount heteroaryl compounds, for example in the pharmaceutical composition may be at a level that will provide the desired effect; for example, about 0.005 mg/kg body weight of subject to about 10 mg/kg of body weight of the subject in the calculation of the standard dose for both oral and parenteral administration.

"Kinase inhibitor" in the context of the present invention is a compound which at a concentration of 10 μm inhibits the ability to fosforilirovanii kinase enzyme at about 50% or more than 50%, as determined using the HTRF enzyme assays, opisannyh this application. In some embodiments embodiment, the kinase is a Syk kinase, in other embodiments embodiment, the kinase is a Syk, FLT3, JAK1 and/or JAK2.

"Fc Receptor" refers to a member of a family of cell surface molecules that bind to the Fc part (containing specific constant region) of an immunoglobulin. Each Fc receptor binds to immunoglobulins specific type. For example, Fc alpha receptor ("FcαR") binds IgA, FcεR binds IgE, and FcγR binds IgG.

FcαR family includes the polymeric Ig receptor involved in epithelial transport of IgA/IgM, the myeloid specific receptor RcαRI (also called CD89), the Fcα/μR and at least two alternative IgA receptors (see review Monteiro &van de Winkel, 2003, Annu. Rev. Immunol, advanced e-publication. FcαRI is expressed on neutrophils, eosinophils, monocytes/macrophages, dendritic cells and kupfer cells. FcαRI includes one alpha chain and the FcR gamma C) an homodimer that contains the activation motif (ITAM) in the cytoplasmic domain and phosphorylates Syk kinase.

FcεR family includes two types, designated as FcεRI and FcεRII (also known as CD23). FcεRI is a high-affinity receptor found in mast cells, basophils and eosinophils, which establishes Monomeric IgE to the cell surface. FcεRI contains one alpha chain, one beta chain and gamma homodimer�, discussed above. FcεRII is a low affinity receptor expressed on mononuclear phagocytes, B lymphocytes, eosinophils and platelets. FcεRII consists of one polypeptide chain and does not include C) an homodimer gamma chain.

FcγR family includes three types, designated as FcγRI (also known as CD64), FcγRII (also known as CD32) and FcγRIII (also known as CD 16). FcγRI is a high affinity receptor found in mast cells, basophils, mononuclear cells, neutrophils, eosinophils, dendritic cells and phagocytes, which establishes Monomeric IgG on the cell surface. FcγRI includes one alpha chain and a dimer of gamma chain shared by FcαRI and FcεRI.

FcγRII is a low affinity receptor expressed on neutrophils, monocytes, eosinophils, platelets and B lymphocytes. FcγRII includes one alpha chain and do not include C) an homodimer gamma chain discussed above.

FcγRIII is a low affinity receptor expressed on NK, eosinophil, macrophage, neutrophil and mast cells. It includes one alpha chain and the gamma C) an homodimer shared by FcαRI, FcεRI and FcγRI.

"Cell-proliferative disorder" refers to disorders characterized by abnormal proliferation of cells. Proliferative disorder does not imply any limitations with regard to �the scab of cell growth, but just indicates loss of normal controls that affect the growth and division of cells. Thus, in some embodiments embodiment, the cell proliferative disorder can have the same speed dividing cells, like normal cells, but do not respond to signals that limit such growth. The term "cell-proliferative disorder is a neoplasm or tumor is an abnormal growth of tissue. Cancer refers to any of various malignant neoplasms characterized by the proliferation of cells that have the ability to invade surrounding tissue, and/or ability to metastasize to new sites of colonization.

"Hematopoietic neoplasm" refers to cellular-proliferative disorders arising from cells of hematopoietic origin. Typically, hematopoesis is a physiological process by which undifferentiated cells or stem cells develop into various cells present in peripheral blood. In the initial phase of development of hematopoietic stem cells, typically present in the bone marrow, undergo a series of cell divisions with the formation of multipotent progenitor cells, which occurs commitirovannah in two main ways: lim�odna line and myeloid line. Committed progenitor cells of myeloid origin differentiate into three main sub-branches, including erythroid, megakaryocytic and granulocytic/monority development path. Additional path leads to the formation of dendritic cells involved in antigen presentation. Erythroid line gives rise to erythrocytes, whereas megakaryocyte line gives rise to blood platelets. Committed cells granulocytes/monocytes line are divided into granulocytes or monority development path, the first path leads to the formation of neutrophils, eosinophils, and basophils, and the last way gives rise to monocytes and macrophages blood.

"Lymphoid neoplasm" refers to a proliferative disorder involving cells of the lymphoid lineage hematopoiesis. Lymphoid neoplasms can arise from hematopoietic stem cells and lymphoid commiteeman (undifferentiated)precursor cells, progenitor cells, and ultimately of differentiated cells. These neoplasms can be subdivided on the basis of phenotypic signs of aberrant cells or differentiated state, from which arise the abnormal cells. The entities include, among others, B-cell neoplasms, T-cell neoplasms, NK-cle�internal neoplasms and Hodgkin's lymphoma.

"Myeloid neoplasm" refers to a proliferative disorder of cells of the myeloid lineage hematopoiesis. Neoplasms may arise from hematopoietic stem cells, myeloid commiteeman (undifferentiated)precursor cells, progenitor cells and, ultimately, differentiated cells. Myeloid neoplasms can be subdivided on the basis of phenotypic signs of aberrant cells or differentiated state, from which arise the abnormal cells. The entities include, among others, myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes, acute myeloid leukemia and acute biphenotypic leukemia.

"Viral-mediated tumor" refers to a neoplasm or tumor associated with viral infection or active viral-encoded product. The tumor may occur as a result of the presence of latent virus that is integrated into the cellular genome, or may arise from the activity of viral-associated gene product. Virus infection need not be precisely correlated in time with the formation of a tumor, since the incubation periods can last from several months to several years before the spacecraft� develops tumor phenotype. Because in some embodiments the embodiment of the treatment disclosed in the present application is directed to the use of Syk-inhibitory Heteroaryl Compounds, viral-associated tumors to which they are applicable, are those in which viral modulation of Syk activity correlates with aberrant cellular proliferation. Using the methods disclosed in the present application, it is possible to target any virus, including RNA and DNA viruses, and viruses that exist episomally or integrated into the cellular genome, in which Syk activation is a consequence of viral infection.

"Tumor metastases" refers to the ability of tumor cells to migrate from the primary tumor and colonize other tissues. Tumors formed from cells that have spread is called a "secondary tumors", and they contain cells that are similar to the cells in the original "primary" tumor. Metastatic tumors typically are formed as a result of migration of tumor cells from the original tumor through the system of blood and lymph to other tissues.

The terms "patient" and "subject" includes an animal, including, but not limited to, such animals as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or sea pig�I. In one embodiment the subject is a mammal, in another person. In some embodiments embodiment, the patient or subject, “need this”, is a patient or subject having a disease or disorder or having the risk that it may have a disease or disorder.

4.2 Heteroaryl compounds

In the present application presents heteroaryl compounds having the following formula (I):

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

R1is a substituted or unsubstituted aryl or substituted or unsubstituted heterocyclyl;

R2is a substituted or unsubstituted C1-8alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted geterotsiklicheskie, a substituted or unsubstituted aralkyl, -NR3R4, -OR3, -C(=O)R5, -C(=O)NR3R4, -NHC(=O)R3, -(CH2)0-2CR6(OR3)R4or substituted or unsubstituted heterocyclyl selected from azetidine, pyrrolidine, piperidine, morpholine, piperazine-2-onila, 1,2,3,6-tetrahydropyridine, isoxazolyl, imidazolyl, indazole, benzimidazole, 1H-benzo[d][1,2,3]triazolyl, benzisoxazole, benzo[d]oxazolyl, isound�Lin-1-onila, 1H-imidazo[4,5-b]pyridyl, izochinolina or chinoline; or R2represents pyridyl, provided that R1is not (2-(pyrrolidin-1-yl)ethoxy)phenyl-4-silt;

R3and R4in each case, independently represent-Η, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted geterotsiklicheskie;

R5is a substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted geterotsiklicheskie; and

R6represents-H or substituted or unsubstituted C1-8alkyl, or together with R4and with atoms to which they are linked, form a substituted or unsubstituted heterocyclyl; provided that the compound is not N5-cyclopentyl-N2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine, is presented below:

In one embodiment, the heteroaryl compound p�establet a compound of formula (I), where R1is a substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl. In some such embodiments embodiment, R1represents phenyl, substituted one or more substituted or unsubstituted C1-4the alkyl, substituted or unsubstituted heterocyclyl, halogen, hydroxyl, alkoxy, carboxy, -CN, -(C0-4alkyl)NR2, -O(C1-4alkyl)NR2, -NR2or-C(=O)NR2where each R independently represents H, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted heterocyclyl. For example, in some embodiments embodiment, R1represents phenyl substituted by one or more-F, -Cl, -CF3, -CN, hydroxyl, carboxy, - bromide, -(C0-4alkyl)NH2, -(C0-4alkyl)NH(C1-4alkyl), -O(C1-4alkyl), -O(C1-4alkyl)O(C1-4alkyl), -O(C1-4alkyl)NH2, -N(C1-4alkyl)2, -C(=O)NH2, -C(=O)NH(C1-4alkyl), -C(=O)NH(substituted or unsubstituted piperidyl), or substituted or unsubstituted heterocyclyl selected from morpholinyl, triazolyl, pyrrolidyl, imidazolyl or pyrrolidinyl.

In some embodiments embodiment, the heteroaryl compound is a compound of formula (I), where R1is a substituted or unsubstituted heterocyclyl. NRA�emer, in some embodiments embodiment, R1is a substituted or unsubstituted heterocyclyl selected from isoindoline-1-onila, pyridyl, pyrimidyl, indazole, indoline, isoindoline, indolin-2-onila, chinoline, dihydroisoquinoline-1-onila, benzotriazolyl, benzimidazolyl, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1H-benzo[d]imidazol-2(3H)-onila, benzisoxazole, izochinolina, dehydrobenzperidol-1,1-dionela or pyrrolopyridine. In some such embodiments embodiment, R1substituted by one or more substituted or unsubstituted C1-4the alkyl, substituted or unsubstituted heterocyclyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, -CN, -OR, -NR2, -(C1-4alkyl)NR2, -C(=O)NR2or-C(O)R where each R independently represents H, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie.

In some such embodiments embodiment, R1is a

where R' represents-H or substituted or unsubstituted C1-6alkyl; each R" independently represents a substituted or unsubstituted C1-4alkyl, substituted or unsubstituted heterocyclyl, the unsubstituted geterotsiklicheskie, hydroxyl, halogen, alkoxy, -CN, -OR, -NR , -(C1-4alkyl)NR2, -C(=O)NR2where each R independently represents H, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie; and n has a value of 0-2.

Specialists in this field should be clear that any of the substituents R" can be attached to any suitable atom of any of the rings in a condensed ring systems. For example, in some embodiments embodiment, R1is a

In some embodiments embodiment, R' represents-H, -CH3, -CH2CH3, isopropyl, -(CH2)2OH, -(CH2)2NH2or -(CH2)2OCH3. In other embodiments embodiment, R" is-F, -CH3, -CH2CH3, isopropyl, -NH(C1-3alkyl)NH2, -NH(CH2)2OH, -CF3, -OH, -OCH3, -O(CH2)2OCH3, -O(CH2)2OH, -O(CH2)2NH2, -O(CH2)2pyrrolidyl, -CH2OH, -(CH2)2OH, -CH2OCH3, -(CH2)2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -C(CH3)2OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NH(CH2)2NH2, -C(=O)NH2, -C(=O)NHCH3, -NH(CH2)2pyrrolidyl, -NH(Zama�military or unsubstituted piperidyl), substituted or unsubstituted piperidyl, -NH(substituted or unsubstituted tetrahydropyranyl) or a substituted or unsubstituted morpholinyl.

In some embodiments embodiment, the heteroaryl compound is a compound of formula (I), where R2represents pyridyl, provided that R1is not (2-(pyrrolidin-1-yl)ethoxy)phenyl-4-yl, i.e., R1cannot be

In some embodiments embodiment, the heteroaryl compound is a compound of formula (I), where R2is a substituted or unsubstituted C1-6alkyl. For example, in some embodiments embodiment, R2is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, optionally substituted by one or more-OH, -C(O)NH2, -NH2alkylamino, -NHCH2C(=O)NH2, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanol or 1-methylcyclohexanol-4-yl. In some embodiments embodiment, R2represents a substituted or unsubstituted cycloalkyl, for example, R2represents cyclohexyl. In other embodiments embodiment, R2represents a substituted or unsubstituted geterotsiklicheskie, for example, -CH2-azetidinol, -CH2-piperidyl, -CH2-pyridine-2(1H)-on�Il, -CH2-pyridyl, -CH2-piperazine-2-o'neill, -CH2-piperazine-2,6-dionyl, -CH2-piperazinyl, -CH2-pyrrolidyl, -CH2-1,4-dioxane, -CH2-piperidine-2,6-dionyl, -CH2-imidazolidinyl ureido, -CH2-imidazolidin-4-o'neill, -CH2-morpholinyl, -CH2-tetrahydropyrimidin-2(1H)-o'neill, -CH2-1,4-diazepan-5-o'neill, -CH2-tetrahydro-2H-pyranyl or-CH2-imidazolidin-2,4-dionyl; where heteroseksualci optionally substituted by one or more bromide, ethyl, isopropyl, halogen, -OH, -(CH2)OH or-C(=O)NH2. For example, in some embodiments embodiment, R2represents-CF2-(tetrahydro-2H-Piran-4-yl) or-CF2-(1,4-dioxane-2-yl).

In some embodiments embodiment, the heteroaryl compound is a compound of formula (I), where R2represents a-NR3R4. For example, in some embodiments embodiment, R2represents-NH(C1-6alkyl), -N(C1-6alkyl)2, -N(C1-6alkyl)(cycloalkyl), -NH(aryl), -NH(heteroaryl), -NH(cycloalkyl), -NH(cycloalkyl), -NH(heterocyclyl), -N(C1-6alkyl)(heterocyclyl) or - NH(geterotsiklicheskie), where each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl and geterotsiklicheskie, independently, is substituted or unsubstituted. In some embodiments embodiment, R2ameri� a-NH(methyl), -N(methyl)2, -N(methyl)(ethyl), -NH(ethyl), -NH(propyl), -NH(isopropyl), -NH(cyclopentyl), -NH(cyclohexyl), -N(cyclohexyl)(methyl), -NHCH2(cyclopentyl), -NHCH2(cyclohexyl), -NH(phenyl), -NH(pyridyl), -NH(piperidyl), -NH(tetrahydro-2H-pyranyl), -N(methyl)(tetrahydro-2H-pyranyl), -NH(azepane), -NH(tetrahydropyranyl), -N(methyl)(tetrahydrofuranyl), -NH(pyrrolidyl) or-NHCH2(tetrahydro-2H-pyranyl), where each methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, piperidyl, pyrrolidyl, tetrahydro-2H-pyranyl, azepane or tetrahydrofuranyl, independently, is substituted or unsubstituted. In some such embodiments embodiment, methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, piperidyl, pyrrolidyl, tetrahydro-2H-pyranyl, azepane or tetrahydrofuranyl substituted by one or more phenyl, C1-4the alkyl, hydroxyalkyl, -NR2, -Or, or-C(=O)NR2where each R independently represents H, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie.

In some embodiments embodiment, the heteroaryl compound is a compound of formula (I), where R2represents-NHC(=O)R3where R3is a substituted or unsubstituted C1-4alkyl. In other parentadolescent, R2represents-C(=O)NR3R4and R3and R4independently represent-H or substituted or unsubstituted C1-4alkyl or substituted or unsubstituted heterocyclyl. In the following embodiments embodiment, R2is a-OR3. In some such embodiments embodiment, R3represents cyclohexyl, methyl, ethyl, propyl, piperidyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, -CH2(pyrrolidyl) or phenyl, optionally substituted by one or more-OH, -NH2or -(C=O)NH2. In the following embodiments embodiment, R2represents-C(=O)R5. For example, in some embodiments embodiment, R5represents phenyl.

In some embodiments embodiment, the heteroaryl compound is a compound of formula (I), where R2represents -(CH2)0-2CR6(OR3)R4. For example, in some embodiments embodiment, R2represents-CH(OR3)R4. In some such embodiments embodiment, R3represents H, and R4represents phenyl, piperidyl, pyridyl, pyrimidine-4(3H)-o'neill or tetrahydrofuranyl. In some other embodiments embodiment, R3represents H, and R4and R6together with the atoms to which they are linked, form piperidyl.

In some� embodiments of the incarnation, heteroaryl compound is a compound of formula (I), where R2is a substituted or unsubstituted heterocyclyl selected from azetidine, pyrrolidine, piperidine, morpholine, piperazine-2-onila, 1,2,3,6-tetrahydropyridine, isoxazolyl, imidazolyl, pyridyl, indazole, benzimidazole, 1H-benzo[d][1,2,3]triazolyl, benzisoxazole, benzo[d]oxazolyl, isoindoline-1-onila, 1H-imidazo[4,5-b]pyridyl, chinoline or izochinolina. In some such embodiments embodiment, R2substituted by one or more substituted or unsubstituted C1-4the alkyl, substituted or unsubstituted heterocyclisation, hydroxyl, -OR, -NR2or-C(=O)NR2where each R independently represents a-Η, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie.

In some embodiments embodiment, R2is a

where R' represents-H or substituted or unsubstituted C1-6alkyl; each R" independently represents a substituted or unsubstituted C1-4alkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, hydroxyl, halogen, alkoxy, -CN, -OR, -NR2, -(C1-4alkyl)NR2, -C(=O)NR2where each�th R independently represents-H, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie; and n=0-2. For example, in some embodiments embodiment, R" is-CH3, -CH2CH3, isopropyl, -CH2OH, -CH2OCH3, -CH(CH3)OH, -(CH2)2NH2, -CH2NHCH3, -CH2N(CH3)2, -OH, -OCH3, -O(CH2)2NH2, -NH2, -NHCH3, -N(CH3)2, -NH(CH2)2OH, -NH(CH2)2NH2, -C(=O)NH2, -CH2(pyrrolidyl) or substituted or unsubstituted piperazinyl.

Specialists in this field should be clear that any of the substituents R" can be attached at any suitable atom of any of the rings in a condensed ring systems. For example, in some embodiments embodiment, R2represents -(C1-4alkyl), -(C1-4alkyl) - OH,

where R' represents-H or substituted or unsubstituted C1-6alkyl; each R" independently represents a substituted or unsubstituted C1-4alkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, hydroxyl, halogen, alkoxy, -CN, -OR, -NR2, -(C1-4alkyl)NR2, -C(=O)NR2where each R independently represents-H,�ewenny or unsubstituted C 1-6alkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie; and X = CH2, CF2or NR'.

In some embodiments embodiment, the heteroaryl compounds contain R1the group described in the present application, and R2the group described in the present application. In some such embodiments of the incarnation, where R2has the meaning specified in the present application, R1is a

where R' represents-H or substituted or unsubstituted C1-6alkyl; each R" independently represents a substituted or unsubstituted C1-4alkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted geterotsiklicheskie, hydroxyl, halogen, alkoxy, -CN, -OR, -NR2, -(C1-4alkyl)NR2, -C(=O)NR2where each R independently represents H, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted geterotsiklicheskie; and n has a value of 0-2. In some such embodiments embodiment, R" is-F, -CH3, -CH2CH3, isopropyl, -NH(C1-3alkyl)NH2, -NH(CH2)2OH, -CF3, -OH, -OCH3, -O(CH2)2OCH3, -O(CH2)2OH, -O(CH2)2NH2, -O(CH2)2pyrrolidyl, -CH2H, -(CH2)2OH, -CH2OCH3, -(CH2)2OCH3, -CH(CH3)OH, -CH2NH2, -(CH2)2NH2, -CH2NHCH3, -CH2N(CH3)2, -C(CH3)2OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NH(CH2)2NH2, -NH(CH2)2OH, -C(=O)NH2, -C(=O)NHCH3, -NH(CH2)2pyrrolidyl, -NH(substituted or unsubstituted piperidyl), -NH(substituted or unsubstituted tetrahydropyranyl), -CH2(pyrrolidyl), substituted or unsubstituted piperidyl, a substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.

In one embodiment, the heteroaryl compound is a compound described in this application, where this compound at a concentration of 10 μm inhibits Syk on at least about 50%.

The following options voplosheniya presented in the present application, include combinations of one or more of the specific embodiments described above.

In some embodiments embodiment, the heteroaryl compound is a:

1-methyl-N3-(tetrahydro-2H-Piran-4-yl)-N6-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1H-indazole-3,6-diamine;

N3-(tetrahydro-2H-Piran-4-yl)-N6-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1H-indazole-3,6-di�min;

1-methyl-N3-(piperidine-4-yl)-N6-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1H-indazole-3,6-diamine;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1H-imidazo[3,2-b]pyridine-2(3H)-he;

CIS-6-(5-(4-hydroxy-4-methylcyclohexylamine)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1,3,3-trimethylindolenine-2-he;

N-(3-(methoxymethyl)-1H-indazol-6-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-4-(2-(5-methyl-6-morpholinopropan-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

N-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine;

CIS-4-(2-(1H-pyrazolo[4,3-b]pyridine-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

N2-(3,4-dimethyl-1H-indazol-6-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3,4-trimethylindolenine-2-he;

TRANS-6-(5-(4-hydroxy-4-methylcyclohexylamine)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1,3,3-trimethylindolenine-2-he;

N2-(1H-pyrazolo[4,3-b]pyridin-6-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-4-(2-(imidazo[1,2-a]pyridine-7-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

3,3-dimethyl-6-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)and�of indolin-1-it;

6-(5-(4-hydroxypiperidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

(R)-N2-(3-methyl-1H-indazol-5-yl)-N5-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N-(3-methyl-1H-indazol-5-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N2-(3-methyl-1H-indazol-5-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

1-methyl-6-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

1-methyl-6-(5-(tetrahydro-2H-Piran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylisoxazole-1-he;

(S)-3,3-dimethyl-6-(5-(methyl(tetrahydrofuran-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

(R)-3,3-dimethyl-6-(5-(methyl(tetrahydrofuran-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

(R)-1,3,3-trimethyl-6-(5-(tetrahydrofuran-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

4-((2-(4-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyridin-2-ol;

3,3,4-trimethyl-6-(5-(tetrahydro-2H-Piran-4-ylamino)-[1,2,4]triazolo [1,5-a]pyridine-2-ylamino)indolin-2-he;

3,3,4-trimethyl-6-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

TRANS-4-(2-(3-methyl-1H-indazol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)C�clohexane;

3,3-dimethyl-6-(5-(tetrahydro-2H-Piran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)isoindoline-1-he;

N5-(tetrahydro-2H-Piran-4-yl)-N2-(3-(trifluoromethyl)-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

4-((2-(2-(methoxymethyl)-1H-benzo[d]imidazole-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyridin-2-ol;

(R)-3,3-dimethyl-6-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

N-(2-(methoxymethyl)-1H-benzo[d]imidazol-6-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-3,3-dimethyl-6-(5-(tetrahydrofuran-3-yloxy)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

(R)-3,3-dimethyl-6-(5-(tetrahydrofuran-3-yloxy)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-2-methylisoquinoline-1-he;

1,3,3-trimethyl-6-(5-((3-oxopiperidin-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

TRANS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylisoxazole-1-he;

3,3-dimethyl-6-(5-(piperidine-4-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

CIS-4-(2-(1-methyl-1H-pyrazolo[3,4-b]pyridine-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-6-(5-((4-hydroxy-4-methylcyclohexyl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

TRANS-6-(5-((4-hydroxy-4-methylcyclohexyl)�ethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

N2-(2-(methoxymethyl)-1H-benzo[d]imidazol-6-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

1,3,3-trimethyl-6-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

2-methyl-5-(5-(tetrahydro-2H-Piran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)isoindoline-1-he;

2-methyl-5-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)isoindoline-1-he;

TRANS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1,3,3-trimethylindolenine-2-he;

N-(1,4-dimethyl-1H-indazol-6-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N2-(l,4-dimethyl-1H-indazol-6-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-4-(2-(4-fluoro-1,3-dimethyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(R)-3,3-dimethyl-6-(5-(tetrahydrofuran-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

1,3,3-trimethyl-6-(5-(tetrahydro-2H-Piran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1,3,3-trimethylindolenine-2-he;

6-(5-((2-hydroxyethyl)(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

(S)-3,3-dimethyl-6-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

4-((2-(3-(trifluoromethyl)-1H-indazol-6-ylamino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

3,3-dimethyl-6-(5-((2-oxo-1,2-dihydropyridine-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

5-(5-((2-hydroxypyridine-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)isoindoline-1-he;

3,3-dimethyl-6-(5-(methyl(tetrahydro-2H-Piran-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

3,3-dimethyl-6-(5-(1-(tetrahydro-2H-Piran-4-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

N-(1-methyl-1H-indazol-6-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N2-(1-methyl-1H-indazol-6-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

TRANS-6-(5-(4-hydroxy-4-methylcyclohexylamine)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

CIS-6-(5-(4-hydroxy-4-methylcyclohexylamine)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

CIS-4-(2-(4-fluoro-3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(±)-CIS-4-(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yloxy)tetrahydrofuran-3-ol;

(±)-TRANS-4-(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)tetrahydrofuran-3-ol;

(R)-N2-(3-methyl-1H-indazol-6-yl)-N5-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

3,3-dimethyl-6-(5-(tetrahydro-2H-Piran-4-yloxy)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

3-methyl-1-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]t�Iesolo[1,5-a]pyridin-5-yl)methyl)azetidin-3-ol;

6-(5-(3-hydroxyazetidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

6-(5-(3-hydroxy-3-methylaziridine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

3,3-dimethyl-6-(5-((3-oxopiperidin-1-yl)methyl)-[1,2,4]triazolo [1,5-a]pyridine-2-ylamino)indolin-2-he;

6-(5-(hydroxy(tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-2-(2-methoxyethyl)isoindoline-1-he;

TRANS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

3,3-dimethyl-6-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

3,3-dimethyl-6-(5-(tetrahydro-2H-Piran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

(1S,3R)-3-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)methyl)Cyclopentanol;

(1R,3S)-3-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)methyl)Cyclopentanol;

(1R,3S)-3-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)methyl)Cyclopentanol;

(1S,3S)-3-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)methyl)Cyclopentanol;

(S)-N2-(3-methyl-1H-indazol-6-yl)-N5-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

4-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin--yl)methyl)pyridin-2(1H)-he;

5-((3,3-deformability-1-yl)methyl)-N-(3-methyl-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(2-hydroxyethyl)indolin-2-he;

2-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methylamino)acetamide;

CIS-1-(methoxymethyl)-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)cyclohexanol;

4-((2-(1-isopropyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

N5-methyl-N2-(3-methyl-1H-indazol-6-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

2-(methyl(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)amino)ethanol;

CIS-4-(2-(1-(2-hydroxyethyl)-3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-methylindolin-2-he;

6-(hydroxy(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyrimidine-4(3H)-he;

CIS-4-(2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(2-(gidroximetil)-1H-benzo[d]imidazole-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(2-(methoxymethyl)-1H-benzo[d]imidazole-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(1-ethyl-3-methyl-1H-indiso�-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-2-(2-hydroxyethyl)isoindoline-1-he;

N-(3-methyl-1H-indazol-6-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)(tetrahydro-2H-Piran-4-yl)methanol;

TRANS-4-(2-(3-methyl-1H-indazol-6-ylamino)-[1,2)4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,4-dihydroisoquinoline-1(2H)-he;

CIS-4-(2-(4-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(R)-3-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methylamino)pyrrolidin-2-he;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-2-(2-hydroxyethyl)isoindoline-1-he;

(±)-3-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methylamino)pyrrolidin-2-he;

4-((2-(3-amino-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)cyclohexanol;

N2-(3-methyl-1H-indazol-6-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-4-(2-(4-fluoro-3-(2-methoxyethoxy)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

4-(1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridi�-5-yl)ethyl)pyridin-2(1H)-he;

(1S,2S)-2-(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

N-methyl-2-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methylamino)acetamide;

4-(5-((3-hydroxycyclopent)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide (diastereoisomer 2);

1-(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)azetidin-3-ol;

CIS-4-(2-(3-amino-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(2,3-dimethyl-2H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(l,3-dimethyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

4-((2-(4-fluoro-3-methylphenylamine)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyridin-2-ol;

N2-(3-methyl-1H-indazol-6-yl)-N5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

4-((2-(6-(4-hydroxypiperidine-1-yl)pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

(S)-2-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methylamino)propanamide;

CIS-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol(enantiomer 1);

CIS-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol (enantiomer 2);

TRANS-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol (enantio�EP 1);

TRANS-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol (enantiomer 2);

CIS-1-(gidroximetil)-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

4-((2-(4-fluoro-3-methylphenylamine)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

4-((2-(1H-imidazo[2,3-b]pyridine-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

(±)-5-isopropyl-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

CIS-4-(2-(3-(methoxymethyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

4-(5-((3-hydroxycyclopent)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide (diastereoisomer 1);

(±)-2-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methylamino)propanamide;

1-(3-methyl-1H-indazol-6-yl)-4-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

4-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

CIS-4-(2-(1-methyl-1H-indazol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(1H-benzo[d][1,2,3]triazole-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

CIS-4-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)cyclohexane�;

TRANS-4-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)cyclohexanol;

4-(5-(1H-imidazol-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(4-hydroxypiperidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

CIS-4-(2-(1-isopropyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

N-methyl-4-(5-(2-methyl-1H-benzo[d]imidazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

CIS-4-(2-(3-ethyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(1R,2R)-2-(4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-ylamino)Cyclopentanol;

N-methyl-4-(5-(piperidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

(±)-TRANS-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(S)-4-(5-(3-hydroxypyrrolidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

(R)-4-(5-(3-hydroxypyrrolidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

N-methyl-4-(5-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)imidazolidin-2,4-dione;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)isoindoline-1-he;

N-methyl-4-(5-(2-(the piperidine-4-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

CIS-4-(5-(4-hydroxy�illogically)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)picolinate;

CIS-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)picolinate;

1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperidine-3-carboxamide;

5-methyl-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

(1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)azetidin-3-yl)methanol;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)isoindoline-1-he;

CIS-4-(2-(2,6-dimethylpyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

4-(5-((4-aminocyclohexyl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethyl)piperazine-2-he;

4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2,6-dione;

CIS-N5-(4-methoxycyclohexyl)-N5-methyl-N2-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-4-(methyl(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)amino)cyclohexanol;

N-methyl-4-(5-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

5-(5-(2-(gidroximetil)-1H-benzo[d]imidazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)pyridin-2-ol;

1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)-1,4-diazepan-5-it;

(1S,2R)-2-(2-(4-(trifluoromethyl)phenylamino)-1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(S)-(1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyrrolidin-2-yl)methanol;

(R)-(1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyrrolidin-2-yl)methanol;

(1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperidine-3-yl)methanol;

(1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperidine-4-yl)methanol;

(S)-3-methyl-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

N-methyl-4-(5-(piperidine-4-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

CIS-4-(2-(2-(2-hydroxyethoxy)pyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(2-(2-(pyrrolidin-1-yl)ethylamino)pyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(4-fluoro-3,5-dimethylphenylimino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(6-(2-(6-methoxypyridine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)methanol;

3-methyl-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

6-methyl-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

CIS-4-(5-(4-aminocyclohexane)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

N-methyl-4-(5-(piperidine-4-yloxy)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

(6-(2-(6-methylpyridin-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)methanol;

1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)tetrahydropyrimidin-2(1H)-he;

1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)azetidin-3-ol;

(R)-(1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyrrolidin-2-yl)methanol;

(S)-(1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyrrolidin-2-yl)methanol;

2-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methylamino)acetamide;

TRANS-4-(5-(4-aminocyclohexane)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(3-hydroxybenzyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

CIS-4-(2-(2-(2-(pyrrolidin-1-yl)ethoxy)pyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-1-(5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo [1,5-a]pyridine-2-ylamino)pyridin-2-yl)piperidine-4-ol;

CIS-4-(2-(6-(methylamino)pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

5-(2-aminoethoxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-4-(2-(1H-imidazo[2,3-b]pyridine-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(6-(2-(6-(dimethylamino)pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)methanol;

(R)-1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperidine-3-ol;

(S)-1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5 a]pyridin-5-yl)methyl)piperidine-3-ol;

1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)imidazolidin-4-it;

(R)-5-(pyrrolidin-2-ylethoxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-5-(pyrrolidin-2-ylethoxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yloxy)propan-1-ol;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)pyridin-2-ol;

4-(5-(2-hydroxy-2-(piperidine-4-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

5-(pyrrolidin-1-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(morpholinomethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)piperidine-3-ol;

(S)-1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)piperidine-3-ol;

CIS-4-(2-(3,4-dipertanyakan)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

2-(4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-ylamino)ethanol;

CIS-4-(2-(6-morpholinopropan-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(3,5-dimethylphenylimino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yloxy)ethanol;

CIS-3-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]Piri�in-2-ylamino)-N-methylbenzamide;

4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyridin-2(1H)-he;

CIS-2-fluoro-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

CIS-4-(2-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(4-fluoro-3-methylphenylamine)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

5-(3-aminopropoxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-4-(2-(2-herperidin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(R)-(1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyrrolidin-3-yl)methanol;

(S)-(1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyrrolidin-3-yl)methanol;

N-methyl-4-(5-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

(R)-(1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyrrolidin-3-yl)methanol;

(S)-(1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyrrolidin-3-yl)methanol;

(R)-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)propan-1-ol;

(S)-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)propan-1-ol;

N5-isopropyl-N2-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)pyridin-2-ol;

(R)-1-(2-(4-(trifluoromethyl)φ�ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyrrolidin-3-ol;

(S)-1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyrrolidin-3-ol;

(1S,2S)-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(R)-1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyrrolidin-3-ol;

(S)-1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyrrolidin-3-ol;

CIS-3-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

CIS-4-(2-(3-methoxybenzylamine)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(2-methoxybenzylamine)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-3-fluoro-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

CIS-3-fluoro-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzonitrile;

CIS-4-(2-(6-methoxypyridine-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(p-tolylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yloxy)cyclohexanecarboxylic;

1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)piperidine-4-ol;

(1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)piperidine-4-yl)methanol;

CIS-2-fluoro-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

CIS-3-(5-(4-hydroxyc�chlorexidine)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzonitrile;

CIS-4-(2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(m-tolylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

5-(piperidine-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-4-(2-(4-chlorpheniramine)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(3-chlorpheniramine)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(3-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(1S,2R)-(2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexyl)methanol;

CIS-4-(2-(2-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

2-methyl-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)propan-1-ol;

CIS-4-(2-(6-(2-hydroxypropan-2-yl)pyridine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

4-(5-(CIS-4-aminocyclohexane)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

(R)-5-(piperidine-3-yloxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-5-(piperidine-3-yloxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-(5-(CIS-4-hydroxycyclohexyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzonitrile;

CIS-4-(2-(1-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]p�ridin-5-ylamino)cyclohexanol;

CIS-4-(2-(1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(2-(methylamino)pyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(2-methylpyridine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(5-methoxypyridine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)nicotinamide;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)picolinate;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)pyridin-2-ol;

5-(pyridin-4-ylmethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(±)-TRANS-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(1S,2S)-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

TRANS-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)methyl)cyclohexanol;

(1S,2R)-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

(1R,2R)-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

CIS-4-(2-(2-methoxypyridine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

2-(6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazol-2-�l)propan-2-ol;

5-(1H-imidazo[4,5-b]pyridin-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)picolinate;

CIS-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)methyl)cyclohexanol;

TRANS-1-methyl-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-1-methyl-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-2-(4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexyl)propan-2-ol;

CIS-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

TRANS-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

CIS-4-(2-(pyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(5-methylpyridine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(6-methoxypyridine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(6-(dimethylamino)pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

5-(piperazine-1-ylmethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

TRANS-4-(5-(4-aminocyclohexane)-[1,2,4]triazolo[1,5-pyridin-2-ylamino)-N-methylbenzamide;

5-(piperidine-4-ylmethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

1-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperidine-4-ol;

TRANS-2-(4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexyl)propan-2-ol;

TRANS-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)cyclohexanol;

CIS-4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)cyclohexanol;

4-(5-(cyclopentylamine)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

5-(2-(methoxymethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

1-(6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)ethanol;

CIS-4-(2-(6-methylpyridine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(S)-N2-(2-(2-aminoethoxy)pyridin-4-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

TRANS-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yloxy)cyclohexanecarboxylic;

(1R,2S)-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

5-((1-ethylpiperazin-4-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazole-2-carboxamide;

(6-(2-(4-(trifluoromethyl)phenylamino)[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)methanol;

CIS-(4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexyl)methanol;

(S)-N2-(6-morpholinopropan-3-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(R)-2-phenyl-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)ethanol;

(S)-2-phenyl-2-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)ethanol;

TRANS-(4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[l>5-a]pyridin-5-ylamino)cyclohexyl)methanol;

4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)pyridin-2-ol;

4-(2-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)picolinate;

CIS-4-(2-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-yloxy)cyclohexanol;

(1S,3R)-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

(1S,3S)-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

(1R,3R)-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

(1R,3S)-3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)Cyclopentanol;

TRANS-5-(4-aminocyclohexane)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-5-(4-aminocyclohexane)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(2-((methylamino)methyl)benzo[d]oxazol-6-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;/p>

2-(2-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1-(piperidine-4-yl)ethanol;

4-(5-(1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

N5-(azepin-3-yl)-N2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N-phenyl-5-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

4-((2-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperidine-4-ol;

2-(2-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1-phenylethanol;

4-(5-(1H-benzo[d][1,2,3]triazole-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

(S)-N5-(piperidine-3-yl)-N2-(pyridin-3-yl)-[1,2,4]triazolo [1,5-a]pyridine-2,5-diamine;

(R)-N5-(piperidine-3-yl)-N2-(pyridin-3-yl)-[1,2,4]triazolo [1,5-a]pyridine-2,5-diamine;

5-(4-methylisoxazol-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-(4-fluorophenyl)-5-(1H-indazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-(4-fluorophenyl)-5-(2-((methylamino)methyl)-1H-benzo[d]imidazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N2-phenyl-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

5-(3-amino-1H-indazol-6-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(2-((methylamino)methyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-methyl-4-(5-(tetrahydrofur�EN-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

3-((2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)benzamide;

2-(4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-ylamino)ethanol;

5-(2-(2-aminoethoxy)pyridin-4-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(2-aminopyridin-4-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(2-(dimethylamino)pyridin-4-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N1-(4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)ethane-1,2-diamine;

(R)-N2-(isoindoline-5-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(S)-N2-(isoindoline-5-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(R)-N2-(3-amino-1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(S)-N2-(3-amino-1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

4-((2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)benzamide;

CIS-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

(S)-N2-(1H-benzo[d][1,2,3]triazole-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(R)-N2-(1H-benzo[d][1,2,3]triazole-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N-methyl-4-(5-(tetrahydro-2H-Piran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

5-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzo[d]izocsazol-3-am�n;

(R)-5-(3-amino-2-methylpropyl")-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-5-(3-amino-2-methylpropyl")-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propanamide;

(S)-2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propanamide;

(R)-N2-(4-fluorophenyl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(R)-N2-(1-methyl-1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(S)-N2-(1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(S)-N2-(4-fluorophenyl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(S)-N2-(1-methyl-1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(R)-N2-(1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(R)-N5-(piperidine-3-yl)-N2-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(S)-N5-(piperidine-3-yl)-N2-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

TRANS-4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

N5-methyl-N2N5-diphenyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

5-(5-methylisoxazol-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-N2/sup> -phenyl-N5-(pyrrolidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(S)-N2-phenyl-N5-(pyrrolidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

(R)-4-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

N5N5-dimethyl-N2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N-phenyl-5-(piperidine-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-1-ol;

(S)-2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-1-ol;

5-(2-(methylamino)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-phenyl-5-(piperidine-4-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-4-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

N2-phenyl-N5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

5-(1H-indazol-6-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(2-((dimethylamino)methyl)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(2-((methylamino)methyl)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-phenyl-5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

7-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoquinoline-1-amine;

5-(1-(2-aminoethyl)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(1-benzylpiperidine-4-yl)(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methanol;/p>

TRANS-4-(5-(4-aminocyclohexane)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

CIS-4-(5-(4-aminocyclohexane)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

2-(2-aminoethyl)-5-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoindoline-1-he;

2-(2-aminoethyl)-6-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoindoline-1-he;

5-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoindoline-1-he;

(R)-N2-phenyl-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

5-(3-aminopropyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoindoline-1-he;

6-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoindoline-1-he;

(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)(pyridin-3-yl)methanol;

(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)(piperidine-4-yl)methanol;

5-phenoxy-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-2-(phenylamino)-N-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide;

5-(4-aminobutyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-benzyl-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-N2-phenyl-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-N5-(4-aminocyclohexyl)-N2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

phenyl(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methanon;

5-(cyclohexyloxy)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

p> 5-(3-amino-1H-indazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-phenyl-5-(piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-phenyl-5-(1,2,3,6-tetrahydropiridine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(1H-benzo[d]imidazol-6-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(1-(2-aminoethyl)-1H-benzo[d]imidazol-6-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-(5-(piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-ol;

TRANS-N5-(4-aminocyclohexyl)-N2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanecarboxylic;

N-phenyl-5-(2-(piperazine-1-yl)pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(2-methoxypyridine-4-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(1H-indazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N2-phenyl-N5-(piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N-phenyl-5-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-cyclohexyl-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isobutyramide;

N-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)acetamide;

N-phenyl-5-(pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N2N5-diphenyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N5-isopropyl-N2-phenyl-[12,4]triazolo[1,5-a]pyridine-2,5-diamine;

N2-(3-methylbenzo[d]izocsazol-6-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

1-methyl-5-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1H-benzo[d]imidazol-2(3H)-he;

4-((2-(3-(methoxymethyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazine-2-he;

N2-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N-(5-methyl-6-morpholinopropan-3-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

6-(5-(debtor(tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

3-methyl-N-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzo[d]izocsazol-6-amine;

3-methyl-N-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine;

N2-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

5-((tetrahydro-2H-Piran-4-yl)methyl)-N-(3-(trifluoromethyl)-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-4-(2-(3-methyl-1H-pyrazolo[3,4-b]pyridine-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

N5-methyl-N2-(1-methyl-1H-indazol-5-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

CIS-4-(2-(3-methylbenzo[d]izocsazol-6-ylamino)-[1,2,4]triaz�lo[1,5-a]pyridin-5-ylamino)cyclohexanol;

3-methyl-N-(5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;

CIS-tert-butyl 6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethyl-2-oxoindole-1-carboxylate;

3,3,4-trimethyl-6-(5-((3-oxopiperidin-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

N2-(5-methyl-6-morpholinopropan-3-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N-(3,4-dimethyl-1H-indazol-6-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

6-(5-(isopropylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

N-(1-methyl-1H-indazol-5-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N2-(1-methyl-1H-indazol-5-yl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

N-(3-(methoxymethyl)-1H-indazol-6-yl)-5-((tetrahydro-2H-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

CIS-4-(2-(1H-pyrazolo[4,3-b]pyridine-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1,6-dimethylindoline-2-he;

(S)-2-methyl-3-(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-1-ol;

CIS-6-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1,4-dimethylindole-2-he;

N-(4-(1H-1,2,4-triazole-3-yl)phenyl)-5-((tetrahedron-Piran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

3,3-dimethyl-6-(5-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

6-(5-(2-methoxypyridine-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

4-(5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

3,3-dimethyl-6-(5-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

5-(debtor(tetrahydro-2H-Piran-4-yl)methyl)-N-(3-methyl-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-((l,4-dioxane-2-yl)deformity)-N-(3-methyl-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

3,3-dimethyl-6-(5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-he;

N2-(4-(1H-1,2,4-triazole-3-yl)phenyl)-N5-(tetrahydro-2H-Piran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;

6-(5-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3,3-dimethylindoline-2-he;

CIS-4-(2-(4-(1H-1,2,4-triazole-3-yl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

CIS-4-(2-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol;

1-methyl-5-(5-(tetrahydro-2H-Piran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1H-benzo[d]imidazol-2(3H)-he;

CIS-5-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-methyl-1H-benzo[d]imidazol-2(3H)-he, or

3,3-dimethyl-6-(5-morpholino-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-2-it.

In addition, the following heteroaryl�nye connections:

N-(2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)-5-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(3-fluorophenyl)-N-(1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(6-(5-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1H-benzo[d]imidazol-2-yl)methanol;

5-(3-fluorophenyl)-N-(1-methyl-1H-benzo[d]imidazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

3'-chloro-5'-(2-(4-(methylcarbamoyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)biphenyl-2-carboxamide;

4-(5-(3-(3-aminopropyl)-5-chlorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(3-(1H-imidazol-5-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(3-(3-aminopropyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(4-(1H-imidazol-4-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

3-(2-(2-methyl-1H-benzo[d]imidazole-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

4-(5-(3-(2-aminoethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(3-chlorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

3-(2-(benzo[d]izocsazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

4-(5-(3-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3-methoxy-N-methylbenzamide;

3-(2-(4-(1H-imidazol-2-yl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

N6-(5-phenyl-[1,2,4]triazolo[1,5-a]feast�DIN-2-yl)quinoline-2,6-diamine;

4-(5-(3-carbamoylphenoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

3-(2-(1-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

4-(5-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(2-chlorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

N6-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N3-(piperidine-4-yl)-1H-indazole-3,6-diamine;

3-(2-(4-(aminomethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

4-(5-(3-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzoic acid;

6-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)quinoline-2-ol;

3-(2-(1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

3-(2-(1-methyl-1H-benzo[d][1,2,3]triazole-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

4-(2-(4-(methylcarbamoyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzoic acid;

3-(2-(4-(methylcarbamoyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzoic acid;

N-(2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

3-(2-(4-morpholinothio)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

4-(5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

4-(5-(3-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-(1-demerol-4-yl)benzamide;

1-methyl-N6 -(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1H-indazole-3,6-diamine;

4-(5-(3-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide;

N-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,3-dihydrobenzo[d]isothiazol-6-amine Dion;

N-(5-methoxypyridine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N2-(2-aminoethyl)-N4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)pyridine-2,4-diamine;

N4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)pyridine-2,4-diamine;

N-(6-morpholinopropan-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N5-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzo[d]izocsazol-3,5-diamine;

N-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzo[d]izocsazol-5-amine;

N6-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzo[d]izocsazol-3,6-diamine;

2-(2-aminoethyl)-5-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)isoindoline-1-he;

N-(2-methyl-1H-benzo[d]imidazol-5-yl)-5-phenyl-[1,2,4]triazolo [1,5-a]pyridin-2-amine;

N-(1-methyl-1H-benzo[d]imidazol-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzo[d]izocsazol-6-amine;

N-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1H-benzo[d][1,2,3]triazole-6-amine;

1-(4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)phenyl)pyrrolidin-2-he;

4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)picolinate;

4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)picolinate;

N-(isoindoline-5-yl)-5-phenyl-[1,2,4]Tria�olo[1,5-a]pyridin-2-amine;

N-(1-methyl-1H-indazol-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-(1-methyl-1H-benzo[d]imidazol-5-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-(4-(1H-1,2,4-triazole-5-yl)phenyl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N6-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1H-indazole-3,6-diamine;

5-phenyl-N-(pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)quinolin-6-amine;

1-(5-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)indolin-1-yl)Etalon;

N-(1H-indazol-5-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(3-(1H-1,2,4-triazole-5-yl)phenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-(5-(3-cyanophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

4-(5-(3-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

2-fluoro-5-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

3-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzonitrile;

3-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

N-(1H-indazol-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)isoindoline-1-he;

5-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)pyridin-2-ol;

N-(6-methoxypyridine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)picolinate;

2-fluoro-4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

5-phenyl-N-(pyrimidine-5-yl)-[1,2,4]triazolo[1,-a]pyridin-2-amine;

5-phenyl-N-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile;

4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-(piperidine-4-yl)benzamide;

N-(3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)acetamide;

N-(4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)acetamide;

5-(2-fluorophenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(3-fluorophenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(4-Dapsone base)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile;

5-(3-(aminomethyl)phenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzamide;

3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzamide;

5-(3-Dapsone base)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide;

5-(4-fluorophenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

2-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenol;

N-(4-morpholinomethyl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

N1N1-dimethyl-N4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzene-1,4-diamine;

N-(3,4-dimethoxyphenyl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

5-(furan-3-yl)-N-phenyl-[1,2,4 triazolo[1,5-a]pyridin-2-amine;

5-(3-chlorophenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine or

N,5-diphenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine; and their pharmaceutically acceptable salts, tautomers, stereoisomers, solvates or prodrugs.

4.3 Methods of obtaining Heteroaryl Compounds

Specialists in this field will be able to get heteroaryl compounds using conventional methods of organic synthesis and commercially available substances. As an example and not for limitation, the heteroaryl compounds can be obtained as shown in schemes 1-12, presented below and in the examples described in Section 5.1. It should be noted that the person skilled in the art will be able to modify the procedures in the illustrative schemes and examples, with access to the desired product.

Scheme 1

Heteroaryl Compounds can be synthesized, based on the compound I by treatment with a suitable Bronevoy acid or boronate ester in the presence of a palladium catalyst (such as palladium acetate), a ligand (such as triphenylphosphine or tricyclohexylphosphine) and base (such as potassium phosphate or cesium fluoride) introduction to R2Deputy (see compound II). The resulting compound can then be subjected to interaction with a suitable halogenated connected�eat in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium (0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium) introduction to R1Deputy.

Alternatively, compound II can be subjected to interaction with sodium nitrite in Hydrobromic acid to produce a compound III, which can then be subjected to interaction with a suitable amine in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium (0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium).

Alternatively, R1Deputy you can enter first through the combination of compound I with a suitable Bronevoy acid or boronate ester in the presence of a copper catalyst such as copper acetate(II)) and a ligand (such as biperiden), or by reacting with a suitable halogen-containing compound in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium (0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino) and base (such as cesium carbonate, tert-butoxide, sodium or tert-butoxide potassium). Compound IV ZAT�m can be subjected to interaction with a suitable Bronevoy acid, boronate ester or tricorporate potassium in the presence of a palladium catalyst (such as, as 1-1'-bis(diphenylphosphino)ferienparadies or tetrakis(triphenylphosphine)palladium(0) or palladium diacetate) and bases (such as sodium carbonate or potassium hydroxide, potassium phosphate or potassium acetate) introduction to R2Deputy.

Scheme 2

Compounds, where R2= OR3, can be obtained as shown in Scheme 2. 2,6-Dichloropyridine is subjected to interaction with a suitably substituted alcohol in the presence of base (such as sodium hydroxide or sodium metal), and the second chlorine atom can be converted into an amino group by treatment para-methoxybenzylamine with subsequent removal of the protection using an acid such as trifluoroacetic acid. The resulting compound can be treated consistently ethoxycarbonylmethylene in dioxane and hydroxylamine with getting cyklinowanie compounds, which then can be subjected to interaction with a suitable halogen-containing compound in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone) dipalladium(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl) and base (such as calcium carbonate price�Oia, tert-butoxide, sodium or tert-butoxide potassium) introduction to R1Deputy.

Scheme 3

Compounds, where R2= NR3R4, can be obtained as shown in scheme 3. Compound IV can be subjected to interaction with a secondary amine using thermal mode, microwave radiation, or by reacting a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl)) and a base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium).

Scheme 4

Compounds, where R2is a-OR3or-NR3R4(where R4can be a (H), can be obtained as shown in Scheme 4. The compound I can be subjected to interaction with sodium nitrite and Hydrobromic acid in the presence of copper bromide (I). Received dibrom connection can then be treated with a suitable alcohol or amine in the presence of base such as sodium hydride or N,N-diisopropylethylamine. R1the Deputy can then be introduced by reacting with a suitable amine in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dialled�(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium).

Scheme 5

Compounds, where R2= NHC(O)R3, can be obtained as shown in Scheme 5. Compound IV can be subjected to interaction with ammonia and copper iodide to introduce an amine group, which can then be subjected to interaction with a suitable acetylchloride in the presence of base, such as triethylamine.

Scheme 6

Compounds, where R2= C(O)NR3R4, can be obtained as shown in Scheme 6. The compound I can be subjected to interaction with zinc dust and zinc cyanide in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)) and a ligand such as 1,1'-bis(diphenylphosphino)ferrocene). The resulting compound can then be treated with a suitable Bronevoy acid or boronate ester in the presence of a copper catalyst such as copper acetate(II)) and a ligand (such as biperiden), or by reacting with a suitable halogen-containing compound in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)), ligand (such as 4,5-bis(diphenyl�Ospina)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl)) and base (such as cesium carbonate, tert-butoxide, sodium or tert-butoxide potassium). The cyano group is then hydrolysed using a base (such as sodium hydroxide) and the resulting acid is subjected to interaction with a suitable amine under standard conditions amide binding.

Scheme 7

Compounds, where R2= C(O)R5, CH(OH)R4or substituted or unsubstituted alkyl, can be obtained as shown in Schemes 7, 8, 9 and/or 11. Compound IV can be subjected to interaction with butyllithium for education liotironina intermediate compound which then can be subjected to interaction with a suitable nitrile or aldehyde. When it is subjected to the interaction with the aldehyde, the resulting alcohol can then be recovered using thionylchloride and zinc dust. Alternatively, lithium-containing substances can be subjected to interaction with N,N-dimethylformamide to form an aldehyde, which can then be subjected to interaction with a suitable ridom (derived from phosphonate and bases, such as aqueous solution of sodium hydroxide). The double bond can then be restored through catalytic hydrogenation using a catalyst such as palladium on carbon, in an atmosphere of hydrogen.

Scheme 8

Compounds, where R2= -CH2-R can �elocity, as shown in Scheme 8. Compound IV can be subjected to interaction with a suitable zinc bromide in the presence of a palladium catalyst (such as tetrakis(triphenylphosphine)palladium(0)). Alternatively, compound I can be subjected to interaction with n-butyllithium and subjected to condensation with a suitable amide Weinrebe. The resulting ketone then you can restore using a reducing agent such as hydrazine. R1the Deputy can be administered by combination with a suitable halogen-containing compound in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium) or by converting the amine in the bromine-containing compound by treatment with sodium nitrite and copper bromide(I) in Hydrobromic acid and then combined with a suitable amine in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium).

Scheme 9

<> Compounds, where R2=-(CH2)-CHRR' can be obtained as shown in Scheme 9. Compound IV can be subjected to interaction with an appropriate alkene in the presence of a borane (such as (1S,5S)-9-borabicyclo[3.3.1]nonane), palladium catalyst such as [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane) and a base such as potassium carbonate. Alternatively, compound I can be subjected to interaction with di-tert-BUTYLCARBAMATE and then treated with an appropriate alkene in the presence of a borane (such as (1S,5S)-9-borabicyclo[3.3.1]nonane), palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane) and a base such as potassium carbonate. R1the Deputy then you can enter by reacting with a suitable halogen-containing compound in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium).

Scheme 10

Compounds, where R1represents a substituted or unsubstituted cycloalkyl, can be obtained as shown in Scheme 10. Compound II can be subjected ot�modestia with a suitably substituted cyclic ketone in the presence of a reducing agent, such as triacetoxyborohydride sodium, in the presence of acid (such as acetic acid).

Scheme 11

Compounds, where R2represents -(CH2CR6(OR3)R4or alkyl, can be obtained as shown in Scheme 11. 6-Methylpyridine-2-amine can be subjected to sequential interaction with ethoxycarbonylmethylene and hydroxylamine in the presence of N,N-diisopropylethylamine. Cyklinowanie compound can then be subjected to interaction with a suitable halogen-containing compound in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium). Then may be formed liotironina intermediate compound by treatment with butyllithium, and it can be subjected to interaction with a suitable aldehyde or ketone. When using the ketone obtained tertiary alcohol can be treated with acid (such as p-toluensulfonate acid) to produce the corresponding alkene, which then can be restored to an appropriate alkane via catalytic hydrogenation.

Scheme 12

Compounds, where R2represents -(CH2)-NR6R7, can be synthesized as shown in Scheme 12. Compound VII can be subjected to interaction with N-bromosuccinimide and 2,2'-azobis(2-methylpropionitrile)ω, with subsequent interaction with a suitable amine in the presence of base such as potassium carbonate. R1the Deputy can be administered by combination with a suitable halogen-containing compound in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'- bis(diphenylphosphino)1,1'-binaphthyl) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium). Alternatively, compound VIII can be restored to the alcohol using a reducing agent such as sodium borohydride or triacetoxyborohydride sodium, and then convert to the deleted group, such as bromide or mesilate, by processing tribromide of phosphorus, methanesulfonamido or methanesulfonic anhydride. The compound obtained can be subjected to interaction with a suitable amine in the presence of base such as potassium carbonate. Alternatively, these compounds can be obtained in one stage, proceeding from compound VIII by reacting with a suitable amine in the presence of restore�Vittel, such as triacetoxyborohydride sodium. Alternatively, 2,5-dibrom-[1,2,4]triazolo[1,5-α]pyridine can be treated with n-butyllithium with subsequent treatment of the N,N-dimethylformamide. The resulting aldehyde can then be subjected to interaction with a reducing agent such as sodium borohydride, to obtain the corresponding alcohol, which, in turn, treated with methanesulfonic anhydride and a suitable amine. R1the group can be entered by interaction with a suitable amino-compound in the presence of a palladium catalyst (such as Tris(dibenzylideneacetone)dipalladium(0)), ligand (such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or (R)-(+)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl) and base (such as cesium carbonate, tert-butoxide sodium, or tert-butoxide potassium).

Pharmaceutically acceptable salt of the Heteroaryl Compounds can be formed using conventional and known methods, for example, by reacting the heteroaryl compound with a suitable acid as disclosed above. Such salts typically receive high yields at moderate temperatures, and they often get just by separating the compound from a suitable acidic wash at the final stage of the synthesis. Salt-forming acid can be dissolved in a suitable organic solvent or a water-body�weekend solvent, such as alkanol, a ketone or an ester. On the other hand, if it is desirable to obtain a heteroaryl compound in free base form, it can be separated from the alkaline washing at the final stage, in accordance with known methods. For example, a typical method of obtaining hydrochloride salt comprises dissolving the free base in a suitable solvent and thorough drying of the solution, for example, over molecular sieves, followed by bubbling with hydrogen chloride gas.

4.4 Methods of application

In one aspect, the present application presents methods for the treatment or prophylaxis of an inflammatory condition of the immunological status, autoimmune conditions, allergic conditions, rheumatic condition, thrombotic condition, cancer, infections, neurodegenerative diseases, neuro-inflammatory diseases, cardiovascular diseases or metabolic condition, comprising administering to a subject in need, an effective amount of the heteroaryl compound or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug. In some embodiments embodiment, the methods further comprise the introduction of additional therapeutic ingredients described in the present application.

In another aspect, in n�present application presents methods for inhibiting kinases in the cell, expressing the indicated kinase, comprising contacting the specified cell with an effective amount of the heteroaryl compound or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug. In one embodiment, the kinase is a Syk, FLT3, JAK1 or JAK2, or their mutants or isoforms, or combinations of two or more of the foregoing. For example, the heteroaryl compound is a compound from Table 1.

Heteroaryl Compounds described in the present application, can be used as pharmaceuticals for the treatment or prevention of diseases in subjects such as animals or people. In addition, the heteroaryl compounds described in the present application, are active against kinases (e.g., protein kinases, including kinases involved in inflammatory condition, an immunological condition, autoimmune conditions, allergic conditions, rheumatic condition, thrombotic conditions, cancer, infections, neurodegenerative diseases, neuro-inflammatory diseases, cardiovascular diseases, and metabolic status. Without any theoretical limitations, believe that heteroaryl compounds are useful for treatment and prevention of inflammatory conditions, immunological status�th, autoimmune conditions, allergic conditions, rheumatic conditions, thrombotic conditions, cancer, infections, neurodegenerative diseases, neuro-inflammatory diseases, cardiovascular diseases and metabolic conditions, thanks to their ability to modulate (e.g., inhibit) kinase, which is involved in the etiology of these conditions. Accordingly, in the present application presents many applications Heteroaryl Compounds, including the treatment or prevention of diseases, described below. The methods presented in this application, include the introduction of an effective amount of one or more Heteroaryl Compounds to a subject in need of it. In some embodiments embodiment the heteroaryl compound is administered in combination with another active agent.

Representative immunological status, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, syndrome Behet, non-allergic mastocytosis (e.g. mastocytosis and treatment of anaphylaxis), ankylosing spondylitis, osteoarthritis, rheumatoid arthritis (RA), multiple sclerosis, lupus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Grave's disease, transplant rejection, humoral� graft rejection, non-humoral graft rejection, cellular graft rejection, immune thrombocytopenic purple (ITP), idiopathic thrombocytopenic purple, diabetes, immunological response to bacterial, parasitic, helminthic infestation or viral infection, eczema, dermatitis, disease graft-versus-host disease Goodpaster, hemolytic disease of newborn, autoimmune hemolytic anemia, anti-phospholipid syndrome, ANCA-associated vasculitis Syndrome, Churg-Strauss, Wegener's granulomatosis, pemphigus vulgaris, serum sickness, mixed cryoglobulinemia type, peripheral neuropathy associated with IgM antibody, microscopic polyangiitis, Hashimoto's thyroiditis, Sjogren's syndrome, fibrosing condition (such as condition-dependent innate or adaptive immune systems or local mesenchymal cells) or primary biliary cirrhosis.

Representative autoimmune conditions, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, autoimmune hemolytic anemia (AIHA), the syndrome of Bechet, Crohn's disease, diabetes type I, a disease of Goodpaster, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purple, lupus, multiple sclerosis, amyotrophies�th lateral sclerosis, myasthenia gravis, pemphigus vulgaris, primary biliary cirrhosis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, ulcerative colitis or Wegener's granulomatosis.

Representative allergic condition, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, anaphylaxis, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, eczema, urticaria, disorders of the mucous membranes, tissue disorders and certain gastrointestinal disorders.

Representative rheumatic condition, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, rheumatoid arthritis, gout, ankylosing spondylitis or osteoarthritis.

Representative inflammatory condition, for treating or prophylaxis of which the heteroaryl compounds are useful include, but are not limited to, non-ANCA (anti-neutrophil cytoplasmic antibodies), vasculitis (for example, where Syk function is associated with adhesion, diapedesis and/or activation of neutrophils), psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, chronic urticaria, urticaria, anaphylaxis, bronchitis, chronic obstructi�Noah pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, gout, Crohn's disease, mucous colitis, ulcerative colitis, Allergy to intestinal antigens (such as celiac disease), diabetes (e.g., diabetes type I and diabetes type II) and obesity. In some embodiments embodiment, the inflammatory condition is a dermatological condition, such as, for example, psoriasis, urticaria, eczema, scleroderma, or dermatitis. In other embodiments embodiment, the inflammatory condition is a pulmonary inflammatory condition, such as, for example, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome in adults (ARDS). In other embodiments embodiment, the inflammatory condition is a gastrointestinal condition, such as, for example, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome or mucous colitis.

Representative infection, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, bacterial, parasitic, prion, viral infection or parasitic infection.

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

Representative cardiovascular diseases, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, restenosis, atherosclerosis and its consequences, such as stroke, myocardial infarction, ischemic heart damage, lung, intestine, kidney, liver, pancreas, spleen or brain.

Representative metabolic condition, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, obesity and diabetes (e.g., diabetes type I and II). In a specific embodiment, the present application presents methods for the treatment or prevention of insulin resistance. In some embodiments embodiment, the present application presents methods for the treatment of Il� prevention of insulin resistance, which leads to diabetes (e.g. type II diabetes). In another embodiment, the present application presents methods for the treatment or prevention of syndrome X or metabolic syndrome. In another embodiment, the present application presents methods for the treatment or prophylaxis of diabetes type II, diabetes type I, slow developing type I diabetes, diabetes insipidus (e.g., neurogenic diabetes insipidus, nephrogenic diabetes insipidus, dipsogenic diabetes insipidus or gestagenic diabetes insipidus), diabetes, gestational diabetes, polycystic ovary syndrome, diabetes that develops in adulthood, juvenile diabetes, insulin-dependent diabetes, insulin-independent diabetes, diabetes associated with poor diet, ketosis-prone diabetes, pre-diabetic condition (e.g., a metabolic disorder of glucose) associated with cystic fibrosis, diabetes, hemochromatosis and ketosis-resistant diabetes.

Representative neurodegenerative and neuro-inflammatory diseases, for the treatment or prevention of which heteroaryl compounds are useful include, but are not limited to, Huntington's disease, Alzheimer's disease, viral (e.g., HIV) or bacterial-associated encephalitis and defeat.

In another�the approach of the incarnation, in the present application presents methods for the treatment or prevention of fibrotic diseases and disorders. In a specific embodiment, the present application presents methods for the treatment or prevention of idiopathic pulmonary fibrosis, myelofibrosis, hepatic fibrosis, sealifebase and steatohepatitis.

In another embodiment, the present application presents methods for the treatment or prevention of diseases associated with thrombotic phenomena, such as, but not limited to, atherosclerosis, myocardial infarction and ischemic stroke.

Provides methods that make possible the regulation and, in particular, the inhibition of further developing processes that are the result of activation of the signaling cascade(cascades) Fc receptor. Such developing further processes include, but are not limited to, FcεRI-mediated and/or FcγRI-mediated the degranulation, cytokine production and/or production and/or release of lipid mediators such as leukotrienes and prostaglandins. The method mainly comprises contacting cells expressing Fc receptors, such as the cell types discussed above, with the amount heteroaryl compounds described in the present application, effective for regulating or inhibiting the signaling cascade Fc receptor, and/or further proce�sa, resulting from activation of this signaling cascade. The method can be carried out in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with the signaling cascades of Fc receptors, such as diseases resulting from the release of granule-specific chemical mediators upon degranulation, the release and/or synthesis of cytokines and/or release and/or synthesis of lipid mediators such as leukotrienes and prostaglandins.

In another aspect, also provided methods for the treatment or prevention of diseases characterized by, caused by or associated with release of chemical mediators as a consequence of the activation of signaling cascades of Fc receptors, such as FcεRI and/or FcγRI signaling cascades. The methods typically include the introduction to the subject of the number heteroaryl compounds useful for treatment or prevention of such diseases. As discussed above, activation of the FcεRI signaling cascade or FcγRI receptor in certain immune cells leads to the release and/or synthesis of various chemical substances that are pharmacological mediators of a wide range of diseases. Any of these diseases can be treated or prevented in accordance with FPIC�the means described in this application.

For example, in mast cells and basophils, activation of the FcεRI or FcγRI signaling cascade leads to the immediate (i.e., within 1-3 min after receptor activation) release of pre-formed mediators of atopic and/or type I allergic reactions (e.g., histamine, proteases such as tryptase etc.) via the degranulation process. Such atopic or type I allergic reactions include, but are not limited to, anaphylactic reactions to those present in the environment and other allergens (e.g., pollens, insect venoms and/or animals, foods, drugs, contrast dyes, etc.), anaphylactoid reactions, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, eczema, urticaria, disorders of the mucous membranes, tissue disorders and certain gastrointestinal disorders. After the immediate release of pre-formed mediators via degranulation is followed by the release and/or synthesis of other chemical mediators, including, among other things, platelet-activating factor (PAF), prostaglandins and leukotrienes (e.g., LTC4) and the de novo synthesis and release of cytokines, such as TNFα, IL-4, IL-5, IL-6, IL-13, etc. the First of these two processes occurs � within 3-30 min after the activation of the receptor; last approximately 30 minutes - 7 hours after the activation of the receptor. It is believed that these mediators are "late stage" partly responsible for the chronic symptoms of the above-listed atopic and allergic reactions type I and in addition are chemical mediators of inflammation and inflammatory diseases (e.g., osteoarthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, spastic colon, etc.), a late stage of scarring (e.g., scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion failure and after myocardial infarction) and complex or syndrome of dryness. All these diseases can be treated or prevented in accordance with the methods described in this application.

Additional diseases that can be treated or prevented in accordance with the methods described in the present application, include diseases associated with the pathology of basophils and/or mast cells. Examples of such diseases include, but are not limited to, diseases of the skin such as scleroderma, cardiac diseases, such as after myocardial infarction, pulmonary diseases such as a change or remodeli�the stripes of the muscles of the lungs, chronic obstructive pulmonary disease (COPD), and bowel diseases, such as syndrome of inflamed colon (spastic colon).

Heteroaryl Compounds described in the present application, are also potent inhibitors tyrosinemia kinase Syk. Thus, in the following aspect, are provided methods of regulation and, in particular, inhibiting the activity of Syk kinase. The method generally comprises contacting Syk kinase or a cell comprising a Syk kinase with an amount of heteroaryl compounds, effective to regulate or inhibit the activity of Syk kinase. In one embodiment, the Syk kinase is an isolated or recombinant Syk kinase. In another embodiment, the Syk kinase is an endogenous or recombinant Syk kinase, a murine cell, such as fat cell or basophiles. The method can be carried out in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with the activity of Syk kinase.

In one embodiment, the present application presents methods for inhibiting Syk kinase in a cell expressing a specified Syk kinase, comprising contacting the specified cell with an effective amount of the heteroaryl with�organisations, where the compound is CIS-4-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino) cyclohexanecarboxylate.

It is known that Syk kinase plays a critical role in other signaling cascades. For example, Syk kinase is an effector of signal transmission B-cell receptor (BCR) (Turner et al., Immunology Today 21:148-154 (2000) and is an essential component of the transmission signal of integrin beta (1) beta(2) and beta(3) in neutrophils (Mocsai et al., Immunity 16:547-558 (2002). Because heteroaryl compounds described in the present application, are potent inhibitors of Syk kinase, they can be used to regulate and, in particular, to inhibit, any signaling cascade where Syk plays a role, such as, for example, the signaling cascades of Fc receptor, BCR and integrin and cell responses, manifested through these signaling cascades. Specific cell response, adjustable or inhibiting will depend, in part, from single cell type and signaling pathway of the receptor, as is well known in the prior art. Non-limiting examples of cellular responses that can regulate or inhibit Heteroaryl Compounds include respiratory impulse, cellular adhesion, cellular degranulation, and the spreading of cells, cell migration, phagocytosis (e.g., in macrophages), calcium flux and�new (for example, in mast cells, basophils, neutrophils, eosinophils and B-cells), platelet aggregation, and cell maturation (e.g. B-cells).

Thus, in another aspect, are provided methods of regulation and, in particular, inhibition of signal transduction cascades in which Syk plays a role. The method generally comprises contacting Syk-dependent receptor or a cell expressing a Syk-dependent receptor with an amount of heteroaryl compounds described in the present application, effective for regulating or inhibiting the signal transduction cascade. The methods can also be used for regulation and, in particular, inhibiting further developing processes or cellular responses induced by activation of specific Syk-dependent signal transduction cascade. The methods can be implemented to any regulation of the signal transduction cascade where Syk, as yet known or can be determined, plays a role. The methods can be carried out in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with activation of the Syk-dependent signal transduction cascade. Non-limiting examples of such diseases include diseases discussed above.

These Zab�the indicated include various tumors and cancers benign or malignant, metastatic or non-metastatic. Specific characteristics of cancer, such as tissue invasiveness or metastasis may represent a target for directional exposure using the methods described in this application. Cell proliferative disorders include various types of cancer, including, among others, breast cancer, ovarian cancer, renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer, pancreatic cancer, squamous cell carcinoma of the lung and adenocarcinoma.

In some embodiments embodiment, the cell-proliferative disorder that can be treated, is a hematopoietic neoplasm, which is an aberrant growth of cells of the hematopoietic system.

In some embodiments embodiment, the hematopoietic neoplasm, which can be treated, is a lymphoid neoplasm, where the abnormal cells originate from and/or display a characteristic phenotype of cells of lymphoid origin. Lymphoid neoplasms can be subdivided into B-cell neoplasms, T - and NK-cell neoplasms, Hodgkin's and non-Hodgkins lymphoma. B-cell neoplasms can be further subdivided into neoplasms, including predestin�Ki B-cells, and tumors, including Mature/peripheral B-cells. Illustrative B-cell neoplasms represent lymphoblastic leukemia/lymphoma with B-cell precursor acute lymphoblastic leukemia with B-cell precursors), while illustrative neoplasms involving Mature/peripheral B-cells are B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolimfocitarnoj leukemia, lymphoplasmacytoid lymphoma, B-cell lymphoma splenic boundary zone, hairy-cell leukemia, plasma cell myeloma/plasmacytoma, B-cell lymphoma of extranodal boundary zone of the MALT type, B-cell lymphoma of nodal boundary zone, follicular lymphoma, lymphoma of mantle field, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, primary effusion lymphoma and Burkitt's lymphoma/Burkitt-cell leukemia. T-cell and Nk-cell neoplasms are divided further into tumors involving the T-cell precursors and tumors involving Mature (peripheral) T-cells. Illustrative tumor involving the T-cell precursors is lymphoblastic lymphoma/leukemia with involvement of T-cell precursors (acute lymphoblastic leukemia involving T cell-predestin�cov), while illustrative neoplasms involving Mature (peripheral) T-cells are T-cell prolimfocitarnoj leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, T-cell lymphoma/leukemia adults (HTLV-I), extranodal NK/T-cell lymphoma, T-cell lymphoma nasal type, enteropathy type, Spoleto-hepatic gamma-Delta T-cell lymphoma, subcutaneous, panniculitis-like T-cell lymphoma, mycosis granuloma/Sezary syndrome, anaplastic large-cell lymphoma, T/nullclient primary cutaneous type, peripheral T-cell lymphoma, not described in any other way, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, T/nullclient, primary systemic type. The third member of lymphoid tumors represents Hodgkin's lymphoma, also referred to as Hodgkin's disease. Illustrative diagnoses in this class, which can be treated with a Heteroaryl Compound, include, among others, nodular Hodgkin's lymphoma with a predominance of lymphocytes and various classical forms of Hodgkin's disease, illustrative members of which are Hodgkin's lymphoma with nodular sclerosis (stages 1 and 2), classical Hodgkin lymphoma with a high content of lymphocytes, mixed-cell lymphs�mA Hodgkin's lymphoma and Hodgkin's lymphoma with a low content of lymphocytes. The fourth member of lymphoid neoplasms is a not-Hodgkins lymphoma, also called non-Hodgkin Bosnu. Illustrative disorders of this class, which can be treated Heteroaryl Compound, include, among others, waldenstrom Waldenstrom; the monoclonal gammopathy of undetermined significance; benign a monoclonal gammopathy; heavy chain disease, lymphoma region of the mantle, MCL, lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma, ILL, diffuse poorly differentiated lymphocytic lymphoma, PDL, centrocytes lymphoma, diffuse small cell lymphoma with crushing, DSCCL, follicular lymphoma, and any type of lymphoma region of the mantle, which can be observed under the microscope (nodular, diffuse, blastic lymphoma and lymphoma of mantle field). In various embodiments, any of the lymphoid neoplasms that are associated with aberrant Syk activity can be treated Heteroaryl Compounds.

In some embodiments embodiment, the hematopoietic neoplasm, which can be treated, is a myeloid neoplasm. Myeloid neoplasms can be divided into myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic SYN�Roma and acute myeloid leukemias. Illustrative myeloproliferative diseases are chronic myelogenous leukemia (e.g., Philadelphia chromosome positive (t(9;22)(qq34;q1 1)), chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndromes, chronic idiopathic myelofibrosis, polycythemia Vera and essential thrombocythemia. Illustrative myelodysplastic/myeloproliferative diseases are chronic mielomonocitarnyi leukemia, atypical chronic myelogenous leukemia and juvenile mielomonocitarnyi leukemia. Illustrative myelodysplastic syndromes are refractory anemia with ring sideroblasts and without ring sideroblasts, a refractory cytopenia (myelodysplastic syndrome) with multilineage dysplasia, multiple myeloma, such as, but not limited to, slowly developing multiple myeloma, non-secretory myeloma, osteoskleroticheskie myeloma, plasma cell leukemia, solitary plasmacytoma and the extramedullary plasmacytoma, refractory anemia (myelodysplastic syndrome) with excess of blast cells, 5q-syndrome, and myelodysplastic syndrome with t(9;12)(q22;pl2) (TEL-Syk hybrid; see, for example, Kuno et al, Blood 97: 1050 (2001). In various embodiments, any of the myeloid neoplasms, which�s associated with aberrant activity of Syk, can be treated Heteroaryl Compounds described in the present application.

In some embodiments embodiment, the heteroaryl compounds can be used for the treatment of acute myeloid leukemia (AML), which represent a large class of myeloid neoplasms having its own subdivision of disorders. These entities include, among others, AMLs with recurrent cytogenetic translocations AML with multilineage dysplasia and other AML not classified in any other way. Illustrative AMLs with recurrent cytogenetic translocations include, among others, AML ct(8;21)(q22;q22), AML1(CBF-alpha)/ETO, acute promyelocytic leukemia (AML with t(15;17)(q22;q11-12) and variants, PML/R AR-alpha), AML with abnormal bone marrow eosinophils (inv(16)(pl3q22) or t(16;16)(pl3;q11), CBFb/MYH1 1X) and AML with I 1q23 (MLL) abnormalities. Illustrative AML with multilineage dysplasia are associated with myelodysplastic syndrome, or without prior myelodysplastic syndrome. Other acute myeloid leukemias that are not assigned to any particular group, include, minimally differentiated AML, AML without maturation, AML with maturation, acute mielomonocitarnyi leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakariocitarnogo leukemia, acute bazo�ilen leukemia and acute Parmalat with myelofibrosis.

In some embodiments embodiment, the heteroaryl compounds can be used to treat sarcomas of the bone and connective tissue, such as, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, permasteelisa sarcoma, soft tissue sarcomas, angiosarcoma (gemangiosarkoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancer, nevrilemmoma, rhabdomyosarcoma, synovial sarcoma; breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary breast cancer, Paget's disease and inflammatory breast cancer; squamous cell carcinoma; carcinoma of the head and neck.

In other aspects, the cell-proliferative disorders that can be targets for Heteroaryl Compounds include viral-mediated tumor. They can occur as a result of infection of cells by oncogenic virus that has the ability to transform normal cell into a tumor cell. In some embodiments, is embodied�Oia, viral-mediated tumor that can be treated by the compounds disclosed in the present application, is associated with any virus that encodes a tyrosine activation motif (ITAM) of immunoreceptor, can modulate the activity of Syk. This motif refers to the conserved amino acid motif sequence that functions through interaction with and activation of non-receptor tyrosinase kinases. ITAM motifs, among others, found in the β and γ chains of FcεRI, the ε subunit of T-cell receptor, and immunoglobulin β (Igβ) and Igα B-cell receptor. The motif with the canonical sequence typically represents Yxx(L/I)x6-8Yxx(L/I), where x represents any amino acid. Typically, tyrosine residues in this motif are involved in signal transmission ITAM and are substrates for phosphorylation of Src family kinases. Phosphorylated forms ITAMs function as sites of interaction for SH2 region of src homology) containing signaling proteins, such as Syk/ZAP-70 kinase. Besides its presence in various cell-surface molecules, ITAM sequences were identified in the viral-encoded proteins. In light of the description contained in this application, indicating the function of Syk kinase as an oncogene, tumors associated with viruses containing genes encoding proteins with ITM sequences, can be treated Heteroaryl Compounds.

Accordingly, in some embodiments embodiment, a viral-mediated tumor that can be treated Heteroaryl Compounds, associated with the herpes virus associated with Kaposi's sarcoma (KS), a lymphotropic virus which is associated with Kaposi's sarcoma, a rare malignant disease, often occurring in HIV-infected. In some embodiments embodiment, a viral-mediated tumor associated with Epstein-Barr (EBV).

In some embodiments embodiment, a viral-mediated tumor that can be treated Heteroaryl Compound, is associated with human T-cell lymphotropic virus (HTLV-I virus), a retrovirus in the same class with the virus such as the AIDS virus, HIV-I.

In some embodiments embodiment, a viral-mediated tumor is associated with the virus breast tumor (MTV). ITAM sequences detected in the Env gene of the virus breast tumor mouse (MMTV), a retrovirus type B, identified as the etiological agent for breast cancer in mice.

It should be clear that the use of Heteroaryl Compounds for the treatment of viral-induced tumors is not limited to tumors associated with viruses mentioned above. As indicated, any tumors associated with oncogenic virus, in which Syk is �aktivirovannoi as part of its oncogenic mechanism, regardless of whether you enable ITAM sequences that can be targeted for directed at them Heteroaryl Compounds.

In other aspects, really, the disclosure is directed to the treatment of metastatic tumors using Heteroaryl Compounds. Metastases are the characteristic symptom of malignant tumor cells, whereby tumor cells are separated from the site of origin and then apply for colonization on other parts. These secondary tumors can form in tissues not related to the cells from which the tumor cells. The formation of these secondary tumours metastases, as it turns out, is a major cause of mortality from malignant forms of cancer. Metastasis begins when cancer cells separate from a primary tumor and enter the bloodstream or lymphatic system and then migrate to other sites of colonization. Generally, normal cells are not separated and not invaziruyut in other tissues due to the different signals that inhibit adhesion dissimilitude cells to each other, as well as signals between cells that inhibit cell growth. Cell transformation, however, these changes are normal regulatory program in such a way that tumor cells interact with the local cell�mi tissue with changes in local extracellular matrix, stimulating the migration and promotive proliferation and survival. Changes of cell adhesion molecules (CAMs), such as members of the families of immunoglobulins and calcium-dependent katerinov, as well as integrins, have been shown to play a critical role in invasion and metastases. For example, changes in N-CAM from visokoaktivniy isoforms to nizkozatratnoj isoform which, along with its down-regulation may lead to invasive cancer of the pancreas.

The activity of Syk kinase is associated with various integrins, expressed in cells of hematopoietic origin, but also in non-hematopoietic cells. Syk kinase is involved in signaling of β1 integrin in epithelial lung cells (Ulanova et al, Am. J. Physiol. Lung Cell Mol. Physiol. 288:L497-L507 (2004) and monocytes (Lin et al, Biol. Chem. 270(27): 16189-97 (1995), signaling of β2 integrin in granulocytes/neutrophils (Miura et al, Blood 96(5): 1733-9 (2000); Kusumoto et al, Microbiol Immunol. 45(3):241-8 (2001) and the signal transmission of β3 integrin in platelet activation and cell adhesion (Gao et al, EMBO J. 16(21):6414-25 (1997). Taking into account this relationship between the activity of Syk kinase and tumorigenesis, using Syk-inhibitory Heteroaryl Compounds to reduce the invasive and metastatic properties of tumors is shown through the relationship between the activity of Syk kinase and certain integrins (Mocsai et al, Immunity 16(4): 547-58 (2002). Thus, in some embodiments, is embodied�I, heteroaryl compounds can be used to modulate metastatic properties of tumors, is mediated through the activity of integrins. In some embodiments embodiment, the heteroaryl compounds can be used to reduce the invasiveness of tumor cells in the tissue and metastatic potential, mediated βl integrins (Lin et al, Biol. Chem. 270:16189-16197 (1995); Kusumoto et al, Microbiol Jmmunol, 45(3):241-8 (2001); Ortiz-Stern et al, J Leukoc Biol. 77(5):787-99 (2005). Illustrative of this integrin is integrin α2β1.

In some embodiments embodiment, the heteroaryl compounds can be used to reduce the invasiveness of tumor cells in the tissue and metastatic potential, mediated by the activity of β2 integrins (CD 18) (Willeke et al, J. Leukoc. Biol. 74(2):260-9 (2003). They include, among others, CD1 1a/CD18, CD1 1b/CD18, CD1 1c/CD18 and CD11d/CD18. In the following embodiments embodiment, the heteroaryl compounds can be used to reduce the invasiveness of tumor cells in the tissue and metastatic potential, mediated by the activity of β3 integrins. Illustrative integrins are αIibβ3and αvβ3.

Different types of tumors are able to metastasize, can be treated Heteroaryl Compounds. Such tumors include, as an example and not for limitation, breast cancer, ovarian cancer, pasechnyuk, gastrointestinal cancer, kidney cancer, bladder cancer, pancreatic cancer, squamous cell carcinoma of the lung and adenocarcinoma (see, e.g., Felding-Habermann et al, Proc Natl Acad Sci USA 98(4): 1853-8 (2001). Therapeutic treatment to reduce metastasis of established tumors can be followed after diagnosis of metastases. If the metastases were not diagnosed, the heteroaryl, the connection can be prophylactically to reduce the possibility of metastasis.

In another embodiment, methods and compositions presented in the present application, are also useful for administration to subjects in need of bone marrow transplantation, for the treatment of malignant disease (e.g., subjects suffering from acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome (pre-leukemia), syndrome monosomy 7, non-Hodgkin's lymphoma, neuroblastoma, brain tumors, multiple myeloma, testicular germ-cell tumors, breast cancer, lung cancer, ovarian cancer, melanoma, glioma, sarcoma or other solid tumors), subjects in need of bone marrow transplantation, for the treatment of non-malignant disease (e.g., subjects, �traduse hematological disorders, congenital immune deficiency, mucopolysaccharidosis, lipidoses, osteoporosis, histiocytosis Langerhans cells, syndrome Lesch-Nyhan or have glycogen storage disease), subjects undergoing chemotherapy or radiation therapy, subjects, preparing for chemotherapy or radiation therapy, and the subjects who had previously received chemotherapy or radiotherapy.

In another embodiment, the present application presents methods for the treatment of cancer or tumors resistant to other kinase inhibitors such as imatinib mesilate (STI-571 or Gleevec™), comprising administering to a subject in need, an effective amount of the heteroaryl compound or its containing composition. In a specific embodiment, the present application presents methods for the treatment of leukemias, including, but not limited to, gastrointestinal stromal tumor (GIST), acute lymphocytic leukemia or chronic miliitary leukemia resistant to imatinib treatment by mesilate (STI-571 or Gleevec™), comprising administering to a subject in need, an effective amount of the heteroaryl compound or its containing composition.

In a special embodiment, the present application presents methods for the treatment or prevention of leukemia (i.e. malignant neoplasms of cerveobraznae tissue) in�Lucie, but not limited to, chronic lymphocytic leukemia, chronic miliitary leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia. Leukemia can be recurrent, refractory or resistant to conventional therapy. The term "recurrent" refers to situations where subjects who had remission of leukemia after therapy has seen a return of leukemia cells in the bone marrow and a decrease in normal blood cells. The term "refractory or resistant" refers to the circumstances when persons, even after intensive treatment, have residual leukemia cells in the bone marrow.

Also in the present application are provided methods of treating subjects who were previously treated for cancer, but who are refractory to standard therapy and those not previously treated. Also in the present application presents methods for the treatment of subjects regardless of age, although some types of cancer are most typical for certain age groups. In addition, in the present application presents methods for the treatment of subjects who underwent surgery as an attempt to treat cancer and those who did not have surgery. Because the subjects with cancer have heterogeneous clinical manifestations and various clinical results, treatment of the subject can argirov�you depending on his/her prognosis. An experienced doctor will be able to easily determine, without undue experimentation secondary funds, types of surgery and the types of non-standard drug therapy that can be effectively used for the treatment of a particular subject suffering from cancer.

It should be understood that heteroaryl compounds can be used independently of any other treatment or used in combination with other cancer treatments, including surgery, radiology or other chemotherapy. Heteroaryl compound can be combined with other pharmacologically active compounds ("second active agents") in methods and compositions described in this application. It is believed that some combination can work synergistically to treat specific types of diseases or disorders, and conditions and symptoms associated with such diseases or disorders. Heteroaryl compound can also be useful to reduce the side effects associated with certain second active agents, and Vice versa.

Accordingly, in some embodiments embodiment, the heteroaryl compounds can be used in combination with other chemotherapeutic agents. Combined treatment Heteroaryl Compounds can be aiming to operate on different cellular components by AP�ceived select the second chemotherapeutic agents. For example, the heteroaryl compounds can be used in some embodiments of the incarnation to limit the metastatic potential of tumor cells, whereas other chemotherapeutic agents can be used to eliminate or killing of aberrant cells.

Various chemotherapeutic agents can be used in combination with the Heteroaryl Compounds for the treatment of cell-proliferative disorders. These chemotherapeutic agents may be a General cytotoxic funds or funds sighting acting on specific cellular molecule. Different classes of anti-cancer chemotherapeutic agents include, among others, antimetabolites, means which interact with DNA {e.g., alkylating agents, coordination compounds, etc.), inhibitors of transcription enzymes, topoisomerase inhibitors, compounds that bind to the minor groove of DNA, antimitotic means {e.g., Vinca alkaloids), antitumor antibiotics, hormones and enzymes. Illustrative alkylating agents include, as an example and not for limitation, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethylenimines, methylmelamine, sulfonates (for example, busulfan) and carmustine. Illustrative of antimetabolites include�t, as an example and not for limitation, Polevoy acid analog methotrexate; pyrimidine analog fluorouracil, cytosine arabinoside; and the purine analogue mercaptopurine, thioguanine and azathioprine. Illustrative Vinca alkaloids include, as an example, but not restricted to, vinblastine, vincristine, paclitaxel and colchicine. Illustrative of antitumor antibiotics include, as an example and not for limitation, actinomycin D, daunorubicin, and bleomycin. Illustrative enzyme that is effective as an antitumor agent is L-asparaginase. Illustrative coordination compounds include, as an example, but not restricted to, cisplatin and carboplatin. Illustrative hormones and hormonal compounds include, as an example and not for limitation, adrenocorticosteroid prednisone and dexamethasone; aromatase inhibitors aminoglutetimid, formestane and anastrozole; progesterone connections the hydroxyprogesterone caproate, medroxyprogesterone; and anti-estrogen compound tamoxifen. Illustrative topoisomerase inhibitors include, as an example, but not restricted to, amsacrine (m-AMSA); mitoxantrone, topotecan, irinotecan and camptothecin.

These and other useful anti-cancer compounds described in Merck Index, 13thEd. (O'neil, MJ. Et al., ed) Merck Publishing Group (2001), and in Goodman and Gilman''s The Pharmaological Basis of Therapeutics, 10thEdition, Hardman, J. G. and Limbird, L. E. eds., pg. 1381-1287, McGraw Hill, (1996), both of which are incorporated in this application by reference.

Typically, any chemotherapeutic agent that has activity against the tumor being treated, can be used in combination with the Heteroaryl Compounds described in this application, provided that the particular agent is clinically compatible with therapy employing a heteroaryl compound as described in the present application. Typical anticancer agents useful in the methods described in the present application include, but are not limited to, funds against the structures of microtubules, such as diterpenoids and Vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen IPrice, oxazaphosphorine, sulfonates, nitrosoanatabine and triazene; antibiotics such as anthracyclines, aktinomitinov and bleomycin; inhibitors of topoisomerase II, such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; inhibitors of topoisomerase I, such as camptothecin; hormones and hormonal analogues; inhibitors of signal transduction pathways; inhibitors associated with angiogenesis non-receptor tyrosine kinases; immunotherapeutic tools; proapoptotic�resources; and inhibitors of signal transmission of the cell cycle.

Inhibitors of signal transduction pathways are those inhibitors that block or inhibit a chemical process which evokes an intracellular change. As used in the present invention, the change represents cell proliferation, survival, angiogenesis or differentiation. The signal transduction inhibitors that are useful in the methods of the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, blockers SH2/SH3 domain, a serine/treoninove kinase, phosphatidyl-Inositol-3 kinases, signal myoinositol and Ras carcinogenesis.

Some tyrosine protein kinases catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth. Such tyrosine protein kinases are divided into broad classes of receptor or non-receptor kinases.

Tyrosine kinase receptors are transmembrane proteins containing an extracellular ligand-binding domain, a transmembrane domain and a tyrosine kinase domain. Tyrosine kinase receptors are involved in the regulation of cell growth, and they are sometimes called receptors of growth factors. Inappropriate or uncontrolled activation of many of atikins, i.e. aberrant kinase activity of the receptor of the growth factor, for example by over-expression or mutation, has been shown to lead to uncontrolled cell growth. Accordingly, the aberrant activity of these kinases is associated with the growth of malignant tissue. Therefore, inhibitors of these kinases could provide methods for the treatment of cancer. The receptors of growth factors include, for example, the receptor of epidermal growth factor (EGFr, ErbB2 and ErbB4), the receptor for the platelet growth factor (PDGFR), the receptor for the growth factor vascular endothelial (VEGFR), tyrosine kinase with immunoglobin-similar and homologous to the epidermal growth factor domains (Tie-2) receptor, insulin growth factor-I (IGF-I) receptors macrophage colony stimulating factor (MCSF), BTK, ckit, cmet, fibroblast growth factor (FGF), Trk receptors (TrkA, TrkB and TrkC), receptors afrina (eph) and the RET proto-oncogene. Some inhibitors of receptors of growth factors are under development and include antagonists of ligands, antibodies, inhibitors tyrosinemia kinase, anti-sense oligonucleotides and aptamers. The receptors of growth factors and agents that inhibit the function of receptors of growth factors, is described, for instance, in Kath, John C, Exp. Opin. Ther. Patents 10{8):803-818 (2000); and Lofts, F. J. et al, "Growth Factor Receptors as Targets", New Molecular Targets for Cancer Chemotherapy, Ed. Workman, Paul and Kerr, David, CRC Press 1994, London.

Tyrosine �Inez, are not kinase receptors of growth factors, called non-receptor tyrosinase kinases. Non-receptor tyrosine kinases useful in the methods of the present invention, are targets or potential targets for anticancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such non-receptor kinases and agents that inhibit the function of non-receptor tyrosine kinases that are described in Sinh, S. et al, J. Hematother. Stem Cell Res. 8 (5): 485-80 (1999); and Bolen, J. B. et al, Ann. Rev. Immunol. 15: 371-404 (1997).

Blockers SH2/SH3 domain represent funds that are destroying the binding of the SH2 or SH3 domain in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, kinase of the Src family, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T. E. (1995), Journal of Pharmacological and Toxicological Methods 34(3) 125-32.

Inhibitors of serine/treoninove kinases, including blockers of the cascade of MAP kinases, which include blockers of Raf kinases (Rafk), mitogen or extracellular regulated kinases (MEKs), and extracellular regulated kinases (ERKs); and blockers of the members of a family of protein kinases C, including blockers of subtypes of PKCs (alpha, beta, gamma, Epsilon, mu, lambda, iota, Zeta), IkB family kinases (IKKa, IKKb), PKB family kinases, h�enow Akt family of kinases and kinase receptors TGF beta. Such serine/treningowy kinases and their inhibitors are described in Yamamoto, T. et al, Biochem J.. 126(5): 799-803 (1999); Brodt, P. et al. Biochem. Pharmacol. 60: 1101-1107 (2000); Massague, J. et al. Cancer Surveys 27:41-64 (1988); Philip, PA. et al, Cancer Treat. Res. 78: 3-27 (1995), Lackey, K. et al. Bioorg. Med. Chem. Lett. 10: 223-228 (2000); and Martinez-Lacaci, L., et al, Int. J. Cancer 88(1): 44-52 (2000).

Inhibitors of members of the family of phosphatidyl-Inositol-3 kinases, including blockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in combination with compounds described in this application. Such kinases are discussed in Abraham, RT. Curr. Op. Jmmunol. 8(3):412-8 (1996); Canman, CE. et al Oncogene 17(25):3301-3308 (1998); Jackson, SP. Int. J. Biochem. Cell Biol 29(7):935-938 (1997); and Zhong, H. et al, Cancer Res. 60(6):1541-1545 (2000).

Also useful in combination with the Heteroaryl Compounds described in the present application, are inhibitors of signal Myo-Inositol, such as phospholipase C blockers and analogues of myoinositol. Such inhibitors of the signals described in Powis, G. et al. New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC Press 1994, London.

Another group of inhibitors of signal transduction pathways that are useful in combination with the Heteroaryl Compounds include inhibitors of Ras oncogene. Such inhibitors include inhibitors farnesyltransferase, geranyl-geranyl-transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. It has been shown that these inhibitors block Ras activation in cells containing mutant Ras wild-type, action�UY, thus, antiproliferative funds. Inhibition of Ras oncogene discussed in Scharovsky, CG. et al. J. Biomed. Sci. 7(4) 292-298 (2000): Ashby, MM, Curr. Op. Lipid. 9(2)99-102 (1998); and Oliff, A., Biochim. Biophys. Acta, 1423(3): C19-C30 (1999).

As indicated above, antibodies to the receptor binding kinase with a ligand can also serve as a signal transduction inhibitor. This group of inhibitors of signal transduction pathways includes the use of humanized antibodies to the extracellular ligand-binding domain of tyrosine kinase receptors. For example, Imclone C225 EGFR specific antibody (see Green, M. C. et al Cancer Treat. Rev., 26(4), 280-286 (2000)); Herceptin® ErbB2 antibody (see Stern, DF Breast Cancer Res., 2(3), 176-183 (2000)); and 2CB VEGFR2 specific antibody (see Brekken, RA et al, Cancer Res. 80, 5117-5124 (2000)).

Inhibitors associated with angiogenesis receptor kinases can also find use in the methods of the present invention. Inhibitors associated with angiogenesis VEGFR and TIE2 are discussed above in connection with signal transduction inhibitors (both receptors are receptor tyrosine kinases). Other inhibitors can be used in combination with the Heteroaryl Compounds described in the present application. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphavbeta3) BU�ut to inhibit angiogenesis: endostatin and angiostatin (non-RTK) may also be useful in combination with PLK inhibitors.

Agents used in immunotherapeutic regimens may also be useful in combination with a Heteroaryl Compound as described in the present application.

Funds used in proapoptotic treatment regimens (e.g., bcl-2 antisense oligonucleotides) can also be used in the combinations disclosed in the present application. Members of the Bcl-2 family proteins inhibit apoptosis. Therefore, activation of bcl-2 is associated with chemoresistance. Studies have shown that epidermal growth factor (EGF) stimulates anti-ipoptions members of the bcl-2 family (i.e., mcl-1). Therefore, strategies designed to down-regulation of expression of bcl-2 in tumors have demonstrated clinical benefit and are now in phase II/III trials, namely Genta''s G3139 bcl-2 antisense oligonucleotide. Such proportionsa strategy using the strategy of antisense oligonucleotide to bcl-2 are discussed in Water JS et al, J. Clin. Oncol. 18:1812-1823 (2000); and Kitada S et al, Antisense Res. Dev. 4:71-79 (1994).

Inhibitors of signals inhibit cell cycle molecules involved in cell cycle control. Cyclin-dependent kinases (CDKs) and their interaction with cyclename controlling the passage through the eukaryotic cell cycle. The coordinated activation and inactivation of different cyclin/CDK complexes is necessary for normal cont�izheniya through the cell cycle. Some of the inhibitors from the cell cycle are under development. For instance, examples of cyclin-dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for example described in Rosania, et al, Exp. Opin Ther, Patents 10(2):215-230 (2000).

Other anti-proliferative compounds useful in combination with the Heteroaryl Compounds include, as an example, and not limitation, antibodies directed against receptors of growth factors {e.g., anti-Her2); cytokines such as interferon-α and interferon-γ, interleukin-2 and GM-CSF; and antibodies for cell-surface markers (e.g., anti-CTLA-4, anti-CD20 (rituximab); an anti-CD33). When using antibodies against cell-surface markers, the chemotherapeutic agent may be anywhereman with this antibody is specific targeting of tumor cells. Suitable conjugates include radioactive compounds (e.g., radioactive metal that is associated with conjugated with the antibody chelating compound), cytotoxic compounds and activating drugs enzymes (e.g., allinase, peptidase, esterase catalytic antibodies, etc.) (see, e.g., Arditti et al, Mol. Cancer Therap. 4(2):325-331 (2005); U.S. Patent No.. 6258360; which are incorporated in this application by reference).

In some embodiments embodiment, the heteroaryl compounds can be used�ü with a second kinase inhibitor, which acts directed at oncogenic kinase that is different from Syk. Although heteroaryl compounds disclosed in the present application for the treatment of hematopoietic tumors, you can also use other compatible kinase inhibitors used for the treatment of hematopoietic neoplasms. In some embodiments embodiment, the second kinase inhibitor is an inhibitor of Abl kinase. Chronic myelogenous leukemia is a myeloid neoplasm characterizing malignant proliferation of leukemic stem cells in the bone marrow. Most cases of chronic myelogenous leukemia is associated with cytogenetic anomaly, defined by the reciprocal translocation t(9;22)(q34;ql 1). This chromosomal aberration leads to the formation of BCR/ABL hybrid protein with activated kinase activity. Inhibitors of the activity of the hybrid protein kinases can be effective in the treatment of chronic myelogenous leukemia, but in long-term treatment may develop a resistant form. The use of heteroaryl compounds in combination with inhibitors of the Abl kinase can reduce the likelihood of resistant cells by directed action to another cellular process that is different from the one on which the action is directed to the second kinase inhibitor. Illustrative inhibito�Ohm Abl kinase is a 2-phenylaminopyrimidine, also known as imatinib mesilate and Gleevec®. Thus, in some embodiments embodiment, the heteroaryl compounds can be used in combination with an inhibitor of the Abl kinase 2-phenylaminopyrimidine and its derivatives. In other embodiments embodiment, the second kinase inhibitor may constitute pyridol[2-3-d]pyrimidine and its derivatives, which were originally identified as inhibitors of Src kinase. In the following embodiments of the incarnation, the second kinase inhibitor, may be tyrphostin and their derivatives (e.g., amifostine), which may affect the Association of the kinase with its substrates. Other compounds as kinase inhibitors should be obvious to specialists in this field.

Other second active agents useful in combination with the Heteroaryl Compounds with activity against Syk kinase include, as an example and not for limitation, the Fc-domain-containing therapeutic antibodies or hybrid proteins, such as infliximab or etanercept. In one embodiment, the present application presents methods for the treatment or prophylaxis of autoimmune disorders, such as disorders, are known in the art or listed in the present application, comprising administering to a subject in need of this combination heteroaryl compounds having Akti�completely against Syk kinase, and Fc-domain-containing antibodies, such as infliximab or etanercept. In one embodiment, the present application presents methods for the treatment or prevention of inflammatory disorders, such as disorders, are known in the art or listed in the present application, comprising administering to a subject in need of this combination heteroaryl compounds having activity against Syk kinase and the Fc-domain-containing antibodies, as infliximab. In a particular embodiment, the heteroaryl compound is administered as a chronic therapy, beginning before or immediately after the initial introduction of the Fc-domain-containing therapeutic antibodies or hybrid protein. Not wanting to be limited by theory, believe that the heteroaryl compound with activity against Syk kinase may prolong half-life in serum Fc-domain-containing therapeutic antibodies and gibridnykh proteins in a subject.

One or more second active ingredients or tools can be used in the methods and compositions described in this application. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, ORGANOMETALLIC, or organic molecules).

Examples of large molecules of the second active�of edst include, but not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Specific examples of active agents include mimetics of thrombopoetin or agonists of the receptors, such as Romiplostim and PROMACTA, anti-CD40 monoclonal antibodies (such as, for example, SGN-40); inhibitors of histone-deacetylase (such as, for example, SAHA and LAQ 824); inhibitors of protein 90 heat shock (such as, for example, 17-AAG); inhibitors of the kinase receptor insulin-like growth factor-1; inhibitors of the kinase receptor growth factor vascular endothelial (such as, for example, PTK787); inhibitors of the receptor of the growth factor insulin; inhibitors acyltransferase lysophosphatidic acid; inhibitors of IkB kinase; p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib and erlotinib HCL); antibodies 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 kinase inhibitors, 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 agents that represent small molecules include, but are not limi�cuautla this, anti-cancer drugs and antibiotics on the basis of small molecules (e.g., clarithromycin).

Specific second active compounds that can be combined with a Heteroaryl Compound vary according to the specific indications to be treated, the prevention or relief.

For example, for the treatment, prevention or alleviation of inflammatory, autoimmune disease or cancer, the second active agents include, but are not limited to: semaxanib; cyclosporine; etanercept; doxycycline; bortezomib; acivicin; aclarubicin; acetasol hydrochloride; Acronis; adozelesin; aldesleukin; altretamin; Albaicin; ametantrone acetate; amsacrine; anastrozole; astromicin; asparaginase; aspirin; azacitidine; asettaa; azithomycin; batimastat; benzodia; bikalutamid; bisantrene hydrochloride; benefit dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; corticosteroids; cactinomycin; calusterone; karatekid; karateman; carboplatin; carmustine; orubicin hydrochloride; carzelesin; Cedeira; celecoxib; chlorambucil; tirolerin; cisplatin; cladribine; krishnalal mesilate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; decarbamylated; deazaguanine; deazaguanine mesilate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; draw�of oxygen; droloxifene citrate; dromostanolone propionate; deatomizer; edatrexate; eflornithine hydrochloride; elsamitrucin; angloplat; impromat; epirubicin; epirubicin hydrochloride; Erbolat; zorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; atopen; fadrozole hydrochloride; pasarin; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocytosine; voskuilen; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; Matorin; maturegay; maintain; miacalcin; mitotropin; mitogillin; mitomycin; mitomycin; mitosis; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysure; paclitaxel; pegaspargase; pediamycin; pentamycetin; peplomycin sulfate; perforated; pipobroman; piposulfan; proxitron hydrochloride; plicamycin; plantan; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin puromycin hydrochloride; pyrazofurin; ibuprin; safingol; safingol hydrochloride; semustine; contrast; spartacat sodium; sparsomycin; spirogermanium hydrochloride; spiramycin; spirometer; streptonigrin; streptozocin; alienor; talisayan; tecogen sodium; Taxotere; tegafur; Alexandre hydrochloride; temoporfin; teniposide; teraxion; testolactone; timeprint; thioguanine; thiotepa; teatterin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate the glucuronate; triptorelin; tubulosa hydrochloride; braziliera; Oradea; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; benefitin sulfate; Inglesina sulfate; Finlepsin 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; aclarubicin; acellular; Adelina; adozelesin; aldesleukin; antagonists ALL-TK; altretamin; abamectin; amidex; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; Andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; entrelacs; anti-dorkalicious morphogenetic protein-1; antiandrogen, from carcinoma of the prostate; anticastro�Yong; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; modulators of apoptotic genes; regulators of apoptosis; apurinovaya acid; ara-CDP-DL-PTBA; argininemia; isolagen; atamestane; attemptin; axenstein 1; axenstein 2; axenstein 3; azasetron; anatoxin; asteroid; derivatives baccatin III; balana; batimastat; antagonists BCR/ABL; benzocaine; benzoylthiourea; beta-lactam derivatives; beta-alamin; butaclamol B; betulinic acid; bFGF inhibitor; bikalutamid; bisantrene; besuseradminclient; benefit; bitraten A; bizelesin; Brevet; bropirimine; bodacity; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxamidates; CaRest M3; CARN 700; isolated from cartilage inhibitor; carzelesin; inhibitors caseinline (ICOS); castanospermine; cecropin B; cetrorelix; chlorine; chlorination a sulfonamide; cicaprost; CIS-porphyrin; cladribine; clatronic; analogues clomiphene; clotrimazole; colimycin a; colimycin B; combretastatin A4; analog combretastatin; convenin; kambezidis 816; krishnalal; cryptophycin 8; derivatives cryptophycin a; curacin A; cyclopentanedione; cyclopean; cephamycin; cytarabine ocfosfate; cytolytic factor; cytostatin; galiximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; Dixit�famid; the dexrazoksana; dexverapamil; diaziquone; didemnin B; detox; diethylnitrosamine; dihydro-5-azacytidine; dihydroxy, 9-; dioxazine; diphenylpyraline; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; elastin; edelfosine; edrecolomab; eflornithine; elements; Amateur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; pasarin; fenretinide; filgrastim; finasteride; flavopiridol; preselection; fluasterone; fludarabine; forceunauthorized hydrochloride; forenames; formestane; fostriecin; fotemustine; the gadolinium texaphyrin; gallium nitrate; Galitsin; ganirelix; inhibitors gelatinase; gemcitabine; inhibitors of glutathione; HaSulam; heregulin; hexamethylene biscyane; hypericin; ibandronate acid; idarubicin; idoxifene; Idamante; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod; immunostimulatory peptide; inhibitor of receptor insulin-like growth factor-1; interferon agonists; interferons; interleukins; iobenguane; iododeoxyuridine; ipomeanol, 4-; ireplace; irsogladine; isomerases; isohemagglutinins B; fusetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; Lannemezan; lenograstim; lentinan sulfate; leprostatic; letrozole leukemia-inhibitory factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; analogue linear polyamine; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinum 7; lobaplatin; lubricin; lometrexol; lonidamine; losoxantrone; doxorubin; lurtotecan; lutetium texaphyrin; lisofylline; lytic peptides; maytansine; sandostatin a; marimastat; masoprocol; maspin; inhibitors matrilysin; inhibitors of matrix metalloproteinases; menogaril; monbaron; peterlin; methionine; metoclopramide; MIF inhibitor; mifepristone; miltefosine; Miramistin; mitoguazone; mitolactol; analogues of mitomycin; mitonafide; mycotoxicosis the fibroblast growth factor-saporin; mitoxantrone; Maarten; molgramostim; Erbitux, human hormony of gonadotropin; monophosphorylated A + sk cell membrane mybattery; mopidamol; iprange anticancer agent; megaproxy B; extract cell wall of mycobacteria; mylapore; N-azetidinone; N-substituted benzamide; nafarelin; Agresti; naloxone+pentazocine; nipawin; Natterer; nutragrain; nedaplatin; nemorubicin; Nerimanov acid; nilutamid; nizamettin; modulators of nitric oxide; nitroxide antioxidant; nitrolon; oblimersen (Genasense®); A6-benzylguanine; octreotide; okizeme; the oligonucleotides; onapristone; ondansetron; oracin; ne�oral inducer of cytokines; ormaplatin; asteron; oxaliplatin; exonomics; paclitaxel; analogues of paclitaxel; paclitaxel derivatives; palyulin; palmitoylation; pamidronate acid; panaxytriol; promife; pyrabactin; pallidin; pegaspargase; pagesin; pentosan polysulfate sodium; pentostatin; petrosal; perflubron; perforated; parallelly alcohol; pentinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placedin a; placein B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; immunomodulator on the basis of A protein; inhibitor of protein kinase C, inhibitors of protein kinase C, microalgal; inhibitors of tyrosine-proteinopathy inhibitors; purine-nucleoside-phosphorylase; purpurin; pyrazoloacridine; peridomiciliary hemoglobin-polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; inhibitors farnesyl-proteincenter ras; ras inhibitors; inhibitors of ras-GAP; relatin demetilirovanny; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginous Bl; robaxin; safingol; syndapin; SarCNU; sarcophyton A; sargramostim; Sdi 1 mimetics; semustine; aging inhibitor 1; with�yslovia 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; superactive vasoactive intestinal peptide antagonist; coralista; suramin; swainsonine; tallimustine; tamoxifen methiodide; terramycin; tazarotene; tecogen sodium; tegafur; tolerability; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrasomy; calibratin; thiocoraline; thrombopoietin; a mimetic of thrombopoetin; thymalfasin; agonist of the receptor of thymopoietin; timorian; thyroid-stimulating hormone; atenololo adipocere; tirapazamine; titanocene bichloride; topsentin; toremifene; inhibitors of translation; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; trosterud; inhibitors tyrosinemia kinase; tyrphostin; UBC inhibitors; ubenimex; originating from the urogenital sinus a growth inhibitor; antagonists of the urokinase receptor; vapreotide; variolin B; valarezo; vermin; verdini; verteporfin; vinorelbine; Wincanton; vitaxin; vorozole; sonotron; senility; salaskar; and zinostatin stimulater.

Specific second active agents include, but are not limited to, 2-me�existencial, 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, Paglierani alpha interferon (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, docetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, and zoledronic acid, palpitant, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac and etoposide.

Similarly, examples of specific second means in accordance with the values prior to treatment, prevention or relief can be found in the following reference documents are all included in the present application in their entirety: U.S. Patent Nos. 7189740, 6281230 and 5635517; Patent application U.S.№№ 11/085905, 11/111188, 11/271963, 11/284403, 11/289723, 11/022075, 10/411656, 10/693794, 10/699154 and 10/981189.

Examples of additional second active agents include, but are not limited to, traditional therapies used to treat or prevent pain such as antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatories, cox-2 inhibitors, immune modulators, agonists or antagonists of alpha-adrenergic receptors, immunosuppressants, corticosteroids, hyperbaric oxygen, ketamine, other anaesthetics, NMDA antagonists, and other therapeutic agents, which can be found, for example, in Physician's Desk Reference 2003. Specific examples include, but are not limited to, salicylic acid acetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin (Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®), oxcarbazepine (Trileptal®), valproate acid (Depakene®), morphine sulfate, hydromorphone, prednisone, griseofulvin, penthium, alendronat, diphenhydramin, guanethidine, Ketorolac (Acular®), thyrocalcitonin, dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin, reserpine, 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®), mexiletine, 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, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neurotrophic factor, a regulator of neovascularization, anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound, or a compound against angiogenesis, or a combination of such means. Specific examples include, but are not limited to, verteporfin, politin, angiostatic steroid, rhuFab, interferon-2α, pentoxifylline, tin adipocere, motexafin lutetium, 9-fluoro-11,21-dihydroxy-16,17-1-methylethylidene-bis(hydroxy) - pregna-1,4-diene-3,20-dione, latanoprost (see U.S. Patent No.. 6225348), tetracycline and its derivatives, rifamycin and its derivatives, macrolides, metronidazole (U.S. Patent Nos. 6218369 and 6015803), genistein, genistin, 6'-O-Mal, genistin, 6'-O-Ac genistin, daidzein, daidzin, 6'-O-Mal daidzin, 6'-O-Ac daidzin, glycitein, glycitin, 6'-O-Mal of glycitin, bihain a, formononetin (U.S. Patent No.. 6001368), triamcinolone of acetonide, dexamethasone (Patent school� No.. 5770589), thalidomide, lenalidomide and pomalidomide or Immunomodulatory product brand IMiDs®, glutathione (U.S. Patent No.. 5632984), basic fibroblast growth factor (bFGF), transforming growth factor b (TGF-b), originating from the brain neuropilins factor (BDNF), plasminogen activator type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant, and RETISERT implant (Bausch & Lomb). All enumerated above reference documents included in this application in their entirety by reference.

Examples of additional second active agents include, but are not limited to, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, soudo-extending means, prostacyclin analogues, endothelin antagonists, phosphodiesterase inhibitors (e.g., inhibitors of PDE V) inhibitors of endopeptidase, means for reducing the level of lipids, 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, soudo extensible, such as prostacyclin (e.g., prostaglandin 12 (PGI2), epoprostenol (EPO, Floran®), treprostinil (Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine, epoprostenol (Floran®), treprostinil (Remodulin®), PR�stacklin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®), irbesartan (ava Pro®), 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®), cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, docetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, and zoledronic acid, palpitant, biaxin, busulfan, prednisone, 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, chloroquine, quinine, quinidine, pyrimethamine, sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine, primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin, suramin, pentamidine, melarsoprol, nifurtimox, benznidazole, amphotericin B, compounds of pentavalent antimony (for example, stibogluconate sodium), interferon gamma, Itraconazole, dead promastigote �ORM and BCG leucovorin, corticosteroids, sulfonamide, spiramycin, IgG (serology), trimethoprim and sulfamethoxazole.

Examples of additional second active agents include, but are not limited to: antibiotics (therapeutic or prophylactic) such as, but not limited to, ampicillin, clarithromycin, tetracycline, penicillin, cephalosporins, streptomycin, kanamycin, and erythromycin; antivirals such as, but not limited to, amantadine, rimantadine, acyclovir, and ribavirin; immunoglobulin; plasma; immunity-boosting medications, such as, but not limited to, levamisole and isoprinosine; biologics such as, but not limited to, gammaglobulin, transfer factor, interleukins and interferons; hormones such as, but not limited to, a hormone of the thymus gland; and other immunologic agents such as, but not limited to, stimulants B-cells (e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4 and IL-5), growth factors (e.g. TGF-β), antibodies (e.g., anti-CD40 and IgM), oligonucleotides containing neetilirovannye CpG motifs, and vaccines (e.g., antiviral and anti-tumor peptide vaccines).

Examples of additional second active agents include, but are not limited to: the agonist or antagonist of dopamine, such as, but not limited to, Left�oops, L-DOPA, cocaine, α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline, fendalton mesilate, cabergoline, pramipexole dihydrochloride, ropinerole, amantadine hydrochloride, selegine 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, the tolkapon and èntakapona; a cholinesterase inhibitor, such as, but not limited to, physostigmine salicylate, physostigmine sulfate, physostigmine bromide, neostigmine bromide, neostigmine methylsulfate, ambenonium chloride, edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide, diacetyl monooxime, 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, sulfasalazine, gold salts, Rho-D Immunoglobulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, impact, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamovuyu �islote, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, gold sodium thiomalate, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone or betamethasone and other corticosteroids; and an antiemetic, such as, but not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondasetron, granisetron, hydroxizin, acetylation monoethanolamine, alizapride, azasetron, benchenane, batanouny, bromopride, buclizine, clebopride, this drug, dimenhydrinate, difenidol, dolasetron, meclizine, metallical, metopimazine, nabilone, oxipurinol, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron and a mixture thereof.

Examples of additional second active agents include, but are not limited to, immunomodulators, immunosuppressants, antihypertensives, anticonvulsants, fibrinolytic agents, antiplatelet agents, antipsychotics, antidepressants, benzodiazepines, buspirone, amantadine, and other known or conventional agents used for subjects with �ramoi/CNS damage 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, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazine, gold salts, Rho-D Immunoglobulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, impact, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamovuyu acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, gold sodium thiomalate, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone; analogue of cAMP, including, but not limited to, db-cAMP; means, including methylphenidate, which includes l-threo-methylphenidate, d-threo-methylphenidate, dl-threo-methylphenidate, l-Erythro-methylphenidate, d-Erythro-methylphenidate, dl-er�tro-methylphenidate, and a mixture thereof; and a diuretic, such as, but not limited to, mannitol, furosemide, glycerol and urea.

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 IL-18; interferons, such as interferon Alfa-2a, interferon alpha-2b, interferon Alfa-n1, interferon alpha-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF; hydroxyurea; butyrate or butyrate derivatives; the oxide of trivalent nitrogen; HEMOXIN™ (NIPRISAN™; see U.S. Patent No. 5800819); antagonists of Gardos channels, such as clotrimazole and triarylmethane derivatives; Deferoxamine; protein C; and preparations for transfusion of blood or blood substitutes such as Hemospan™ or Hemospan™ PS (Sangart).

Certain heteroaryl compounds described in the present application, are inhibitors of PLK, particularly PLK1. Under the PLK inhibitor is meant a compound that demonstrates the value IR50less than 10 μm in the analysis of inhibition of PLK described below in the examples, or the value IR50less than 10 microns in tests using Cell-Titer Glo or p-TCTP biomarkers described below in the examples; more particularly a PLK inhibitor is a compound that demonstrates the value IR50less than 10 μm in the analysis of inhibition of PLK or value IR50less than 1 m�M in the analysis using the Cell-Titer Glo or p-TCTP biomarkers, using the methods described in the examples below.

As described in the present application, are provided methods of regulating, modulating, binding or inhibiting PLK for treating conditions mediated by PLK, particularly PLK1. "Regulating, modulating, binding or inhibiting PLK" refers to regulating, modulating, binding or inhibiting the activity of PLK, particularly PLK1, as well as regulating, modulating, binding or inhibiting sverkhekspressiya PLK, particularly PLK1. Such conditions include certain neoplasms (including cancer and tumors) that are associated with PLK, particularly PLK1, and condition characterized by abnormal cell proliferation.

Also provided methods of treating PLK-sensitive neoplasms (cancer or tumor) in a subject such as a mammal (e.g., human) in need, wherein the method comprises administering to the subject a therapeutically effective amount of the heteroaryl compounds described in the present application. "PLK-sensitive tumor", as used in the present invention refers to neoplasms which can be treated with an inhibitor of PLK, particularly PLK1. Neoplasms that are associated with PLK and are therefore amenable to treatment with a PLK inhibitor, is known in the art and include both primary � metastatic tumors and cancers. See, for example, M. Whitfield el al, Nature Reviews Cancer, 6:99 (2006). For example, PLK-sensitive tumors include, but are not limited to, breast cancer, colon cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), prostate cancer, endometrial cancer, gastric cancer, melanoma, ovarian cancer, pancreatic cancer, squamous cell carcinoma, carcinoma of the head and neck, carcinoma of the esophagus, hepatocellular carcinoma, cancer cells, kidney, sarcoma (cancer of connective tissues), bladder cancer, glioma and hematologic malignancies such as lymphoma, including aggressive lymphomas and non-Hodgkins lymphoma, and leukemia, including acute leukemias. In one specific embodiment, the present method of treating breast cancer in a subject such as a mammal (e.g., human) in need, by introducing a therapeutically effective amount of the heteroaryl compounds described in the present application. In another specific embodiment, the present method of treatment of ovarian cancer in a subject such as a mammal (e.g., human) in need, by introducing a therapeutically effective amount of the heteroaryl compounds described in the present application. In another specific embodiment, presented �] treatment of non-small cell lung cancer in a subject such as a mammal (e.g., human) in need, by introducing a therapeutically effective amount of the heteroaryl compounds described in the present application. In another specific embodiment, the present method of treating prostate cancer in a subject such as a mammal (e.g., human) in need, by introducing a therapeutically effective amount of the heteroaryl compounds described in the present application. In another specific embodiment, the present method of treatment of hematologic malignancies, including lymphoma, such as an aggressive lymphoma and non-Hodgkin's lymphoma, and leukemia, such as acute leukemia, in a subject such as a mammal (e.g., human) in need, by introducing a therapeutically effective amount of the heteroaryl compounds described in the present application. Acute leukemia includes acute myeloid leukemia and acute lymphoid leukemias. See, H. Harris, et al, J Clin. Onc. 17(12):3835-3849, (1999). "Aggressive lymphoma" is the term used in this area, See, J. Chan, Hematological Onc. 19:128-150 (2001).

Also provided methods for the treatment of a condition characterized by abnormal cell proliferation, in a subject such as a mammal (e.g., human) in need. Method incl�et the introduction of a therapeutically effective amount of heteroaryl compounds described in the present application. Under "abnormal cell proliferation" refers to cell proliferation resulting from abnormal cell growth, cellular proliferation resulting from excessive cell division, cell proliferation, which is the result of cell division at high speeds, cellular proliferation resulting from abnormal cell survival and/or cell proliferation in a normal cell, what is happening at normal speed, which, however, is undesirable. Condition characterized by abnormal cell proliferation include, but are not limited to, cancer, proliferative disorders of blood vessels, fibrotic disorders, mesangial cell proliferative disorders and inflammatory/immune-mediated diseases. Proliferative disorders of the blood vessels include arthritis and restenosis. Fibrotic disorders include hepatic cirrhosis and atherosclerosis. Mesangial cell proliferative disorders include glomerulonephritis, malignant nephrosclerosis and glomerulopathy. Inflammatory/immune-mediated disorders include psoriasis, a long wound healing, graft rejection of authority, thrombotic microangiopathic syndrome ' where�s and neurodegenerative diseases. Osteoarthritis and other dependent proliferation of osteoclasts diseases with excessive bone resorption, are examples of conditions characterized by abnormal cell proliferation, in which cell proliferation occurs in normal cells with normal speed, but, nevertheless, is undesirable.

Also provided methods for inhibiting proliferation of cells, wherein such methods comprise contacting the cells with the number heteroaryl compounds described in this application, sufficient to inhibit cell proliferation. In one particular embodiment the cell is a tumor cell. In one specific embodiment, the cell is an abnormally proliferating cell. The term "abnormally proliferating cell", as used in the present invention, refers to cells that grow the wrong way (abnormally), the cells that divide excessively or rapidly, the cells that inappropriate way (abnormally) survive and/or normal cells that proliferate at normal speed, but for which proliferation is undesirable. Tumor cells (including cancer cells) are examples of abnormally proliferous cells but are not the only abnormally proliferously.

PLK is essential for cell mitosis and, accordingly, the compounds described in the present application, are considered to be effective for the inhibition of mitosis. "Inhibition of mitosis" refers to the inhibition of entry into M phase of the cell cycle, inhibition of the normal functioning of the M phases of the cell cycle after entry into M phase and inhibition of normal exit from M phase of the cell cycle. Thus, the heteroaryl compounds described in the present application, may inhibit mitosis by inhibiting the entry of cells into mitosis by inhibiting the passage of cells through mitosis or by inhibiting the exit of cells from mitosis. In one aspect, are provided methods for inhibiting mitosis in a cell, which include the introduction into the cell of the number of compounds described in this application, sufficient to inhibit mitosis, and, in one specific embodiment, the cell is a tumor cell. In one specific embodiment, the cell is an abnormally proliferating cell.

Furthermore, it enables the use of heteroaryl compounds described in this application, to obtain drugs for the treatment of a condition mediated by PLK, particularly PLK1, in a subject such as a mammal {e.g., people). Also about�specialsa the use of heteroaryl compounds for obtaining a medicinal product for the treatment of PLK-sensitive tumors in a subject in particular, a mammal (e.g. human). In particular, provided the use of heteroaryl compounds for obtaining a medicinal product for the treatment of breast cancer. In addition, also provided the use of heteroaryl compounds for obtaining a medicinal product for the treatment of ovarian cancer, the use of heteroaryl compounds for obtaining a medicinal product for the treatment of non-small cell lung cancer, the use of heteroaryl compounds for obtaining a medicinal product for the treatment of prostate cancer and the use of heteroaryl compounds for obtaining a medicinal product for the treatment of hematological malignancies such as acute leukemia, aggressive lymphoma and non-Hodgkin's lymphomas. Furthermore, it enables the use of heteroaryl compounds for obtaining a medicinal product for the treatment of a condition characterized by abnormal cell proliferation, the use of a heteroaryl compound to obtain a medicine for inhibiting cell proliferation, and the use of a heteroaryl compound to obtain a medicine for inhibiting mitosis in a cell.

The above-described methods of treatment and uses, the compound described in the present application, can be used for�available separately in combination with one or more other compounds described in this application, or in combination with other therapeutic drugs and/or in combination with other anticancer therapies. In particular, in methods of treating conditions mediated by PLK, and in the methods of treatment PLK-sensitive tumors, provides for the combination with other chemotherapeutic agents, as well as combination with surgical therapy and radiotherapy. The term "chemotherapeutic" as used in the present invention refers to any chemical substance, the means of having a therapeutic effect in a subject to whom it is administered. "Chemotherapy" means include, but are not limited to, anticancer agents, analgesics and antiemetics. As used in the present invention, "anticancer agents" include both cytostatic and cytotoxic agents such as, but not limited to, cytotoxic chemotherapy, hormonal therapy, targeted existing kinase inhibitors and therapeutic monoclonal antibodies. Combination therapies described in the present application, therefore, include the introduction of at least one heteroaryl compounds described in the present application, and the application, at measures�, one other way of treating cancer. In one embodiment, combination therapies described in this application, include the introduction of at least one of the compounds described in the present application, and at least one other chemotherapeutic agents. One particular variant embodiment includes the introduction of at least one heteroaryl compounds described in the present application, and at least one antitumor agent. As a further aspect, also provided methods of treatment and uses as described above, which include the introduction of a heteroaryl compound as described in the present application, together with at least one chemotherapeutic agent. In one specific embodiment, the chemotherapeutic agent is an antitumor agent. In another embodiment, the present application includes a pharmaceutical composition as described above further comprising at least one other chemotherapeutic agent, more specifically, the chemotherapeutic agent is an antitumor agent.

As described later in this application, the introduction of other chemotherapeutic agents can be realized in the form of compositions, or they can be entered as an auxiliary CP�of DSTV in combination with a Heteroaryl Compound. When they are ancillary to, chemotherapeutic agents can be administered simultaneously or sequentially with the introduction of a heteroaryl compound.

Methods and applications of using these combinations may include the introduction of a heteroaryl compound as described in the present application, and the second active agents, either sequentially in any order or simultaneously in separate or combined pharmaceutical compositions. When combined in a single composition, it is necessary that these two compounds were stable and compatible with each other and with other components of the composition, and to formulate for administration.

The introduction of a heteroaryl compound and the second active agents to a subject can be done simultaneously or sequentially by the same or different routes of administration. Whether the specific route of administration appropriate to the particular active means, depends on the active tool (for example, whether it is suitable for oral administration without decomposing prior to entering the blood stream) and the disease being treated. One route of administration to Heteroaryl Compounds is an oral way. Preferred routes of administration for the second active agents or ingredients described in the present claims�, known to specialists in this field. See, for example, Physicians' Desk Reference, 1755-1760 (56thed., 2002).

In one embodiment, the second active agent is administered intravenously or subcutaneously. In another embodiment, the second active agent is administered intravenously or subcutaneously once or twice daily in an amount of 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 a second active agents depends on the means used, the type of disease to be treated or alleviating, severity and stage of the disease and quantities(amounts) heteroaryl compounds and any optional additional active agents simultaneously administered to the subject.

In addition, in the present application presents methods of reducing, treating and/or preventing adverse or undesired effects associated with conventional treatment, including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. Heteroaryl compounds and other active ingredients can be administered to the subject before, during or after the occurrence of adverse effects associated with conventional treatment.

4.5 Pharmaceutical compositions and routes of administration

In one aspect, the present application includes pharmaceutical compositions comprising an effective amount heteroaryl compound or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug; and a pharmaceutically acceptable carrier, excipient or filler.

In one embodiment, the present application includes pharmaceutical compositions suitable for oral, parenteral administration, the introduction through the mucous membrane, or percutaneous local injection.

Heteroaryl compounds can be administered to the subject orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, pills, pills, suppositories, injections, suspensions and syrups. Suitable compositions can be obtained widely known methods using conventional organic or inorganic additives, such as excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polipropilenglicol, polyvinylpyrrolidone, gelatin, acacia gum, polyethyleneglycol, sucrose or starch), a disintegrant (e.g., starch, carboxymethylcellulose, hydroxypropylmethyl, low-substituted hydroxypropyl cellulose, sodium bicarbonate, phosphate, calc�I or calcium citrate), lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), odorant (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g. sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), suspending agent (e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate), a dispersing agent (e.g., methylcellulose), a diluent (e.g., water) and waxy base (for example, cocoa butter, petrolatum or polyethylene glycol). The effective amount of the heteroaryl compound in the pharmaceutical composition may be at a level that will give the desired effect; for example, from about 0.005 mg/kg body weight of subject to about 10 mg/kg of body weight of the subject, in a standard dosage form for oral and parenteral administration.

Dose heteroaryl compounds for administration to a subject varies within broad limits and depends on the judgment of the attending physician. Typically, the heteroaryl compounds can be administered to the subject one to four times per day in a dose of from about 0.005 mg/kg body weight of subject to about 10 mg/kg of body weight of the subject, but the above dosage will accordingly vary in z�depending on their age, body weight and medical condition of the subject and type of administration. In one embodiment, the dose is from about 0.01 mg/kg body weight of subject to about 5 mg/kg of body weight of the subject, from about 0.05 mg/kg body weight of subject to about 1 mg/kg of body weight of the subject, from about 0.1 mg/kg body weight of subject to about 0.75 mg/kg body weight of subject, or from about 0.25 mg/kg body weight of subject to about 0.5 mg/kg of body weight of the subject. In one embodiment, administered one dose per day. In each case, the quantity entered heteroaryl compounds will depend on such factors as the solubility of the active component used in the composition and route of administration.

In another embodiment, the present application presents methods for the treatment or prophylaxis of a disease or disorder, comprising administering from about 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, 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 subject in need of it.

In another embodiment, the present application presents methods for the treatment or prophylaxis of a disease or disorder, comprising administering 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 100 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 subject in need of it. In a specific embodiment, the methods disclosed in the present application, include the introduction of 400 mg/day, 600 mg/day or 800 mg/day heteroaryl compound to a subject in need of it.

In another embodiment, the present application provides a standard dosage forms, including in its composition from about 1 mg to 200 mg, from about 35 mg to about 1400 mg, from 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 specific embodiment, the present application provides a standard dosage form, comprising a membership of about 100 mg or 400 mg heteroaryl compounds.

In another embodiment, the present application provides a standard dosage form, which includes in its composition of 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 Compound you can enter once, twice, three, four or more times a day. In a specific embodiment, the dose of 600 mg or less TSB�Yat in the form of a single daily dose, and doses over 600 mg administered twice daily in an amount equal to half the total daily dose.

Heteroaryl Compound can be administered orally for convenience. In one embodiment, in the case of oral administration, the heteroaryl compound is administered with food and water. In another embodiment, the heteroaryl compound is dispersed in water or juice (e.g., Apple juice or orange juice) and administered orally as a suspension.

Heteroaryl Compound can also enter intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, percutaneous, rectal, through the mucous membranes, by inhalation or topically, by injection into the ear, the nose, eyes or skin. The method of administration is prescribed by your doctor, and it partially depends on the location of the medical condition.

In one embodiment, the present application presents capsules containing heteroaryl compound without an additional carrier, excipient or filler.

In another embodiment, the present application includes compositions comprising an effective amount heteroaryl compounds and a pharmaceutically acceptable carrier or excipient, where the pharmaceutically acceptable carrier or napolnitel� may include excipient, the diluent or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, tablets, suppositories and suspensions, etc. of the Composition can be formulated so that they contain a daily dose, or a convenient part of the daily dose, in a standard dosage form, which can be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions prepared from water soluble salts, such as hydrochloride salt. As a rule, all the compositions have, in accordance with methods known in pharmaceutical chemistry. Capsules can be obtained by mixing a heteroaryl compound with a suitable carrier or diluent and filling capsules with a suitable amount of the mixture. Commonly used carriers and diluents include, but are not limited to, inert poroshkoobraznye substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, flour from cereals and similar edible powders.

Tablet obtainable by direct compression, wet granulation or dry granular�tion. The compositions typically include diluents, binders, lubricants and disintegrants 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 sugar powder. Powdered cellulose derivatives are also useful. In one embodiment, the pharmaceutical composition does not contain lactose. Typical binders for tablets are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic resins are also convenient to use, including acacia gum, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as a binder.

Lubricant may be necessary in the composition of tablets for preventing the sticking of tablets and punches in the die. Lubricant can be selected from such moving substances 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 the compound. They include starches, clays, cellulose�, algini and resin. More specifically, it is possible to use, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, and sodium lauryl sulfate. The tablets can be coated using sugar as a flavoring and a sealing agent or film-forming protective agents for modifying properties of tablet dissolution. The compositions can also be formulated as chewable tablets, for example, with the use of the composition of substances such 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 addition of waxes to some increase in its melting point. Widely used miscible with water bases for suppositories, including, in particular, polyethylene glycols with different molecular mass.

Action heteroaryl compounds can be delayed or prolonged by proper formulation. For example, you can get a slowly soluble granules heteroaryl compounds and include in the pill Il� capsule or use an implantable slow release device. Such methods also include obtaining pellets of several different dissolution rates of filling capsules with a mixture of the granules. Tablets or capsules may have a film coating, which delays the dissolution for a certain period of time. Even the parenteral preparations can be done long-acting, by dissolving or suspending heteroaryl compound in oily or emulsified media who make it all possible slow dispersion in the serum.

5. Examples

The following abbreviations are used in the description and examples:

9-BBN 9-Borabicyclo[3.3.1]nonane

ATP adenosine Triphosphate

BSA Bovine serum albumin

DPBS with phosphate-buffered saline, Dulbecco

DCM dichloro methane

DIPEA N,N-Diisopropylethylamine

DMF N,N-Dimethylformamide

DMSO dimethyl Sulfoxide

DNP 2,4-Dinitrophenol

DTT of Dithiotreitol

EDTA Ethylenediaminetetraacetic acid

ESI Ionization electrospray

FBS Fetal bovine serum

HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

HPLC High-performance liquid chromatography

HTRF Homogeneous fluorescence with a time resolution of

IHMS Liquid chromatography - mass spectrometry

MS Mass spectrometry

n-BuLi n-Butyllithium

NMR Nuclear magnetic resonance

p-TsOH para-Tolu�Sultanova acid

RPMI Medium Roswell Park Memorial Institute

SN Supernatant

TFA Trifluoroacetic acid

TLC Thin layer chromatography

TsCl 4-Methylbenzenesulfonate

μw Microwave

Compounds are named using automated tool for naming compounds provided in the program Chemdraw Ultra 9.0 (Cambridgesoft), which forms the systematic names for chemical structures, using the rules of Cahn-Ingold-Prelog for stereochemistry.

The following Examples are presented to illustrate and not to limit.

5.1 Examples of synthesis

5.1.1 Synthesis of intermediate compounds

Intermediate 1: tert-Butyl 5-bromo-1-occaisonaly-2-carboxylate

A. Methyl 4-bromo-2-methylbenzoate. To a stirred solution of 4-bromo-2-methylbenzoic acid (1 g, 4.7 mmol) in methanol (20 ml) was added dropwise sulfur dichloride (1.4 g, 11,7 mmol) at 0°C and the mixture was heated at boiling with reflux for 2 hours. After TLC analysis (ethyl acetate) showed that the starting material consumed, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Sul�fathom sodium and evaporated in vacuum to give methyl 4-bromo-2-methylbenzoate (0.8 g, 75% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,80 (d, J=8.4 Hz, 1H), of 7.46-7,38 (m, 2H), 3,90 (s, 3H), 2,60 (s, 3H).

B. Methyl 4-bromo-2-(methyl bromide)benzoate. A suspension of methyl 4-bromo-2-methylbenzoate (0.8 g, 3.5 mmol), N-bromosuccinimide (0,69 g, 3,8 mmol), benzoilperoksida (15 mg, 0,06 mmol) in carbon tetrachloride (10 ml) was heated at boiling with reflux for 5 hours. When TLC (ethyl acetate) showed that the starting material consumed, the mixture was cooled to room temperature. The precipitate was filtered and the filtrate concentrated to give methyl 4-bromo-2-(methyl bromide)benzoate (0.9 g, 84% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,86 (d, J=8,8 Hz, 1H), 7,65 (s, 1H), 7,52 (DD, J=8.4 Hz, J=2,0 Hz, 1H), 4,91 (s, 2H), 3,95 (s, 3H).

C. 5-Promisingly-1-it. To a solution of methyl 4-bromo-2-(methyl bromide)benzoate (0.8 g, 2.6 mmol) in tetrahydrofuran (40 ml) was added aqueous ammonia solution (5 ml) in a sealed vessel and the reaction mixture was stirred at 40°C for 3 days. The precipitate was collected and dried in vacuum to give 5-promisingly-1-one (220 mg, 40% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,62 (lat.s, 1H), 7,81 (s, 1H), of 7.64 (d, J=8 Hz, 1H), EUR 7.57 (d, J=8 Hz, 1H), 4,34 (s, 2H).

D. tert-Butyl 5-bromo-1-occaisonaly-2-carboxylate. A mixture of 5-promisingly-1-one (40 mg, 0,19 mmol), di-tert-BUTYLCARBAMATE (41 mg, 0,19 mmol), N,N-dimethylpyridin-4-amine (2.3 mg, 0.02 mmol) in dihormati�e (3 ml) was stirred at room temperature over night. When TLC analysis (etoac) showed that the starting material consumed, the reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and was evaporated in vacuum to give tert-butyl 5-bromo-1-occaisonaly-2-carboxylate (30 mg, 51% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) to 7.89 (s, 1H), 7,71-7,65 (m, 2H), 4.75 in (s, 2H), 1,49 (C, 9H).

Intermediate compound 2: tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate

A. tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate. A solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.5 g, 1,729 mmol) in dichloromethane (13 ml) was cooled to 0°C and treated with triethylamine (0,265 ml 1,902 mmol), followed by treatment with di-tert-BUTYLCARBAMATE (0,377 g, 1,73 mmol). The reaction mixture was slowly warmed to room temperature. The reaction mixture was washed with water. The organic phase was dried over magnesium sulfate and evaporated to dryness. The product was dried overnight under vacuum at room temperature, tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (0,606 g, 1,557 mmol, 90% yield) was isolated as a white solid. MS (ESI) m/z 290 [M-Boc+1]+.

Promezhutochnoyee 3: 4-(5-Bromopyrimidine-2-yl)morpholine

A. 4-(5-Bromopyrimidine-2-yl)morpholine. A solution of 5-bromo-2-chloropyrimidine (0.5 g, 2,58 mmol) in acetonitrile (10.5 ml) was treated with morpholine (0.225 g, 2,58 mmol) and diisopropylethylamine (0,677 ml, 3.88 mmol) and stirred at room temperature over night. The solvent was removed under reduced pressure (white sticky stuff). The remainder could not be distributed between water and ethyl acetate, but the formation of white solids were suspendirovanie mixture in a saturated aqueous solution of ammonium chloride, this substance was collected by filtration and washed with water. 4-(5-Bromopyrimidine-2-yl)morpholine (0,550 g, 2,253 mmol, 87% yield) was isolated as a white solid. MS (ESI) m/z 244 [M]+246 [M+2]+.

Intermediate compound 4: tert-Butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)ethylcarbamate

A. tert-Butyl 2-(5-bromo-2-nitrophenylamino)ethylcarbamate. A solution of 4-bromo-2-fluoro-1-nitro-benzene (3 g, of 13.7 mmol), tert-butyl-2-aminoethylamino (2.2 g, and 13.7 mmol) and triethylamine (2,78 g, to 27.4 mmol) in N,N-dimethylacetamide (25 ml) was stirred at room temperature over night. The reaction mixture was concentrated under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira using 5-15% ethyl�of Etat in petroleum ether) to give tert-butyl 2-(5-bromo-2-nitrophenylamino)ethylcarbamate in the form of a yellow solid substance. (3.1 g, 63% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,24 (lat.s, 1H), 8,07 (d, J=9,2 Hz, 1H), 7,10 (s, 1H), about 6,82 (d, J=9,2 Hz, 1H), 4,82 (lat.s, 1H), 3,47 (s, 4H), to 1.48 (s, 9H).

B. tert-Butyl 2-(2-amino-5-brompheniramine)ethylcarbamate. A mixture of tert-butyl 2-(5-bromo-2-nitrophenylamino)ethylcarbamate (2.0 g, to 5.57 mmol), zinc dust (of 3.64 g, 55,70 mmol) and ammonium chloride (3.0 g, up 55.7 mmol) in a mixture of tetrahydrofuran and methanol (1:1, 30 ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was distributed between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate three times. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuum to give tert-butyl 2-(2-amino-5-brompheniramine)ethylcarbamate (1.65 g, 90% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 6.79 (DD, J1=8,1 Hz, J2=2,1 Hz, 1H), 6,71 (d, J=2.1 Hz, 1H), 6,59 (d, J=8,1 Hz, 1H), 4,87 (lat.s, 1H), 3.46 in (s, 4H), 3,24 (lat.s, 2H), to 1.48 (s, 9H).

C. tert-Butyl 2-(6-bromo-1H-benzo[d]imidazol-1-yl)ethylcarbamate. To a mixture of tert-butyl 2-(2-amino-5-brompheniramine)ethylcarbamate (1.55 g, 4.7 mmol) in acetic acid (1 ml) was added triethylorthoformate (65 ml) dropwise at room temperature and the mixture was heated at boiling with reflux for 0.5 hours. Three!�earthformed was removed under reduced pressure and the residue was diluted with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated to obtain tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-1-yl)ethylcarbamate (1.4 g, 87% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 7.77 (s, 1H), 7,53 (DD, J1=8,0 Hz, J2=2,0 Hz, 1H), 7,28 (d, J=8,0 Hz, 1H), of 7.19 (d, J=2,0 Hz, 1H), 4,84 (lat.s, 1H), 4,24 (t, J=6,0 Hz, 2H), of 3.45 (t, J=6,0 Hz, 2H), 1,38 (s, 9H); MS (ESI): m/z 339,9 [M+1]+.

D. tert-Butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)ethylcarbamate. After a mixture of tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-1-yl)ethylcarbamate (1.29 g, 3,81 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)and (1.45 g, 5,71 mmol) and potassium acetate (0,93 g, 9,51 mmol) in N,N-dimethylformamide (10 ml) was degassed three times, was added 1,1'-bis(diphenylphosphino)ferienparadies (0,129 g, 0,17 mmol) and the mixture was heated at 100°C overnight. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give tert-butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cf]imidazol-1-yl)ethylcarbamate (0.89 g, 59.3% of output) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d)δ (M. D.) of 8.33 (s, 1H), 7,95 (s, 1H), to 7.89-of 7.82 (m, 2H), to 4.81 (lat.s, 1H), 4,47 (t, J=6,0 Hz, 2H), 3,62 (t, J=6,0 Hz, 2H), 1,38 (s, 21H); MS (ESI): m/z 388,1 [M+1]+.

Intermediate compound 5: 2-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-�l)aniline

A. 2-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. After a mixture of 4-bromo-2-nitro-phenylamine (3,09 g, 13.89 per mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)and (3.9 g, 15,28 mmol) and potassium acetate (2.7 g, 27.8 mmol) in N,N-dimethylformamide (20 ml) was degassed three times, was added 1,1'-bis(diphenylphosphino)- ferienparadies (0.3 g, 0,40 mmol) and the mixture was heated at 100°C overnight. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (elwira using 10-15% ethyl acetate in petroleum ether) to give 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 g, 81% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,24 (s, 1H), 7,68 (lat.s, 2H), 7,54 (d, J=8.4 Hz, 1H), of 6.96 (d, J=8.4 Hz, 1H), 1,25 (s, 12H); MS (ESI): m/z 265,0 [M+1]+.

Intermediate compound 6: 1-(Tetrahydro-2H-Piran-2-yl)-1H-indazol-6-amine

A. 6-Nitro-1H-indazole. To a stirred solution of 2-methyl-5-nitro-phenylamine (50 g, 0.33 mole) in acetic acid (500 ml) was added dropwise a solution of sodium nitrite (34 g, 0.49 mole) in water (100 ml) at 0°C and the reaction mixture stirred at room temperature for 1 hour. When the starting material was consumed, the reaction mixture was poured into water. The precipitate was collected by filtration and was purified on a column of silica gel (elwira dichloro�ETANA) to give 6-nitro-1H-indazole (40 g, 75% of output) in the form of solids.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) and 8.50 (s, 1H), 8,23 (s, 1H), 8,02-to 7.95 (m, 2H); MS (ESI): m/z 164,1 [M+1]+.

B. 6-Nitro-1-(tetrahydro-Piran-2-yl)-1H-indazol. A stirred mixture of 6-nitro-1H-indazole (5.0 g, 30 mmol), 3,4-dihydro-2H-PYRAN (5.2 g, 60 mmol) and 4-methylbenzenesulfonic acid (516 mg, 3 mmol) in tetrahydrofuran (25 ml) was heated at boiling with reflux during the night. After removal of solvent, the residue was purified using column chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 6-nitro-1-(tetrahydro-2H - Piran-2-yl)-1H-indazole (4 g, 52% yield) as a yellow solid. MS (ESI): m/z 248,1 [M+1]+.

C. 1-(Tetrahydro-2H-Piran-2-yl)-1H-indazol-6-amine. To a solution of 6-nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (1.0 g, 4.0 mmol) in a mixture of tetrahydrofuran and methanol (V/V, 1:1, 20 ml) was added zinc dust (2.6 g, 40 mmol) and ammonium chloride (2.2 g, 40 mmol) in a nitrogen atmosphere. The mixture was stirred at room temperature overnight and TLC analysis (50% ethyl acetate in petroleum ether) showed that the starting material was consumed. The reaction mixture was filtered and the filtrate concentrated. The residue was diluted with water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous solfatare and concentrated under reduced pressure to obtain 1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-6-amine (750 mg, 85% yield). MS (ESI): m/z 218,1 [M+1]+.

Intermediate compound 7: tert-Butyl 5-promisingly-2-carboxylate

A. 5-Promisingly. To a stirred solution of 5-promisingly-1,3-dione (10 g, 0,044 mol) in anhydrous tetrahydrofuran (500 ml) at 0°C was added sodium borohydride (17.5 g, 0.46 mole) in portions. The reaction mixture was cooled to -10°C and added dropwise a complex of boron TRIFLUORIDE diethyl ether (63 ml, 0.5 mol). Upon completion of the addition, the reaction mixture was heated at boiling with reflux for 4 hours. After cooling to room temperature the reaction mixture was poured slowly into cold water (100 ml) at 0-5°C. the Mixture was diluted with ethyl acetate (480 ml) and podslushivaet by adding 6 n aqueous sodium hydroxide solution at 0~5°C and pH=10. The organic layer was washed with saturated brine (4×100 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was diluted with diethyl ether (100 ml) and made acidic with pH~2) 6 n aqueous hydrochloric acid solution at 0°C. the Aqueous layer was podslushivaet 6 n aqueous solution of sodium hydroxide and was extracted with ethyl acetate (400 ml). The organic layer was washed with saturated brine (3×150 ml), dried over sodium sulfate and concentrated under reduced pressure with more inform�m untreated 5-promisingly (4 g, 46% yield) as brown oil. MS (ESI): m/z 199,7 [M+1]+.

B. tert-Butyl 5-promisingly-2-carboxylate. To a mixture of 5-promisingly (4.0 g, 20 mmol) and triethylamine (10.1 g, 100 mmol) in dichloromethane (20 ml) was added a solution of di-tert-BUTYLCARBAMATE (6,54 g, 30 mmol) in dichloromethane (30 ml) at 0°C and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified using chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether) to give tert-butyl 5-promisingly-2-carboxylate (3.9 g, 65% yield). MS (ESI): m/z 297,7 [M+1]+.

Intermediate compound 8: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-he

A. 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-it. Degassed mixture of 6-promisingly-1-one (2.8 g, 13.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane)and (6.9 g, 27 mmol), potassium acetate (3.33 g, 34 mmol) and 1,1'-bis(diphenylphosphino)ferienparadies (1 g, 1.3 mmol) in dioxane (50 ml) was heated at 90°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira using 10% ethyl acetate in petrol�nom ether) to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-one (2.2 g, 62% yield) as a white solid. MS (ESI): m/z 259,9 [M+1]+.

Intermediate compound 9: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-he

A. Methyl 4-bromo-2-(methyl bromide)benzoate. A mixture of methyl 4-bromo-2-methylbenzoate (22,8 g, 0.1 mol), 2,2'-azobis(2-methylpropionitrile)and (1.64 g, 0.01 mol) and N-bromosuccinimide from 17.7 g, 0.1 mol) was heated at boiling with reflux during the night. The solvent was removed and the residue was distributed between water and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried and evaporated to obtain crude methyl 4-bromo-2-(methyl bromide)benzoate (30 g), which was used for next step without further purification.1H NMR (400 MHz, CHLOROFORM-d) δ (MD), 7,83 (m, 1H), 7,63 (s, 1H), 7,51 (m, 1H), 4,90 (s, 2H), 3,94 (s, 3H).

B. 5-Promisingly-1-it. To a solution of methyl 4-bromo-2-(methyl bromide)benzoate (15 g, 0.05 mol) in methanol (20 ml) was added ammonium hydroxide (200 ml) and the mixture stirred at room temperature for 18 hours. The solvent was removed and the residue was washed with ethyl acetate and methanol (V/V, 10:1, 110 ml), to obtain 5-promisingly-1-one (4.5 g, 42% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,65 (lat.s, 1H), 7,84 (s, 1H), 7,65 (m, 1H), members, 7.59 (m, 1H), 4,37 (s, 2H).

C. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-it. Deg�zeerovannyy a mixture of 5-promisingly-1-one (1.05 g, 5,0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane)and (2,54 g, 10 mmol), potassium acetate (1.20 g, 12.5 mmol) and 1,1'-bis(diphenylphosphino)ferienparadies (0,38 g, 0.5 mmol) in dioxane (50 ml) was heated to 80°C in a nitrogen atmosphere over night. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-one (400 mg, 31% yield) as a white solid. MS (ESI): m/z 259,9 [M+1]+.

Intermediate 10: 1-Occaisonaly-4-Voronova acid

A. 1-Occaisonaly-4-Voronova acid. To a solution of 4-promisingly-1-one (3.0 g, of 14.2 mmol) in anhydrous tetrahydrofuran (50 ml) was added dropwise n-butyllithium (2.5 M in hexane, 12 ml, 30 mmol) at -78°C in a nitrogen atmosphere. After stirring for 1 hour at this temperature was added dropwise a solution of triethylborane (to 4.41 g of 40.0 mmol) in anhydrous tetrahydrofuran (20 ml). The reaction mixture was stirred at -78°C for 2 hours and at room temperature over night. The reaction was quenched by adding 1 n aqueous hydrochloric acid solution and the precipitate was collected and about�see a significant water with obtaining 1-occaisonaly-4-Voronovo acid (400 mg, 16% yield) as a solid substance. MS (ESI): m/z 178,1 [M+1]+.

An intermediate connection 11: tert-Butyl 2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-yl)ethylcarbamate

A. tert-Butyl 2-(6-bromo-1-occaisonaly-2-yl)ethylcarbamate. A solution of methyl 5-bromo-2-(methyl bromide)benzoate (3 g, 0.01 mol) and tert-butyl 2-aminoethylamino (3,15 g, 0.02 mmol) in methanol (50 ml) was heated at boiling with reflux in a nitrogen atmosphere over night. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified on a column of silica gel (elwira using 50% ethyl acetate in petroleum ether) to give tert-butyl 2-(6-bromo-1-occaisonaly-2-yl)ethylcarbamate (2.5 g, 71% yield) in the form of solids.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) a 7.85 (s, 1H), 7,72 (d, J=8,0 Hz, 1H), 7,49 (d, J=7,6 Hz, 1H), 4,52 (s, 2H), 3,68 (t, J=5.6 Hz, 2H), 3,34 (t, J=5.6 Hz, 2H), 1,30 (C, 9H).

B. tert-Butyl 2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-yl)ethylcarbamate. Degassed solution of tert-butyl 2-(6-bromo-1-occaisonaly-2-yl)ethylcarbamate (750 mg, 2,11 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)and (1,07 g, 4,22 mmol), potassium acetate (409 mg, 4,22 mmol) and 1,1'- bis(diphenylphosphino)ferienparadies (153 mg, 0,2 mmol) in dioc�ane (20 ml) was heated to 90°C in a nitrogen atmosphere over night. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified using chromatography on silica gel (elwira using 50% ethyl acetate in petroleum ether) to give tert-butyl 2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-yl)ethylcarbamate (600 mg, 71% yield) in the form of solids.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,12 (s, 1H), 7,95 (d, J=7,6 Hz, 1H), 7,56 (d, J=7,2 Hz, 1H), 4,58 (s, 2H), 3,70 (t, J=5.6 Hz, 2H), 3,35 (t, J=5.6 Hz, 2H), of 1.36 (s, 9H), of 1.30 (s, 6H), 1,24 (s, 6H).

Intermediate compound 12: tert-Butyl 2-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-yl)ethylcarbamate

A. tert-Butyl 2-(5-bromo-1-occaisonaly-2-yl)ethylcarbamate. To a solution of methyl 4-bromo-2-(methyl bromide)benzoate (5 g, 16.3 mmol) in methanol (50 ml) was added tert-butyl 2-aminoethylamino (5,12 g, 32 mmol) and the mixture was stirred at 65°C over night. The solvent was removed and the residue was purified on a column of silica gel to obtain tert-butyl 2-(5-bromo-1-occaisonaly-2-yl)ethylcarbamate (3,58 g, 63% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) a 7.85 (s, 1H), 7,63 (d, J=8,0 Hz, 1H), 7,56 (d, J=8,0 Hz, 1H), at 6.92 (lat.s, 1H), 4,46 (s, 2H), 3,50 (t, J=6,0 Hz, 2H), 3,14 (t, J=6,0 Hz, 2H), 1.26 in (s, 9H).

B. tert-Butyl 2-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-yl)ethylcarbamate. �gazirovannuyu a mixture of tert-butyl 2-(5-bromo-1-occaisonaly-2-yl)ethylcarbamate (0.89 g, 2.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)and (1,27 g, 5.0 mmol), 1,1'-bis(diphenylphosphino)ferienparadies (0.19 g, 0.25 mmol) and potassium acetate (0,61 g, 6.25 mmol) in dioxane (25 ml) was heated at 80°C in a nitrogen atmosphere over night. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude product, which was purified using chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether) to give tert-butyl 2-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-yl)ethylcarbamate (600 mg, 60% yield) as a white solid. MS (ESI): m/z 303,0 [M-99]+.

Intermediate compound 13: tert-Butyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)ethylcarbamate

A. tert-Butyl 2-(4-bromo-2-nitrophenylamino)ethylcarbamate. A solution of 4-bromo-1-fluoro-2-nitro-benzene (3.2 g, and 13.7 mmol), tert-butyl 2-aminoethylamino (4.8 g, 30.0 mmol) in N,N-dimethylformamide (100 ml) was stirred at 120°C overnight. The reaction mixture was concentrated under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give crude tert-butyl 2-(4-bromo-2-nitrophenylamino�)ethylcarbamate (5.4 g, 100% yield) as a yellow solid. MS (ESI): m/z 305,8 [M+1]+.

B. tert-Butyl 2-(2-amino-4-brompheniramine)ethylcarbamate. A solution of tert-butyl 2-(4-bromo-2-nitrophenylamino)ethylcarbamate (5.4 g, 15 mmol), zinc dust (9,80 g, 150 mmol) and ammonium chloride (8,10 g, 150 mmol) in a mixture of tetrahydrofuran and methanol (V/V, 1:1, 100 ml) was stirred at room temperature for 12 hours. After filtration the filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was washed with water three times, dried over sodium sulfate and concentrated in vacuum to give tert-butyl 2-(2-amino-4-brompheniramine)ethylcarbamate (4.8 g, 97% yield) as a yellow solid. MS (ESI): m/z 329,9 [M+1]+.

C. tert-Butyl 2-(5-bromo-1H-benzo[d]imidazol-1-yl)ethylcarbamate. A mixture of tert-butyl 2-(2-amino-4-brompheniramine)ethylcarbamate (1.55 g, 4.7 mmol) in triethylorthoformate (100 ml) was heated at 100°C for 1.5 hours. Triethylorthoformate was removed under reduced pressure and the residue was purified on a column of silica gel (elwira using 5% ethyl acetate in petroleum ether) to give tert-butyl 2-(5-bromo-1H-benzo[d]imidazol-1-yl)ethylcarbamate (3.0 g, 61% yield). MS (ESI): m/z 341,7 [M+1]+.

D. tert-Butyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)ethylcarbamate. Degassed mixture of tert-butyl 2-(5-bromo-1H-benzo[d]them�dasol-1-yl)ethylcarbamate (1,02 g, 3,00 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)and (2,29 g, 9.00 mmol), 1,1'-bis(diphenylphosphino)ferienparadies (0,23 g, 0.30 mmol) and potassium acetate (0.74 g, 7,50 mmol) in 1,4-dioxane (30 ml) was heated at 100°C overnight under an atmosphere of nitrogen. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (elwira ethyl acetate) to give tert-butyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-benzo[d]imidazol-1-yl)ethylcarbamate (0,90 g, 77% yield) as a solid substance. MS (ESI): m/z 388,2 [M+1]+.

Intermediate compound 14: N-Methyl-6-(4,4,S,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-amine

A. 5-Bromo-1H-benzo[d]imidazol-2(3H)-he. A solution of 4-Brabanthal-1,2-diamine (5 g, of 27.0 mmol), triethylamine (8.1 g, 81.0 mmol) and triphosgene (3,96 g, 14,0 mmol) in dioxane (20 ml) was stirred at 120°C overnight. The precipitate was collected and washed with water to obtain 5-bromo-1H-benzo[d]imidazol-2(3H)-she (3 g, 52% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,75 (lat.s, 2H), to 7.04 (d, J=8.4 Hz, 1H), 7,02 (s, 1H), at 6.84 (d, J=8,0 Hz, 1H); MS (ESI): m/z 212,8 [M+1]+.

B. 6-Bromo-2-chloro-1H-benzo[d]imidazole. A mixture of 5-bromo-1H-benzo[d]imidazol-2(3H)-she (2 g, 9.4 mmol) in phosphoryl the trichloride (20 ml) was heated at boiling with reflux during the night. The reaction mixture was concentrated in vacuo. To the residue �obavljale ice water and the aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate. The solvent was removed under vacuum to give 6-bromo-2-chloro-1H-benzo[d]imidazole (1.5 g, 69% yield) in the form of solids. MS (ESI): m/z 232,7 [M+1]+.

C. 6-Bromo-N-methyl-1H-benzo[d]imidazol-2-amine. A solution of 6-bromo-2-chloro-1H-benzo[J]imidazole (1 g, of 4.35 mmol), triethylamine (1.4 g, of 13.8 mmol) and methylaminopropane (430 g, is 6.42 mmol) in 1-methyl-2-pyrrolidinone (10 ml) was stirred at 120°C overnight. After cooling to room temperature the reaction mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated to give crude product, which was purified on a column of silica gel (elwira using 50% ethyl acetate in petroleum ether) to give 6-bromo-N-methyl-1H-benzo[d]imidazol-2-amine (400 mg, 43% yield). MS (ESI): m/z 227,8 [M+1]+.

D. N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-amine. A mixture of 6-bromo-N-methyl-1H-benzo[d]imidazol-2-amine (500 mg, 2.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)and (1.13 g, 4.4 mmol) and potassium acetate (540 g, 5.5 mmol) in dioxane (5 ml) was degassed three times and then added 1,1'-bis(diphenylphosphino)ferienparadies (170 g, 0,22 mmol). The mixture was heated at 100°C in an atmosphere of nitrogen overnight and the solvent was removed under reduced pressure. The residue was purified on a column of silica gel (elwira using 50% ethyl acetate in petrol�Inom ether) to give N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-amine (500 mg, 83% yield) as a solid substance. MS (ESI): m/z 273,9 [M+1]+.

Intermediate compound 15: 1-Chloroisoquinoline-7-Voronova acid.

A. 1-Chloroisoquinoline-7-Voronova acid. A solution of 7-bromo-1-chloroisoquinoline (1 g, 4.1 mmol) in tetrahydrofuran (5 ml) was cooled to -78°C in a nitrogen atmosphere and added triisopropylsilyl (2.4 g, 11.5 mmol) followed by the addition dropwise n-utility (5 ml, 1.5 M). The reaction mixture was warmed to -20°C for 30 minutes, quenched with 1 M aqueous hydrochloric acid solution and neutralized with triethylamine to pΗ=7. The residue was distributed between water and ethyl acetate, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate and concentrated to give crude product, which was purified on a column of silica gel (elwira ethyl acetate), to obtain l-chloroisoquinoline-7-Voronovo acid (0.5 g, 58.8% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) is 8.74 (s, 1H), 8,58 (lat.s, 2H), 8,28 (d, J=5,2 Hz, 1H), to 8.19 (d, J=8.4 Hz, 1H), 7,98 (d, J=8.4 Hz, 1H), a 7.85 (d, J=5.6 Hz, 1H); MS (ESI): m/z 208,1 [M+1]+.

Intermediate compound 16: tert-Butyl 6-bromobenzo[d]izocsazol-3-ylcarbamate

A. 4-Bromo-2-(propane-2-ylideneamino)benzonitrile. A mixture of about�EN-2-oxime (730 mg, 10 mmol) and tert-butoxide potassium (24 mg, of 0.58 mmol) in tetrahydrofuran (10 ml) was stirred at 0°C for 1 hour and was added 4-bromo-2-perbenzoate (1.0 g, 5,02 mmol) at 0°C. the Mixture was heated at 55°C for 2 hours. After cooling to room temperature the reaction mixture was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4-bromo-2-(propane-2-ylideneamino)benzonitrile (1.2 g, 94% yield) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (MD), of 7.75 (s, 1H), 7,53 (d, J=8,0 Hz, 1H), 7,27 (d, J=8,0 Hz, 1H), 2,14 (s, 3H), 2,07 (s, 3H); MS (ESI): m/z 254,8 [M+1]+.

B. 6 Bromobenzo[d]izocsazol-3-amine. A solution of 4-bromo-2-(propane-2-ylideneamino)benzonitrile (1.2 g, 4.76 mmol) in a mixture of hydrochloric acid (5 M, 1 ml) and 2,2,2-trifluoroacetic acid (4 ml) was stirred at room temperature over night. The solvent was evaporated under reduced pressure to obtain 6-bromobenzo[d]izocsazol-3-amine (900 mg, 90% yield) in the form hydrochloride salt.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,76 (m, 2H), 7,41 (m, 1H), 6,50 (lat.s, 2H).

C. tert-Butyl 6-bromobenzo[d]izocsazol-3-ylcarbamate. A mixture of 6-bromobenzo[d]izocsazol-3-amine (900 mg, 4,25 mmol), di-tert-BUTYLCARBAMATE (1.2 g, 5.1 mmol), triethylamine (686 mg, 6.8 mmol) and N,N-dimethyle�idin-4-amine (72 mg, 0.6 mmol) in dichloromethane (10 ml) was stirred at room temperature over night. Added water and the organic layer was separated, the aqueous phase was extracted with dichloromethane. The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified on a column of silica gel to obtain tert-butyl 6-bromobenzo[d]izocsazol-3-ylcarbamate (900 mg, 68% yield) as a solid substance. MS (ESI): m/z 313,9 [M+1]+.

Intermediate compound 17: 6-Bromo-1-methyl-1H-benzo[d]imidazole

A. 5-Bromo-N-methyl-2-nitroaniline. To a solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 0,043 mol) in ethanol (100 ml) was added metaluminous alcohol solution (3 g, 0.1 mol) slowly at 0°C and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to give 5-bromo-N-methyl-2-nitroaniline as a white solid (9 g, 85.7 percent).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,23 (s, 1H), 7,98 (d, J=8,8 Hz, 1H), 7,14 (s, 1H), 6,80 (DD, J1=9,2 Hz, J2=2,0 Hz, 1H), 2,92 (d, J=4,8 Hz, 3H); MS (ESI): m/z amount of 231.1 [M+1]+.

B. 5-Bromo-N-methylbenzol-1,2-diamine. 5-Bromo-N-methyl-2-nitroaniline (9 g, 0,039 mol), ammonium chloride (53 g, 0.39 mol) and zinc powder (21 g, 0.39 mole) were mixed in methanol and tetrahydrofuran (V/V, 1:1, 80 ml) and the mixture stirred at room tempera�ur for 4 hours. The solution was filtered and the filtrate was concentrated to give crude product, which was distributed between ethyl acetate and water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to give 5-bromo-N-methylbenzol-1,2-diamine in the form of a solid (7.5 g, 60% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 6,50 (d, J=8,0 Hz, 1H), to 6.42 (d, J=8.4 Hz, 1H), 6,38 (s, 1H), 4,87 (d, J=4,8 Hz, 1H), 4,59 (lat.s, 2H), 2,66 (d, J=5,2 Hz, 3H); MS (ESI): m/z 201,1 [M+1]+.

C. 6-Bromo-1-methyl-1H-benzo[d]imidazole. A solution of 5-bromo-N-methylbenzol-1,2-diamine (7.5 g, 0,037 mmol) in formic acid (25 ml) was heated at boiling with reflux during the night. The solvent was removed under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira using 20-30% ethyl acetate in petroleum ether), to obtain 6-bromo-1-methyl-1H-benzo[d]imidazole in the form of a solid (6.5 g, 86% yield).1H NMR (400 MHz, DMSO-d6) δ (MD), 8,21 (s, 1H), of 8.85 (s, 1H), 7,55 (d, J=8,0 Hz, 1H), 7,32 (d, J=8.4 Hz, 3H), 3,81 (s, 3H); MS (ESI): m/z 211,1 [M+1]+.

Intermediate 18: 6-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

A. 6-Bromo-2-methyl-1H-benzo[d]imidazole. A solution of 4-Brabanthal-1,2-diamine (3 g, 0.02 mmol) in acetic acid (20 ml) was stirred at 120°C overnight. When TLC analysis (3% dichloromethane in methanol) showed that the starting material was consumed, the mixture was adjusted to pH=7 with an aqueous sodium carbonate solution and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated to give 6-bromo-2-methyl-1H-benzo[d]imidazole (2.8 g, 83% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 12,34 (lat.s, 1H), 7,60 (s, 1H), value of 7, 37 (d, J=8,8 Hz, 1H), 7,20 (DD, J1=SA Hz, J2=2,0 Hz, 1H), 2,44 (s, 3H).

B. 6-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole. A mixture of 6-bromo-2-methyl-1H-benzo[d]imidazole (1 g, 4.76 mmol) and sodium hydride (60% in mineral oil, 226 mg, 5.17 mmol) in N,N-dimethylformamide (10 ml) was stirred at 0°C for 1 hour. Was added dropwise at this temperature, a solution of (2-(chloromethoxy)ethyl)trimethylsilane (948 mg, 5.17 mmol) in N,N-dimethylformamide (2 ml) and the resulting mixture was stirred at room temperature over night. Added water and the mixture was extracted with ethyl acetate. The organic layer was dried, concentrated in vacuo and was purified using chromatography on silica gel (elwira using 50% ethyl acetate in petroleum ether) to give 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (1.2 g, 75% yield) in the form of solids. MS (ESI): m/z 341,9 [M+1]+.

Intermediate with�connected 19: tert-Butyl 5-bromobenzo[d]izocsazol-3-ylcarbamate

A. 5-Bromo-2-(propane-2-ylideneamino)benzonitrile. A mixture of propane-2-oxime (730 mg, 10 mmol) and tert-butoxide potassium (1.12 g, 10 mmol) in tetrahydrofuran (10 ml) was stirred at 0°C for 1 hour and was added 5-bromo-2-perbenzoate (1.0 g, 5,02 mmol) at 0°C. the mixture was heated at 55°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5-bromo-2-(propane-2-ylideneamino)benzonitrile (800 mg, 64% yield) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 7.64 (m, 2H), δ (MD), 7,47 (d, J=9,2 Hz, 1H), δ (M. D.) 2,17 (s, 3H), δ (M. D.) 2,07 (s, 3H); MS (ESI): m/z 254,7 [M+1]+.

B. 5 Bromobenzo[d]izocsazol-3-amine. A solution of 5-bromo-2-(propane-2-ylideneamino)benzonitrile (504 mg, 2.0 mmol) in a mixture of hydrochloric acid (5 M, 1 ml) and 2,2,2-trifluoroacetic acid (4 ml) was stirred at room temperature over night. The solvent was evaporated under reduced pressure to obtain 5-bromobenzo[d]izocsazol-3-amine (324 mg, 76% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 7.70 (d, J=1.6 Hz, 1H), δ (M. D.), a 7.62 (DD, J1=2,0 Hz, J2=8,8 Hz, 1H), δ (M. D.) 7,35 (d, J=9,2 Hz, 1H), 4,43 (lat.s, 2H).

C. tert-Butyl 5-br�benzo[d]izocsazol-3-ylcarbamate. A mixture of 5-bromobenzo[d]izocsazol-3-amine (424 mg, 2.0 mmol), di-tert-BUTYLCARBAMATE (654 mg, 3.0 mmol), triethylamine (808 mg, 8.0 mmol) and N,N-dimethylpyridin-4-amine (24 mg, 0.2 mmol) in dichloromethane (10 ml) was stirred at room temperature over night. Was added water, the organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give tert-butyl 5-bromobenzo[d]izocsazol-3-ylcarbamate (476 mg, 76% yield) as a solid substance. MS (ESI): m/z 313,9 [M+1]+.

Intermediate 20: 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A. 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile. A mixture of 5-bromo-2-perbenzoate (3 g, 0,015 mol), 4,4,4',4',5,5,5,5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)and (7.6 g, 0.03 mole) and potassium acetate (3.6 g, 0,038 mmol) in dioxane (10 ml) was degassed three times and was added 1,1'-bis(diphenylphosphino)ferienparadies (1.1 g, 1.5 mmol). The mixture was heated at 100°C overnight and the solvent was removed under reduced pressure. The residue was purified on a column of silica gel (elwira using 25% of etelaat�and in petroleum ether) to give 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1 g, 27.0% of output) in the form of solids.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) with 8.05 (m, 2H), value of 7, 37 (t, J=9,2 Hz, 1H), of 1.37 (s, 12H); MS (ESI): m/z 248,1 [M+1]+.

Intermediate 21: 6-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol

A. 6-Nitro-1H-indazole. To a solution of 2-methyl-5-nitro-phenylamine (50 g, 329 mmol) in hydrochloric acid (5 M, 200 ml) was added a solution of sodium nitrite (45 g, 658 mmol) at 0°C and the reaction mixture was heated at 60°C over night. The precipitate was collected by filtration, washed with water and dried in vacuum to give 6-nitro-1H-indazole (40 g, 75% yield) in the form hydrochloride salt.

B. 6-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol. To a solution of 6-nitro-1H-indazole (8 g, 49 mmol) in N,N-dimethylformamide (80 ml) was added sodium hydride (60% in mineral oil, 4 g, 100 mmol) in portions at 0°C. After stirring at this temperature for 1 hour was added dropwise a solution of (2-chloromethoxy-ethyl)trimethylsilane (8.3 g, 50 mmol) in N,N-dimethylformamide (30 ml) and the resulting mixture was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (elwira using 5-20% ethyl acetate in petroleum ether) to give 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (5.8 g, 40% yield). MS (ESI): m/z 293,9 [M1] +.

C. 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine. To a mixture of 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (5.8 g, and 19.8 mmol) and ammonium chloride (53.5 g, 198 mmol) in a mixture of methanol and tetrahydrofuran (100 ml, V/V=1:1) was added zinc dust (13 g, 198 mmol) at 0°C and the reaction mixture was stirred at room temperature over night. The reaction mixture was filtered and the filtrate was concentrated to give crude product, which was purified on a column of silica gel (elwira using 5% ethyl acetate in petroleum ether), to obtain 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (3.5 g, 67% yield) as a solid substance. MS (ESI): m/z 263,9 [M+1]+.

D. 6-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol. To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (3.4 g, 13 mmol) in hydrochloric acid (20 ml, 6 M) was added a solution of sodium nitrite (0.9 g, 13 mmol) in water (5 ml) at 0°C. After stirring for 30 minutes was added a solution of potassium iodide (2.2 g, 13 mmol) in water (10 ml) was added over 30 minutes and the reaction mixture was stirred at room temperature over night. The precipitate was collected by filtration, washed with water and dried in vacuum to give 6-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.64 g, 33% yield) as a solid substance. MS (ESI): m/z 375,1 [M+1]+.

Intermediate 22: 6-Iodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole

A. 4-Iodobenzoyl-1,2-diamine. To a mixture of 4-iodo-2-nitroaniline (10 g, of 37.8 mmol) and ammonium chloride (20 g, 378 mmol) in a mixture of methanol and tetrahydrofuran (400 ml, V/V=1:1) was added zinc dust (24.6 g, 378 mmol) in portions at 0°C and the reaction mixture was stirred at room temperature over night. The mixture was filtered and the organic layer was concentrated to give crude product, which was purified on a column of silica gel (elwira using 1% methanol in dichloromethane), to obtain 4-iodobenzoyl-1,2-diamine (7.6 g, 88% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 6.75 (s, 1H), to 6.58 (m, 1H), 6,21 (m, 1H), 4,59 (lat.C, 4H).

B. 6-Iodo-1H-benzo[d][1,2,3]triazole. To a solution of 4-iodobenzoyl-1,2-diamine (6 g, 25,6 mmol) in aqueous sulfuric acid solution (23,7 ml, 40%) was added dropwise a solution of sodium nitrite (2,36 g, to 34.3 mmol) in water (10 ml) at 0°C. the Mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with water and dried under high vacuum to give 6-iodo-1H-benzo[d][1,2,3]triazole (5.6 g, 90% yield) as the sulfate salt.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,32 (s, 1H), 7,72 (d, J=8 Hz, 1H), 7,65 (d, J=8 Hz, 1H).

C. 6-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole. To a mixture of 6-iodo-1H-benzo[d][1,2,3]triazole (5.6 g, 20 mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (0% in mineral oil, 1.44 g, 36 mmol) in portions at 0°C. After stirring at 0°C for 1 hour, was added dropwise a solution of (2-chloromethoxy-ethyl)trimethylsilane (3.98 g, 24 mmol) in N,N-dimethylformamide (10 ml) and the reaction mixture was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (elwira using 5-15% ethyl acetate in petroleum ether) to give 6-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (6.6 g, 88% yield). MS (ESI): m/z 376,2 [M+1]+.

Intermediate 23: 6-Iodo-1-methyl-1H-indazol

A. 1-methyl-6-nitro-1H-indazole. To a solution of 6-nitro-1H-indazole (20 g, 0.1 mol) in N,N-dimethylformamide (250 ml) was added sodium hydride (60% in mineral oil, 6.0 g, 0.15 mole) in portions at 0°C. Upon completion of addition the mixture was stirred for 30 minutes at 0°C and added itmean (14.2 g, 0.1 mmol). The resulting mixture was stirred at room temperature over night. The reaction was quenched by adding water (500 ml) and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated. The residue was purified on a column of silica gel (elwira using 5-10% ethyl acetate in petroleum ether) to give 1-methyl-6-nitro-1H-�of desola (11 g, 62% yield) as a yellow solid. MS (ESI): m/z 178,7 [M+1]+.

B. 1-methyl-1H-indazol-6-amine. To a mixture of 1-methyl-6-nitro-1H-indazole (1,77 g, 10 mmol) and ammonium chloride (5.3 g, 100 mmol) in a mixture of methanol and tetrahydrofuran (25 ml, V/V=l:l) was added zinc dust (6.5 g, 100 mmol) in portions at 0°C. Upon completion of addition the reaction mixture was stirred at room temperature over night. The reaction mixture was filtered and the filtrate was concentrated to give crude product, which was purified on a column of silica gel (elwira using 1% methanol in dichloromethane) to give 1-methyl-1H-indazol-6-amine (1.1 g, 74,8% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,65 (s, 1H), 7,31 (d, J=8,0 Hz, 1H), 6,48 (d, J=8,0 Hz, 1H), to 6.42 (s, 1H), and 5.30 (lat.s, 2H), of 3.78 (s, 3H).

C. 6-Iodo-1-methyl-1H-indazol. To a solution of 1-methyl-1H-indazol-6-amine (1.0 g, 7 mmol) in hydrochloric acid (15 ml, 6 M) was added dropwise a solution of sodium nitrite (0,48 g, 7 mmol) in water (2 ml) at 0°C. After stirring at this temperature for 30 minutes was added a solution of potassium iodide (1.16 g, 7 mmol) in water (10 ml) and the reaction mixture was stirred at room temperature over night. The precipitate was collected by filtration, washed with water to obtain 6-iodo-1-methyl-1H-indazole (0.8 g, 44% yield) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,95 (s, 1H), 7,84 (s, 1H), of 7.48 (q, j =8,0 Hz, 1H), of 7.42 (d, J=8,0 Hz, 1H), 4,06 (s, 3H).

Intermediate 24: tert-Butyl 5-editingdomain-2-carboxylate

A. 5-Editingdomain-1,3-dione. To a solution of 5-aminoisoquinoline-1,3-dione (5 g, 0.03 mole) in 2 n hydrochloric acid (20 ml) was added dropwise a solution of sodium nitrite (2.1 g, 0.03 mole) in water (10 ml) at 0°C and the mixture was stirred at this temperature for 0.5 hours. Added a solution of sodium iodide (5.1 g, 0.03 mole) and the reaction mixture was stirred at room temperature over night. The precipitate was collected by filtration, washed with water to obtain 5-editingdomain-1,3-dione (4 g, 48% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,38 (s, 1H), 8,17 (d, J=7,6 Hz, 1H), 8,11 (s, 1H), 7,56 (d, J=8,0 Hz, 1H), 2,07 (s, 3H).

B. 5-Editingdomain. To a stirred solution of 5-editingdomain-1,3-dione (700 mg, 2.57 mmol) in anhydrous tetrahydrofuran (20 ml) at 0°C was added sodium borohydride (974 g of 25.7 mmol) in portions and the reaction mixture was cooled to -10°C. was Added dropwise a complex of boron TRIFLUORIDE diethyl ether (3.9 ml of 25.7 mmol). The reaction mixture was heated at boiling with reflux during the night. After cooling to room temperature the reaction mixture was poured slowly into cold water (100 ml) at 0-5°C. the Mixture was diluted with ethyl acetate (480 ml) and the mixture was podslushivaet aqueous solution of HYDR�of ksid sodium (6 M) at 0-5°C and pH=10. The organic layer was separated and washed with saturated brine (4×100 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was diluted with diethyl ether (100 ml) and made acidic with pH~2) with an aqueous hydrochloric acid solution (6 M) at 0°C. the Aqueous layer was separated and podslushivaet aqueous solution of sodium hydroxide (6 n), the mixture was extracted with ethyl acetate (400 ml). The organic layer was washed with saturated brine (3×150 ml), dried over sodium sulfate and concentrated under reduced pressure to obtain 5-editingdomain (300 mg, 48% yield) as a solid substance. MS (ESI): m/z 245,7 [M+1]+.

C. tert-Butyl 5-editingdomain-2-carboxylate. A mixture of 5-editingdomain (730 mg, 2,95 mmol), di-tert-BUTYLCARBAMATE (1.2 g, 5,95 mmol), triethylamine (600 mg, 5,95 mmol) and N,N-dimethylpyridin-4-amine (72 mg, 0.6 mmol) in dichloromethane (10 ml) was stirred at room temperature over night. Added water and the organic layer was separated. The aqueous phase was extracted with dichloromethane. The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified on a column of silica gel with obtaining tert-butyl 5-editingdomain-2-carboxylate (800 mg, 79% yield) in the form of solids.

Intermediate with�unity 25: N-(4-Chloropyridin-2-yl)pivalate

A. N-(4-Chloropyridin-2-yl)pivalate. To a mixture of 4-chloropyridin-2-amine (1.7 g, 13,28 mmol) and triethylamine (1,61 g, 15,94 mmol) in dichloromethane (30 ml) was added dropwise pualeilani (1,91 g, 15,94 mmol) at 0°C. Upon completion of addition the mixture was stirred at room temperature over night. The mixture was washed with water three times, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dried in vacuum to give N-(4-chloropyridin-2-yl)palamida (2.67 g, 95,0% yield) as a white solid. MS (ESI) m/z: 212,8 [M+1]+.

Intermediate compound 26: 4-Iodo-N-methylbenzamide

A. 4-Iodo-N-methylbenzamide. To a solution of methanamine (15 ml) in water (15 ml) was added dropwise to 4-iodo-benzoyl chloride (6 g, 22.6 mmol) at 0°C. the Mixture was stirred at room temperature and reaction was monitored using TLC. After 5 hours the reaction mixture was extracted with dichloromethane, the organic layer was dried over sodium sulfate and was evaporated to obtain 4-iodo-N-methylbenzamide (4.0 g, 68% yield) which was used without further purification. MS (ESI): m/z 262,1[M+1]+.

Intermediate 27: 4-Iodo-N-(1-demerol-4-yl)benzamide

A. 4-Iodo-N-(1-methyl-piperidine-4-yl)benzamide. To a solution of 1-demerol-4-amine (0,91 g, 8 mmol) and triethyl�in (1.21 g, 12 mmol) in dichloromethane (10 ml) was added dropwise to 4-iodo-benzoyl chloride (1,06 g, 4 mmol) at 0°C in an atmosphere of nitrogen. The mixture was heated slowly to room temperature and stirred over night. The reaction mixture was poured into ice water and the organic layer was separated, the aqueous phase was extracted with dichloromethane. The combined organic layer was dried over sodium sulfate and was evaporated to obtain 4-iodo-N-(1-methyl-piperidine-4-yl)benzamide derivative (1.10 g, 79.7% of the yield) which was used without further purification.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,72 (m, 2H), of 7.42 (d, J=8.4 Hz, 2H), of 5.92 (lat.s, 1H), 3,92 (m, 1H), 2,79 (d, J=11.2 Hz, 2H), 2,24 (s, 3H), 2,12 (t, J=11.2 Hz, 2H), of 1.97 (d, J=11.2 Hz, 2H), of 1.57 (m, 3H).

Intermediate 28: tert-Butyl 6-bromo-1-methyl - 1H-indazol-3-ylcarbamate

A. 6-Bromo-1H-indazol-3-amine. To a solution of 4-bromo-2-perbenzoate (2 g, 10 mmol) in butan-1-Ola (30 ml) was added dropwise hydrazine hydrate (2 ml, 40 mmol) and the reaction mixture was heated at 100°C overnight. The solvent was removed under reduced pressure and the precipitate was collected by filtration, washed with water and dried in vacuum to give 6-bromo-1H-indazol-3-amine (2.11 g, 98% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,47 (s, 1H), 7,32 (d, J=8.4 Hz, 1H), 7,39 (s, 1H), 6,99 (d, J=8.4 Hz, 1H), 5,42 (lat.s, 2H).

B. 6-Bromo-1-methyl-1H-indazol-3-amine. To a solution of 6-bromo-1H-indazol--amine (2.11 g, 10 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in mineral oil, 0.4 g, 10 mmol) in portions at 0°C. Upon completion of addition the mixture was stirred for 30 minutes at 0°C and added itmean (1.42 g, 10 mmol). The resulting mixture was stirred at room temperature over night. The reaction was quenched by adding water (50 ml) and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated. The residue was purified on a column of silica gel (elwira using 10-25% ethyl acetate in petroleum ether) to give 6-bromo-1-methyl-1H-indazol-3-amine (1,36 g, 61% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) and 7.60 (m, 2H), 6,99 (d, J=8,0 Hz, 1H), 5,52 (s, 2H), 3,68 (s, 3H); MS (ESI): m/z to 326.1 [M+1]+.

C. tert-Butyl 6-bromo-1-methyl-1H-indazol-3-ylcarbamate. A mixture of 6-bromo-1-methyl-1H-indazol-3-amine (1,36 g, 6 mmol), di-tert-BUTYLCARBAMATE (2,62 g, 12 mmol), triethylamine (1.22 g, 12 mmol) and N,N-dimethylpyridin-4-amine (24 mg, 0.2 mmol) in dichloromethane (40 ml) was stirred at room temperature over night. Added water and the organic layer was separated, the aqueous phase was extracted with dichloromethane. The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product eyes�Ali on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give tert-butyl 6-bromo-1-methyl-1H-indazol-3-ylcarbamate (480 mg, 25% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,80 (s, 1H), 7,29 (d, J=8.4 Hz, 1H), made 7.16 interest (d, J=8.4 Hz, 1H), 3,98 (s, 3H), of 1.41 (s, 9H); MS (ESI): m/z 426,1 [M+1]+.

Intermediate compound 29: to a Mixture of 1-(tetrahydro-2H-Piran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 1-(tetrahydro-2H-Piran-2-yl)-5-(4,4,5,5 - tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole

A. 6-Bromo-1H-benzo[d]imidazole. A mixture of 4-Brabanthal-1,2-diamine (2 g, 0,011 mol), triethylorthoformate (10 ml) and pyridine p-toluensulfonate (300 mg, 0.001 mole) was heated at boiling with reflux during the night. The mixture was evaporated in vacuum. The residue was purified on a column of silica gel (elwira using 10-20% ethyl acetate in petroleum ether) to give 6-bromo-1H-benzo[d]imidazole (1.3 g, 65% yield).1H NMR (300 MHz, DMSO-d6) δ (M. D.) 12,60 (lat.s, 1H), 8,24 (s, 1H), 7,83 (m, 1H), 7,60 (m, 1H), 7,32 (m, 1H).

B. 6-Bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-benzo[d]imidazole and 5-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-benzo[d]imidazole. A mixture of 6-bromo-1H-benzo[d]imidazole (1.3 g, 6,6 mmol), 3,4-dihydro-2H-PYRAN (7 ml) and p-toluensulfonate acid (300 mg, 1,57 mmol) in tetrahydrofuran (50 ml) was heated at 60°C over night. The reaction mixture was poured into ice water and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate pack�Riva under reduced pressure. The residue was purified on a column of silica gel (elwira using 2-10% ethyl acetate in petroleum ether) to give a mixture of 6-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-benzo[d]imidazole and 5-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-benzo[d]imidazole (800 mg, 44% yield).

C. 1-(Tetrahydro-2H-Piran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 1-(tetrahydro-2H-Piran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole. Degassed mixture of 6-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-benzo[d]imidazole and 5-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-benzo[d]imidazole (800 mg, 2.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)a (1.4 g, 5.6 mmol), of palladium acetate (65 mg, 0.28 mmol), triphenylphosphine (220 mg, 0,84 mmol) and potassium phosphate (1 g, 4.7 mmol) in 1,2-dimethoxyethane (15 ml) was heated at 100°C in a nitrogen atmosphere over night. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under die cast technology. The residue was purified on a column of silica gel with obtaining a mixture of 1-(tetrahydro-2H-Piran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 1-(tetrahydro-2H-Piran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (470 mg, yield 51%).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8.48 to (C, H 0,55), to 8.42 (s, 0,45 H), 7,95 (s, 0,45 H), 7,93 (C, H 0,55), 7,60-7,54 (m, 2H), 5,79 (DD, J1=10,4 Hz, J2=2,0 Hz, 0,55 H), 5,69 (DD, J1=10,4 Hz, J2=2,0 Hz 0,45 H), 3,99 (m, 1H), of 3.77 (m, 1H), 2,0-1,60 (m, 6H), 1,32 (s, 12H).

Intermediate compound 30: 1-(Tetrahydro-2H-Piran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol

A. 6-Bromo-1H-indazole. A mixture of 4-bromo-2-forventelige (2 g, 10 mmol) and an aqueous solution of hydrazine (10 ml, 85%) was heated at boiling with reflux during the night. After cooling to room temperature the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified on a column of silica gel (elwira using 10-20% ethyl acetate in petroleum ether) to give 6-bromo-1H-indazole (1.3 g, 68% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 13,17 (lat.s, 1H), 8,09 (s, 1H), of 7.75 (s, 1H), 7,73 (d, J=8,8 Hz, 1H), 7.23 percent (DD, J1=8,8 Hz, J2=1.6 Hz, 1H).

B. 6-Bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol. A mixture of 6-bromo-1H-indazole (1.3 g, 6,6 mmol), 3,4-dihydro-2H-PYRAN (7 ml) and p-toluensulfonate acid (300 mg, 1,57 mmol) in tetrahydrofuran (50 ml) was heated at 60°C over night. The reaction mixture was poured into ice water and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a column of silica gel (elwira using 5-15% ethyl acetate in petroleum ether) with�teaching 6-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (800 mg, yield 44%).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,13 (s, 1H), 8,03 (s, 1H), 7,74 (d, J=8.4 Hz, 1H), 7,32 (DD, J1=8.4 Hz, J2=1.6 Hz, 1H), 5,88 (DD, J1=9,6 Hz, J2=2.4 Hz, 1H), 3,90-3,70 (m, 2H), is 2.40 (m, 1H), 2,05-1,90 (m, 2H), 1,65 (m, 1H), 1,53-of 1.45 (m, 2H).

C. 1-(Tetrahydro-2H-Piran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol. Degassed mixture of 6-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (800 mg, 2.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)a (1.4 g, 5.6 mmol), palladium acetate (65 mg, 0.28 mmol), triphenylphosphine (220 mg, 0,84 mmol) and potassium phosphate (1 g, 4.7 mmol) 1.2-dimethoxyethane (15 ml) was heated at 100°C in a nitrogen atmosphere over night. After cooling to room temperature the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a column of silica gel (elwira using 5-15% ethyl acetate in petroleum ether) to give 1-(tetrahydro-2H-Piran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (470 mg, 51% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,13 (s, 1H), 7,99 (s, 1H), to 7.77 (d, J=8.4 Hz, 1H), 7,45 (d, J=8,0 Hz, 1H), 5,98 (DD, J1=9,6 Hz, J2=2.4 Hz, 1H), 3,83-of 3.77 (m, 2H), 2,39 (m, 1H), 2,01-of 1.96 (m, 2H), is 1.81 (m, 1H), 1,58-of 1.56 (m, 2H), 1,32 (s, 12H).

Intermediate 31: 1-(6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylethanamine

A. 6-Bromo-2-(chloromethyl)-1H-benzo[d]imides�L. A mixture of 4-Brabanthal-1,2-diamine (1.8 g, 0.01 mol) and hydrochloride of ethyl 2-chloracetamide (1.59 g, 0.01 mol) in anhydrous ethanol (20 ml) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, the residue was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuum to give 6-bromo-2-(chloromethyl)-1H-benzo[d]imidazole (2.0 g, 82% yield) as a solid substance. MS (ESI): m/z 246,7 [M+1]+.

B. 1-(6-Bromo-1H-benzo[d]imidazol-2-yl)-N,N-dimethylethanamine. A mixture of 6-bromo-2-(chloromethyl)-1H-benzo[d]imidazole (2.0 g, 8,23 mmol) and aqueous dimethylamine (6.7 g, 0.04 mole) in acetonitrile (25 ml) was stirred at room temperature over night. The solvent was removed under reduced pressure to obtain crude product, which was purified using chromatography on silica gel (elwira ethyl acetate) to give 1-(6-bromo-1H-benzo[d]imidazol-2-yl)-N,N-diethylethanamine (1.2 g, 57.7% of output) in the form of solids. MS (ESI): m/z 255,8 [M+1]+.

C. 1-(6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylethanamine. To a solution of 1-(6-bromo-1H-benzo[d]imidazol-2-yl)-N,N-dimethylethanamine (1.1 g, of 4.35 mmol) in N,N-dimethylformamide (10 ml) at 0°C was added sodium hydride (191 mg, 4,78 mmol) in portions under a nitrogen atmosphere. On superseniority the mixture was stirred at 0°C for 30 minutes, was added (2-(chloromethoxy)ethyl)trimethylsilane (794 mg, 4,78 mmol) and the resulting mixture was stirred at 0°C for 1 hour, then was warmed to room temperature and stirred over night. Added water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuum and the residue was purified on a column of silica gel (elwira using 50% ethyl acetate in petroleum ether) to give 1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-N,N-diethylethanamine (1.2 g, 72.3 percent yield) in the form of solids. MS (ESI): m/z 385,9 [M+1]+.

Intermediate 32: 6-Bromo-2-methoxyquinoline

A. 3,4-Dihydroquinoline-2(1H)-he. A mixture of (E)-3-(2-nitrophenyl)acrylic acid (60 g, 0,31 mol) and palladium on charcoal (10% mass/mass, 6 g) in methanol (1 l) was gidrirovanie at a hydrogen pressure of 50 lb/inch2(3,515 kg/cm2) at room temperature over night. The catalyst was filtered and the filtrate concentrated to give 3,4-dihydroquinoline-2(1H)-he (36 g, 79% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,01 (s, 1H), 7,07 (m, 2H), 6,84 (m, 1H), of 6.79 (m, 1H), 2,80 (t, J=7,2 Hz, 2H), of 2.38 (t, J=7,2 Hz, 2H).

B. 6-Bromo-3,4-dihydroquinoline-2(1H)-he. A mixture of 3,4-dihydroquinoline-2(1H)-she (10 g, 0,068 mol) and N-bromosuccinimide (4.3 g, 0,075 mol) in dichloromethane (300 ml) was heated at 80°C over night. Pic�e cooling to room temperature, the precipitate was filtered and the filtrate concentrated. The residue was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 6-bromo-3,4-dihydroquinoline-2(1H)-she (9.5 g, 62% yield) as a solid substance. MS (ESI): m/z 226,1 [M+1]+.

C. 6-Bromo-2-chlorhydrin. A mixture of 6-bromo-3,4-dihydroquinoline-2(1H)-it (1 g, 4.4 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1 g, 4.5 mmol) and oxytrichloride phosphorus (3 ml) in toluene (10 ml) was stirred at 90°C overnight. The solvent was evaporated in vacuo, the residue was diluted with water and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira using 10-15% ethyl acetate in petroleum ether), to obtain 6-bromo-2-chlorhydrin (960 mg, 91% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) to 8.38 (d, J=8,8 Hz, 1H), 8,32 (s, 1H), 7,91 (d, J=8,8 Hz, 1H), a 7.85 (d, J=8,8 Hz, 1H), 7.62 mm (d, J=8,8 Hz, 1H).

D. 6-Bromo-2-methoxyquinoline. Metallic sodium (95 mg, 4.1 mmol) was dissolved in anhydrous methanol (50 ml) was added 6-bromo-2-chlorhydrin (500 mg, 2.1 mmol), then the mixture was heated to 80°C for 5 hours. The solvent was evaporated under reduced pressure and the residue was diluted with water. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate� and evaporated under reduced pressure to obtain 6-bromo-2-methoxyquinoline (483 mg, 98% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,10 (d, J=9,2 Hz, 1H), 8,04 (s, 1H), 7,65 (d, J=8,8 Hz, 1H), members, 7.59 (d, J=8,8 Hz, 1H), of 6.96 (d, J=9,2 Hz, 1H), 3,86 (s, 3H).

Intermediate 33: 6-Bromo-1-methyl-1H-benzotriazole

A. 6-Bromo-1-methyl-1H-benzo[d][1,2,3]triazole. To a solution of 5-bromo-N1-methylbenzol-1,2-diamine (1.6 g, 8 mmol) in hydrochloric acid (5 M, 20 ml) was added a solution of sodium nitrite (1.1 g, 16 mmol) at 0°C and the reaction mixture was stirred at room temperature for 2 hours. The solution was neutralized to pΗ=7~8 using a saturated solution of sodium bicarbonate and the mixture was extracted with ethyl acetate (20 ml×3). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuum to give crude product, which was purified on a column of silica gel (elwira using 0-10% ethyl acetate in petroleum ether), to obtain 6-bromo-1-methyl-1H-benzo[d]1,2,3]triazole (800 mg, 47% yield) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) a 7.85 (d, J=8,8 Hz, 1H), of 7.64 (d, J=1.6 Hz, 1H ), 7,40 (DD, J1=8,8 Hz J2=1.6 Hz, 1H), 4,19 (s, 3H); MS (ESI): m/z 212,2 [M+1]+.

Intermediate 34: hydrochloride (±)-CIS-3-aminocyclohexanol

A. 2-(Cyclohex-2-enyl)isoindoline-1,3-dione. Triphenylphosphine on a polymeric substrate (12,01 g, 30,6 mmol),�of indoline-1,3-dione (5,01 g, To 34.1 mmol) and cyclohex-2-enol (3,05 ml, 30,6 mmol) was weighed in a 200-ml flask. Was added tetrahydrofuran (60 ml). The mixture was stirred and cooled to 0°C, was then added dropwise, diisopropylcarbodiimide (DIAD) (6.5 ml, the 33.4 mmol) for 2 minutes. The reaction mixture was stirred and gave to slowly warm to room temperature. After 20 hours the reaction mixture was filtered through celite using ethyl acetate, then concentrated to obtain a yellow solid substance. This substance was dissolved in hot ethyl acetate (~40 ml) and hexane was added (~15 ml) to initiate crystallization by-product. The yellow supernatant was decanted, concentrated, then dissolved in tetrahydrofuran and purified flash chromatography on silica gel (0-20% ethyl acetate in hexane) to give 2-(cyclohex-2-enyl)isoindoline-1,3-dione (3,2053 g, 14,10 mmol, 46.1 per cent of output). (ESI): m/z to 228.6 [M+1]+.

B. Intermediate compound A. In a 200-ml flask was added 2-(cyclohex-2-enyl)isoindoline-1,3-dione (3,2053 g, 14,10 mmol), chloroform (50 ml) and ethanol (2.0 ml). The solution was stirred at room temperature was added N-bromosuccinimide (3.19 g, 17,92 mmol) (svejeprigotovlenny from the hot water). The flask was closed and the reaction mixture tameshiwari at room temperature. After 16 hours the reaction was quenched by adding 10% solution of sodium bisulfite, then� was diluted with ethyl acetate and water. The organic layer was removed and the aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over magnesium sulfate, filtered and concentrated, then dissolved in dichloromethane and injected into the column 40 biotage AB+M. Elution of the product was carried out using 0-20% ethyl acetate/hexane, obtaining the desired Intermediate compound A (1,975 g, 5,61 mmol, 39.8% of output) in the form of a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,78 (l, J=of 7.03 Hz, 1H), members, 7.59-7,66 (m, 1H), 7,50-EUR 7.57 (m, 2H), to 5.58 (lat.s, 1H), 4,57 (lat.s, 1H), 4.38 gigabytes (lat.s, 1H), 3,33-3,49 (m, 1H), 2,98-3,11 (m, 1H), of 2.57 (d, J=14,45 Hz, 1H), 2,06-2,30 (m, 2H), 1,67 (d, J=14,84 Hz, 1H), 1,30-of 1.43 (m, 2H), of 1.15 (t, J=of 7.03 Hz, 3H).

C. (±)-2-((1S,2R,3R)-2-Bromo-3-hydroxycyclohexyl)isoindoline-1,3-dione. Intermediate compound A (1,975 g, 5,61 mmol) was dissolved in methanol (25 ml) and added 2n hydrochloric acid solution (water.) (5 ml, 10,00 mmol). The reaction mixture was stirred at room temperature for 5 hours, then filtered through a glass filter with an average pore size and a white solid substance was washed with water. This solid substance was dried at room temperature in vacuum to give (±)-2-((1S,2R,3R)-2-bromo-3-hydroxycyclohexyl)isoindoline-1,3-dione (1,2218 g, 3.77 mmol, 67.2 per cent of output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,68-8,13 (m, 4H), 5,39 (d, J=6,64 Hz, 1H), 4,42-4,78 (m, 1H), 4,25 (TD, J=11,71, 4,30 Hz, 1H), 3,47-3,71 (m, 1H), 1,90-2,12 (m, 2H), 1,79-1,89 (m, 1H), 1,67-to 1.77 (m, 1H), ,40-1,56 (m, 1H), 1,25-1,40 (m, 1H). (ESI): m/z 326,5 [M+1]+.

D. (±)-CIS-2-(3-Hydroxycyclohexyl)isoindoline-1,3-dione. (±)-2-((1S,2R,3R)-2-Bromo-3-hydroxycyclohexyl)isoindoline-1,3-dione (1,0933 g, 3,37 mmol), tributylstannyl (1,10 ml, 4,15 mmol), toluene (18 ml), methanol (2 ml) and (E)-2,2'-(diazen-1,2-diyl)bis(2-methylpropionitrile) (AIBN) (0,039 g, of 0.236 mmol) was added to a 100 ml flask. The flask was fitted with a reflux condenser and input for nitrogen, and the apparatus is purged with nitrogen. The flask was then placed in a 120°C oil bath for mixing. After 16 hours, LC/MS analysis showed the ratio ~1:1 product:starting material. To the reaction mixture was added another portion of tributylstannyl (1.1 ml, 3,37 mmol) and (E)-2,2'-(diazen-1,2-diyl)bis(2-methylpropionitrile)and (AIBN) (0,051 g, 0,311 mmol) and the solution was heated to boiling temperature with reflux for 24 hours. The cooled reaction mixture was then concentrated until a white semi-solid substance was dissolved again in tetrahydrofuran and methanol and injected in column (biotage AB 40+M. Flash chromatography in 10-60% ethyl acetate/hexane gave the desired (±)-CIS-2-(3-hydroxycyclohexyl)isoindoline-1,3-dione (0,5213 g, 2,125 mmol, 63,0% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,78-7,91 (m, 2H), 7,66-7,76 (m, 2H), 4,18 (t, J=12,49 Hz, 1H), 3,71 (TD, J=10,25, of 5.27 Hz, 1H), 2,27 (sq, J=11,84 Hz, 1H), 1,98-2,19 (m, 3H), 1.85 to of 1.96 (m, 1H), 1,69 (d, J=12,49 Hz, 1H)Of 1.51 (d, J=5,47 Hz, 1H), 1,25-of 1.44 (m, 3H). (ΕSI): m/z to 246.4 [M+1]+.

Ε. Hydrochloride (±)-CIS-3-amine�of cyclohexanol. In a flask containing (±)-CIS-2-(3-hydroxycyclohexyl)isoindoline-1,3-dione (0,5213 g, 2,125 mmol) was added ethanol (10 ml), then hydrazine hydrate (0,12 ml, 2,474 mmol). The flask was closed and placed for stirring in a 80°C oil bath. Within 5 hours, all the contents were dissolved. After 20 hours the reaction mixture was again added hydrazine (0.04 ml) and the reaction mixture was heated to boiling temperature with reflux for 5 hours, by which time TLC analysis showed that the starting material consumed. The reaction mixture was concentrated to about half volume, was then added 1 ml of concentrated HCl. The suspension was concentrated to obtain a solid, and this solid was ground into powder with water, filtered to remove the solid precipitate. The filtrate was concentrated to give the desired hydrochloride (±)-CIS-3-aminocyclohexanol (0,3338 g, 2,201 mmol, 104% yield) as HCl salt.1H NMR (400 MHz, DMSO-d6) δ (M. D.) and 8.04 (lat.s, 3H), 3,32-3,54 (m, 1H), 2,96 (d, J=4,69 Hz, 1H), 2,11 (d, J=11,71 Hz, 1H), 1,57-1,90 (m, 3H), of 1.08 and 1.33 (m, 3H), 0,93-1,07 (m, 1H).

Intermediate 35: hydrochloride of TRANS-(4-aminocyclohexyl)methanol

A. the hydrochloride of TRANS-(4-aminocyclohexyl)methanol. TRANS-4-(tert-Butoxycarbonylamino)cyclohexanecarbonyl acid (2.5 g, 10,28 mmol) was dissolved in tetrahydrofuran (00 ml) was then added and the complex of 1M borane•tetrahydrofuran (10,28 ml 10,28 mmol). The solution was heated to 60°C and then the reaction mixture was added dropwise methanol (25 ml). The reaction mixture was stirred 30 minutes and then concentrated. To the residue was added 4n solution of hydrogen chloride in dioxane, stirred for 5 minutes and then concentrated. This solid substance was ground into powder in 10% methanol in ethyl acetate to give a white solid (1.11 g, 6,70 mmol, 65.2% of output). MS (ESI) m/z 230,4 [M]+.

Intermediate 36: hydrochloride of CIS-(4-aminocyclohexyl)methanol

A. the Hydrochloride of CIS-(4-aminocyclohexyl)methanol. To CIS-4-aminocyclohexanecarboxylic acid (2 g, of 13.97 mmol) was added tetrahydrofuran (100 ml) and borane-methylsulfinyl complex (13,26 ml, 140 mmol). The solution was heated to 60°C for 24 hours in a nitrogen atmosphere. The reaction was quenched with methanol and then concentrated. The residue was purified on a column of silica gel (0-100% ethyl acetate in hexane). The fractions containing the product were concentrated and then was added a 4n solution of hydrogen chloride in dioxane. The solution was concentrated and then triturated to powder with a 10% solution of methanol in ethyl acetate to give a white solid (1.6 g, 9.66 as per mmol, 69.1%, and output). MS (ESI) m/z of 130.1 [M]+.

Intermediate 37: hydrochloride of TRANS-2-(4-Aminocyclohexyl)propane-2-ol

A. TRANS-Methyl 4-(tert-butoxycarbonylamino)cyclohexanecarboxylate. TRANS-4-(tert-Butoxycarbonylamino)cyclohexanecarbonyl acid (2 g, 8,22 mmol), itmean (0,771 ml, 12,33 mmol), potassium carbonate (3,41 g, to 24.66 mmol) and acetone (20 ml) was heated in a flask high pressure up to 70°C for 16 hours. The reaction mixture was filtered, concentrated and purified on a column of silica gel (elwira using 0-20% ethyl acetate in hexane). The fractions containing the product were concentrated and then triturated to powder in hexane to give a white solid (1,08 g, 4.20 mmol, 51.1% of the output). MS (ESI) m/z 258,4 [M]+.

B. Hydrochloride of TRANS-2-(4-aminocyclohexyl)propane-2-ol. TRANS-Methyl 4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (0.5 g, 1,943 mmol) was dissolved in tetrahydrofuran (3 ml) and then cooled to -78°C in a nitrogen atmosphere. Added methylmagnesium (6,48 ml, 19,43 mmol, 3M in diethyl ether) and the reaction mixture was allowed to warm to room temperature for 18 hours. The reaction was quenched by adding a saturated solution of ammonium chloride and then was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and then concentrated. The residue was treated with a 4n solution of hydrogen chloride in dioxane at room temperature for 4 hours and then concentrated to give a white solid prophetic�STV. MS (ESI) m/z 158,3 [M+1]+.

Intermediate compound 38: N2-(4-methoxybenzyl)quinoline-2,6-diamine

A. 2-Chloro-6-nitroanilin. To a mixture of 6-nitro-3,4-dihydroquinoline-2(1H)-she (1.5 g, 7.8 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1,77 g, 7.8 mmol) in toluene (20 ml) was added dropwise phosphorus oxychloride (3,75 mmol) and the resulting solution was heated at 90°C for 3 hours. After cooling to room temperature the reaction was quenched by adding 50 ml of ice water. The mixture was podslushivaet using a 4n aqueous solution of sodium hydroxide to pH=7. The precipitate was collected by filtration, washed with ethyl ether and dried under high vacuum to give 2-chloro-6-nitroaniline (550 mg, 34% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 9.15 (s, 1H), 8,76 (d, J=8,8 Hz, 1H), 8,51 (m, 1H), 8,15 (d, J=9,2 Hz, 1H), 7,81 (d, J=8.4 Hz, 1H).

B. N-(4-Methoxybenzyl)-6-nitroindoline-2-amine. A mixture of 2-chloro-6-nitroaniline (500 mg, 2.4 mmol) and 4-methoxybenzylamine (10 ml) was heated at 120°C overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and the organic layer was washed with water 3 times, dried over anhydrous sodium sulfate and concentrated. The residue was purified on a column of silica gel (elwira using 2-10% ethyl acetate in petroleum ether) to give N-(4-methoxybenzyl)-6-nitroindoline-2-amine (96 mg, 13% yield) in the form of elm�Oh fluid. MS (ESI): m/z of 309.9 [M+1]+.

C. N2-(4-Methoxybenzyl)quinoline-2,6-diamine. To a solution of N-(4-methoxybenzyl)-6-nitroindoline-2-amine (96 mg, 0,31 mmol) in a mixture of tetrahydrofuran and methanol (V/V, 1:1, 20 ml) was added zinc powder (202 mg, 3.1 mmol) and ammonium chloride (167 mg, 3.1 mmol) at room temperature and the mixture was stirred at room temperature over night. TLC and LC/MS analysis showed that the reaction was completed. After filtration the filtrate was concentrated and the residue was purified on a column of silica gel (elwira using 10-50% ethyl acetate in petroleum ether) to give N2-(4-methoxybenzyl)quinoline-2,6-diamine (50 mg, 57.7% of output) in the form of liquid. MS (ESI): m/z 279,9 [M+1]+.

Intermediate 39: (±)-tert-Butyl 3-aminoadipic-1-carboxylate

A. (±)-Azepin-3-amine. To a solution of (±)-3-aminoadipic-2-she (3,65 g, 28.5 mmol) in tetrahydrofuran (30 ml) at 0°C in an atmosphere of nitrogen was added sociallyengaged (2.71 g, a 71.3 mmol) in portions. Upon completion of addition the reaction mixture was allowed to warm to room temperature, then heated at boiling with reflux for 5 days. Was slowly added water and the reaction mixture was filtered, the filter cake was washed with tetrahydrofuran (3×100 ml). United tetrahydropyranol phase was evaporated in vacuum to give ASEP�n-3-amine (2,28 g, 69,5% yield) as a yellow oil which was used directly in the next step.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 2,85 (m, 2H), 2,75 (m, 2H), 1,76 (m, 1H), 1,60 (m, 9H); MS (ESI): m/z 115,3 [M+1]+.

B. (±)-N-Benzylidene-3-amine. To a solution of (±)-azepin-3-amine (2,28 g, 0.02 mole) in dichloromethane (100 ml) was added benzaldehyde (2,54 g, 0,024 mol) followed by the addition of anhydrous sodium sulfate (3,41 g, 0,024 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated to give crude (±)-N-benzylidene-3-amine (4,61 g) which was used directly in the next step. MS (ESI): m/z 203,4 [M+1]+.

C. (±)-tert-Butyl 3-(benzylideneamino)azepin-1-carboxylate. To a mixture of (±)-N-benzylidene-3-amine (4,04 g, 0.02 mmol) and triethylamine (6,06 g, 0,06 mmol) in dichloromethane (60 ml) was added dropwise a solution of di-tert-BUTYLCARBAMATE (5,18 g, 0,024 mmol) in dichloromethane (20 ml) and the mixture was stirred at room temperature over night. Added water and the mixture was extracted with dichloromethane (3×50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give crude (±)-tert-butyl 3-(benzylideneamino)azepin-1-carboxylate (to 4.98 g) as a viscous liquid. MS (ESI): m/z 303,2 [M+1]+.

D. (±)-tert-Butyl 3-aminoadipic-1-carboxylate. The solution tre�-butyl 3-(benzylideneamino)azepin-1-carboxylate (1 g, And 3.31 mmol) in a mixture of acetic acid and dichloromethane (1:4, 20 ml) was stirred at room temperature for 24 hours. The solvent was removed and the residue was podslushivaet with sodium bicarbonate solution, the mixture was extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated to give crude product, which was purified on a column of silica gel (elwira using 5% methanol in dichloromethane) to give (±)-tert-butyl 3-aminoadipic-1-carboxylate (360 mg, 42% yield for three steps).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 2,87 (m, 1H), 2,77 (m, 1H), 2,52 (m, 1H), 1,80-of 1.30 (m, 8H); MS (ESI): m/z to 215, 4 [M+1]+.

Intermediate 40: CIS-4-(tert-Butyldimethylsilyloxy)cyclohexanol

A. CIS-4-(tert-butyldimethylsilyloxy)cyclohexanol. To a solution of CIS-cyclohexane-1,4-diol (500 mg, 4,31 mmol) and tert-butylcholinesterase (650 mg, 4,31 mmol) in N,N - dimethylformamide (3 ml) was added dropwise a solution of triethylamine (436 mg, 4,31 mmol) and 4-(dimethylamino)pyridine (21 mg) in N,N-dimethylformamide (1 ml) at 0°C. Upon completion of addition the mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated ol� reduced pressure and the residue was purified on a column of silica gel (elwira using 20% ethyl acetate in petroleum ether) to give CIS-4-(tert-butyldimethylsilyloxy)cyclohexanol (420 mg, 42,4% yield) as a liquid.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 3,81 (m, 2H), of 1.84 (m, 8H), of 0.90 (s, 9H), of 0.03 (s, 6H).

Intermediate 41: 2-(4-Itfinal)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

A. 2-(4-Itfinal)-1H-imidazole. To a solution of 4-iodobenzaldehyde (500 mg, 2.16 mmol) in methanol (20 ml) was added oxalanilide (40%) (5 ml) and 25% aqueous ammonium hydroxide solution (5 ml) and the mixture was stirred at room temperature over night. The precipitate was collected by filtration, washed with petroleum ether and dried under high vacuum to give 2-(4-itfinal)-1H-imidazole (500 mg, 86% yield). MS (ESI): m/z 270,9 [M+1]+.

B. 2-(4-Itfinal)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. To a solution of 2-(4-itfinal)-1H-imidazole (268 mg, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60 mg, 1.5 mmol) at 0°C in portions. After stirring the mixture at room temperature for one hour was added dropwise (2-(chloromethoxy)ethyl)trimethylsilane (196 mg, 1.2 mmol) and the mixture was stirred at room temperature over night. Was added water, the mixture was extracted with ethyl acetate 3 times, the organic layer was concentrated and washed with saturated sodium chloride solution 3 times. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-(4-itfinal)-1-((2-trimethylsilyl)ethoxy)meth�l)-1H-imidazole (217 mg, 54.7% of output) in the form of liquid, which was used directly in the next step. MS (ESI): m/z 400,9 [M+1]+.

Intermediate 42: 6-Morpholinopropan-3-amine

A. 4-(5-Nitropyridine-2-yl)morpholine. 2-Bromo-5-nitropyridine (1 g, 5 mmol) was dissolved in morpholine (5 ml) and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with n-hexane, dried under high vacuum to give 4-(5-nitropyridine-2-yl)morpholine (0.9 g, 90% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 9,04 (s, 1H), 8,23 (d, J=6,8 Hz, 1H), 8,51 (d, J=9,2 Hz, 1H), 3,83 (m, 4H), of 3.75 (m, 4H).

B. 6-Morpholinopropan-3-amine. To a solution of 4-(5-nitro-pyridin-2-yl)morpholine (0.8 g, 3,83 mmol) in a mixture of methanol and tetrahydrofuran (V/V, 1:1, 40 ml) at room temperature was added ammonium chloride (2,07 g, a 38.3 mmol), followed by the addition of zinc dust (2,49 g, a 38.3 mmol), the mixture is then stirred at room temperature over night. The reaction mixture was filtered on celite and washed with methanol. The combined filtrates were concentrated and the residue was diluted with saturated brine (20 ml) and was extracted with ethyl acetate (15 ml ×3). The organic layers were dried over sodium sulfate and concentrated to give crude product, which was purified on a column of silica gel (elwira by 10 - 70% atilas�Tata in petroleum ether), obtaining 6-morpholinopropan-3-amine (330 mg, 48.2% of output) in the form of a black solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) members, 7.59 (s, 1H), 6,91 (m, 1H), 6,60 (d, J=8,8 Hz, 1H), 4,57 (lat.s, 2H), 3,66 (m, 4H), 3,16 (m, 4H); MS (ESI): m/z 180,0 [M+1]+.

Intermediate 43: CIS-4-Amino-1-methylcyclohexanol

A. TRANS-4-(Dibenzylamino)cyclohexanol. TRANS-4-Aminocyclohexanol (15,69 g, 136 mmol) and sodium bicarbonate (37,8 g, 450 mmol) was suspended in ethanol (300 ml), treated with benzylchloride (45.9 per ml, 395 mmol) and stirred at 75°C for 16 hours. The suspension was filtered and the filtrate obtained was concentrated to give a yellow waxy solid. This solid was then dissolved in methylene chloride (400 ml) and washed with 1 n sodium hydroxide solution (2×100 ml), saturated brine (1×100 ml), dried over magnesium sulfate and concentrated to give an off-white waxy solid which when left standing at room temperature formed a yellow liquid containing waxy solid, which according to TLC analysis contained both the product and the excess benzylchloride. This substance was dissolved in a simple ether (300 ml) and the desired product extracted in the form of an amine salt with 1N aqueous hydrochloric acid solution (1×300 ml). TLC analysis of n�ordered benzylchloride in the ether layer and the product in aqueous layer. The aqueous layer was then washed with ethyl acetate (200 ml), then neutralized using 6N aqueous sodium hydroxide solution, then 1N aqueous sodium hydroxide solution and extracted in the form of a free amine using ethyl acetate (300 ml). The organic layer is then dried over magnesium sulfate and concentrated to give the product as a white solid (37,12 g, 92%).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,31 (dt, J=7,26, 14,47 Hz, 8H), up 7.17-7.23 percent (m, 2H), 4,42-to 4.46 (m, 1H), 3,55 (s, 4H), 3,26-of 3.33 (m, 1H), 2,29-2,41 (m, 1H), 1,71-of 1.88 (m, 5H), 1,34-of 1.46 (m, 2H), of 0.91-of 1.12 (m, 3H). Rf= 0,11 (TLC, 20% ethyl acetate in hexane); MS (ESI) m/z 296,5 [M+1]+.

B. 4-(Dibenzylamino)cyclohexanone. A solution of dimethyl sulfoxide (5,77 ml, 81 mmol) in methylene chloride (20 ml) was added dropwise to a solution of oxalicacid (3,26 ml and 37.2 mmol) in methylene chloride (150 ml) with stirring at -78°C. After stirring for 15 minutes at -78°C was added dropwise a solution of TRANS-4-(dibenzylamino)cyclohexanol (10.0 g, to 33.9 mmol) in methylene chloride (100 ml). After stirring at -78°C for 15 minutes was added dropwise triethylamine (23,59 ml, 169 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture became a suspension, and it was washed with saturated brine (100 ml). The organic layer was separated, dried over magnesium sulfate � concentrated to give a colorless oil, which was purified using column flash chromatography on silica gel (5-100% ethyl acetate in hexane) obtaining specified in the header connection in the form of a colorless oil (8,11 g, 82% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,35-7,39 (m, 4H), 7,28-to 7.33 (m, 4H), 7,18-7,24 (m, 2H), 3,61 (s, 4H), 2,89-to 2.99 (m, 1H), 2.26 and-of 2.38 (m, 2H), 2,14-of 2.24 (m, 2H), of 2.06 (dt, J=2,81, gold 6.43 Hz, 2H), 1,81 (HPC, J=4,27, 12,49 Hz, 2H), Rf= 0,36 (TLC, 20% ethyl acetate in hexane); MS (ESI) m/z 294,4 [M+1]+.

C. CIS-4-(Dibenzylamino)-1-methylcyclohexanol and TRANS-4-(dibenzylamino)-1-methylcyclohexanol. A solution of 3.0 M of methylmagnesium/ether (11,95 ml and 35.8 mmol) in anhydrous simple ether (100 ml) was added dropwise during 15 minutes to a solution of 4-(dibenzylamino)cyclohexanone (8,09 g, 27.6 mmol) in anhydrous simple ether (200 ml). The turbid reaction mixture was stirred at room temperature for 16 hours. It was found that the reaction is completed only 75% according to NMR and LC/MS (using TIC). Additionally, there was added 3.0 M of methylmagnesium/ether (3 ml, 9 mmol) and the mixture was stirred for 20 hours. The reaction was quenched when carefully poured into an aqueous solution of ammonium chloride (250 ml), causing the formation of sludge. Both layers (and suspension) was stirred for 10 minutes, causing a transition of the precipitated substances in the solution. The ether layer was separated, dried over magnesium sulfate and koncentrirovalisb yield a colorless oil, which was purified using column flash chromatography on silica gel (0-50% ethyl acetate in hexane) to separate the CIS and TRANS isomers (CIS: Rƒ= 0,33; TRANS: Rƒ= 0,20, 20% ethyl acetate in hexane). For both isomers was required further chromatography. The fractions containing the CIS-isomer was purified using column flash chromatography on silica gel (0-20% ethyl acetate in hexane) to give product as a white solid (1,54 g, 18%).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,32-value of 7, 37 (m, 4H), 7,25-7,32 (m, 4H), made 7.16 interest-7,22 (m, 2H), 4,00 (s, 1H) and 3.59 (s, 4H), 2,29-to 2.40 (m, 1H), 1,66-to 1.79 (m, 2H), 1,54 (d, 4H), 1,07-1,19 (m, 2H), of 1.02 (s, 3H).

TRANS-isomer also needed additional column chromatography (0-20% ethyl acetate in hexane), to obtain the TRANS-isomer as a white solid (1.70 g, 20%).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,32-value of 7, 37 (m, 4H), 7,26-7,32 (m, 4H), made 7.16 interest of 7.24 (m, 2H), 4,18 (s, 1H), only 3.57 (s, 4H), of 2.33 is 2.44 (m, 1H), 1,69 (d, J=10,15 Hz, 2H), of 1.55 (d, J=12,20 Hz, 2H), 1,36-1,49 (m, 2H), 1,16-of 1.29 (m, 2H), Of 1.09 (s, 3H). MS (ESI) m/z 310.5 to [M+1]+.

D. CIS-4-Amino-1-methylcyclohexanol. CIS-4-(Dibenzylamino)-1-methylcyclohexanol (0,770 g, 2,488 mmol) was dissolved in ethanol (25 ml), treated with 20% palladium hydroxide on carbon (0,349 g, 2,488 mmol) and stirred in hydrogen atmosphere for 2 days. The suspension was filtered through Celite and the obtained filtrate was concentrated to give product as a pale behold�CSO solids (0,308 g, 96% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 2,42 (TT, 1H), 1,29-of 1.54 (m, 6H), 1,18-of 1.29 (m, 2H). MS (ESI) m/z of 130.1 [M+1]+.

Intermediate 44: TRANS-4-Amino-1-methylcyclohexanol

A. TRANS-4-Amino-1-methylcyclohexanol. TRANS-4-(Dibenzylamino)-1-methylcyclohexanol (at 0.787 g, 2.54 mmol) was dissolved in ethanol (25 ml), treated with 20% palladium hydroxide on carbon (0,357 g, 2.54 mmol) and stirred in an atmosphere of hydrogen for 16 hours. The suspension was filtered through a layer of celite and concentrated to give the product as an off-white solid (0,311 g, 95% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 3,44 (sq, J=6,98 Hz, 2H), 2,55-of 2.66 (m, 1H), of 1.64 (DD, J=3,83, 12,96 Hz, 2H), 1,50 (d, J=13,03 Hz, 2H), 1,25-1,38 (m, 2H), 1,00-1,15 (m, 6H). MS (ESI) m/z of 130.1 [M+1]+.

Intermediate 45: tert-Butyl 4-methyleneimine-1-carboxylate

A. tert-Butyl 4-methyleneimine-1-carboxylate. To a solution of 1-benzyl-4-methyleneimine (1.0 g, of 5.34 mmol) in dichloromethane (53,4 ml) at 0°C was added dropwise 1-chloroethylnitrosourea (0,840 g, 5,87 mmol). The reaction mixture is then heated to the boiling point of the solvent for 2 hours. The solvent was removed under reduced pressure and replaced with methanol (20 ml). The solution was then heated to 75°C for 4 hours. The solvent was removed under reduced pressure and �the STATCOM was dissolved in 5 ml of 0.5 n aqueous HCl. The solution was washed with diethyl ether 3 times, and the aqueous phase was evaporated to dryness. The water was subjected to azeotropic distillation with methanol (2×5 ml). LC/MS analysis confirmed the absorption of the starting material. The substance (colorless needle crystals) was used without further purification.

A solution of 4-methylenetetrahydrofolate (0,714 g, of 5.34 mmol) in dichloromethane (39.6 ml) was cooled to 0°C and treated with triethylamine (1,563 ml, 11.21 per mmol) and then di-tert-BUTYLCARBAMATE (1,240 ml of 5.34 mmol). The bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water and the organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel (5-20% ethyl acetate in hexane). tert-Butyl 4-methyleneimine-1-carboxylate (0,974 g, 4,94 mmol, 92% yield) was isolated as a colorless oil.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) to 4.75 (s, 2H), 3,40 (t, J=5,86 Hz, 4H), 2,11-of 2.21 (m, 4H), 1,40-of 1.47 (m, 9H).

Intermediate 46: tert-Butultimately(4-methyltrichlorosilane)silane

A. tert-Butultimately(4-methyltrichlorosilane)silane. To a suspension of methyltriphenylphosphonium (6,26 g, 17,51 mmol) in tetrahydrofuran (88 ml) at 0°C was added dropwise a solution of n-utility in hexane (2.5 M, 7,29 ml, 18,21 mmol) with vigorous stirring. With�Spence became bright orange. The reaction mixture was warmed to room temperature, then was added a solution of 4-(tert-butyldimethylsilyloxy)cyclohexanone (4.0 g, 17,51 mmol) in anhydrous tetrahydrofuran (10 ml) at room temperature. When you add a yellow precipitate was formed, and its amount has increased by the end of the Appendix. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then decanted and filtered. The obtained solid substance was washed with hexane and the filtrate was evaporated to dryness. The residue was purified using column chromatography (2 columns, the sample was loaded in the form of a solution in dichloromethane) and was suirable using 5-10% ethyl acetate in hexane. tert-Butultimately(4-methyltrichlorosilane)silane (3,339 g of 14.75 mmol, 84% yield) was isolated as a bright yellow-green oil.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 4,52 (s, 2H), 3,76-3,86 (m, 1H), 2,23-of 2.32 (m, 2H), 1,92-2,03 (m, 2H), 1,61-of 1.74 (m, 2H), 1,35-1,49 (m, 2H), 0,78-0,85 (m, 9H), -0,04-0,03 (m, 6H).

Intermediate compound 47: 2-(5-Bromopyridin-2-yl)propan-2-ol

A. 2-(5-Bromopyridin-2-yl)propan-2-ol. 2,5-Dibromopyridine (15 g, at 63.3 mmol) was dissolved in toluene (750 ml) and then cooled to -78°C in a nitrogen atmosphere. To the solution was added dropwise n-butyllithium (about 1.7 M in pentane, with 30.4 ml, 76 mmol) and then stirred for 2 hours. To the solution was added acetone (to 5.58 ml, 76 mm�l) and then stirred for 1 hour at -78°C. The reaction mixture was allowed to warm to -10°C and then was added a saturated solution of ammonium chloride (150 ml). The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and then concentrated. The residue was purified using chromatography on silica gel (0-30% ethyl acetate in hexane) to give a clear, slightly colored oil (11.6 g, of 53.7 mmol, 85% yield). MS (ESI) m/z 216,1 [M]+.

Intermediate compound 48: N2N2-Dimethylpyridine-2,5-diamine

A. N,N-Dimethyl-5-nitropyridine-2-amine. 2-Bromo-5-nitropyridine (5 g of 24.8 mmol) in an aqueous solution of dimethylamine (33%, 20 ml) was stirred at room temperature over night. The precipitate was collected by filtration and recrystallized from methanol to obtain N,N-dimethyl-5-nitropyridine-2-amine (2.6 g, 63% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,95 (d, J=2,0 Hz, 1H), 8,18 (DD, J1=9,6 Hz, J2=2,0 Hz, 1H), 6,73 (d,J=9,6 Hz, 1H), 3,18 (s, 6H).

B. N2N2-Dimethylpyridine-2,5-diamine. A mixture of N,N-dimethyl-5-nitropyridine-2-amine (500 mg, 3 mmol) and 10% palladium on carbon (10% mass/mass, 50 mg) in ethanol (20 ml) were gidrirovanie under a hydrogen pressure of 1 ATM at room temperature for 1 hour. The catalyst was filtered and the filtrate concentrated to give N2N2 -dimethylpyridine-2,5-diamine (340 mg, 83% yield) as a viscous liquid. MS (ESI): m/z 138,1 [M+1]+.

Intermediate 49: 5-Aminonicotinamide

A. 5-Aminonicotinamide. A mixture of methyl 5-aminonicotinate (500 mg, or 3.28 mmol) in a mixture of methanol (5 ml) and ammonium hydroxide (5 ml) was stirred at room temperature over night. Was added water (30 ml) and the mixture was extracted with dichloromethane (15 ml ×4). The combined organic layer was washed with saturated brine (25 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain 5-aminonicotinamide (300 mg, 67% yield) in the form of solids.

Intermediate compound 50: 5-Methoxypyridine-3-amine

A. 2,6-Dibromopyridine-3-ol. Chilled with ice, a solution of bromine (50 g, 320 mol) in 10% aqueous sodium hydroxide solution (320 ml) was added dropwise to a stirred solution of pyridin-3-ol (10 g, 105 mmol) in 10% aqueous sodium hydroxide solution (110 ml). The solution was stirred at 0°C for 1 hour and then at room temperature for 4 hours. A small amount of white solid was filtered. The filtrate was cooled and was added concentrated hydrochloric acid to pH=1. The solid was filtered, washed with water, dried and recrystallized from carbon tetrachloride�kind of obtaining 2,6-dibrom-pyridin-3-ol (to 9.93 g, 37% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) is 11.17 (s, 1H), 7,47 (m, 1H), 7,25 (m, 1H); MS (ESI): m/z at 253.7 [M+H]+.

B. 2,6-Dibrom-3-methoxypyridine. A mixture of 2,6-dibromopyridine-3-ol (9,49 g, 37.5 mmol), potassium carbonate (4.75 g, to 34.4 mmol), dimethylsulfoxide (16 ml) and methyliodide (8 ml) was heated at boiling with reflux for 2 hours. The reaction mixture was poured into water (50 ml), the mixture was heated gently with stirring to evaporate the residual methyliodide. Methoxypyridine, precipitated by cooling the aqueous solution, and the solid is recrystallized from hexane to obtain 2,6-dibrom-3-methoxypyridine (4.0 g, 40% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,66 (d, J=8,0 Hz, 1H), 7,52 (d, J=8.4 Hz, 1H), 3,89 (s, 3H); MS (ESI): m/z 267,6 [M+H]+.

C. 2,6-Dibrom-3-methoxy-5-nitropyridine. To a solution of 2,6-dibrom-3-methoxypyridine (4.0 g, 0,015 mol) in sulfuric acid (20 ml) was added a mixture of sulfuric acid and nitric acid (V/V, 1:1) (40 ml) at 0°C. the Mixture was heated at 60-65°C overnight, cooled and neutralized with a saturated aqueous solution of sodium carbonate. The resulting mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layer was dried over sodium sulfate and concentrated to give 2,6-dibrom-3-methoxy-5-nitropyridine (1.3 g, 28% yield) in the form of solids.1H NMR (400 MHz, DMSO- 6) δ (M. D.) 8,24 (s, 1H), 3,99 (s, 3H).

D. 5-Methoxypyridine-3-amine. A mixture of 2,6-dibrom-3-methoxy-5-nitropyridine (0.3 g, 0.98 mmol), 10% palladium on carbon (50% mass/mass, 30 mg) in methanol (20 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature over night. The catalyst was filtered and the filtrate was concentrated in vacuum to give 5-methoxypyridine-3-amine (0.1 g, 92% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,54 (d, J=2,0 Hz, 1H), 7,45 (d, J=2,8 Hz, 1H), 6,48 (t, J=2.4 Hz, 1H), 5,31 (s, 2H), 3,71 (s, 3H).

Intermediate compound 51: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine

A. 6-Bromo-1H-imidazo[4,5-b]pyridine. A solution of 4-Brabanthal-1,2-diamine (2 g, 11 mmol) in formic acid (20 ml) was heated at boiling with reflux for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 6-bromo-1H-imidazo[4,5-b]pyridine as brown solid (2 g, 94% yield).

B. 6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine. To a solution of 6-bromo-1H-imidazo[4,5-b]pyridine (1 g, 5 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (300 mg, 7.5 mmol) in portions at 0°C. After stirring for 0.5 hours was added dropwise (2-hermeticity)-trimethylsilane (996 mg, 6 mmol). The resulting mixture was stirred at �anatoy temperature over night. Was added a saturated aqueous solution of ammonium chloride (20 ml) and the mixture was extracted with ethyl acetate (15 ml ×3). The combined organic layer was washed with saturated brine (20 ml), dried over sodium sulfate and concentrated. The residue was purified on a column of silica gel (elwira using 10-15% ethyl acetate in petroleum ether) to give 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (600 mg, 36.6% yield) as a pale yellow oil. NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 8.47 (s, 1H), 8,23 (s, 1H), to 8.19 (s, 1H), 5,65 (s, 2H), 3,61 (m, 2H), 0,93 (m, 2H), of 0.04 (s, 9H).

C. 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine. A mixture of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (400 mg, 1,22 mmol), bis(pinacolato)Debora (466 mg, to 1.83 mmol), tricyclohexylphosphine (68 mg, 0,24 mmol), Tris(dibenzylideneacetone)palladium(0) (112 mg, 0.12 mmol) and potassium acetate (240 mg, 2.4 mmol) in dioxane (10 ml) degassed and heated at 100°C in a nitrogen atmosphere over night. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified on a column of silica gel (elwira using 0-1% methanol in dichloromethane), to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (330 mg, 72% yield) as an oil.1H NMR (400 MHz, CL�ROFORM-d) δ (M. D.) 8,78 (s, 1H), 8,49 (s, 1H), 8,21 (s, 1H), 5,70 (s, 2H), 3,61 (t, J=8,0 Hz, 2H), of 1.36 (s, 12H), 0,92 (t, J=8,0 Hz, 2H), 0 (s, 9H); MS (ESI): m/z 376,1 [M+1]+.

Intermediate 52: 2-Methylpyridine-4-amine

A. 2-Methylpyridine-4-amine. A mixture of 2-methyl-4-nitropyridine (500 mg, 3.6 mmol) and iron powder (1 g, 18 mmol) in acetic acid (20 ml) was stirred 110°C for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using preparative TLC (elwira using 5% methanol in dichloromethane) to give 2-methylpyridine-4-amine (100 mg, 26% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,81 (d, J=5.6 Hz, 1H), 6,28 (s, 1H), of 6.25 (d, J=5.6 Hz, 1H), 5,82 (lat.s, 2H), 2,19 (s, 3H).

Intermediate compound 53: 2-(Benzyloxy)pyridin-4-amine

A. 2-(Benzyloxy)pyridin-4-amine. To a solution of benzyl alcohol (2.53 g, 23.4 mmol) in dioxane (10 ml) was added sodium hydride (1.15 g, of 28.75 mmol) at room temperature and the mixture was heated at boiling with reflux for 1.5 hours. After cooling to room temperature was added 2-chloropyridin-4-amine (1.5 g, 11.7 mmol) and the mixture was heated to 160°C for 12 hours in a nitrogen atmosphere. After cooling to room temperature the reaction mixture was poured into water (30 ml) and the mixture was extracted with ethyl acetate (20 ml ×3). Org�organic layer was concentrated under reduced pressure and the residue was purified on a column of silica gel (elwira using 10% methanol in ethyl acetate) to give 2-(benzyloxy)pyridin-4-amine (800 mg, 34.1% of output) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,95 (d, J=5.6 Hz, 1H), 7,51 (lat.s, 5H), 6,27 (s, 1H), 6,01 (s, 1H), 5,39 (s, 2H), 4,11 (lat.s, 2H).

Intermediate compound 54: 2-Methoxypyridine-4-amine

A. 2-Methoxypyridine-4-amine. A mixture of methanol (10 ml) and sodium hydride (60% in mineral oil, 624 mg, 15.6 mmol) was heated at boiling with reflux for 1.5 hours. The mixture was cooled to room temperature and was added 2-chloropyridin-4-amine (1.0 g, 7.8 mmol). The reaction mixture was heated to 160°C for 12 hours in a nitrogen atmosphere. After cooling to room temperature the reaction mixture was poured into water (30 ml) and the mixture was extracted with ethyl acetate (15 ml ×3). The combined organic layer was concentrated under reduced pressure and the residue was purified on a column of silica gel (elwira using 10% methanol in ethyl acetate) to give 2-methoxypyridine-4-amine (210 mg, 21.6% of output) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (MD), 7,83 (d, J=6,0 Hz, 1H), 6,21 (DD, J1=2,0 Hz, J1=6,0 Hz, 1H), 5,93 (d, J=1.6 Hz, 1H), 4,07 (lat.s, 2H), a 3.87 (s, 3H).

Intermediate compound 55: N2-(4-Methoxybenzyl)-N2-methylpyridine-2,4-diamine

A. N-(4-Methoxybenzyl)-N-methyl-4-nitropyridine-2-amine. A solution of 2-chloro-4-nitropyridine (1.0 g, 6.3 mmol) and 1-(4-methoxyphenyl)--methylmethanamine (1.5 g, 9,6 mmol) in dimethoxyethane (15 ml) was stirred at 100°C for 4 hours. The solvent was evaporated under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira petroleum ether) to give N-(4-methoxybenzyl)-N-methyl-4-nitropyridine-2-amine (0.65 g, 38% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 8.39 (d, J=4,2 Hz, 1H), 7,22 (m, 2H), made 7.16 interest (d, J=8,8 Hz, 2H), to 6.88 (d, J=8.4 Hz, 2H), 4,80 (s, 2H), 3,71 (s, 3H), 3,10 (s, 3H).

B. N2-(4-Methoxybenzyl)-N2-methylpyridine-2,4-diamine. A mixture of N-(4-methoxybenzyl)-N-methyl-4-nitropyridine-2-amine (0.5 g, to 1.83 mmol) and 10% palladium on carbon (50 mg, 50% mass/mass) in methanol (20 ml) under a hydrogen pressure of 1 atmosphere was stirred at room temperature over night. The reaction mixture was filtered and the filtrate concentrated to give N2-(4-methoxy-benzyl)-N2-methyl-pyridine-2,4-diamine (0,41 g, 92% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,60 (d, J=5.6 Hz, 1H), 7,10 (d, J=8.4 Hz, 2H), of 6.85 (d, J=8,8 Hz, 2H), 5,86 (m, 1H), 5,69 (d, J=1.6 Hz, 1H), of 5.60 (s, 2H), 4,62 (s, 2H), 3,71 (s, 3H) 2,84 (s, 3H); MS (ESI): m/z 244,0 [M+1]+.

Intermediate compound 56: 1-methyl-1H-indazol-6-amine

A. 1-methyl-6-nitro-1H-indazole. A mixture of 6-nitro-1H-indazole (3.3 g, 20 mmol) and sodium hydride (60% in mineral oil, 1.2 g, 30 mmol) in N,N-dimethylformamide (15 ml) was stirred at 0°C for 1 hour. Added methyliodide (8,5, 60 mmol) and the reaction mixture was stirred at room temperature over night. The reaction was quenched with water (50 ml) and was extracted with ethyl acetate (50 ml ×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a column of silica gel (elwira using 2-5% ethyl acetate in petroleum ether) to give 1-methyl-6-nitro-1H-indazole (1.9 g, 53% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,52 (m, 1H), 8,08 (d, J=1.2 Hz, 1H), 7,81 (m, 2H), 3,98 (s, 3H).

B. 1-methyl-1H-indazol-6-amine. A mixture of 1-methyl-6-nitro-1H-indazole (1 g, 5.6 mmol) in ethanol (50 ml) and 10% palladium on carbon (50% mass/mass, 100 mg) was gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature for 2 hours. The catalyst was filtered and the filtrate was concentrated to obtain 1-methyl-1H-indazol-6-ylamine (790 mg, 95,1%) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,67 (s, 1H), to 7.33 (d, J=8.4 Hz, 1H), 7,49 (m, 2H), 5,31 (lat.s, 2H), 3,80 (s, 3H).

Intermediate compound 57: 3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine

A. S-Iodo-6-nitro-1H-indazole. A solution of 6-nitro-1H-indazole (2.0 g, 12 mmol) in a mixture of 1,4-dioxane (50 ml) and aqueous sodium hydroxide solution (7.5 ml, 2 M) was stirred at room temperature for about 1 hour. Added iodine crystals (3.8 g, 15 mmol) and Rea�; the mixture was stirred at room temperature for 12 hours. The reaction was quenched with 10% aqueous citric acid solution and was extracted with ethyl acetate (100 ml ×3). The organic layer was washed with 10% aqueous sodium bicarbonate solution (100 ml) and saturated brine (100 ml), dried over sodium sulfate, filtered and concentrated to give 3-iodo-6-nitro-1H-indazole (3.2 g, 92% yield) as an orange solid substance. MS (ESI): m/z 289,9 [M+1]+.

B. 3-Iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol. To a solution of 3-iodo-6-nitro-1H-indazole (1.45 g, 5 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in mineral oil, 0.24 g, 6 mmol) at 0°C. After stirring for 1 hour to the mixture was added dropwise (2-hermeticity)trimethylsilane (1.0 g, 6 mmol) at 0°C and the reaction mixture was stirred at room temperature over night. Was added water (50 ml) and the mixture was extracted with ethyl acetate (30 ml ×4). The combined organic layer was dried and evaporated under reduced pressure and the residue was purified on a column of silica gel (elwira using 2-5% ethyl acetate in petroleum ether) to give 3-iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.78 g, 37% yield). MS (ESI): m/z 420,9 [M+1]+.

This reaction also was carried out using tetrahydrofuran as solvent, to obtain a 57% yield of 3-iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole.

C. 3-M�Teal-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol. Degassed mixture of 3-iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (754 mg, 1.8 mmol), methylboronic acid in tetrahydrofuran (432 mg, 3.6 mmol), an aqueous solution of potassium phosphate (2 M, 5 ml) and tetrakis(triphenylphosphine)palladium(0) (104 mg, 0.09 mmol) in dioxane (5 ml) was heated at 100°C overnight. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (elwira using 25-50% ethyl acetate in petroleum ether) to give 3-methyl-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0,48 g, crude). MS (ESI): m/z 308,1 [M+1]+.

This reaction can also be carried out in anhydrous dioxane using 3 equivalents of methylboronic acid, 3 equivalents of cesium carbonate as the base and 0.1 equivalent of tetrakis(triphenylphosphine)palladium(0) at 90°C overnight. Following this procedure, 3-methyl-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole was obtained with 82% yield after chromatography.

D. 3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine. To a solution of 3-methyl-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0,48 g, crude) in methanol (5 ml) was added 10% palladium on carbon (0.3 g, 50% wt/wt) and the mixture was gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature for 30 minutes. The catalyst was filtered and the filtrate concentrated. The residue was purified n� a column of silica gel (elwira using 3-5% ethyl acetate in petroleum ether) to give 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (138 mg, 32% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 7.42 (d, J=8.4 Hz, 1H), 6,66 (d, J=2,0 Hz,1H), to 6.58 (DD, J1=2,0 Hz, J2=8.4 Hz, 1H), 5,54 (s, 2H), of 5.34 (s, 2H), 3,89 (lat.s, 2H), 3,56 (t, J=8,0 Hz, 2H), 2,48 (s, 3H), of 0.91 (m, 2H), to -0.05 (d, J=3.2 Hz, 9H).

The output of this stage was increased to 100% when used purified 3-methyl-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol, eliminating the need for chromatography.

An intermediate connection 58: 4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

A. 4-(4-Bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. To a stirred solution of 4-(4-bromophenyl)-1H-imidazole (446 mg, 2 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added sodium hydride (60% in mineral oil, 96 mg, 2.4 mmol) at 0°C and the mixture was stirred at this temperature for 2 hours. Was added dropwise a solution of (2-(chloromethoxy)ethyl)trimethylsilane (545 mg, 3 mmol) in N,N-dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature for 4 hours. When the starting material was consumed, the reaction was quenched with water (50 ml) and the mixture was extracted with ethyl acetate (15 ml ×3). The combined organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and evaporated in vacuum. The residue was purified on a column of silica gel (elwira with POM�soup 5-10% ethyl acetate in petroleum ether) to give 4-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (440 mg, 62% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,80-7,84 (m, 2H), 7,71 (d, J=8.4 Hz, 2H), 7,52 (d, J=8.4 Hz, 2H), 5,32 (s, 2H), 3,49 (t, J=8,0 Hz, 2H), from 0.84 (t, J=8,0 Hz, 2H), or 0.06 (s, 9H); MS (ESI): m/z 353,0 [M+1]+.

B. 4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. Degassed mixture of 4-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (200 mg, 0,56 mmol), bis(pinacolato)Debora (158 mg, 0,62 mmol), potassium acetate (139 mg, of 1.42 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42 mg, 0,06 mmol) in N,N-dimethylformamide (5 ml) was stirred at 80°C over night. The reaction mixture was poured into ice water (30 ml) and the mixture was extracted with ethyl acetate (15 ml ×2). The organic layer was dried over sodium sulfate and evaporated in vacuum. The residue was purified on a column of silica gel (elwira using 10-20% ethyl acetate in petroleum ether) to give 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (120 mg, 62% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,90 (s, 1H), to 7.77 (s, 4H), 7,69 (s, 1H), 5,42 (s, 2H), 3,62 (t, J=8,0 Hz, 2H), of 1.37 (s, 12H), were 0.94 (t, J=8,0 Hz, 2H), of 0.01 (s, 9H); MS (ESI): m/z 386,2 [M+1]+.

Intermediate compound 59: tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)venaticorum

A. tert-Butyl 3-bromophenethylamine. A mixture of 2-(3 - bromophenyl)ethanamine (1 g, of 5.03 mmol), di-tert-boutillier�of Anata (1,64 mg, 7.5 mmol) in dichloromethane (20 ml) was stirred at room temperature for 1 hour. The solvent was removed to give tert-butyl 3-bromophenethylamine (1.5 g, 99.1% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) value of 7, 37 (d, J=7,6 Hz, 2H), 7.23 percent (m, 2H), 6,87 (t, J=5.6 Hz, 1H), 3,13 (m, 2H), 2,69 (t, J=7,2 Hz, 2H), of 1.35 (s, 9H).

B. tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)venaticorum. Degassed mixture of tert-butyl 3-bromophenethylamine (1.9 g, 6,35 mmol), bis(pinacolato)Debora (2.4 g, was 9.53 mmol), potassium acetate (1,56 g, 19 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (475 mg, 0,64 mmol) in dioxane (20 ml) was heated at 100°C in a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water (50 ml) and the mixture was extracted with ethyl acetate (20 ml ×2). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified on a column of silica gel (elwira using 0-5% ethyl acetate in petroleum ether) to give tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenetylamine (1.9 g, 86.4% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 7.48 (m, 2H), 7,30 (m, 2H), 6,86 (t, J=5.6 Hz, 1H), 3,10 (m, 2H), 2,68 (t, J=7,2 Hz, 1H), 1,29 (s, 12H), of 1.16 (s, 9H).

An intermediate connection 60: 3-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanenitrile

A. 3-(3-(4,4,,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanenitrile. Degassed mixture of 3-(3-bromophenyl)propanenitrile (1.05 g, 5 mmol), bis(pinacolato)Debora (1.9 g, 7.5 mmol), potassium acetate (1.47 g, 15 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0,37 g, 0.5 mmol) in dioxane (10 ml) was heated at 120°C in a nitrogen atmosphere for 4 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was purified using column chromatography on silica gel (elwira using 5% ethyl acetate in petroleum ether) to give 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanenitrile (1 g, 74% yield) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,73-of 7.70 (m, 2H), of 7.64 (s, 1H), of 7.36-7,32 (m, 2H), of 2.97 (t, J=7,6 Hz, 2H), 2,63 (t, J=7,6 Hz, 2H), of 1.35 (s, 12H).

An intermediate connection 61: 6-Methoxypyridine-2-amine

A. 6-Methoxypyridine-2-amine. A mixture of sodium (0.8 g, 34.8 mmol) in methanol (20 ml) was heated at boiling with reflux at 80°C. After absorption of sodium was added 6-bromopyridin-2-amine (3 g, to 17.4 mmol) and the reaction mixture was heated to 160°C in an autoclave for 3 hours. After cooling to room temperature, was added ethyl acetate (30 ml) and the mixture was filtered. The filtrate was concentrated in vacuum to give 6-methoxypyridine-2-amine (1.4 g, 63.6 per cent of the output).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) to 7.33 (t, J=8,0 Hz, 1H), of 6.06 (m, 2H), 3,83 (s, 1H).

An intermediate connection 62: 4-(4,,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate

A. 4-Bromopyridine 1-oxide. To a suspension of 4-broneeringukoodid (5.0 g of 25.9 mmol) in dichloromethane (50 ml) was added triethylamine (2,62 g of 25.9 mmol) at room temperature. After stirring for 0.5 hours was added in portions 3-chlorobenzotrichloride (4,46 g of 25.9 mmol) and the reaction mixture was stirred at room temperature for 5 hours. The solution was washed with a saturated aqueous solution of sodium thiosulfate (30 ml), saturated aqueous sodium carbonate solution (30 ml) and saturated brine (30 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira using 50-100% ethyl acetate in methanol), to obtain 4-bromopyridine 1-oxide in the form of a solid (2.1 g, 44.8% of output).

B. 4-Bromopicolinic. A mixture of 4-bromopyridine 1-oxide (2.0 g, 11,56 mmol), trimethylsilylacetamide (3,43 g, 34,68 mmol) and triethylamine (2,34 g, 23,12 mmol) in acetonitrile (10 ml) was stirred at 110°C in a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified on a column of silica gel (elwira using 20% ethyl acetate in petroleum ether) to give 4-bromopicolinic (1.52 g, 72.4% of the output).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 8.56 (d, J=4,2 Hz, 1H), of 7.88 (s, 1H), 7,73 (�, J=4,2 Hz, 1H).

C. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate. Degassed mixture of 4-bromopicolinic (1,50 g, 8,24 mmol), bis(pinacolato)Debora (4,19 g, 16,48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (600 mg, 0,82 mmol) and potassium acetate (2.0 g, 20.6 mmol) in dioxane (10 ml) was heated at 100°C in a nitrogen atmosphere over night. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified using chromatography on silica gel (elwira using 0-30% ethyl acetate in petroleum ether) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (1.8 g, 9.2% of output) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (MD), 8,73 (d, J=3.3 Hz, 1H), 8,02 (s, 1H), 7,83 (d, J=3,6 Hz, 1H), of 1.35 (s, 12H).

Intermediate 63: tert-Butyl 2-(4-aminopyridin-2-yloxy)ethylcarbamate

A. 2-Chloropyridin-4-amine. To a solution of 2-chloro-4-nitropyridine (13 g, of 82.3 mmol) in a mixture of 80% aqueous ethanol (50 ml) and concentrated hydrochloric acid (5 ml) was added iron powder (20 g, 357,1 mmol) and the mixture was heated at boiling with reflux for 3 hours. Was added sodium carbonate to neutralize the residual acid. The resulting mixture was filtered through Celite and concentrated. The residue was purified on a column of silica gel (LWIR�I'm using 0-10% methanol in dichloromethane) to give 2-chloropyridin-4-amine (6.8 g, 53,1 mmol, 64.5% of output) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) a 7.92 (t, J=7,6 Hz, 1H), 6,47 (d, J=2,0 Hz, 1H), 6,38 (DD, J1=7,6 Hz, J2=2,0 Hz, 1H), 4,36 (lat.s, 2H).

B. 2-(2-Aminoethoxy)pyridin-4-amine. A mixture of 2-aminoethanol (2.1 g, to 34.4 mmol) and sodium hydride (825 mg, to 34.4 mmol) in dioxane (20 ml) was heated at boiling with reflux for 1.5 hours and the mixture was cooled to room temperature and was added 2-chloropyridin-4-amine (4.0 g, 31,3 mmol). The mixture was heated to 160°C in a nitrogen atmosphere for 12 hours. After cooling to room temperature the reaction mixture was poured into water (50 ml). The mixture was extracted with ethyl acetate (30 ml ×3), the organic layer was combined, dried and concentrated under reduced pressure. The residue was purified on a column of silica gel (elwira using 10% methanol in ethyl acetate) to give 2-(2-aminoethoxy)pyridin-4-amine (1.0 g, 20,9% yield) in the form of solids. MS (ESI): m/z 154,2 [M+1]+.

C. tert-Butyl 2-(4-aminopyridin-2-yloxy)ethylcarbamate. A mixture of 2-(2-aminoethoxy)pyridin-4-amine (1.0 mg, of 6.54 mmol), di-tert-BUTYLCARBAMATE (1,42 mg of 6.54 mmol) in dichloromethane (20 ml) was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified using column chromatography on silica gel (elwira using 30-50% ethyl acetate in petroleum ether) to give tert-Buti� 2-(4-aminopyridin-2-yloxy)ethylcarbamate (900 mg, 54.5% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) members, 7.59 (d, J=6,0 Hz, 1H), 6,90 (lat.s, 1H), 6,15 (DD, J1=2,0 Hz, J2=5,6 Hz, 1H), 5,90 (lat.s, 2H), 5.78% was established (d, J=1.6 Hz, 1H), 4,10 (t, J=6,0 Hz, 2H), up 3.22 (m, J=6,0 Hz, 2H), of 1.37 (s, 9H).

Intermediate 64: 6-(Benzyloxy)pyridin-2-amine

A. 6-(Benzyloxy)pyridin-2-amine. A mixture of sodium (0.54 g, of 23.2 mmol) and benzyl alcohol (2.5 g, of 23.2 mmol) in dioxane (20 ml) was heated at boiling with reflux. After absorption of sodium dioxane was removed and was added 6-bromopyridin-2-amine (2 g, 11.6 mmol). The mixture was heated at 160°C for 3 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified on a column of silica gel (elwira using 10-100% ethyl acetate in petroleum ether) to give 6-(benzyloxy)pyridin-2-amine (0.6 g, 26% yield).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) of 7.83 (t, J=8,8 Hz, 1H), 7,45 (d, J=7,2 Hz, 2H), value of 7, 37 (d, J=7,6 Hz, 2H), 7,28 (d, J=6,4 Hz, 1H), of 6.49 (d, J=8,8 Hz, 1H), 6,39 (d, J=8.4 Hz, 1H), of 5.29 (s, 2H).

Intermediate compound 65: 2-Herperidin-3-amine

A. 2-Herperidin-3-amine. To a solution of 2-fluoro-3-nitropyridine (600 mg, 4.2 mmol) in 80% aqueous ethanol (50 ml) and concentrated x�aristolochiaceae acid (1 ml) was added iron powder (2.4 g, 42 mmol) and the mixture was heated at boiling with reflux for 3 hours. Was added sodium carbonate to neutralize the residual acid and the resulting mixture was filtered through Celite. The filtrate was concentrated to dryness and the residue was purified on a column of silica gel (elwira using 0-10% methanol in dichloromethane) to give 2-herperidin-3-amine (300 mg, 63% yield) as a solid substance. MS (ESI): m/z 112,9 [M+1]+.

Intermediate compound 66: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazo[2,3-b]pyridin-5-amine

A. 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazo[2,3-6]pyridin-5-amine. To a solution of 1H-imidazo[2,3-6]pyridin-5-amine (250 mg, of 1.88 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (75 mg, at 1.88 mmol) in portions at 0°C in an atmosphere of nitrogen. The reaction mixture was stirred at this temperature for 1 hour, was added dropwise 2-(trimethylsilyl)ethoxymethylene (312 g of 1.88 mmol) and the resulting mixture was stirred at room temperature over night. When TLC analysis showed that the starting material consumed, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, the organic layer was washed with water and saturated brine, dried and evaporated. The crude product was purified on a column of silica gel (elwira using 10% ethyl acetate in pet�alanon ether) to give 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[2,3-b]pyridin-5-amine (300 mg, 67.6% of output) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 7.93 (d, J=2.4 Hz, 1H), 7,27 (m, 2H), system 6.34 (d, J=3,6 Hz, 1H), of 5.60 (s, 2H), 3,54 (m, 4H), of 0.92 (m, 2H), to -0.05 (s, 9H).

Intermediate compound 67: tert-Butyl-3-hydroxypropionate

A. tert-Butyl 3-hydroxypropionate. To a solution of 3-aminopropan-1-ol (4.6 g, 61 mmol) in dichloromethane (40 ml) was added a solution of di-tert-BUTYLCARBAMATE (14 g, 64 mmol) in dichloromethane (40 ml) for 30 minutes and the mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to obtain crude product, which was washed with petroleum ether and dried to obtain tert-butyl-3-hydroxypropionate (8.9 g, 83.1% of output) in the form of a colorless oil.

Intermediate compound 68: N2-Methylpyridine-2,5-diamine

A. N-Methyl-5-nitropyridine-2-amine. A solution of 2-bromo-5-nitropyridine (1.2 g, 5.9 mmol) in methylamine (aqueous, 10 ml) was stirred at room temperature for 5 hours. Was added a saturated salt solution and the precipitate was collected and washed with water to obtain N-methyl-5-nitropyridine-2-amine (870 mg, 96% yield) in the form of solids.

B. N2-Methylpyridine-2,5-diamine. A mixture of N-�ethyl-5-nitropyridine-2-amine (870 mg, The 5.7 mmol) and 10% palladium on coal (50% moisture content, mass/mass, 170 mg) in methanol was gidrirovanie under a hydrogen pressure of 1 atmosphere for 4 hours. The catalyst was filtered and the filtrate concentrated. The residue was purified on a column of silica gel (elwira using 10-33% ethyl acetate in petroleum ether) to give N2-methylpyridine-2,5-diamine (300 mg, 42% yield) as an oil.1H NMR (400 MHz, CHLOROFORM-d) δ (MD), 7,63 (s, 1H), 6,90 (d, J=8.4 Hz, 1H), of 6.25 (d, J=8.4 Hz, 1H), 4,05 (lat.s, 1H), 3,15 (lat.s, 1H), 2,77 (s, 3H).

Intermediate 69: 6-(4-(tert-Butyldimethylsilyloxy)piperidine-1-yl)pyridin-3-amine

A. 1-(5-Nitropyridine-2-yl)piperidine-4-ol. A mixture of 2-bromo-5-nitropyridine (1 g, to 4.98 mmol), piperidine-4-ol (503 mg, to 4.98 mmol), triethylamine (503 mg, to 4.98 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuum to give crude product, which was purified using chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether), to obtain 1-(5-nitropyridine-2-yl)piperidine-4-ol (1 g, 90,5% output).

B. 2-(4-(tert-Butyldimethylsilyloxy)piperidine-1-yl)-5-nitropyridine. To a solution of 1-(5-nitropyridine-2-yl)piperidine-4-ol (2 g, 8,96 mmol) and tert-butylcholinesterase (1,34 g, 8,96 mmol) in N,N-dimethylformamide (15 ml) was added dropwise RA�creative ways of triethylamine (0.9 g, 8,96 mmol) and 4-(dimethylamino)pyridine (110 mg, 0,896 mmol) in N,N-dimethylformamide (5 ml) at 0°C. After stirring for one hour the reaction mixture was distributed between water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (elwira using 20% ethyl acetate in petroleum ether) to give 2-4-(tert-butyldimethylsilyloxy)piperidine-1-yl-5-nitropyridine (2 g, 75% yield).

C. 6-(4-(tert-Butyldimethylsilyloxy)piperidine-1-yl)pyridin-3-amine. A mixture of 2-(4-(tert-butyldimethylsilyloxy)piperidine-1-yl)-5-nitropyridine (500 mg, of 1.48 mmol), 10% palladium on carbon (50% moisture, 50 mg) in methanol (2 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature over night. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified on a column of silica gel (elwira using 50% ethyl acetate in petroleum ether), to obtain 6-(4-(tert - butyldimethylsilyloxy)piperidine-1-yl)pyridin-3-amine (200 mg, 44.0 per cent of the output).

Intermediate 70: 2-(2-(Pyrrolidin-1-yl)ethoxy)pyridin-4-amine

A. 2-(2-(Pyrrolidin-1-yl)ethoxy)pyridin-4-amine. A mixture of Guidry�and sodium (0.4 g, 8,6 mmol) and 2-(pyrrolidin-1-yl)ethanol (0,98 g, 8,6 mmol) in dioxane (20 ml) was heated at boiling with reflux for 1 hour (110°C). After absorption of sodium, the mixture was concentrated to remove dioxane. Was added 2-chloropyridin-4-amine (1 g, 7.8 mmol) and the mixture was heated to 160°C for 3 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified on a column of silica gel (elwira using 33-100% ethyl acetate in petroleum ether) to give 2-(2-(pyrrolidin-1-yl)ethoxy)pyridin-4-amine (0.5 g, 31,3%).1H NMR (400 MHz, METHANOL-d4) δ (MD), 7,58 (d, J=6,0 Hz, 1H), 6,23 (m, 1H), 5,95 (d, J=1.6 Hz, 1H), 4,25 (t, J=6,0 Hz, 2H), 2,89 (t, J=6,0 Hz, 2H), 2,67 (m, 4H), 1,82 (m, 4H).

Intermediate compound 71: N2-(2-Pyrrolidin-1-yl-ethyl)-pyridine-2,4-diamine

A. 2-Chloropyridine 1-oxide. To a solution of 2-chloropyridine (5 g, 0.04 mole) in dichloromethane (50 ml) was added 3-chlorobenzotrichloride (15.2 g, 0.08 mmol) in portions at room temperature. The mixture was stirred at room temperature for 1 hour. After the starting material was consumed, was added a saturated aqueous solution of sodium thiosulfate. The organic layer Department�Lee and was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to obtain 2-chloropyridine 1-oxide (4 g, 71% yield) in the form of solids.

B. 2-Chloro-4-nitropyridine 1-oxide. 2-Chloropyridine 1-oxide (4 g, 0.03 mole) was mixed with sulfuric acid (16 g, 0,18 mol) and fuming nitric acid (9 g, 0.15 mole) and the mixture was stirred at 90°C for 2.5 hours. After cooling to room temperature the reaction mixture was poured slowly into cold water (100 ml) at 0-5°C. the Mixture was diluted with ethyl acetate (480 ml) and podslushivaet by adding 6N aqueous sodium hydroxide solution at 0-5°C and pH=10. The organic layer was separated, washed with saturated brine (100 ml ×4), dried over sodium sulfate and concentrated under reduced pressure to obtain 2-chloro-4-nitropyridine 1-oxide (1.2 g, 24% yield) in the form of solids.

C. 4-Nitro-2-(2-(pyrrolidin-1-yl)ethylamino)pyridine 1-oxide. A mixture of 2-chloro-4-nitropyridine 1-oxide (400 mg, 2.3 mmol) and 2-(pyrrolidin-1-yl)ethanamine (524 mg, 4.6 mmol) in ethanol (5 ml) was heated at 80°C over night. The reaction mixture was concentrated in vacuum and the residue was purified on a column of silica gel (10% methanol in ethyl acetate) to give 4-nitro-2-(2-(pyrrolidin-1-yl)ethylamino)pyridine 1-oxide (300 mg, 51% yield) in the form of solids.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) of 8.33 (d, J=7,2 Hz, 1H), 7,71 (d, J=4,2 Hz, 1H), 7,50 (DD, J1DC,2 Hz, J2=2,8 Hz, 1H), to 3.64 (t, J=6,4 Hz, 2H), 2,96 (s, 2H), 2,80 (s, 4H), 1,90 (s, 4H).

D. N2-(2-Pyrrolidin-1-yl-ethyl)-pyridine-2,4-diamine. A mixture of 4-nitro-2-(2-(pyrrolidin-1-yl)ethylamino)pyridine 1-oxide (300 mg, 1,19 mmol) and Raney-Nickel (50 mg) in methanol (10 ml) were gidrirovanie under a hydrogen pressure of 1 ATM for 1 hour. The catalyst was filtered and the filtrate concentrated to give N2-(2-(pyrrolidin-1-yl)ethyl)pyridine-2,4-diamine (210 mg, 85% yield). MS (ESI): m/z to 206.9 [M+1]+.

Intermediate 72: 2,6-Dimethylpyridin-4-amine

A. 2,6-Dimethylpyridine 1-oxide. To a solution of 2,6-dimethylpyridine (10.7 g, 0.1 mol) in dichloromethane (100 ml) was added 3-chlorobenzotrichloride (32,4 g, 0,15 mmol) in portions at room temperature. The mixture was stirred at room temperature for 1 hour. After the starting material was consumed, was added a saturated aqueous solution of sodium thiosulfate. The organic layer was separated, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to obtain 2,6-dimethylpyridine 1-oxide (12 g, 97% yield) in the form of solids.

B. 2,6-Dimethyl-4-nitropyridine 1-oxide. To a solution of 2,6-dimethylpyridine 1-oxide (7 g, 0,057 mol) in sulfuric acid (20 ml) was added a mixture of sulfuric acid and nitric acid (V/V, 1:1, 50 ml) at 0°C. the Mixture was heated PR� 100°C until the absorption of the starting material. The mixture was cooled, neutralized with saturated sodium carbonate solution and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 2,6-dimethyl-4-nitropyridine 1-oxide (3.1 g, 33% yield) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,01 (s, 2H), of 2.57 (s, 6H).

C. 2,6-Dimethylpyridin-4-ylamine. To a solution of 2,6-dimethyl-4-nitropyridine 1-oxide (2 g, to 11.9 mmol) in glacial acetic acid was added 10% palladium on charcoal (0.2 g) and the mixture was gidrirovanie at a hydrogen pressure of 45 lb/inch2(3,164 kg/cm2) at 50°C for 19 hours. The reaction mixture was filtered and the filtrate was adjusted to pH=12 with the help of 6N sodium hydroxide solution. The mixture was extracted with chloroform, dried, filtered and evaporated to obtain 2,6-dimethylpyridin-4-ylamine (600 mg, 47% yield). MS (ESI): m/z of 113.1 [M+1]+.

Intermediate 73: tert-Butyl 6-amino-1-occaisonaly-2-carboxylate

A. Methyl 2-methyl-5-nitrobenzoate. To a stirred solution of 2-methyl-5-nitrobenzoic acid (2 g, 11 mmol) in methanol was added dropwise thionylchloride (3.2 g, 27.5 mmol) at 0°C and the mixture was heated at boiling with reflux for 2 hours. After thin layer chromatography showed that the starting material used, solvent residual,�RER was removed under reduced pressure and the residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate three times. The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain methyl 2-methyl-5-nitrobenzoate (2.08 g, 96.7% of output) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,69 (s, 1H), 8,16 (d, J=6,0 Hz, 1H), of 7.36 (d, J=8.4 Hz, 1H), 3,89 (s, 3H), 2,65 (s, 3H).

B. Methyl 2-(methyl bromide)-5-nitrobenzoate. A suspension of methyl 2-methyl-5-nitrobenzoate (2.08 g, of 10.67 mmol), N-bromosuccinimide (of 2.06 g, an 11.58 mmol), 2,2'-azobis(2-methylpropionitrile)and (AIBN) (40 mg, 0,244 mmol) in carbon tetrachloride (25 ml) was heated at boiling with reflux for 5 hours. When thin layer chromatography showed that the starting material consumed, the mixture was cooled to room temperature. The precipitate was filtered and the filtrate was concentrated to obtain methyl 2-(methyl bromide)-5-nitrobenzoate (2.2 g) which was used directly in the next step.

C. 6-Nitroisoquinoline-1-it. The crude methyl 2-(methyl bromide)-5-nitrobenzoate (2.2 g) was dissolved in methanol solution of ammonia (7n) and the mixture was stirred at room temperature over night. The precipitate was filtered and washed with ethanol to obtain 6-nitroisoquinoline-1-one (616 mg, 32% yield for two steps) as a solid substance.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,97 (s, 1H), 8,44 (d, J=2,0 Hz, 1H), of 8.33 (s, 1H), 7,86 (d, J8,4 Hz, 1H), a 4.53 (s, 2H).

D. tert-Butyl 6-nitro-1-occaisonaly-1-carboxylate. To a mixture of 6-nitroisoquinoline-1-she (500 mg, 2.8 mmol) and di-tert-BUTYLCARBAMATE (610 mg, 228 mmol) in dichloromethane (50 ml) was added N,N-dimethylpyridin-4-amine (34 mg, 0.28 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain tert-butyl 6-nitro-1-occaisonaly-2-carboxylate (778 mg, 90.6% of output) in the form of solids.

E. tert-Butyl 6-amino-1-occaisonaly-2-carboxylate. A mixture of tert-butyl 6-nitro-1-occaisonaly-2-carboxylate (426 mg, 1,53 mmol) and 10% palladium on charcoal (40 mg) in methanol (50 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature for 40 minutes. The catalyst was filtered and the filtrate concentrated to give tert-butyl 6-amino-1-occaisonaly-2-carboxylate (273 mg, 64% yield). MS (ESI): m/z 249,2 [M+1]+.

tert-Butyl 5-amino-1-occaisonaly-2-carboxylate was obtained by following the procedure similar to that used to obtain tert-butyl 6-amino-1-occaisonaly-2-carboxylate, using 2-methyl-4-nitrobenzoic acid as the starting material.

Intermediate 74: 3-Ethyl-1-((2-(trimethylsilyl)ethoxy)IU�yl)-1H-indazol-6-amine

A. 6-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-3-vinyl-1H-indazole. Degassed mixture of 3-iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.1 g, 2,63 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (486 mg, 3,16 mmol), sodium carbonate (558 mg, and 5.26 mmol) and 1,1'-bis(diphenylphosphino)ferienparadies (191 mg, 0,26 mmol) in a mixture of dioxane and water (V/V, 3:1, 24 ml) was heated at 100°C overnight under an atmosphere of nitrogen. The reaction mixture was poured into water and was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, was evaporated under reduced pressure and was purified on a column of silica gel (elwira using 0-2% ethyl acetate in petroleum ether) to give 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-3-vinyl-1H-indazole (610 mg, 72,8% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,79 (t, J=1.6 Hz, 1H), 8,30 (d, J=9,2 Hz, 1H), 8,04 (m, 1H), was 7.08 (m, 1H), 6,23 (m, 1H), 5,91 (s, 2H), 5,63 (m, 1H), 3,55 (t, J=8,0 Hz, 2H), to 0.80 (t, J=7,6 Hz, 2H), -0,12 (s, 9H).

B. 3-Ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine. A mixture of 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-3-vinyl-1H-indazole (610 mg, 1,91 mmol) and 10% palladium on charcoal (30 mg) in methanol (10 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature over night. The catalyst was filtered and the filtrate was concentrated in vacuo, the crude product is about�imali on a column of silica gel (elwira using 4-20% ethyl acetate in petroleum ether) to give 3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (390 mg, 69.9% of output).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 7,43 (m, 1H), 6,70 (t, J=0.8 Hz, 1H), 6,63 (m, 1H), 5,51 (s, 2H), 3,51 (t, J=7,6 Hz, 2H), 2,86 (m, 2H), 1,32 (sq, J=7,6 Hz, 1H), of 0.82 (t, J=8,0 Hz, 8H), and 0.09 (m, 9H); MS (ESI): m/z 292,18 [M+1]+.

Intermediate 75: 1-Isopropyl-1H-indazol-6-amine

A. 1-Isopropyl-6-nitro-1H-indazole. To a solution of 6-nitro-1H-indazole (5 g, 31 mmol) in N,N-dimethylformamide (75 ml) was added sodium hydride (60% in mineral oil, 1.4 g, 34 mmol) in portions at 0°C. Upon completion of addition the mixture was stirred for 30 minutes at 0°C was added 2-iodo-2-methylpropane (27.6 g, 150 mmol). The resulting mixture was stirred at room temperature overnight, quenched by adding water (250 ml) and was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate and evaporated. The residue was purified on a column of silica gel (elwira using 5-10% ethyl acetate in petroleum ether) to give 1-isopropyl-6-nitro-1H-indazole (2.48 g, 40% yield) as a yellow solid.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) and 8.50 (s, 1H), 8,08 (d, J=8,0 Hz, 1H), 7,86 (d, J=8,0 Hz, 1H), 7,82 (s, 1H), 5,02 (m, 1H), of 1.47 (d, J=4.0 Hz, 6H).

B. 1-Isopropyl-1H-indazol-6-amine. To a mixture of 1-isopropyl-6-nitro-1H-indazole (1 g of 4.88 mmol) and ammonium chloride (2.6 g, of 4.88 mmol) in methanol (30 ml) was added zinc dust (3,18 g of 4.88 mmol) in porciani 0°C. Upon completion of addition the reaction mixture was stirred at room temperature overnight, filtered, concentrated and purified on a column of silica gel (elwira using 1% methanol in dichloromethane) to give 1-isopropyl-1H-indazol-6-amine (0.56 g, 65.9 per cent of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (MD), of 7.75 (s, 1H), 7,41 (d, J=8,0 Hz, 1H), 6,56 (d, J=8,0 Hz, 2H), is 5.33 (lat.s, 2H), to 4.68 (m, 1H), 1,50 (s, 6H).

Intermediate 76: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-5-amine

A. 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-5-amine. To a solution of 1H-benzo[d][1,2,3]triazole-5-amine (500 mg, 3,73 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (149 mg, 3,73 mmol, 60% in mineral oil) at 0°C in a nitrogen atmosphere and the mixture was stirred for 1 hour at room temperature. (2-(Chloromethoxy)ethyl)trimethylsilane (619 mg, 3,73 mmol) was added dropwise at 0°C and the resulting mixture was continued to stir for 2 hours at room temperature. The reaction mixture was poured into ice water (50 ml), was extracted with ethyl acetate (100 ml ×3). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product, which was purified on a column of silica gel (elwira using 5-10% ethyl acetate in Petro�lane ether), obtaining 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-5-amine (400 mg, 40.6% of yield) was obtained as oil.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 7,60 (d, J=9,2 Hz, 1H), 6,98 (m, 1H), 6,83 (d, 1=I,6 Hz, 1H), of 5.81 (s, 2H), 3,68 (t, J=8,0 Hz, 2H), 0,88 (t, J=8,0 Hz, 2H), -0,07 (s, 9H); MS (ESI): m/z 265,2 [M+1]+.

Intermediate compounds 77 and 78: 6-Bromo-1,3-dimethyl-1H-indazole and 6-bromo-2,3-dimethyl-2H-indazol

A. 6-Bromo-1,3-dimethyl-1H-indazole and 6-bromo-2,3-dimethyl-2H-indazol. 6-Bromo-3-methyl-1H-indazole (3 g, 14,21 mmol) was dissolved in 20 ml of N,N-dimethylformamide was added sodium hydride (60% dispersion in mineral oil, 0,682 g; 17,06 mmol) at 0°C in an atmosphere of nitrogen. The reaction mixture was stirred at 0°C for 1 hour and added itmean (of 1.06 ml, 17,06 mmol). The reaction mixture was stirred at room temperature overnight in a nitrogen atmosphere. When the reaction was completed, as shown by the LC/MS analysis, the reaction mixture was poured into water/saturated salt solution and was extracted with ethyl acetate several times. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified using chromatography using a gradient of 0-100% ethyl acetate in hexane to obtain 6-bromo-1,3-dimethyl-1H-indazole as a yellow solid (2,04 g, 64% yield) and 6-bromo-2,3-dimethyl-2H-indazole in the form of yellow firmly�about substances (1,02 g, 32% yield).

1H NMR of 6-bromo-1,3-dimethyl-1H-indazole (400 MHz, DMSO-d6) δ (M. D.) of 7.88-a 7.92 (m, 1H), of 7.64-7,69 (m, 1H), 7,21 (DD, J=1,64, 8,52 Hz, 1H), 3,94 (s, 3H), 2,46 (s, 3H). MS (ESI) m/z 226 [M+1]+

1H NMR of 6-bromo-2,3-dimethyl-2H-indazole (400 MHz, DMSO-d6) δ (M. D.) 7,71-to 7.77 (m, 1H), 7,62-to 7.68 (m, 1H), 7,05 (DD, J=1,68, 8,81 Hz, 1H), 4,03 (s, 3H), 2,60 (s, 3H). MS (ESI) m/z 226 [M+1]+

Intermediate compound 79: 4-Fluoro-3-(2-methoxyethoxy)-aniline

A. 1-Fluoro-2-(2-methoxyethoxy)-4-nitrobenzene. Diisopropylcarbodiimide (1,356 ml, 7,00 mmol) was added dropwise to a stirred solution of 2-fluoro-5-NITROPHENOL (1.00 g, 6,37 mmol), triphenylphosphine (1,837 g, 7,00 mmol) and 2-methoxyethanol (of 0.533 g, 7,00 mmol) in tetrahydrofuran (10 ml) which was cooled in a water bath. The obtained dark-red mixture was stirred at room temperature in a nitrogen atmosphere for 1.5 hours. The resulting mixture was purified using flash chromatography (biotage AB) (0-30% ethyl acetate in hexane). Fractions containing the desired product were pooled and washed twice with water and once with saturated brine. The organic layers were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator almost dry. The residue was diluted with cold hexane. The solids were collected via suction filtration, washed with cold hexane and dried under conditions of high vacuu�and to obtain the desired product (0,865 g, 4,02 mmol, 63% yield) as yellowish needle-like crystals.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,01 (DD, J=2,73, of 7.42 Hz, 1H), 7,91 (DDD, J=2,73, 3,90, 8,98 Hz, 1H), 7,54 (DD, J=8,98, 10,93 Hz, 1H), 4,31-4,39 (m, 2H), 3,67-to 3.76 (m, 2H), 3,32 (s, 3H); MS (ESI) m/z 216,3 [M+1]+.

B. 4-Fluoro-3-(2-methoxyethoxy)aniline. 1-Fluoro-2-(2-methoxyethoxy)-4-nitrobenzene (0,862 g, 4,01 mmol) was dissolved in ethyl acetate (5 ml) and ethanol (15 ml) with stirring at room temperature. Was plugged nozzle vacuum/nitrogen/hydrogen. The atmosphere in the flask was removed and replaced with nitrogen twice. Was added palladium (10 wt%. on charcoal) (0,213 g, 0,200 mmol) and the atmosphere in the flask was removed and replaced with hydrogen three times. The resulting mixture was intensively stirred under a balloon of hydrogen at room temperature for 2.5 hours. Received the black mixture was filtered through Celite filter cake was thoroughly washed with methanol. The filtrate was concentrated on a rotary evaporator and dried under high vacuum to give the desired product (0,731 g 3,95 mmol, 99% yield) as a solid amber color.1H NMR (400 MHz, DMSO-d6) δ (M. D.) is 6.81 (DD, J=8,59, 11,71 Hz, 1H), 6.32 per (DD, J=2,73, of 7.42 Hz, 1H), 6,01-6,09 (m, 1H), to 4.92 (s, 2H), 3,99-of 4.05 (m, 2H), 3,61-to 3.67 (m, 2H), and 3.31 (s, 3H);19F NMR (376 MHz, DMSO-d6) δ (M. D.) -151,45 (m, 1F); MS (ESI) m/z 186,2 [M+1]+.

Intermediate compound 80: 2-(2-(tert-Butultimately-silyloxy)ATOX�)pyridin-4-amine

A. 2-(tert-Butyldimethylsilyloxy)ethanol. The mixture ethane-1,2-diol (6.2 g, 0.1 mol), imidazole (10 g, 0.15 mole) and tert-butylcholinesterase (10 g, 0.15 mole) in N,N-dimethylformamide (15 ml) was stirred at room temperature over night. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give 2-(tert-butultimately-silyloxy)ethanol as an oil (10 g, 56.8% of output).

B. 2-(2-(tert-Butyldimethylsilyloxy)ethoxy)pyridin-4-amine. To a solution of 2-(tert-butyldimethylsilyloxy)ethanol (4.1 g, with 23.3 mmol) in dioxane (20 ml) was added sodium hydride (60% in mineral oil, 0.96 g, 24 mmol). The mixture was heated at boiling with reflux for 1.5 hours. When the reaction mixture was cooled to room temperature, was added 2-chloropyridin-4-amine (2.0 g, 15.5 mmol) and the reaction mixture was heated at 160°C for 7 hours in a nitrogen atmosphere. After cooling to room temperature the reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and was purified on a column of silica gel (elwira using 1-10% ethyl acetate in petroleum ether) to give 2-(2-(tert-butyldimethylsilyloxy)ethoxy)pyridin-4-amine (180 mg, 4.4% yield) in the form of a solid in�society. MS (ESI): m/z 268,9 [M+1]+.

Intermediate 81: CIS-4-Amino-1-((tert-butyldiphenylsilyl)methyl)cyclohexanol

A. CIS-tert-Butyl-1-oxaspiro[2,5]Octan-6-ylcarbamate. To a solution of iodide trimethylsulfoxonium (12.5 g, 57 mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (2.5 g. of 62.5 mmol, 60% in mineral oil) at 10°C and the mixture was stirred at room temperature for 40 minutes. The mixture was cooled to 10°C, was added tert-butyl 4-oxocyclohexanecarboxylate (9.5 g, of 44.6 mmol) and stirred at room temperature for 2 hours. Was added water (150 ml) and the mixture was extracted with ethyl acetate (200 ml). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified using column chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether) to give CIS-tert-butyl-1-oxaspiro[2,5]Octan-6-ylcarbamate (5 g, 50% yield) as a white powder.1H NMR (400 MHz, DMSO-d6)δ (M. D.) 6,78 (d, J=7,6 Hz, 1H), 3,39 (m, 1H), 2,56 (s, 2H), to 1.87 (m, 4H), of 1.45 (m, 11H), 1,22 (m, 2H).

B. CIS-tert-Butyl-4-hydroxy-4-(gidroximetil)-cyclohexylcarbamate. To a solution of CIS-tert-butyl-1-oxaspiro[2,5]Octan-6-ylcarbamate (of 4.54 g, 20 mmol) in 1,2-dimethoxyethane (50 ml) was added potassium hydroxide (5.6 g, 100 mmol) in 200 ml of water. The mixture was stirred at the boiling point with reverse re�by these lamps for 10 hours, concentrated until then, until 150 ml of the solvent. After filtration the filter cake was washed with water (50 ml) and simple ether (20 ml) to give CIS-tert-butyl-4-hydroxy-4-(gidroximetil)cyclohexylcarbamate (2.8 g, 57% yield) as a white powder.1H NMR (400 MHz, DMSO-d6)δ (M. D.) 6,70 (d, J=8,0 Hz, 1H), 4,49 (lat.s, 1H), 3,83 (lat.s, 1H), 3,15 (m, 3H), 1,50 (m, 17H).

C. CIS-tert-Butyl-4-((tert-butyldiphenylsilyl)methyl)-4-hydroxycyclohexanone. To a mixture of CIS-tert-butyl-4-hydroxy-4-(gidroximetil)cyclohexylcarbamate (735 mg, 3 mmol) and imidazole (340 mg, 5 mmol) in N,N-dimethylformamide (10 ml) was added tert-butylchloroformate (2.2 g, 8 mmol) and the mixture was stirred at 50°C for 12 hours. Was added water (30 ml) and the solution was extracted with ethyl acetate (30 ml). The organic phase was dried over sodium sulfate, concentrated and purified using column chromatography on silica gel (elwira using 7-10% ethyl acetate in petroleum ether) to give CIS-tert-butyl-4-((tert-butyldiphenylsilyl)methyl)-4-hydroxycyclohexanecarboxylate (420 mg, 29% yield).1H NMR (400 MHz, DMSO-d6)δ (M. D.), a 7.62 (m, 4H), 7,49 (m, 6H), 6,74 (d, J=7,6 Hz, 1H), of 4.09 (s, 1H), and 3.31 (s, 2H), 3,12 (lat.s, 1H), 1,58 (m, 6H), of 1.44 (m, 11H), and 1.00 (s, 9H).

D. CIS-4-Amino-1-((tert-butyldiphenylsilyl)methyl)cyclohexanol. To a stirred solution of CIS-tert-butyl-4-((tert-buildi�analsilicone)methyl)-4-hydroxycyclohexanecarboxylate (966 mg, 2 mmol) in dichloromethane (15 ml) was added dropwise trifluoroacetic acid (2 ml) at -5°C and the mixture was stirred at 0°C for 2 hours. When LC-MS analysis showed that the remaining 70% of the precursor added another 2 ml of trifluoroacetic acid and the mixture was stirred for 6 hours at 0°C until the starting material was not consumed. The mixture was brought to pH=8 using saturated aqueous sodium carbonate solution and the resulting mixture was extracted with ethyl acetate (20 ml). The organic phase was dried using sodium sulfate and concentrated to give crude CIS-4-amino-1-((tert-butyldiphenylsilyl)methyl)cyclohexanol, which was used directly without further purification.

Intermediate 82: 6-Bromo-1-methylindolin-2,3-dione

A. 6-Bromo-1-methylindolin-2,3-dione. To a solution of 6-bromoindoline-2,3-dione (4.5 g, 20 mmol) in N,N-dimethylformamide (20 ml) was added potassium carbonate (4.14 g, 30 mmol) was added dropwise dimethylsulfate (3,15 g, 25 mmol) with stirring. After stirring at room temperature for 2 hours the reaction mixture was poured into ice water (400 ml) and was extracted with ethyl acetate (200 ml). The organic layer was dried with sodium sulfate, concentrated and was purified column chromatography on silica gel (elwira with the help�and 15% ethyl acetate in petroleum ether) to give 6-bromo-1-methylindolin-2,3-dione (3.7 g, 77% yield) as a red solid.

Intermediate compound 83: 3-(Methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine

A. Methyl 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-carboxylate. Degassed mixture of 3-iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (4,62 g, 11 mmol), potassium carbonate (4,55 g, 33 mmol), palladium acetate (250 mg, 1.1 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (610 mg, 1.1 mmol) in a mixture of methanol (25 ml) and N,N-dimethylformamide (25 ml) intensively stirred and heated at 80°C under pressure of carbon monoxide (50 f/inch2(3,515 kg/cm2)) within 24 hours. After cooling to room temperature the reaction mixture was filtered and the filtrate was diluted with water (100 ml). The aqueous mixture was extracted with ethyl acetate (250 ml ×3). The extracts were washed with water and saturated brine, dried over sodium sulfate, concentrated in vacuo and purified on a column of silica gel (elwira using 10-25% ethyl acetate in petroleum ether) to give methyl 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-carboxylate as an orange oil (1.8 g, 47% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) to 8.36 (d, J=8,8 Hz, 1H), 8,29 (s, 1H), 8,04 (d, J=8,8 Hz, 1H), 5,93 (s, 2H), of 4.09 (s, 3H), 3,63 (t, J=8.4 Hz, 2H), 0,92 (t, J=8.4 Hz, 2H), or 0.06 (s, 9H).

B. (6-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)�ethanol. To a solution of methyl 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-carboxylate (1.8 g, 5.1 mmol) in anhydrous tetrahydrofuran (100 ml) was added hydride (5,81 g, of 15.3 mmol) in portions at 0°C. When the starting material was consumed, the reaction was quenched with an aqueous sodium hydroxide solution (0.15 M, 100 ml) and filtered. The filtrate was extracted with ethyl acetate (150 ml ×3). The extracts were washed with saturated brine, dried over sodium sulfate and concentrated in vacuum to give (6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)methanol (800 mg, 48% yield) as an orange oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,16 (s, 1H), 7,90 (m, 2H), 5.78% was established (s, 2H), 5,10 (s, 2H), 3,61 (m, 2H), 0,93 (m, 2H), to -0.05 (s, 9H).

C. 3-(Methoxymethyl)-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol. To a solution of (6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)methanol (800 mg, 2,47 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% in mineral oil, 148 mg, 3,71 mmol) in portions at 0°C and the mixture was stirred at 0°C for 30 minutes. Added itmean (527 mg, 3,71 mmol) and the reaction mixture was stirred at room temperature for 2 hours. Was added water (50 ml) and aqueous mixture was extracted with ethyl acetate (50 ml ×3). The extracts were washed with water and saturated brine, dried over sodium sulfate, concentrated in vacuo and purified n� a column of silica gel (elwira using 20-30% ethyl acetate in petroleum ether) to give 3-(methoxymethyl)-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (500 mg, 60% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,18 (s, 1H), 7,95 (d, J=8,0 Hz, 1H), 7,90 (d, J=8,0 Hz, 1H), of 5.81 (s, 2H), of 4.88 (s, 2H), 3,62 (m, 2H), 3.46 in (s, 3H), of 0.93 (m, 2H), to -0.05 (s, 9H).

D. 3-(Methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine. Degassed mixture of 3-(methoxymethyl)-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (500 mg, of 1.48 mmol) and Raney Nickel(100 mg) in methanol (150 ml) was stirred at room temperature under a hydrogen pressure of 1 atmosphere during the night. The catalyst was filtered and the solution concentrated in vacuum to give 3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (380 mg, 83% yield).1H NMR (400 MHz, DMSO-d6)δ (M. D.) 7,39 (d, J=8.4 Hz, 1H), a 6.53 (m, 2H), were 5.47 (s, 2H), 5,43 (s, 2H), 4,56 (s, 2H), of 3.46 (t, J=8,0 Hz, 2H), 3,23 (s, 3H), 0,78 (t, J=8,0 Hz, 2H), -0,10 (s, 9H); MS (ESI): m/z 308,1 [M+1]+.

Intermediate 84: tert-Butyl 6-bromo-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate

A. 6-Bromo-3,4-dihydroisoquinoline-1(2H)-it. To a stirred solution of 5-bromo-2,3-dihydro-1H-indene-1-one (10 g, 47.6 per mmol) in a mixture of methylsulfonic acid and dichloromethane (V/V = 1:1, 100 ml) was added sodium azide (6 g, of 95.2 mmol) in portions at a temperature range from 22°C to 29°C. When the addition was complete, the mixture was stirred at room temperature for 16 hours, cooled to 0°C and neutralized by adding 5 n aqueous �of astora sodium hydroxide. The aqueous layer was extracted with dichloromethane (250 ml ×3). The combined organic layers were washed with water (100 ml ×3) and saturated brine (100 ml ×3), dried over anhydrous sodium sulfate, concentrated and purified on a column of silica gel (elwira using 10-33,3% ethyl acetate in petroleum ether) to give 6-bromo-3,4-dihydroisoquinoline-1(2H)-she (2.1 g, 19.6% of the output).1H NMR (400 MHz, DMSO-d6)δ (M. D.) 8,03 (s, 1H), of 7.75 (d, J=8,0 Hz, 1H), 7,54 (d, J=8,0 Hz, 1H), 7,51 (s, 1H), 3,35 (t, J=6,4 Hz, 2H), 2,90 (d, J=6,4 Hz, 2H).

B. tert-Butyl 6-bromo-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate. To a mixture of 6-bromo-3,4-dihydroisoquinoline-1(2H)-she (600 mg, 2,67 mmol) and di-tert-BUTYLCARBAMATE (872 mg, 4.0 mmol) in dichloromethane (50 ml) was added N,N-dimethylpyridin-4-amine (49 mg, 0,40 mmol) and the resulting mixture was stirred at room temperature over night. The reaction mixture was concentrated under reduced pressure and the residue was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give tert-butyl 6-bromo-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (730 mg, 84.2 per cent yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,86 (d, J=8,8 Hz, 1H), 7,61 (d, J=8,0 Hz, 1H), 7,58 (s, 1H), 3,88 (t, J=7,2 Hz, 2H), 3,00 (d, J=6,0 Hz, 2H), 1,49 (C, 9H).

Intermediate 85: 5-Amino-2-(2-(tert-butyldimethylsilyloxy)ethyl)isoindoline-1-he

A. 2-(tert-Butyldimethylsilyloxy)ethanamine. To a solution of 2-aminoethanol (6.12 g, 0.1 mol) and tert-butylcholinesterase (18: 22C g, 0.12 mole) in dichloromethane (200 ml) was added dropwise a solution of triethylamine (46 ml, 0.3 mole) and 4-(dimethylamino)pyridine (68 mg) in dichloromethane (100 ml) at 0°C. Upon completion of addition the mixture was stirred at room temperature for 24 hours. Added water and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain crude product, which was used directly in the next step.

B. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-nitroisoquinoline-1-it. To a mixture of methyl 2-(methyl bromide)-4-nitrobenzoate (2.0 g, 7.3 mmol) in methanol (30 ml) was added 2-(tert-butyldimethylsilyloxy)ethanamine (3.5 g, 20 mmol). The mixture was heated at boiling with reflux for 6 hours. The reaction mixture was concentrated and the residue was purified using column chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 2-(2-(tert-butyldimethylsilyloxy)ethyl)-5-nitroisoquinoline-1-one as a white solid (1.1 g, 44.9 percent output).

C. 5-Amino-2-(2-(tert-butyldimethylsilyloxy)ethyl)isoindoline-1-it. A mixture of 2-(2-(tert-butyldimethylsilyloxy)ethyl)-5-nitroisatin�Olin-1-one (1.1 g, 3,27 mmol) and 10% palladium on charcoal (0.2 g) in methanol (10 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere (using a balloon) at 30°C for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (elwira using 20-30% ethyl acetate in petroleum ether) to give 5-amino-2-(2-(tert-butyldimethylsilyloxy)ethyl)isoindoline-1-one (600 mg, 60% yield).1H NMR (400 MHz, DMSO-d6) δ (MD), 7,29 (d, J=8,0 Hz, 1H), 6,61 (m, 2H), 5,71 (s, 2H), 4,34 (s, 2H), 3,74 (t, J=6,4 Hz, 2H), 3,50 (t, J=6,4 Hz, 2H), and 0.83 (s, 9H), 0,00 (s, 6H).

Intermediate 86: 6-Amino-2-(2-(tert-butyldimethylsilyloxy)ethyl)isoindoline-1-he

A. 2-(2-(tert-Butyldimethylsilyloxy)ethyl)-6-nitroisoquinoline-1-it. The crude methyl 2-(methyl bromide)-5-nitrobenzoate (2.2 g), 2-(tert-butyldimethylsilyloxy)ethanamine (10.5 g, 60 mmol) was dissolved in methanol and the mixture was stirred at room temperature over night. The precipitated substance was filtered and washed with ethanol to obtain 2-(2-(tert - butyldimethylsilyloxy)ethyl)-6-nitroisoquinoline-1-one (800 mg, 32% yield) as a solid substance. MS (ESI): m/z 337,1 [M+1]+.

B. 6-Amino-2-(2-(tert-butyldimethylsilyloxy)ethyl)isoindoline-1-it. A mixture of 2-(2-(tert-butyldimethylsilyloxy)ethyl)-6-nitroisoquinoline-1-one (900 mg, 2,67 mmol�) and 10% palladium on charcoal (90 mg) in methanol (50 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature over night. The catalyst was filtered and the filtrate concentrated to give 6-amino-2-(2-(tert-butyldimethylsilyloxy)ethyl)isoindoline-1-she (500 mg, 60.9% of output). MS (ESI): m/z 307,2 [M-H]+.

Intermediate compound 87: 6-Bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)indolin-2,3-dione

A. 6-Bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)indolin-2,3-dione. To a solution of 6-bromoindoline-2,3-dione (4.5 g, 20 mmol) in N,N-dimethylformamide (20 ml) was added potassium carbonate (4.14 g, 30 mmol) and (2 bromoethoxy)(tert-butyl)dimethylsilane (5,95 g, 25 mmol) dropwise with stirring. After stirring for 2 hours the reaction mixture was poured into ice water (400 ml) and was extracted with ethyl acetate (200 ml). The organic layer was dried with sodium sulfate, concentrated and was purified column chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 6-bromo-1-(2-(tert - butyldimethylsilyloxy)ethyl)indolin-2,3-dione (3.2 g, 41.7 per cent yield) as a red solid.

An intermediate connection 88: 6-Bromo-1-ethyl-3-methyl-1H-indazol

A. 6-Bromo-1-ethyl-3-methyl-1H-indazol. To a solution of 6-bromo-3-methyl-1H-indazole (2 g, 9.5 mmol) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in mineral oil, 0,23 g, to 11.4 mmol) in portions at 0°C. Upon completion of addition the mixture premesis�whether for 30 minutes at 0°C, added Iodate (1,48 g, and 19.4 mmol) and the resulting mixture was stirred at room temperature over night. The reaction was quenched by adding water (50 ml) and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, evaporated and purified on a column of silica gel (elwira using 5-10% ethyl acetate in petroleum ether) to give 6-bromo-1-ethyl-3-methyl-1H-indazole (1.2 g, 53% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,39 (m, 2H), 7,07 (m, 1H), 4,20 (s, 2H), is 2.40 (s, 3H), 1,32 (s, 3H).

Intermediate 89: 6-Bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methyl-1H-indazol

A. 6-Bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methyl-1H-indazol. To a solution of 6-bromo-3-methyl-1H-indazole (2.1 g, 10 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (440 mg, 11 mmol) in portions at 0°C. After stirring for 0.5 hours was added (2-bromoethoxy)(tert-butyl)dimethylsilane (2,38 g, 10 mmol). The reaction mixture was stirred at room temperature over night. Was added water (100 ml) and the mixture was extracted with ethyl acetate (100 ml ×3). The combined organic layer was washed with saturated brine (200 ml), dried over sodium sulfate, concentrated and purified using chromatography on silica gel (elwira when s�relics of 0-10% ethyl acetate in petroleum ether) to give 6-bromo-1-(2-(tert - butyldimethylsilyloxy)ethyl)-3-methyl-1H-indazole (1.5 g, 40,7% yield). MS (ESI): m/z 371,0 [M+1]+.

Intermediate 90: 6-Iodo-4-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol

A. 6-Iodo-4-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol. 6-Iodo-4-methyl-1H-indazol (0,250 g, 0,969 mmol) was dissolved in tetrahydrofuran (10 ml) was added 3,4-dihydro-2H-Piran (of 0.133 ml, 1,453 mmol) and methanesulfonic acid (9,44 µl, 0,145 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture was stirred at 75°C overnight. When the reaction was completed, as shown by the LC/MS analysis, the reaction mixture was diluted with triethylamine (0.5 ml) and condensible under reduced pressure. The crude mixture was purified using chromatography using a gradient of 0-50% ethyl acetate in hexane to obtain 6-iodo-4-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole in the form of a white solid (0,336 g, 99% yield);1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 8.16 (DD, J=0,10, of 0.93 Hz, 1H), 7,96-8,03 (m, 1H), 7,29 (DD, J=0,63, 1,71 Hz, 1H), 5,84 (DD, J=2,64, 9,71 Hz, 1H), 3,83-3,90 (m, 1H), 3,71-3,81 (m, 1H), 2,29-2,43 (m, 1H), 1,99-of 2.06 (m, 1H), 1,88-of 1.97 (m, 1H), 1,65-1,80 (m, 1H), 1,52-1,62 (m, 2H); MS (ESI) m/z 343 [M+1]+.

Intermediate compound 91: 2-(Methoxymethyl)-1-tosyl-1H-benzo[d]imidazol-6-amine

A. 2-(Methoxymethyl)-6-nitro-1H-benzo[d]imidazole. 4-Nitrobenzene-1,2-diamine (1.5 g, 9,80 mmol) and 2-methoxybutanol acid (0,882 g 9,80 mmol) was dissolved in 4 M chloritoid�one acid (20 ml, 80 mmol) and heated to 100°C for 2 hours. The reaction mixture was cooled to 0°C and neutralized using 1M sodium hydroxide (80 ml). The resulting precipitate was filtered and dried, obtaining the desired product as a light yellow solid which was then further purified by crystallization using ethyl acetate and hexane. The obtained solid substance was dried under high vacuum at 50°C with obtaining the desired product as a white solid (1,23 g, 60.6% of output). MS (ESI) m/z 207,9 [M+1]+.

B. 2-(Methoxymethyl)-5-nitro-1-tosyl-1H-benzo[d]imidazole. 2-(Methoxymethyl)-5-nitro-1H-benzo[d]imidazole (1,23 g, 5,94 mmol) and 4-methylbenzol-1-sulphonylchloride (1,358 g, 7.12 mmol) was dissolved in tetrahydrofuran (50 ml) was added tert-butoxide sodium (1,141 g, 11,87 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into deletelog funnel containing water and 50% ethyl acetate. The organic layer was concentrated on a rotary evaporator almost to dryness and purified on a column of silica, elwira using 0-50% ethyl acetate in hexane. The fractions containing the product were concentrated on a rotary evaporator to obtain the desired product as a white solid (0.9 g, 42% yield). MS (ESI) m/z 362,3 [M+1]+.

C. 2-(Methoxymethyl)-1-tosyl-1H-benzo[d]imidazole-5-amine. 2-(Methoxymethyl)-5-nitro-tosyl-1H-benzo[d]imidazole (0.9 g, 2,491 mmol) was dissolved in ethanol and purged with nitrogen. Was added palladium on charcoal (0,530 g, 0,498 mmol), the nitrogen was evacuated and the reaction mixture was stirred under a hydrogen pressure of 1 atmosphere for 16 hours. The reaction mixture was filtered through Celite and washed with ethanol. The organic layer was concentrated on a rotary evaporator to dryness to obtain the desired product as a purple solid which was then crystallisable of ethyl acetate in hexane to obtain the desired compound as a white solid (0.7 g, 85% yield). MS (ESI) m/z 332,2[M+1]+.

Intermediate 92: 6-Bromo-1-isopropyl-1H-indazol

A. 6-bromo-1-isopropyl-1H-indazol. A solution/suspension of 6-bromo-1H-indazole (1 g, 5.08 mmol) in N,N-dimethylformamide (5 ml) was cooled to 0°C followed by the addition of sodium hydride (0,244 g, 6,09 mmol). The reaction mixture was left for stirring for 10 minutes, then was added 2-iodopropane (0,609 ml, 6,09 mmol). The reaction mixture was allowed to warm to room temperature and stirred over night. LC/MS analysis showed only product. To the reaction mixture were added water and the product was extracted with ethyl acetate twice, the organic layers were washed with saturated brine, then dried over sodium sulfate. The solvent was removed in vacuum. Neoch�sacred oil was loaded on a column (biotage AB and suirable using 0-100% ethyl acetate in hexane. Collected two regioisomer and implemented a number ΝOE analyses to determine regioselectively. First manifested peak represented the desired regioisomer 6-bromo-1-isopropyl-1H-indazol (638 mg, 2,67 mmol, 52.6% of output), which was collected as a clear oil.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,10 (s, 1H), 8,04 (s, 1H), 7,72 (d, J=8,59 Hz, 1H), 7,25 (DD, J=1,76, of 8.39 Hz, 1H), 5,02 (s, 1H), 1,46 (d, J=6,64 Hz, 6H). MS (ESI): m/z 241,2 [M+1]+.

Intermediate 93: 6-Amino-2,3-dihydro-1,2-benzisothiazol-1,1-dioxide

A. 6-Nitro-1,2-benzisothiazol-3(2H)-he-1,1-dioxide. A mixture of dihydrate periodnow acid (42 g, 0,184 mol), chromium oxide (VI) (0,23 g, 2.3 mmol) and 2-methyl-5-nitrobenzenesulfonamide (5 g, is 0.023 mol) in acetonitrile (100 ml) was heated at boiling with reflux until complete oxidation (the reaction was monitored using TLC). Was added dropwise isopropyl alcohol (25 ml). When you are finished adding the mixture was heated to boiling temperature with reflux for 10 minutes, the mixture was cooled to room temperature, filtered and the solids were washed with acetone (60 ml). The filtrates were combined and concentrated under reduced pressure. The residue was ground into powder with a solution of sulfuric acid (2 n, 69 ml) and 6-nitro-1,2-benzisothiazol-3(2H)-he-1,1-dioxide (2.5 g, 47.2% of yield) was collected by filtration.1H NMR (400 MHz, LCA�-d 6) δ (M. D.) of 8.82 (s, 1H), to 8.57 (DD, J1=8.4 Hz, J2=2,0 Hz, 1H), of 8.0 (d, J=8,0 Hz, 1H); MS (ESI): m/z at 228.9 [M+1]+.

B. 6-Amino-1,2-benzisothiazol-3(2H)-he-1,1-dioxide. Platinum dioxide (259 mg, 1.2 mmol) and 6-nitro-1,2-benzisothiazol-3(2H)-he-1,1-dioxide (1 g, 4.4 mmol) was suspended in a mixture of ethanol (52 ml) and dimethylformamide (4 ml) and the mixture was stirred under hydrogen atmosphere overnight. The mixture was filtered through celite and the filtrate was concentrated in vacuum to give 6-amino-1,2-benzisothiazol-3(2H)-he-1,1-dioxide (700 mg, 80.6% of output).

C. 6-Amino-2,3-dihydro-1,2-benzisothiazol-1,1-dioxide. To a suspension of 6-amino-1,2-benzisothiazol-3(2H)-he-1,1-dioxide (700 mg, of 3.53 mmol) in a mixture of ethanol (39 ml), dimethylformamide (3 ml) and concentrated hydrochloric acid (10 ml) was added zinc dust (2,95 g, 31.8 mmol) in portions and the reaction mixture was stirred at room temperature over night. The mixture was carefully podslushivaet with the help of a saturated aqueous solution of sodium bicarbonate and solid sodium bicarbonate and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 6-amino-2,3-dihydro-1,2-benzisothiazol-1,1-dioxide in the form of a solid (250 mg, 38.5% of the output).1H NMR (400 MHz, DMSO-d6): δ (M. D.) 7,53 (s, 1H), 7,12 (d, J=8.4 Hz, 1H), about 6,82 (DD, J1=8.4 Hz, J2=2,0 Hz, 1H), was 6.77 (s, 2H), of 4.16 (q, j =3.2 Hz, 2H); MS (ESI): m/z 184,9 [M+1]+.

Intermediate 94: tert-Butyl 6-amino-3,3-dimethyl-2-oxoindole-1-carboxylate

A. 2-Bromo-5-nitroaniline. To a solution of 2-bromoaniline (20 g, 0,117 mol) in a solution of concentrated sulfuric acid (120 ml) was added potassium nitrate (11,8 g, 0,117 mol) at 0°C in portions over 1.5 hours. The mixture was stirred at the same temperature for 0.5 hours and neutralized with an aqueous ammonia solution (800 ml) to pH>5. The yellow precipitate was collected by filtration, washed with water (300 ml ×3) and dried in vacuum to give 2-bromo-5-nitroaniline (25 g, 100% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.), a 7.62 (m, 2H), 7,49 (DD, J1=2.4 Hz, J2=8.4 Hz, 1H), 4,46 (lat.s, 2H).

B. N-(2-Bromo-5-nitrophenyl)methacrylamide. To a stirred solution of methacrylic acid (2.0 g, 23 mmol) in N,N-dimethyl-acetamide (15 ml) was added dropwise thionylchloride (2,77 g, 23 mmol) at 0°C in a nitrogen atmosphere and the mixture was stirred for 0.5 hours at this temperature. Was added 2-bromo-5-nitroaniline (5.0 g, 23 mmol). The resulting mixture was stirred at room temperature over night. Was added water (150 ml). The yellow precipitate was collected by filtration, washed with water (50 ml ×3) and dried in vacuum to give N-(2-bromo-5-nitrophenyl)methacrylamide (5.2 g, 80% yield) as a yellow solid. H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,78 (s, 1H), and 8.50 (s, 1H), 8,07 (m, 2H), 6,03 (s, 1H), 5,69 (s, 1H), of 2.06 (s, 3H).

C. 3,3-Dimethyl-6-nitroindoline-2-it. A solution of N-(2-bromo-5-nitrophenyl)methacrylamide (5.0 g, 17,6 mmol), diacetonitrile(II) (79 mg, 0.35 mmol), tetrabutylammonium (5.7 g, a 17.6 mmol) and triethylamine (6.1 ml, 44 mmol) in anhydrous N,N-dimethylformamide (150 ml) in a nitrogen atmosphere was heated at 80°C for 1 hour. Was added sodium formate (1.2 g, 17,6 mmol) and the mixture was stirred at 80°C for 10 hours. Was added water (600 ml) and the mixture was extracted with ethyl acetate (400 ml ×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate, concentrated and purified using column chromatography on silica gel (elwira using 10-25% ethyl acetate in petroleum ether) to give 3,3-dimethyl-6-nitroindoline-2-one (2.5 g, 69% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 10.73 (s, 1H), 7.87 ft (m, 1H), 7,55 (m, 2H), of 1.28 (s, 6H).

D. tert-Butyl 3,3-dimethyl-6-nitro-1-oxoindole-1-carboxylate. To a solution of 3,3-dimethyl-6-nitroindoline-2-one (250 mg, to 1.21 mmol) in a solution of sodium bicarbonate (204 mg, 2,43 mmol) in tetrahydrofuran (10 ml) was added di-tert-BUTYLCARBAMATE (529 mg, 2,43 mmol) at 0°C in a nitrogen atmosphere and the mixture was stirred for 6 hours at room temperature. The reaction mixture was poured into water and the resulting mixture extra�Aravali ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified on a column of silica gel (elwira using 1-10% ethyl acetate in petroleum ether) to give tert-butyl 3,3-dimethyl-6-nitro-2-oxoindole-1-carboxylate (290 mg, 78.4% of output).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) to 8.70 (d, J=1.6 Hz, 1H), 8,04 (DD, J1=2,0 Hz, J2=8,0 Hz, 1H), 7,30 (d, J=8,0 Hz, 1H), to 1.61 (s, 9H), of 1.40 (s, 6H).

E. tert-Butyl 6-amino-3,3-dimethyl-2-oxoindole-1-carboxylate. To a solution of tert-butyl 3,3-dimethyl-6-nitro-2-oxoindole-1-carboxylate (0.29 g, 0.95 mmol) in methanol (5 ml) was added 10% palladium on charcoal (0.15 g) and the mixture was gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature for 3 hours. When TLC analysis (50% ethyl acetate in petroleum ether) showed that the starting material was consumed, the reaction mixture was filtered and the filtrate concentrated to give tert-butyl 6-amino-3,3-dimethyl-2-oxoindole-1-carboxylate (230 mg, 88% yield). MS (ESI): m/z 211 (A [M+1]+.

Intermediate 95: 6-Iodo-3,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-he

A. 6-Amino-3,3-dimethylindoline-2-it. A mixture of 3,3-dimethyl-6-nitroindoline-2-one (2.5 g, 12.1 mmol) and 10% palladium on carbon (50% moisture content, mass/mass, 250 mg) in a mixture� of methanol and ethyl acetate (about:about=1:1, 20 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature for 3 hours. The catalyst was filtered and the filtrate was concentrated in vacuum to give 6-amino-3,3-dimethylindoline-2-one (2.0 g, 95% yield).

B. 6-Iodo-3,3-dimethylindoline-2-it. To a solution of 6-amino-3,3-dimethylindoline-2-one (1.04 g, 5.9 mmol) in hydrochloric acid (3 M, 30 ml) was added sodium nitrite (406 mg, 5.9 mmol) at 0°C. After stirring for 0.5 hours was added dropwise a solution of potassium iodide (978 mg, 5.9 mmol) and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was neutralized with sodium carbonate and was extracted with ethyl acetate. The organic layer was combined, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified using chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether), to obtain 6-iodo-3,3-dimethylindoline-2-one as pale yellow solid (780 mg, yield 46%); MS (ESI): m/z 287,9 [M+1]+.

C. 6-Iodo-3,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-it. To a solution of 6-iodo-3,3-dimethylindoline-2-one (780 mg, 2.7 mmol) in N,N-dimethylformamide (20 ml) was added sodium hydride (162 mg, 4.1 mmol, 60% in mineral oil) in portions at 0°C. the Mixture was stirred for 0.5 hours at 0°C was added (2-(chloromethoxy)ethyl)trimethy�silane (678 mg, 4,1 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding aqueous ammonium chloride (30 ml) and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated. The residue was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 6-iodo-3,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one (950 mg, 84% yield) as a yellow oil.1H NMR (300 MHz, CHLOROFORM-d) δ (MD), 7,47 (d, J=7,8 Hz, 1H), 7,44 (s, 1H), 6,99 (d, J=7,8 Hz, 1H), 5,16 (s, 2H), only 3.57 (t, J=8,1 Hz, 2H), 1,41 (s, 6H), of 0.96 (t, J=8,1 Hz, 2H), 0 (s, 9H).

Intermediate compound 96: 4-Iodo-3-methoxy-N-methylbenzamide

A. 4-Iodo-3-methoxybenzoic acid. A solution of sodium nitrite (1.7 g, is 24.4 mmol) in water (3.5 ml) was added slowly to a stirred solution of 4-amino-3-methoxybenzoic acid (4.0 g, 23,9 mmol) in a mixture of water (61 ml) and concentrated hydrochloric acid (18 ml) at 0°C. After stirring for 1 hour at 0°C was added sodium iodide (3,67 g, a 24.4 mmol). The resulting mixture was slowly warmed to room temperature for 5 minutes and heated at 60°C for 2 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with water to obtain 4-iodo-3-m�oxybenzoic acid (4.0 g, 60.1% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,92 (d, J=8,0 Hz, 1H), of 7.42 (d, J=1.6 Hz, 1H), 7,31 (DD, J1=7,6 Hz, J2=1.6 Hz, 1H), 2,27 (s, 3H).

B. 4-Iodo-3-methoxy-N-methylbenzamide. N,N-Dimethylformamide (0.1 ml) was added to a solution of 4-iodo-3-methoxybenzoic acid (2.0 g, 7.2 mmol) in sulfurylchloride (20 ml) and the mixture was heated to boiling temperature with reflux for 2 hours. Excess sulfurylchloride was removed under reduced pressure to obtain crude product 4-iodo-3-methoxy-benzoyl chloride. To a solution of methylamine (0,72 g, the 10.8 mmol) and triethylamine (2.18 g, 21.6 mmol) in dichloromethane (20 ml) was added dropwise a solution of the above 4-iodo-3-methoxy-benzoyl chloride in dichloromethane (15 ml) at 0°C. After completion of the reaction was added water, the organic layer was separated, dried over sodium sulfate, evaporated to obtain crude product, which was purified on a column of silica gel (elwira with the help of 10-17% ethyl acetate in petroleum ether), obtaining 4-iodo-3-methoxy-N-methylbenzamide (0.92 g, 46% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,92 (d, J=8,0 Hz, 1H), of 7.42 (d, J=5.6 Hz, 1H), 7,31 (DD, J1=8,0 Hz, J2=2,0 Hz, 1H), 3,88 (s, 3H).

Intermediate 97: 5-(3-Bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

5-(3-Bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. To a stirred� a solution of 5-(3-bromophenyl)-1H-imidazole (1 g, 4.5 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added sodium hydride (60% in mineral oil, 160 mg, 4.7 mmol) at 0°C and the mixture was stirred at this temperature for 0.5 hours. Was added dropwise a solution of (2-(chloromethoxy)ethyl)trimethylsilane (0.9 ml, of 5.36 mmol) in N,N-dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature for 4 hours. When the starting material was consumed, the reaction was quenched with water. The mixture was extracted with ethyl acetate and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated in vacuum. The residue was purified on a column of silica gel (elwira using 5-10% ethyl acetate in petroleum ether) to give 5-(3-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.1 mg, 69.6% of yield) as a yellow solid. MS (ESI): m/z 353,0 [M+1]+.

Intermediate compound 98: (R)-piperidine-3-ylmethanol

A. (R)-piperidine-3-ylmethanol. (R)-piperidine-3-carboxylic acid (2 g, 15,49 mmol) was added to tetrahydrofuran (20 ml). To the suspension was added dropwise to the hydride (23,23 ml, 23,23 mmol, 1M solution in tetrahydrofuran) and then heated to 60°C for 18 hours in a nitrogen atmosphere. The reaction mixture was cooled, and quenched with heptahydrate sodium sulfate (0.5 g). The mixture was stirred p�and room temperature for 2 hours and then filtered. The filtrate was passed through ion-exchange column (Strata-XC) and then was extracted using 2M ammonia in methanol. The solution was concentrated to give a clear oil (0.55 g, 4,78 mmol, 30.8% of output). MS (ESI) m/z USD 116.2 [M+1]+.

(S)-piperidine-3-ylmethanol synthesized by following the same procedure, on the basis of (S)-piperidine-3-carboxylic acid.

Intermediate 99: hydrochloride (S)-piperidine-3-carboxamide

A. (S)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid. To (S)-piperidine-3-carboxylic acid (1 g, 7,74 mmol) was added ethanol (50 ml) and N,N-dimethylformamide (1 ml) followed by the addition of di-tert-BUTYLCARBAMATE (2,157 ml 9,29 mmol) and then stirred at room temperature for 16 hours. The reaction mixture was concentrated and then purified using chromatography on silica gel (0-100% ethyl acetate in hexane) to give a white solid, (1.6 g, 6,98 mmol, 90% yield). MS (ESI) m/z 230,4 [M+1]+.

B. Hydrochloride (S)-piperidine-3-carboxamide. To (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1.6 g, 6,98 mmol) was added acetonitrile (70 ml), triethylamine (2,92 ml 20,94 mmol) and O-benzotriazole-N,N,N',N'-tetramethyl-urani-hexaflurophosphate (2,91 g, to 7.68 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then was added ammonium chloride (0,747 g, RUR 13.96 mmol) and TRANS�Merivale at room temperature for 20 minutes. The reaction mixture was concentrated in vacuo and then purified using chromatography on silica gel (0-100% ethyl acetate in hexane). The fractions containing the product were concentrated and then treated with 4n solution of hydrogen chloride in dioxane (5 ml). The solution was stirred at room temperature for 1 hour and then concentrated. The residue was filtered and washed with ethyl acetate to give a white solid (0.32, 1,944 mmol, 27.9 percent yield). MS (ESI) m/z 129,0 [M+1]+.

Hydrochloride (R)-piperidine-3-carboxamide synthesized by following the same procedure using (R)-piperidine-3-carboxylic acid as the starting material.

Intermediate compound 100: 5-Bromo-1-tosyl-1H-imidazo[2,3-b]pyridine

A. 5-Bromo-1-tosyl-1H-imidazo[2,3-6]pyridine. A stirred solution of 5-bromo-1H-imidazo[2,3-b]pyridine (0,682 g, and 3.46 mmol) in tetrahydrofuran (10 ml) was cooled to -50°C in a nitrogen atmosphere. Was added p-toluensulfonate (0,693 g 3,63 mmol) and the resulting mixture was stirred at -50°C until complete dissolution of the p-toluensulfonate. Was added sodium hydride (0,100 g, 4,15 mmol), to obtain cloudy orange mixture. The resulting mixture was slowly heated to 0°C for 40 minutes and then was added an aqueous solution of ammonium hydroxide to quench the reaction. The resulting mixture was diluted with water and ethyl�the Etat and was shaken in a separatory funnel. The layers were separated and the organics were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was dissolved in dichloromethane and purified using flash chromatography (biotage AB) (2-40% ethyl acetate in hexane) to give the desired product (1,133 g, 3.23 mmol, 93% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (MD), of 8.47 (d, J=2,34 Hz, 1H), of 8.33 (d, J=2,34 Hz, 1H), 7,92-8,02 (m, 3H), 7,43 (d, J=8,20 Hz, 2H), 6,80 (d, J=3,90 Hz, 1H), 2,35 (s, 3H); MS (ESI) m/z 351,1 [M]+, To 353.2 [M+2]+.

Intermediate 101: 6-Bromo-3-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol

A. 6-Bromo-3-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol. 6-Bromo-3-methyl-1H-indazole (2.5 g, 11,85 mmol), tetrahydrofuran (20.0 ml), monohydrate p-toluensulfonate acid (0,113 g, 0,592 mmol), 3,4-dihydro-2H-Piran (1,625 ml, 17,77 mmol) and magnesium sulfate (1,426 g, 11,85 mmol) was added to a microwave reaction vessel was tightly closed and heated to 70°C for 4 hours. The reaction mixture was filtered, concentrated and then purified using chromatography on silica gel biotage AB Emrys SP1 (elwira using 0-50% ethyl acetate in hexane). The desired fractions were combined and the organic volatiles were removed under reduced pressure to obtain 6-bromo-3-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (1,6103 g,5,46 mmol, Only 46.1% yield) as a white solid. MS (ESI) m/z 295,2 [M]+, 297,2 [M+2]+.

Intermediate 102: 6-Bromo-3-methyl-1-tosyl-1H-indazol

A. 6-Bromo-3-methyl-1-tosyl-1H-indazol. A stirred mixture of 6-bromo-3-methyl-1H-indazole (2.33 g, the 11.04 mmol) and p-toluensulfonate (2,126 grams of 11.15 mmol) in 1,4-dioxane (25 ml) under an atmosphere of nitrogen was rapidly heated by using the apparatus for heating a stream of warm air to dissolve all solids. The resulting clear amber-colored solution was cooled in a bath of ice water. Was added sodium hydride (0,318 g, at 13.25 mmol), the cooling bath was removed and the resulting mixture was stirred at room temperature in a nitrogen atmosphere for 1 hour. Was added a saturated aqueous solution of ammonium chloride (2 ml) followed by addition of water (40 ml). The solids were collected via suction filtration and washed with water. The solids were then washed with 50% solution of diethyl ether in hexane (50 ml) and dried in vacuum to give the desired product (3,66 g, of 10.02 mmol, 91% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,23 (d, J=1,56 Hz, 1H), 7,76-a 7.87 (m, 3H), 7,60 (DD, J=1,56, 8,59 Hz, 1H), 7,41 (d, J=8,20 Hz, 2H), 2,48 (s, 3H), 2,34 (s, 3H); MS (ESI) m/z 365,2 [M]+, 367,1 [M+2]+.

Intermediate 103: 8-Methylene-1,4-dioxaspiro[4,5]Dean

A. 8-Methylene-1,4-dioxaspiro[4,5]decane. To a suspension of methyltriphenylphosphonium (9,15 g, 25,6 mmol) in anhydrous tetrahydrofuran (88 ml) at 0°C was added dropwise n-butyllithium (16,65 ml, 26.6 mmol, 1.6 M solution in hexane) under vigorous stirring. The suspension was bright orange and transparent. The reaction mixture was warmed to room temperature for 1 hour, then was added a solution of 1,4-dioxaspiro[4,5]Dean-8-she (4.0 g, 25,6 mmol) in anhydrous tetrahydrofuran (10 ml) at room temperature. After the addition was slowly formed a yellow precipitate. The reaction mixture was stirred over night at room temperature. The reaction mixture was filtered and the solid was washed with hexane. The filtrate was evaporated to dryness and the residue was purified using column chromatography using biotage AB (elwira using 5-15% ethyl acetate in hexane). 8-Methylene-1,4-dioxaspiro[4,5]Dean (3.1 g, 20,10 mmol, 78% yield) was isolated as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 4.66 (s, 2H), a 3.87 (s, 4H), 2,11-of 2.25 (m, 4H), 1,50-of 1.66 (m, 4H).

Intermediate 104: 3-Chloro-5-hydroxyflavanone acid

A. 1-Bromo-3-chloro-5-methoxybenzo. To a solution of 1-bromo-3-chloro-5-torbenson (10 g, 48 mmol) in methanol (250 ml) was added sodium methoxide (5,18 g, 96 mmol) at room temperature in the atmosphere of Attai the mixture was heated at boiling with reflux for 24 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was washed with water and saturated brine, dried over anhydrous sodium sulfate and was evaporated in vacuum to give 1-bromo-3-chloro-5-methoxybenzene (4 g, 36% yield) as a white solid.

B. 3-Chloro-5-methoxyphenylalanine acid. To a stirred solution of 1-bromo-3-chloro-5-methoxybenzene (4.0 g, 18 mmol) in tetrahydrofuran (50 ml) was added dropwise n-butyllithium (0,76 ml, 1.9 mmol, 2.5 M in hexane) at -78°C in a nitrogen atmosphere. After stirring the mixture for 1 hour at this temperature was added trimethylboron (of 5.68 g, 54 mmol). The resulting mixture was stirred at room temperature over night. Was added water (100 ml) dropwise, and then added concentrated hydrochloric acid to bring the pH=3. The organic solvent was removed in vacuo and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and was evaporated in vacuum to give crude product, which was washed with simple ether to obtain 3-chloro-5-methoxyphenylalanine acid (1.2 g, 36% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,26 (lat.s, 1H), of 7.36 (s, 1H), 7,30 (s, 1H), to 7.04 (m, 1H), 3,74 (s, 3H).

C. 3�or-5-hydroxyflavanone acid. To a stirred solution of 3-chloro-5-methoxyphenylalanine acid (1.2 g, 66 mmol) in dichloromethane (20 ml) was added dropwise to tribromsalan (4.8 g, 20 mmol) at -78°C and the mixture was stirred at room temperature over night. The mixture was quenched with methanol at -78°C, warmed to room temperature and concentrated in vacuo. The residue was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and was evaporated in vacuum to give 3-chloro-5-hydroxyphenylarsonic acid (1,08 g, 95% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,71 (lat.s, 1H), 8,14 (lat.s, 2H), 7,35 (s, 1H), 7,21 (s, 1H), about 6,82 (s, 1H).

Intermediate compound 105: 5-Methyl-6-morpholinopropan-3-amine

A. 4-(3-Methyl-5-nitropyridine-2-yl)morpholine. 2-Chloro-3-methyl-5-nitropyridine (5 g, 29,0 mmol), potassium carbonate (8,01 g of 57.9 mmol), dimethylsulfoxide (20 ml) and morpholine (5,05 ml of 57.9 mmol) were heated together to 80°C for 16 hours. The reaction mixture was diluted with water, filtered and then dried to obtain 4-(3-methyl-5-nitropyridine-2-yl)morpholine (7.1 g, 31.8 mmol, 110% yield) as a bright yellow solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) is 8.91 (d, J=2.7 Hz, 1H), 8,24 (DD, J=0,8, a 2.7 Hz, 1H), 3,67-to 3.76 (m, 4H), 3,44 (m, 4H), 2,34 (s, 3H). MS (ESI) m/z 224,2[M+1] +.

B. 5-Methyl-6-morpholinopropan-3-amine. To 4-(3-methyl-5-nitropyridine-2-yl)morpholine (6,47 g, 29 mmol) was added 4n solution of hydrogen chloride in dioxane (4 ml), 10% palladium on carbon (100 mg), methanol (60 ml) and then shaken in hydrogenator Parra at a hydrogen pressure of 40 lb/inch2(2,812 kg/cm2) for 16 hours. The reaction mixture was filtered through celite, concentrated and then purified on silica gel (0-100% methanol in ethyl acetate) and dried with getting a rusty-brown solid, 5-methyl-6-morpholinopropan-3-amine, which was obtained as hydrochloride salt (2.7 g, of 11.75 mmol, 40.5% of the output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) to 2.29 (s, 3H) 3,08-3,16 (m, 4H) 3,69-with 3.79 (m, 4H) 7,51 (d, J=2,34 Hz, 1H) 7,78 (lat.s, 1H). MS (ESI) m/z 194,1 [M+1]+.

Intermediate 106: tert-Butyl 6-amino-3,3,4-trimethyl-2-oxoindole-1-carboxylate

A. 2-Bromo-3-methyl-5-nitroaniline. 2-Bromo-3-methylaniline (4,420 g, 23,76 mmol) was dissolved in sulfuric acid (25 ml, 469 mmol) at room temperature using ultrasonic treatment. The solution was cooled to 0°C was added potassium nitrate (2,62 g of 25.9 mmol) in one portion. The solution after some time became brown. LC/MS analysis after 45 minutes showed a ratio of ~10:1 product:starting material. Added another portion of potassium nitrate (240 mg, 2,374 mmol). After 2 hours reaction�ion mixture was poured slowly into a mixture of 100 ml of ammonium hydroxide solution and crushed ice maintaining the temperature below room temperature with the use of additional quantities of crushed ice. A reddish-yellow solid substance was collected by filtration and dried in a vacuum oven at 60°C for 16 hours to obtain the desired 2-bromo-3-methyl-5-nitroaniline (5,3792 g, 23,28 mmol, 98% yield).1H NMR analysis of crude product showed two regioisomer nitration, the desired regioisomer was ~85% of the mixture. Crude nitroaniline was used directly in the next reaction.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) quick 8.94 (s, 1H), a 7.85 (d, J=8,98 Hz, 1H), of 7.48 (d, J=2,34 Hz, 1H), 7,44 (d, J=2,73 Hz, 1H), 4,46 (lat.s, 2H), 2,46 (s, 3H); MS (ESI): m/z 233,2 [M+1]+.

B. N-(2-Bromo-3-methyl-5-nitrophenyl)methacrylamide.

Methacrylic acid (1,961 ml 23,12 mmol) was weighed in a 200-ml flask and dissolved in anhydrous N,N-dimethylacetamide (30 ml). The solution was cooled to 0°C and added dropwise thionylchloride (1,70 ml, 23,29 mmol) in 1 minute. The solution was stirred for 20 minutes and then was added 2-bromo-3-methyl-5-nitroaniline (3,8150 g, 16,51 mmol) as solids. After 30 minutes the cooling bath was removed. After 1 hour, LC/MS analysis showed a strong peak of the product. Was added water (~100 ml), causing precipitation of brown solids. This solid was collected using vacuum filtration in 60-ml funnel with a glass filter with an average� pore size, then dried in a vacuum oven at 60°C for 2 hours, the crude N-(2-bromo-3-methyl-5-nitrophenyl)methacrylamide (4,5198 g, 15,11 mmol, 92% yield). MS (ESI): m/z 299,4 [M+1]+.

C. 3,3,4-Trimethyl-6-nitroindoline-2-it. N-(2-bromo-3-methyl-5-nitrophenyl)methacrylamide (2,5451 g, 8,51 mmol), palladium acetate (II) (106,4 mg, 0,474 mmol), tetrabutylammonium (2,80 g, of 8.69 mmol) and N,N-dimethylformamide (24 ml) was added to 200-ml flask, which was then closed by a membranous septum, and purged with nitrogen. Was added N,N-dimethylformamide (24 ml) via syringe and the solution was barbotirovany nitrogen through a needle for 5 minutes. Was added triethylamine (3.0 ml, 21,52 mmol) via a syringe and the vessel was placed for stirring in a 80°C oil bath for 30 minutes. The cover is then quickly removed and the hot reaction mixture was added sodium formate (0,675 g, to 9.93 mmol). The vessel was then closed, and the solution was barbotirovany nitrogen for 2 minutes with the needle and the reaction mixture was placed for mixing in conditions of 80°C for 15 hours. The reaction mixture was filtered through celite and concentrated to obtain brown oil. Flash chromatography on silica gel gave the desired 3,3,4-trimethyl-6-nitroindoline-2-he (0,9092 g, 4,13 mmol, 48.5% of the output).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,44 (lat.s, 1H), 7,76 (d, J=1,56 Hz, 1H), 7,61 (d, J=1,95 Hz, 1H), 2,50 (s, 3H), of 1.52 (s, 6H). MS (ESI): m/z 221,4 [M+1]+.

D. tert-Butyl 3,3,4-trimethyl-6-nitro-1-oxo�of indolin-1-carboxylate. 3,3,4-Trimethyl-6-nitroindoline-2-he (0,9092 g, 4,13 mmol), di-tert-BUTYLCARBAMATE (1,602 ml 6,90 mmol), tetrahydrofuran (10 ml) and sodium bicarbonate (748,8 mg, is 8.91 mmol) was placed in a 100-ml flask. Was added 4-(dimethylamino)pyridine (51,8 mg, 0,424 mmol) and tightly closed flask was left for thorough mixing at 60°C in an oil bath. After 1.5 hours the reaction mixture was diluted with ethyl acetate and 10% citric acid. Using a certain amount of saturated salt solution to the emulsion separation the organic layer was removed and the aqueous layer was extracted with ethyl acetate. The combined organic solutions were dried over magnesium sulfate, filtered and concentrated. Flash chromatography on silica gel elution with 0-25% ethyl acetate in hexane gave the desired tert-butyl 3,3,4-trimethyl-6-nitro-2-oxoindole-1-carboxylate (1,1263 g 3,52 mmol, 85% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,64 (d, J=1,95 Hz, 1H), a 7.87 (d, J=1,56 Hz, 1H), 2,52 (s, 3H), by 1.68 (s, 9H), 1.55 V (s, 6H). MS (ESI): m/z 265,2 [M+1]+.

E. tert-Butyl 6-amino-3,3,4-trimethyl-2-oxoindole-1-carboxylate. 10% Palladium on carbon (72,3 mg, 0,068 mmol) and tert-butyl 3,3,4-trimethyl-6-nitro-2-oxoindole-1-carboxylate (1,1263 g 3,52 mmol) was dissolved in ethyl acetate (15 ml). The flask was purged with hydrogen and left to stir under a balloon of hydrogen for 3 days, then filtered through celite and concentrated to obtained�eat the desired tert-butyl 6-amino-3,3,4-trimethyl-2-oxoindole-1-carboxylate (1,0589 g, 3,65 mmol, 104% yield). MS (ESI): m/z 291,1 [M+1]+.

Intermediate compound 107: 6-Aminoindole-2-he

A. Methyl 2-(2,4-dinitrophenyl)acetate. To a stirred solution of 2-(2,4-dinitrophenyl)acetic acid (11.3 g, 0.5 mol) in methanol (150 ml) was added concentrated sulfuric acid (2 ml) and the mixture was stirred at the temperature of reflux for 10 hours. The reaction mixture was concentrated under vacuum and the residue was washed with water to obtain methyl 2-(2,4-dinitrophenyl)acetate (9.4 g, 78,3% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (MD), 8,73 (d, J=2.4 Hz, 1H), 8,51 (DD, J=2,4, and 8.4 Hz, 1H), 7,83 (d, J=8.4 Hz, 1H), 4,19 (s, 2H), only 3.57 (s, 3H); MS (ESI): m/z: 241,0 [M+H]+.

B. 6-Aminoindole-2-it. A mixture of methyl 2-(2,4-dinitrophenyl)acetate (4.8 g, 20 mmol) and 10% palladium on carbon (50% moisture content, mass/mass, 100 mg) in methanol (50 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature over night. The suspension was filtered, the filtrate was heated at 60°C for 12 hours. The mixture was cooled to room temperature and concentrated. The residue was purified using column chromatography on silica gel (elwira using 60% ethyl acetate in petroleum ether) to give 6-aminoindole-2-one (220 mg, 7.4 per cent yield) as a gray solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 6,80 (�, J=8.4 Hz, 1H), 6,12 (m, 2H), 5,01 (s, 2H), 3,24 (s, 2H).

Intermediate 108: 6-Bromo-3-ethyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol

A. 1-(4-Bromo-2-fluorophenyl)propan-1-ol. Ethylmagnesium (64,3 ml, 192,9 mmol, 3 M solution in tetrahydrofuran) was added dropwise to a solution of 4-bromo-2-forventelige (30,0 g, 148 mmol) in tetrahydrofuran (500 ml) in a nitrogen atmosphere at 0°C for 30 minutes. The mixture was heated to room temperature for 2 hours, quenched with an aqueous solution of ammonium chloride and was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, was evaporated under reduced pressure and dried in vacuum to give 1-(4-bromo-2-fluorophenyl)propan-1-ol (16 g, 47%) as an oil.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,45 (m, 3H), and 5.36 (s, 1H), 4,70 (t, J=6,4 Hz, 1H), 1,63 (sq, J=7.2 Hz, 2H), 0,80 (m, 3H).

B. 1-(4-Bromo-2-fluorophenyl)propane-1-he. A mixture of 1-(4-bromo-2-fluorophenyl)propan-1-ol (15 g, and 64.6 mmol) and manganese oxide (IV) (22,5 g, 258 mmol) in dichloromethane (250 ml) was heated at boiling with reflux during the night. After cooling to room temperature the reaction mixture was filtered and the filtrate was removed under reduced pressure to obtain 1-(4-bromo-2-fluorophenyl)propane-1-one (9 g, 60.5 per cent) in the form of solids. MS (ESI): m/z to 230.8 [M+1]+.

C. 6-Bromo-3-ethyl-1H-indazol. A mixture of 1-(4-bromo-2 - fluorophenyl)propane-1-one (9 g, 39,0 mmol) and an aqueous solution of hydrazine (50 ml, 85%) was heated at boiling with reflux during the night. After cooling to room temperature the reaction mixture was filtered and the filter cake was dried in vacuum to give 6-bromo-3-ethyl-1H-indazole (4.4 g, 50.3% of output) in the form of solids. MS (ESI): m/z 224,8 [M+1]+.

D. 6-Bromo-3-ethyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol. A mixture of 6-bromo-3-ethyl-1H-indazole (4.4 g, 19.5 mmol), 3,4-dihydro-2H-PYRAN (3.3 g, 39 mmol) and p-toluensulfonate acid (374 mg, of 1.95 mmol) in tetrahydrofuran (60 ml) was heated at 60°C over night. The reaction mixture was poured into ice water and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on a column of silica gel to obtain 6-bromo-3-ethyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (4.4 g, was 73.2% yield). MS (ESI): m/z 310,8 [M+3]+.

Intermediate compound 109: 5-Bromo-2-(2-methoxyethyl)isoindoline-1-he

A. 5-Bromo-2-(2-methoxyethyl)isoindoline-1-it. A mixture of methyl 4-bromo-2-(methyl bromide)benzoate (2.4 g, 7.8 mmol) and 2-methoxyethylamine (2.9 g, 39 mmol) in methanol (20 ml) was stirred at room temperature over night. The reaction mixture was concentrated and purified using column chromatography on silica gel (elwira using 5-20% ethyl acetate in petroleum ether) semi�the group of 5-bromo-2-(2-methoxyethyl)isoindoline-1-one as a white solid (1.2 g, 57% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,71 (d, J=7,6 Hz, 1H), members, 7.59 (m, 2H), 7,45 (s, 2H), of 3.78 (t, J=6,4 Hz, 2H), 3,63 (t, J=6,4 Hz, 2H), 3,39 (s, 3H).

Intermediate 110: 6-Bromo-4-fluoro-3-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol

A. (4-Bromo-2,6-differenl)methanol. To a solution of 4-bromo-2,6-diferential acid (5 g, 21 mmol) in tetrahydrofuran (200 ml) was added dropwise a solution of borane•dimethylsulfide complex (16,1 g, 212 mmol) in tetrahydrofuran (100 ml) at 0°C in a nitrogen atmosphere and the resulting mixture was stirred at room temperature for 3 hours. Was added methanol (300 ml) to quench the reaction and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, the solution was washed with saturated brine, dried over anhydrous sodium sulfate and was evaporated in vacuum to give (4-bromo-2,6 - differenl)methanol (4,56 g, 97% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,13 (d, J=8,8 Hz, 2H), 4.75 in (s, 2H).

B. 4-Bromo-2,6-differentally. A mixture of (4-bromo-2,6-differenl)methanol (4,56 g, 20.5 mmol) and manganese dioxide (IV) (7,14 g, with 82.2 mmol) in dichloromethane (200 ml) was heated at boiling with reflux during the night. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 4-bromo-2,6-diferentialglea (3,54 g, 8%) as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 10,22 (s, 1H), of 7.19-7,14 (m, J=8,8 Hz, 2H).

C. 1-(4-Bromo-2,6-differenl)ethanol. Methylanisole (6.4 ml and 19.3 mmol, 3 M solution in tetrahydrofuran) was added dropwise to a solution of 4-bromo-2,6-diferentialglea (3,54 g, 16,1 mmol) in tetrahydrofuran (100 ml) in a nitrogen atmosphere at 0°C for 30 minutes. The mixture was heated to room temperature for 2 hours, quenched with an aqueous solution of ammonium chloride and was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, was evaporated under reduced pressure and dried in vacuum to give 1-(4-bromo-2,6-differenl)ethanol (2.2 g, 58%) as an oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,12 (m, 2H), 5,14 (m, 1H), 1,54 (m, 3H).

D. 1-(4-Bromo-2,6-differenl)Etalon. A mixture of 1-(4-bromo-2,6-differenl)ethanol (2.2 g, 9.3 mmol) and manganese dioxide (IV) (3,2 g of 37.3 mmol) in dichloromethane (50 ml) was heated at boiling with reflux during the night. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 1-(4-bromo-2,6-differenl)ethanone (1.7 g, 78%) as an oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,14 (m, 2H), 1,54 (s, 3H).

E. 6-Bromo-4-fluoro-3-methyl-1H-indazol. A mixture of 1-(4-bromo-2,6-differenl)ethanone (1.1 g, 4.7 mmol) and an aqueous solution of hydrazine (235 mg, 4.7 mmol, 85%) in tetrahydrofuran was heated �ri boiling to reflux over night. After cooling to room temperature the reaction mixture was concentrated and the residue was dissolved with ethyl acetate, the solution was washed with saturated brine, dried over anhydrous sodium sulfate, was evaporated under reduced pressure and was purified on a column of silica gel to obtain 6-bromo-4-fluoro-3-methyl-1H-indazole (510 mg, 47.7% of the output).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 9,85 (lat.s, 1H), 7,31 (d, J=0.8 Hz, 1H), 6,86 (DD, J1=1.2 Hz, J2=9,2 Hz, 1H), 2,60 (s, 3H).

F. 6-Bromo-4-fluoro-3-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol. A mixture of 6-bromo-4-fluoro-3-methyl-1H-indazole (510 mg, 2,24 mmol), 3,4-dihydro-2H-PYRAN (376 mg, 4,47 mmol), and p-toluensulfonate acid (42,5 mg, 0,224 mmol) in tetrahydrofuran (20 ml) was heated at 80°C over night. The reaction mixture was poured into ice water and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, was evaporated under reduced pressure and was purified on a column of silica gel to obtain 6-bromo-4-fluoro-3-methyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (590 mg, 84.5% of the output).1H NMR (300 MHz, δ (M. D.) a 7.85 (s, 1H), 7,20 (d, J=to 8.7 Hz, 1H), of 5.81 (d, J=9,2 Hz, 1H), 3,88 (m, 2H), by 2.55 (s, 3H), 1,98-of 1.91 (m, 2H), 1,67-of 1.47 (m, 4H).

Intermediate 111: 6-Bromo-4-fluoro-1,3-dimethyl-1H-indazol

A. 6-Bromo-4-fluoro-1,3-dimethyl-1H-indazol. To a solution of 6-bromo-4-fluoro-3-methyl-1H-indazole (500 mg, 2,19 mmol) in N,N-dimethylformamide (15 m�) was added sodium hydride (100 mg, 2,49 mmol, 60% in mineral oil) in portions at 0°C. Upon completion of addition the mixture was stirred for 30 minutes at 0°C, was added itmean (1.25 g, 8,8 mmol) and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water (10 ml) and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate, evaporated and purified on a column of silica gel (elwira using 5% ethyl acetate in petroleum ether) to give 6-bromo-4-fluoro-1,3-dimethyl-1H-indazole (426 mg, 80% yield) as a white solid.1H NMR (300 MHz, CHLOROFORM-d) δ (M. D.) of 7.19 (d, J=1.2 Hz, 1H), 6,80 (DD, J1=1.5 Hz, J2=9,6 Hz, 1H), a 3.87 (s, 3H), of 2.54 (s, 3H).

Intermediate compound 112: Diethyl 2-(5-bromo-3-nitropyridine-2-yl)malonate

A. Diethyl 2-(5-bromo-3-nitropyridine-2-yl)malonate. To a solution of diethylmalonate (6,35 g, 40 mmol) in N,N-dimethylformamide (30 ml) was added sodium hydride (2.0 g, 50 mol, 60% in mineral oil) at 0-2°C in a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at the same temperature for 10 minutes. Was slowly added a solution of 5-bromo-2-chloro-3-nitropyridine (5 g, 21 mmol) in N,N-dimethylformamide (10 ml) and the reaction mixture maintained at a temperature of about 40°C in tech�of 1 hour. The reaction was quenched with water (50 ml), was extracted with diethyl ether (150 ml ×3), dried over sodium sulfate and evaporated in vacuum to give brown oil, which was purified on a column of silica gel (elwira using 0-10% ethyl acetate in petroleum ether), to obtain diethyl 2-(5-bromo-3-nitropyridine-2-yl)malonate (5 g, 65.6% of the output).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,87 (d, J=2,0 Hz, 1H), 8,62 (d, J=2,0 Hz, 1H), the 5.45 (s, 1H), 4,32 (m, 4H), of 1.30 (m, 6H).

Intermediate compound 113: 1-methyl-1H-pyrazolo[3,4-6]pyridin-5-amine

A. 5-Bromo-1-methyl-1H-pyrazolo[3,4-6]pyridine. To a solution of 1-methyl-1H-pyrazol-5-amine (5 g, 51,5 mmol) in acetic acid (50 ml) was added 2-bromomalonaldehyde (7.5 g, 50 mmol) and concentrated sulfuric acid (0.5 ml) and the mixture was heated at boiling with reflux for 2 days. The solution was concentrated and partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml ×2). The combined organic layers were dried, concentrated and purified using column chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (3.0 g, 27% yield) as a white powder.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,63 (d, J=2,0 Hz, 1H), 8,53 (d, J=2,0 Hz, 1H), 8,13 (s, 1H), of 4.05 (s, 3H).

B. 1-methyl-1H-pyrazolo[3,4-b]pyridine-5-AMI�. Degassed mixture of 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (880 mg, 4 mmol), diphenylmethylene (1,08 g, 6 mmol), Tris(dibenzylideneacetone)palladium (0) (734 mg, 0.8 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.24 g, 2 mmol) and tert-butoxide sodium (576 mg, 6 mmol) in toluene (18 ml) heated at 115°C in a nitrogen atmosphere over night. The reaction mixture was purified using column chromatography on silica gel (elwira using 4% ethyl acetate in petroleum ether) to give N-(diphenylmethylene)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (1.2 g, crude). The crude N-(diphenylmethylene)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine was dissolved in tetrahydrofuran (10 ml) was added hydrochloric acid (2 n, 5 ml). The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pΗ=8 using a saturated solution of sodium carbonate and was extracted with ethyl acetate. The organic phase was dried, concentrated and purified using column chromatography on silica gel (elwira using 33% ethyl acetate in petroleum ether) to give 1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (420 mg, 68.4% of yield) as an off-white solid.

Intermediate 114: 3-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine

A. 6-Nitro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)�ethyl)-1H-indazol. A stirred solution of 3-iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (15 g, with 35.8 mmol), methyl 2,2-debtor-2-(persulfuric)acetate (3.4 g, of 17.9 mmol) and copper iodide (I) (1,36 g, 7.2 mmol) in dimethylsulfoxide (50 ml) was heated at 120°C for 3 hours in a nitrogen atmosphere. Added additional amount of methyl 2,2-debtor-2-(persulfuric)acetate (1.72 g, 8,95 mmol) and the mixture was heated at 120°C for 16 hours. The reaction mixture was concentrated in vacuo and purified on a column of silica gel (elwira using 1% ethyl acetate in petroleum ether) to give 6-nitro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.0 g, 15.5% of output) in the form of oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,63 (s, 1H), 8,22 (d, J=8,8 Hz, 1H), 8,01 (d, J=8,8 Hz, 1H), 5,87 (s, 2H), 3,62 (t, J=8.4 Hz, 1H), of 0.93 (t, J=8.4 Hz, 1H), to -0.05 (s, 9H).

B. 3-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine. A mixture of 6-nitro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.0 g, 2,77 mmol) and 10% palladium on carbon (50% moisture content, mass/mass, 100 mg) in methanol (10 ml) were gidrirovanie under a hydrogen pressure of 1 atmosphere at room temperature for 2 hours. The suspension was filtered and the filtrate concentrated to give 3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (900 mg, 98% yield) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (MD), EUR 7.57 (d, J=8.4 Hz, 1H), 6,71 (m, H), To 5.62 (s, 2H), 4,00 (lat.s, 2H), 3,56 (t, J=8.4 Hz, 2H), 0,88 (t, J=8.4 Hz, 2H), to -0.05 (s, 9H).

Intermediate 115 connection: tert-Butyl 4-(6-bromo-1-methyl-1H-indazol-3-ylamino)piperidine-1-carboxylate

A. tert-Butyl 4-(6-bromo-1-methyl-1H-indazol-3-ylamino)piperidine-1-carboxylate. To 6-bromo-1-methyl-1H-indazol-3-amine (400 mg, 1,77 mmol) in a mixture of acetic acid (2 ml) and methanol (40 ml) was added tert-butyl 4-oxopiperidine-1-carboxylate (525 mg, 2.65 mmol) and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0°C and added cyanoborohydride sodium (223 mg, was 3.54 mmol). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and was purified on a column of silica gel (elwira using 5-25% ethyl acetate in petroleum ether) to give tert-butyl 4-(6-bromo-1-methyl-1H-indazol-3-ylamino)piperidine-1-carboxylate (700 mg, 97% yield) in the form of solids. MS (ESI): m/z 309,0 [M+1]+.

Intermediate 116: 6-Bromo-1-(tetrahydro-2H-Piran-2-yl)-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine

A. 6-Bromo-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine. A solution of 6-bromo-1H-indazol-3-amine (915 mg, 4.34 mmol) in a mixture of acetic acid (4 ml) and methanol (80 ml) was added dihydro-2H-Piran-4(3H)-he (650 mg, 6.50 mmol) and the mixture stirred at room temperature� for 10 minutes. The mixture was cooled to 0°C and added cyanoborohydride sodium (547 mg, 8.68 mmol). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and was purified on a column of silica gel (elwira using 5-25% ethyl acetate in petroleum ether) to give 6-bromo-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine (860 mg, 67% yield) as a solid substance. MS (ESI): m/z 295,9 [M+1]+.

B. 6-Bromo-1-(tetrahydro-2H-Piran-2-yl)-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine. To a mixture of 6-bromo-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine (860 mg, 2,91 mmol) and p-toluensulfonate acid (50 mg, 0.29 mmol) in tetrahydrofuran (40 ml) was added 3,4-dihydro-2H-Piran (489 mg, 5,82 mmol) and the mixture was heated at boiling with reflux at 70°C in a nitrogen atmosphere over night. The reaction mixture was concentrated and was purified on a column of silica gel (elwira using 5-25% ethyl acetate in petroleum ether) to give 6-bromo-1-(tetrahydro-2H-Piran-2-yl)-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine.

Intermediate 117: 6-Bromo-1-methyl-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine

A. 6-Bromo-1-methyl-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine. To a mixture of 6-bromo-1-methyl-1H-indazol-3-amine (420 mg, 1.86 mmol) in a mixture of acetic acid (2 ml) and methanol (40 ml) was added dihydro-2H-Piran-4(3H)-he (279 mg, 2,79 mmol�) and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0°C, was added cyanoborohydride sodium (234 mg, 3.72 mmol). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and was purified on a column of silica gel (elwira using 5-25% ethyl acetate in petroleum ether) to give 6-bromo-1-methyl-N-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-amine (570 mg, 84% yield, 85% purity) in the form of solids. MS (ESI): m/z of 309.9 [M+1]+.

Intermediate compound 118: tert-Butyl 5-amino-3-methyl-1H-indazol-1-carboxylate

A. tert-Butyl 3-methyl-5-nitro-1H-indazol-1-carboxylate. To a solution of 3-methyl-5-nitro-1H-indazole (0.95 g, of 5.36 mmol) in ethanol (12 ml) was added di-tert-BUTYLCARBAMATE (1,755 g, and 8.04 mmol). The reaction mixture was stirred at 50°C for 5 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude substance was diluted with ethyl acetate (150 ml), washed with saturated sodium bicarbonate solution (100 ml) and saturated brine (100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain specified in the title compound as an off-white solid which was used in next step without further purification. MS (ESI) m/z 278,4 [M+1]+.

B. tert-Butyl 5-amino-3-m�Teal-1H-indazol-1-carboxylate. To a solution of tert-butyl 3-methyl-5-nitro-1H-indazol-1-carboxylate (1,486 grams of 5.36 mmol) in ethanol (25 ml) was added palladium on carbon (0,057 g, 0,536 mmol) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen pressure of 1 atmosphere. The reaction mixture was filtered through Celite and concentrated. The crude substance was purified using column chromatography (biotage AB, elwira 0-100% ethyl acetate in hexane) to give the desired compound as a yellow solid (1 g, 75% yield). MS (ESI) m/z 248,9 [M+1]+.

Intermediate 119: 6-Amino-3,3-dimethylisoxazole-1-he

A. 3,3-Dimethylisoxazole-1-it. 2-Cyanobenzoic acid (3 g, 20,39 mmol) was dissolved in tetrahydrofuran (300 ml) and then cooled to -78°C. was Added dropwise motility (127 ml, 204 mmol) and the reaction mixture was slowly warmed to room temperature for 2 hours. The reaction was quenched with saturated brine, and then extracted twice with ethyl acetate. The combined organic layers were washed with 1 n HCl solution, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated. The residue was purified using column chromatography to obtain the desired product.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,58-8,69 (m, 1H), 7,53-7,66 (m, 3H), 7,45 (DD, J=1,56, of 7.42 Hz, 1H), of 1.44 (s, 6H). MS (ESI)m/z 162,2 [M+1] +.

B. 3,3-Dimethyl-6-nitroisoquinoline-1-it. 3,3-Dimethylisoxazole-1-he (0,600 g, 3.72 mmol) was dissolved in sulfuric acid (6,7 ml) and then cooled to 0°C. To the solution was added potassium nitrate (0,587 g, of 5.81 mmol). The mixture was stirred overnight, gradually raising the temperature to room temperature. The reaction solution was poured into ice water and then was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried and evaporated to obtain 3,3-dimethyl-6-nitroisoquinoline-1-she (0,700 g, 3,39 mmol, 91% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,67 (d, J=1,95 Hz, 1H), of 8.47 (DD, J=2,15, 8,40 Hz, 1H), members, 7.59 (d, J=8,20 Hz, 1H), 7,08-7,25 (m, 1H), 1,63 (s, 6H).

C. 3,3-Dimethyl-6-aminoisoquinoline-1-it. 3,3-Dimethyl-6-nitroisoquinoline-1-he (1.5 g, 7,27 mmol) was taken for absorption in methanol (60 ml) was added a catalytic amount of palladium on carbon. The reaction mixture was then stirred under the pressure of the hydrogen gas at 1 atmosphere for 18 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure to obtain 6-amino-3,3-dimethylisoxazole-1-she (1,218 g, 6,91 mmol, 95% yield). MS (ESI) m/z 177,1 [M+1]+.

Intermediate 120: 3,4-Dimethyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-6-amine

A. 2,3-Dimethyl-5-in RTD�aniline. In a 250-ml round bottom flask was added concentrated sulfuric acid (40 ml, 750 mmol) at 0°C. To this was added 2,3-dimethylaniline (5 g, up 41.3 mmol) in small portions and after completion of the addition the flask was cooled to -10°C. was Added a mixture of fuming nitric acid (2.2 ml, to 49.2 mmol) and concentrated sulfuric acid (6.6 ml) for 45 minutes and the mixture was stirred for another hour at 0°C. the Mixture was poured onto ice water, the resulting precipitate was filtered, was washed with water and dried in vacuum to give 2,3-dimethyl-5-nitroaniline (3,63 g, of 21.84 mmol, 52.9% of yield) as a yellow solid. MS (ESI) m/z 167,4 [M+1]+.

B. 4-Methyl-6-nitro-1H-indazole. A solution of sodium nitrite (0,415 g, of 6.02 mmol) in water (1.4 ml) was added to a solution of 2,3-dimethyl-5-nitroaniline (1 g, of 6.02 mmol) in acetic acid (137 ml). The resulting solution was stirred at room temperature for 24 hours. The solvent was removed under vacuum to give a solid which was dissolved in ethyl acetate and filtered through a plug of silica. Ethyl acetate at the end was removed to give 4-methyl-6-nitro-1H-indazole (to 0.900 g, 5.08 mmol, 84% yield) as a yellow solid. MS (ESI) m/z to 178.2 [M+1]+.

C. 3-Iodo-4-methyl-6-nitro-1H-indazole. A solution of 4-methyl-6-nitro-1H-indazole (to 0.900 g, 5.08 mmol) in a mixture of dioxane (25 ml) and hydroxid sodium (2 n in water, of 3.81 ml, 7.62 mmol) was stirred at room �temperature for 1 hour. Was added iodine (1,547 g, 6,10 mmol) and the reaction mixture stirred at room temperature for 12 hours. The aqueous layer was neutralized using hydrochloric acid (6 n in water) and extracted three times with ethyl acetate. Then the combined organic layers were washed with a saturated aqueous solution of sodium thiosulfate, water and saturated brine, dried over magnesium sulfate and concentrated to give 3-iodo-4-methyl-6-nitro-1H-indazole (1,38 g, 4,55 mmol, 90% yield). MS (ESI) m/z 304,2 [M+1]+.

D. 3-Iodo-4-methyl-6-nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol. 3-Iodo-4-methyl-6-nitro-1H-indazole (1,38 g, 4,55 mmol), 3,4-dihydro-2H-Piran (0,457 ml, 5,01 mmol) and methanesulfonic acid (0,035 ml 0,546 mmol) was dissolved in tetrahydrofuran (15 ml) and stirred at 75°C. After 6 hours the solution was diluted with triethylamine (0.5 ml) and condensible under reduced pressure. The residue was purified using chromatography on silica gel (0-15% ethyl acetate in hexane) to give 3-iodo-4-methyl-6-nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (1.4 g, 3,62 mmol, 79% yield). MS (ESI) m/z 388,2 [M+1]+.

E. 3,4-Dimethyl-6-nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol. A mixture of 3-iodo-4-methyl-6-nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (1.4 g, 3,62 mmol), methylboronic acid (0,649 g, 10,85 mmol), tetrakis(triphenylphosphine)-palladium(0) (of 0.418 g, 0,362 mmol) and cesium carbonate (3,53 g, 10,85 mmol) in dioxane (15 ml), degassed and heated to 90°C over night. After cooling to room temperature the mixture was filtered through Celite, the solvent was removed under reduced pressure and the residue was purified using chromatography on silica gel (0-20% ethyl acetate in hexane) to give 3,4-dimethyl-6-nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole (0,897 g, 3,26 mmol, 90% yield). MS (ESI) m/z 276,5 [M+1]+.

F. 3,4-Dimethyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-6-amine. 3,4-Dimethyl-6-nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol (0,897 g, 3,26 mmol) was dissolved in ethyl acetate (60 ml) and methanol (10 ml) and purged with nitrogen, was treated using 10% palladium on charcoal (0,173 g, 1,629 mmol) and stirred in hydrogen atmosphere for 24 hours. The reaction mixture was filtered through a layer of celite and concentrated to give a dark orange solid which was purified using reverse-phase preparative HPLC (10-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 30 min) to give 3,4-dimethyl-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-6-amine (0,528 g, 2,150 mmol, 66% yield). MS (ESI) m/z 246,5 [M+1]+.

Intermediate 121: 6-Amino-1,3,3-trimethylindolenine-2-he

A. 1,3,3-Trimethyl-6-nitroindoline-2-it. To a brown suspension of 3,3-dimethyl-6-nitroindoline-2-she (1,82 g, 8,83 mmol) in N,N-dimethylformamide (15 ml) at room temperature add�Yali potassium carbonate (1,830 g, 13,24 mmol), followed by the addition of dimethyl sulfate (1,054 ml, 11,03 mmol) dropwise (neat). After stirring for 24 hours the reaction was completed according to TLC analysis. Added additional amount of dimethyl sulfate (0.5 ml, 5.5 mmol) and the reaction mixture was stirred over night. The reaction mixture was distributed between ethyl acetate (100 ml) and water (30 ml). The organic layer was separated, dried over magnesium sulfate and concentrated to give brown oil, which was purified using column flash chromatography on silica gel (elwira using 100% dichloromethane), to give product as a yellow solid (1.46 g, 54%).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,98 (DD, 1H), 7,83 (d, J=2,15 Hz, 1H), 7,66 (d, J=8,10 Hz, 1H), 3,23 (s, 3H), 1,32 (s, 6H); Rf= 0,50, (33% ethyl acetate in hexane).

B. 6-Amino-1,3,3-trimethylindolenine-2-it. 1,3,3-Trimethyl-6-nitroindoline-2-he (1.42 g, of 6.45 mmol) was suspended in ethyl acetate (30 ml) and methanol (5 ml) was added 10% palladium on carbon (0,343 g, up 3.22 mmol). The reaction mixture was stirred under a hydrogen pressure of 1 atmosphere at 30°C for 1 hour, then at room temperature for 4 hours. The reaction mixture was purged with nitrogen and filtered through a layer of celite by washing the ethyl acetate and methanol. The filtrate was concentrated to give 6-amino-1,3,3-trimethylindolenine-2-he� in the form of a pale grey solid (0,997 g, An 81% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 6,83-of 6.99 (m, 1H), 6,12-6,27 (m, 2H), 5,10 (s, 2H), 3,03 (s, 3H), of 1.17 (s, 6H); MS (ESI) m/z 191,0 [M+1]+.

Intermediate compound 122: N,2-Dimethoxy-N-methylethanolamine

A. N,2-Dimethoxy-N-methylethanolamine. Oxaliplatin (6,27 ml, 71,8 mmol) was slowly added dropwise to a stirred suspension of 2-methoxyethylamine acid (10.00 g, was 65.3 mmol) and N,N-dimethylformamide (0,101 ml, 1,306 mmol) in dichloromethane (300 ml). Received the white mixture was stirred at room temperature in a nitrogen atmosphere for 2 hours. Was nabludalos the evolution of gas, but didn't happen to any generation of heat. The mixture was cooled to 0°C in an atmosphere of nitrogen. Was added the hydrochloride of N,O-dimethylhydroxylamine (of 9.56 g, 98 mmol) followed by slow addition of triethylamine (45,5 ml, 327 mmol). The obtained viscous suspension was stirred at room temperature in a nitrogen atmosphere. LC/MS analysis after 10 minutes showed complete conversion to the desired product. Added water and the reaction mixture was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified using flash chromatography (5-60% ethyl acetate in hexane) to give N,2-dimethoxy-N-methylethanolamine (11.0 g, 56,0 mmol, 86% yield) as a yellow oil. MS (ESI) m/z of 197.3[M+1]+.

Intermediate 123: 5-Amino-2-(2,4-dimethoxybenzyl)isoindoline-1-he

A. Methyl 2-(methyl bromide)-4-nitrobenzoate. Methyl 2-methyl-4-nitrobenzoate (5 g, up to 25.6 mmol) was dissolved in carbon tetrachloride (60 ml) and then purged with nitrogen for 10 minutes. To the solution was added N-bromosuccinimide (5,47 g, 30.7 mmol) and benzoylperoxide (0,124 g, 0,512 mmol) and then heated to 70°C for 16 hours. The reaction mixture was concentrated and then purified using chromatography on silica gel (0-60% ethyl acetate in hexane) to give an orange solid (3.5 g, 12,77 mmol, 49,8% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,35 (d, J=2,34 Hz, 1H), 8,16-of 8.25 (m, 1H), 8,12 (d, J=8,59 Hz, 1H), to 4.98 (s, 2H), 3,97 of 4.09 (m, 3H).

B. 2-(2,4-Dimethoxybenzyl)-5-nitroisoquinoline-1-it. A mixture of methyl 2-(methyl bromide)-4-nitrobenzoate (2.5 g, 9,12 mmol), (2,4-dimethoxyphenyl)methanamine (1,525 g, 9,12 mmol), triethylamine (38.1 ml of 27.4 mmol) in methanol (25 ml) was heated at boiling with reflux for 16 hours. The mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to dryness. Flash chromatography (30-50% ethyl acetate in hexane) gave the desired product as a yellow solid (2.5 g, to 7.68 mmol, 84% o�d). MS (ESI) m/z 329,9[M+1]+.

C. 5-Amino-2-(2,4-dimethoxybenzyl)isoindoline-1-it. 2-(2,4-Dimethoxybenzyl)-5-nitroisoquinoline-1-it (1 g, of 3.05 mmol) was dissolved in ethanol and purged with nitrogen. Was added palladium on carbon (0,530 g, 0,498 mmol) and the reaction mixture was stirred under a hydrogen pressure of 1 atmosphere for 16 hours. The reaction mixture was filtered through Celite and washed with ethanol. The organic layer was concentrated on a rotary evaporator to dryness to obtain the desired product as a purple solid. The crude substance was crystallisable of ethyl acetate and hexane to obtain 5-amino-2-(2,4-dimethoxybenzyl)isoindoline-1-one as a white solid (0.9 g, 3,02 mmol, 99%). MS (ESI) m/z 299,2[M+1]+.

Intermediate compound 124: N-Methoxy-N-methyltetrahydro-2H-Piran-4-carboxamide

A. N-Methoxy-N-methyltetrahydro-2H-Piran-4-carboxamide. N-Methoxy-N-methyltetrahydro-2H-Piran-4-carboxamide was obtained in accordance with the procedure described to obtain N,2-dimethoxy-N-methylethanolamine, tetrahydro-2H-Piran-4-carboxylic acid (10 g, 77 mmol), oxalicacid (7,40 ml, 85 mmol), hydrochloride of N,O-dimethylhydroxylamine (9.4 g, 115 mmol) and triethylamine (53.5 ml, 384 mmol). After purification using flash chromatography (suirable using 30-70% ethyl acetate in hexane) was obtained N-methoxy-N-methyl�tetrahydro-2H-Piran-4-carboxamide as a yellow oil (11.3 g, For 65.2 mmol, 85% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 4,02 (DDD, J=11,52, 4,10, 1,95 Hz, 2H), 3,73 (s, 3H), 3,47 (TD, J=11,81, of 2.15 Hz, 2H), 3,19 (s, 3H), 2,81-2,98 (m, 1H), 1,75-of 1.97 (m, 2H), of 1.66 (DD, 2H); MS (ESI) m/z 174,2 [M+1]+.

Intermediate compound 125: 1-(Tetrahydro-2H-Piran-2-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine

A. 6-Nitro-1H-pyrazolo[4,3-b]pyridine. A solution of sodium nitrite (2,163 g, 31,3 mmol) in water (20 ml) was added to a stirred solution of 2-methyl-5-nitropyridine-3-amine (4 g, 26,1 mmol) in acetic acid (70 ml). The obtained orange solution was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C and the reaction mixture was adjusted to pH=7 by adding an aqueous solution of sodium hydroxide (6 M). Was added water and ethyl acetate. The mixture was shaken in a separatory funnel and the layers were separated. The organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was ground into powder with diethyl ether. The solids were collected via suction filtration, washed with diethyl ether and dried under high vacuum to give the desired product as a dark orange solid (2.3 g, 14,01 mmol, 53.7% on exit).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,29 (d, J=2,34 Hz, 1H), 8,91 (lat.s, 1H), 8,59 (lat.s, 1H). MS (SI) m/z 165,2 [M+1] +.

B. 6-Nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-pyrazolo[4,3-b]pyridine. A solution of 6-nitro-1H-pyrazolo[4,3-b]pyridine (2 g, 12,19 mmol), 3,4-dihydro-2H-PYRAN (1,538 g, 18,28 mmol) and methanesulfonic acid (0,119 ml 1,828 mmol) in tetrahydrofuran (100 ml) was heated to 70°C over night. The reaction mixture was cooled and neutralized with an aqueous sodium bicarbonate solution to pΗ 7 and then was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, concentrated on a rotary evaporator. Flash chromatography (suirable using 0-50% ethyl acetate in hexane) gave the desired product as an off-white solid (1.3 g, 5,24 mmol, 43.0% of output). (ESI) m/z 249,3[M+1]+.

C. 1-(Tetrahydro-2H-Piran-2-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine. 6-Nitro-1-(tetrahydro-2H-Piran-2-yl)-1H-pyrazolo[4,3-b]pyridine (1 g, is 4.03 mmol) was dissolved in 50% ethanol in ethyl acetate and the reaction mixture was purged with nitrogen. Was added palladium on carbon (0.6 g, 0,564 mmol) and the reaction mixture was stirred under a hydrogen pressure of 1 atmosphere for 16 hours. The reaction mixture was filtered through Celite and washed with ethanol. The organic layer was concentrated on a rotary evaporator to dryness to obtain the desired product as a purple solid which was purified through crystallization from ethyl acetate in hexane to obtain 1-(�etrahydro-2H-Piran-2-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine (0.8 g, 3,67 mmol, 91% yield) as a white solid. (ESI) m/z 219 (A [M+1]+.

Intermediate 126: 1,4-Dimethyl-1H-indazol-6-amine

A. M-Dimethyl-6-nitro-1H-indazole. 4-Methyl-6-nitro-1H-indazole (0.75 g, to 4.23 mmol) was dissolved in N,N-dimethylformamide (10 ml). Was then added sodium hydride (0,203 g, 5.08 mmol, 60% dispersion in mineral oil) at ambient temperature. After 15 minutes the solution was added dropwise methyliodide (0,318 ml, 5.08 mmol) in N,N-dimethylformamide (0.5 ml) and kept stirring at ambient temperature. After 2 hours, LC/MS analysis showed two peaks in the UV region, both with the same mass of product as a geometric s. The solution was condensible under reduced pressure to obtain brown solid. This solid was diluted with water (25 ml) and treated with ultrasound for 5 minutes. The obtained solid was filtered and washed with additional water and then hexane to obtain a rusty-brown solid. This solid was purified using column chromatography (biotage AB, suirable using 0-100% ethyl acetate in hexane) obtaining specified in the header connection (0,480 g, 2.51 mmol, 59% yield), as confirmed by1H NMR and NOE NMR.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 4,18 (Emitting peak).1H NMR (400MHz, DMSO-d6) δ (M. D.) 8,55 (s, 1H), 8,35 (s, 1H), to 7.77 (s, 1H), 4,18 (s, 3H), of 2.66 (s, 3H); MS (ESI) m/z 192,4 [M+1]+.

B. 1,4-Dimethyl-1H-indazol-6-amine. 1,4-Dimethyl-6-nitro-1H-indazole (0.49 g, 2.56 mmol) was diluted with ethanol (20 ml) and then palladium on carbon (0,049 g, 0,460 mmol). From the solution withdrawn gas and purged with hydrogen gas twice. The solution was left for stirring at ambient temperature. After 1 hour, LC/MS analysis showed the overwhelming amount of the starting materials at a certain defined quantity hydroxylamino intermediate compounds. The solution continued to stir at ambient temperature. After 4 hours, LC/MS analysis showed complete absorption of the starting materials. The solution was filtered through celite and the filtrate was condensible under reduced pressure to obtain a reddish solid (0,409 g, 2.54 mmol, 99% yield). MS(ESI) m/z to 162.5 [M+1]+.

Intermediate 127: 5-Amino-2-methylisoquinoline-1-he

A. 2-Methyl-5-nitroisoquinoline-1-it. To a solution/suspension of methyl 2-(methyl bromide)-4-nitrobenzoate (7 g, 25.5 mmol) in methanol (50 ml) was added methanimidamide (1,724 g, 25.5 mmol) and triethylamine (17,80 ml, 128 mmol). The reaction mixture was heated to 70°C and stirred overnight. The reaction mixture was cooled to room temperature, and there was a formation of crystals about�of ucta. The product was then left to crystallize in for the weekend at 0°C. the Resulting solids were filtered and dissolved in dichloromethane. This crude solution was loaded into a column and was purified using column chromatography (elwira using 0-10% methanol in dichloromethane). The fractions containing the product were combined and the solvent was removed in vacuum. 2-Methyl-5-nitroisoquinoline-1-he (3 g, 15,61 mmol, 61,1% yield) was obtained as the crude orange-yellow solids. This solid substance was used in the next reaction without further purification. MS (ESI): m/z 193,0 [M+1]+.

B. 5-Amino-2-methylisoquinoline-1-it. To a solution/suspension of 2-methyl-5-nitroisoquinoline-1-one (3 g, 15,61 mmol) in methanol (50 ml) and ethanol (50,0 ml) was added palladium on carbon. Set the balloon is filled with hydrogen gas, and the reaction mixture was stirred over night. The reaction mixture was filtered and the solvent was removed in vacuum. 5-Amino-2-methylisoquinoline-1-he (2 g, 12,33 mmol, 79% yield) was obtained as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,27 (d, J=7,81 Hz, 1H), 6,47-to 6.66 (m, 2H), 5,70 (s, 2H), 4,24 (s, 2H), 2,96 (s, 3H); MS (ESI): m/z 163,0 [M+1]+.

Intermediate 128: 6-Bromo-3-methylbenzo[d]izocsazol

A. (E)-1-(4-Bromo-2-hydroxyphenyl)Etalon oxime. To a solution of 1-(4-bromo-2-hydroc�iphenyl)ethanone (2.8 g, 13,02 mmol) and water (10 ml) was added sodium acetate (1,602 g, 19,53 mmol) and hydroxylamine hydrochloride (1,176 g, 16,93 mmol). The mixture was left for stirring at ambient temperature for 16 hours. The solution was condensible under reduced pressure and diluted with water and treated with ultrasound. The obtained solid was filtered and dried in a vacuum oven to obtain specified in the title compound (1.90 g, compared to 8.26 mmol, 63.4% of output). MS(ESI) m/z 230,3 [M]+, 232,4 [M+2]+.

B. (E)-1-(4-Bromo-2-hydroxyphenyl)acanon About-acetyloxy. (E)-1-(4-Bromo-2-hydroxyphenyl)Etalon oxime (0.75 g, 3,26 mmol) was diluted with acetic anhydride (7,69 ml, 82 mmol). The solution was left for stirring at 110°C in a flask with a screw cap. After 5 minutes the mixture was left for stirring at ambient temperature for 30 minutes. The solution was condensible under reduced pressure and partitioned between pH 7 phosphate buffer and ethyl acetate (×2). The organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to obtain the oxime acetate as a white solid (0,880 g). LC/MS analysis of this substance showed that it looks like 2 different peaks, both with a mass product, but they both showed different high fission Br lines of the mass spectrum. This solid was purified using column chromatog�aafia using biotage AB (100% hexane (100 ml), then 0-45% ethyl acetate in hexane (700 ml), then 45-100% ethyl acetate (100 ml)) to give two pure separated product.1H-NMR confirmed (E)-1-(4-bromo-2-hydroxyphenyl)Etalon O-acetyloxy as a first eluate (0,252 g, 0,926 mmol, 28% yield) and bis-acetate as a second eluate (0,487 g, 1,550 mmol, 48% yield). The first eluate:1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 11,46 (s, 1H), 7,32 (d, J=8,59 Hz, 1H), 7,22 (d, J=1,95 Hz, 1H), 7,05 (DD, J=8,59, of 1.95 Hz, 1H), 2,43 (s, 3H), and 2.26 (s, 3H); Second eluate:1H NMR (400 MHz, CHLOROFORM-d) δ (MD), 7,41-of 7.46 (m, 1H), value of 7, 37 (s, 1H), 7,34-of 7.36 (m, 1H), 2,31 (s, 3H), 2,30 (s, 3H), of 2.23 (s, 3H).

C. 6-Bromo-3-methylbenzo[d]izocsazol. (E)-(4-Bromo-2 - hydroxyphenyl)acanon About-acetyloxy (1.6 g, to 6.95 mmol) was diluted with pyridine (10 ml) in a flask with a screw cap and heated to 125°C for 16 hours. TLC analysis (40% ethyl acetate in hexane) confirmed the takeover of the initial substance and the formation of the product. The solution was condensible under reduced pressure and the oil was purified using column chromatography using biotage AB (100% hexane (100 ml), then 0-50% ethyl acetate in hexane (750 ml)) to give 6-bromo-3-methylbenzo[d]isoxazole (1.19 g, 5.6 mmol, 68% yield).1H NMR (400 MHz, CHLOROFORM-d) δ (MD), of 7.75 (d, J=1,17 Hz, 1H), of 7.48-7,52 (m, 1H), of 7.42-7,47 (m, 1H), 2,58 (s, 3H); MS(ESI) m/z 212,2 [M] +, 214,2 [M+2]+.

Intermediate 129: 1-methyl-1H-indazol-5-amine

A. 1-methyl-1H-indazol-5-AMI�. To a solution of 1-methyl-5-nitro-1H-indazole (1 g, 5,64 mmol) in ethanol (10 ml) was added palladium on carbon (0,060 g, 0,564 mmol) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen pressure of 1 atmosphere. The reaction mixture was filtered through Celite and concentrated. The crude substance was ground into powder with ethyl acetate and dichloromethane to obtain specified in the title compound as a light purple solid (0.65 g, 78% yield). MS (ESI) m/z 148,2 [M+1]+.

Intermediate 130: tert-Butyl 3-methyl-6-amino-2-oxo-3-gidrolesomelioratsii

A. (2-Amino-4-nitrophenyl)methylamine. 2-Fluoro-5-nitroaniline (2 g, 12,81 mmol) was added in a sealed tube with methylamine (5 ml, 40% in water) and the reaction mixture was heated at 95°C overnight. The reaction mixture was evaporated and the residue was purified on silica gel (0 to 85% ethyl acetate in hexane) to give (2-amino-4-nitrophenyl)methylamine in the form of a red-orange solid substance. MS (ESI) m/z 168,2 [M+1]+.

B. 1-Methyl-5-nitro-3-hydroestimator-2-it. A solution of (2-amino-4-nitrophenyl)methylamine (1.62 g, 9,69 mmol) and di(1H-imidazol-1-yl)methanone (1,571 g, 9,69 mmol) in tetrahydrofuran (25 ml) was stirred at 65°C for 18 hours. The reaction mixture was then cooled to 0°C. the resulting precipitate was filtered and sushi�and obtaining 1-methyl-5-nitro-3-hydroestimator-2-she (1,81 g, 9,37 mmol, 97% yield) as pure beige solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,36-11,49 (m, 1H), 8,03 (DD, J=2,34, 8,59 Hz, 1H), 7,76 (d, J=2,34 Hz, 1H), 7,31 (d, J=8,98 Hz, 1H), 3,36 (s, 3H); MS (ESI) m/z 194,5 [M+1]+.

C. tert-Butyl 3-methyl-6-nitro-2-oxo-3-gidrolesomelioratsii. A mixture of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-it (1 g, 5,18 mmol), di-tert-BUTYLCARBAMATE (2,404 ml of 10.35 mmol) and sodium bicarbonate (0,870 g of 10.35 mmol) in tetrahydrofuran (37 ml) was stirred at room temperature for 3 days. The obtained white solid substance was filtered, washed with water and tetrahydrofuran and dried to obtain tert-butyl 3-methyl-6-nitro-2-oxo-3-gidrolesomelioratsii (1,39 g, 4,74 mmol, 92% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,52 (d, J=2,34 Hz, 1H), 8,22 (DD, J=2,34, 8,59 Hz, 1H), 7,43 (d, J=8,59 Hz, 1H), 3,37 (s, 3H), 1,62 (s, 9H).

D. tert-Butyl 3-methyl-6-amino-2-oxo-3-gidrolesomelioratsii. tert-Butyl 3-methyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (1,38 g, 4,71 mmol) was taken for absorption in methanol (30 ml) was added a catalytic amount of palladium on carbon. The reaction mixture was stirred in an atmosphere of hydrogen gas for 18 hours, filtered through celite and then evaporated to obtain tert-butyl 3-methyl-6-amino-2-oxo-3-gidrolesomelioratsii (1.12 g, 4,25 mmol, 90% yield). MS (ESI) m/z 264,2 [M+1]+.

Intermediate�: the connection 131: 3-Methyl-[1,2,4]triazolo[4,3-α]pyridin-7-amine

A. Di-tert-butyl 1-(4-nitropyridine-2-yl)hydrazine-1,2-dicarboxylate. In the test tube was loaded with Tris(dibenzylideneacetone)dipalladium(0) (0,695 g, 0,759 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1,277 g, 2,278 mmol), cesium carbonate (6,19 g of 18.99 mmol) and di-tert-butyl hydrazine-1,2-dicarboxylate (3,53 g, was 15.19 mmol). The tube was purged with argon and then was added toluene (20 ml) and 2-chloro-4-nitropyridine (3,01 g, of 18.99 mmol). The reaction mixture was heated at 100°C with stirring for 16 hours. The reaction mixture was cooled, filtered through Celite and concentrated in vacuo. The crude residue was purified using chromatography on silica gel (0-20% ethyl acetate in hexane) to give di-tert-butyl 1-(4-nitropyridine-2-yl)hydrazine-1,2-dicarboxylate (4.5 g, of 12.70 mmol, 66.9 per cent yield). MS (ESI) m/z of 355.2 [M+1]+.

B. Dihydrochloride 2-hydrazine-4-nitropyridine. To a stirred mixture of di-tert-butyl-1-(4-nitropyridine-2-yl)hydrazine-1,2-dicarboxylate (6.7 g, 18,91 mmol) in ethanol (30 ml) at room temperature was added hydrogen chloride (142 ml, 567 mmol, 4 n in dioxane). The resulting mixture was stirred under a nitrogen atmosphere for 16 hours. The resulting suspension was concentrated to half volume on a rotary evaporator, filtered and washed with a small amount of diethyl ether to obtain the dihydrochloride of 2-hydrazine-4-nitropyridine (3,09 g, 13,61 �mol, 72% yield) as a yellow solid. MS (ESI) m/z: 155,2 [M+1]+.

C. N'-(4-Nitropyridine-2-yl)acetohydrazide. To a stirred mixture of the dihydrochloride of 2-hydrazine-4-nitropyridine (1.6 g, 7,05 mmol) in pyridine (54 ml) at room temperature was added acetic anhydride (0,799 ml is 8.46 mmol). The resulting mixture was stirred in a nitrogen atmosphere at 50°C for 16 hours. The resulting suspension was concentrated on a rotary evaporator and the residue was purified using flash chromatography (0-10% methanol in dichloromethane) to give N'-(4-nitropyridine-2-yl)acetohydrazide (0,646 g, 3,29 mmol, 46.7% of yield) as a yellow solid. MS (ESI) m/z of 197.3 [M+1]+.

D. 3-Methyl-7-nitro-[1,2,4]triazolo[4,3-α]pyridine. To a solution of N'-(4-nitropyridine-2-yl)acetohydrazide (0,641 g 3,27 mmol) in tetrahydrofuran (25 ml) was added at room temperature (methoxycarbonylamino)triethylammonium, inner salt (2,336 g 9,80 mmol). The mixture was heated at 65°C for 18 hours and cooled to room temperature. The reaction mixture was concentrated and the residue was loaded on column (biotage AB and purified flash chromatography (0-10% methanol in dichloromethane) to give 3-methyl-7-nitro-[1,2,4]triazolo[4,3-α]pyridine (0,467 g, 2,62 mmol, 80% yield) as yellowish-white solid. MS (ESI) m/z 179,2 [M+1]+.

E. 3-Methyl-[1,2,4]triazolo[4,3-α]pyridin-7-amine. 3-Methyl-7-nitro-[1,2,4]triazolo[,3-α]pyridine (0,467 g, 2,62 mmol) was suspended in methanol (10 ml) followed by the addition of platinum, 1% on activated carbon, and the introduction of vanadium (powder 50% humidity)Evonik F4 (0,100 g). From the solution took away the gas and blew fresh gaseous hydrogen three times and the mixture was left for stirring at ambient temperature for 4 hours. The solution was filtered through Celite and the solvent was removed under reduced pressure to obtain 3-methyl-[1,2,4]triazolo[4,3-α]pyridin-7-amine (0,388 g, 2,62 mmol, 100% yield) as brown solid substance. MS (ESI) m/z 149,3 [M+1]+.

Intermediate 132: 3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-amine

A. 5-Bromo-1-chloro-N-methoxy-N-methyl nicotine amide. To a mixture of 5-bromo-2-chloronicotinic acid (6 g, 25.5 mmol) in thionylchloride (30 ml) was added a drop of N,N-dimethylformamide, and the reaction mixture was heated at 80°C for 2 hours. The mixture was cooled to room temperature and concentrated to give crude 5-bromo-2-chloronicotinamide. The solution hydrochlorides About salt,N-dimethyl-hydroxylamine (3,45 g and 35.6 mmol) and triethylamine (of 7.48 g, is 74.1 mmol) in dichloromethane (80 ml) and the solution obtained above 5-bromo-2-chloronicotinamide in dichloromethane (20 ml) was added and the reaction mixture was stirred over night. The mixture was poured into water and extragear�Wali dichloromethane (50 ml ×3). The combined organic layer was concentrated under reduced pressure and was purified on a column of silica gel (elwira using 5-10% ethyl acetate in petroleum ether) to give 5-bromo-2-chloro-N-methoxy-N-methyl nicotine amid in the form of a solid (6.2 g, 71.4% of the output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,65 (s, 1H), of 8.39 (s, 1H), 3,49 (s, 3H), 3,30 (s, 3H).

B. 1-(5-Bromo-2-chloropyridin-3-yl)alanon. Methylanisole (6.0 ml, 18 mmol, 3 M solution in tetrahydrofuran) was added dropwise to a solution of 5-bromo-2-chloro-N-methoxy-N-methyl nicotine amid (5 g, 18 mmol) in tetrahydrofuran (80 ml) in a nitrogen atmosphere at 0°C for 30 minutes. The mixture was heated to room temperature for 2 hours, quenched with an aqueous solution of ammonium chloride and was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, was evaporated under reduced pressure and dried in vacuum to give 1-(5-bromo-2-chloropyridin-3-yl)ethanone (3.1 g, 73.8 per cent of output) in the form of oil.1H NMR (400 MHz, CHLOROFORM-d) δ (MD), 8,54 (s, 1H), 8,00 (s, 1H), 2,69 (s, 3H).

C. 5-Bromo-3-methyl-1H-pyrazolo[3,4-6]pyridine. A mixture of 1-(5-bromo-2-chloropyridin-3-yl)-ethanone (3.1 g, a 13.3 mmol), an aqueous solution of hydrazine (782 mg, 13,3 mmol, 85%) and potassium carbonate (1,83 g, a 13.3 mmol) in tetrahydrofuran (20 ml) was heated at boiling with reflux during the night. After cooling to room temperature, the reaction was semiconcentrated and the residue was dissolved in ethyl acetate. The organic solution was washed with saturated brine, dried over anhydrous sodium sulfate, was evaporated under reduced pressure and was purified on a column of silica gel with obtaining 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (2.0 g, 71.4% of the output).1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 12,33 (lat.s, 1H), 8,58 (s, 1H), 8,16 (s, 1H), 2,58 (s, 3H).

D. 5-Bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine. To a solution of 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (2.0 g, for 9.47 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (455 mg, to 11.4 mmol, 60% in mineral oil) at 0°C in a nitrogen atmosphere and the mixture was stirred for 1 hour at 0°C. Then was added dropwise (2-(chloromethoxy)ethyl)trimethylsilane (1.88 g, to 11.4 mmol), the mixture is kept stirred for 1 hour at 0°C, poured into ice water (50 ml) and was extracted with ethyl acetate (100 ml ×3). The combined organic layer was dried over anhydrous sodium sulfate, was evaporated under reduced pressure and was purified on a column of silica gel (elwira using 20-25% ethyl acetate in petroleum ether) to give 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (1.6 g, 50% yield) as an oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,55 (s, 1H), 8,12 (s, 1H), 5,76 (s, 2H), 3,62 (t, J=8,8 Hz, 2H), by 2.55 (s, 3H), of 0.93 (t, J=8.4 Hz, 2H), or 0.06 (s, 9H); MS (ESI): m/z 341,9 [M+1]+.

E. 3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrid�n-5-amine. Degassed mixture of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-6]pyridine (1.7 g, 5 mmol), diphenylmethylene (1,36 g, 7.5 mmol), Tris(dibenzylideneacetone)palladium(0) (920 mg, 1 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.55 g, 2.5 mmol) and tert-butoxide sodium (720 mg, 7.5 mmol) in toluene (30 ml) was heated at 115°C in a nitrogen atmosphere over night. The reaction mixture was concentrated and purified using column chromatography on silica gel (elwira using 5-20% ethyl acetate in petroleum ether) to give N-(diphenylmethylene)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (2.5 g, crude), which was dissolved in tetrahydrofuran (10 ml) was added hydrochloric acid (2 n, 10 ml). The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pΗ=8 with a saturated solution of sodium carbonate, was extracted with ethyl acetate, dried, concentrated and purified using column chromatography on silica gel (elwira using 10-25% ethyl acetate in petroleum ether) to give 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-δ]pyridin-5-amine (1.1 g, 79,1% yield) as an oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,10 (s, 1H), 7,18 (s, 1H), and 5.7 (s, 1H), 3,58 (d, J=11.2 Hz, 2H), 3,34 (s, 2H), 2,47 (s, 3H), of 0.90 (t, J=11.2 Hz, 2H), -0,09 (s, 9H).

Intermediate compound 133: N-Methoxy-N-methyltetrahydrofuran-3-�Roxane

A. N-Methoxy-N-methyltetrahydrofuran-3-carboxamide. A mixture of tetrahydrofuran-3-carboxylic acid (5 g, 43 mmol), hydrochloride of N,O-dimethylhydroxylamine (4,58 g, 48 mmol), hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (of 9.55 g, 50 mmol), 1-hydroxybenzotriazole (6.75 g, 50 mmol) and 4-methylmorpholine (10.1 g, 100 mmol) in anhydrous dichloromethane (200 ml) was stirred at 0°C for 1 hour. The mixture was heated to room temperature, stirred overnight and poured into water (200 ml). The organic layer was separated, the aqueous layer was extracted with dichloromethane. The combined organic phase was dried over sodium sulfate, concentrated in vacuo and was purified column chromatography on silica gel (elwira using 8% ethyl acetate in petroleum ether) to give N-methoxy-N-methyltetrahydrofuran-3-carboxamide (3 g, 44,1% yield) as a colorless oil.

Intermediate 134: 4-(1-(Tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)aniline

A. 3-Bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole. To a solution/suspension of 3,4-dihydro-2H-PYRAN (0,674 ml, the 7.43 mmol), 3-bromo-1H-1,2,4-triazole (1 g, 6,76 mmol) in tetrahydrofuran (15 ml) was added methanesulfonic acid (0,053 ml, 0,811 mmol). The reaction mixture was heated at boiling with reflux for 2 hours at 75°C. the Reaction�nnow the mixture is then cooled and the solvent was removed in vacuum. To the mixture was added water and the mixture was extracted three times with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was removed in vacuum to give 3-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (1,493 g, gold 6.43 mmol, 95% yield) in the form of an oil, which was used for next step without further purification. MS (ESI): m/z 232,0 [M+1]+.

B. 3-(4-Nitrophenyl)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole. To a suspension/solution of 4-nitrophenylarsonic acid (1 g, 5.99 mmol) in dimethoxyethane (20 ml) and water (10 ml) was added 3-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (1,390 g, 5.99 mmol) followed by the addition of potassium carbonate. The reaction mixture was barbotirovany nitrogen for 3 minutes. Was added tetrakis(triphenylphosphine)palladium(0) (0,346 g, 0,300 mmol) and the sealed reaction flask was stirred at 120°C overnight. The reaction mixture was cooled and added water (50 ml). The mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuum. The residue was purified using column chromatography (elwira using 0-100% ethyl acetate in hexane) to give 3-(4-nitrophenyl)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (400 mg, 1,458 mmol, 24,34% yield) as a yellow solid.1H NMR (400 MHz, DM�Oh-d 6) δ (M. D.) 8,91 (s, 1H), 8,31 is 8.38 (m, 2H), 8,22-8,30 (m, 2H), for 5.66 (DD, J=2,73, 9,76 Hz, 1H), 3,98 (DWI, 1H), 3,58-of 3.80 (m, 1H), 1,86-of 2.35 (m, 3H), of 1.48-1,83 (m, 3H). MS (ESI): m/z 275,2 [M+1]+.

C. 4-(1-(Tetrahydro-2 H-PYRAN-2-yl)-1H-1,2,4-triazole-3-yl)aniline. To a degassed solution of 3-(4-nitrophenyl)-1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole (400 mg, 1,458 mmol) in methanol (100 ml) was added palladium on carbon (155 mg, 1,458 mmol). The reaction mixture was stirred at room temperature under the conditions of hydrogen pressure of 1 atmosphere during the night. The solution was filtered and the solvent was removed under vacuum to give 4-(1-(tetrahydro-2H-Piran-2-yl)-1H-1,2,4-triazole-3-yl)aniline (0,356 g, 1,458 mmol, 100% yield) which was used for next step without further purification. MS (ESI): m/z 245,0 [M+1]+.

Intermediate compound 135: N-Methoxy-N-methyl-1,4-dioxane-2-carboxamide

A. 1,4-Dioxane-2-carbonitrile. 4 M of hydrogen Chloride in 1,4-dioxane (23 ml, 93 mmol) was added dropwise to a stirred solution of 2,3-dihydro-1,4-dioxin (8 g, 93 mmol) in toluene (20 ml) at room temperature in a nitrogen atmosphere. After 15 minutes, the colorless solution was transferred into a dropping funnel and added dropwise to a stirred suspension of lanserer (12,44 g, 93 mmol) in toluene (100 ml) at room temperature in a nitrogen atmosphere. When you are finished adding the mixture was heated at 115°C under conditions �of apachenya to reflux in a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and was filtered through Celite and the filter cake was washed with diethyl ether. The filtrate was concentrated on a rotary evaporator and purified using flash chromatography (elwira using 0-100% ethyl acetate in hexane). Fractions containing the desired product were combined and the solvent was removed on a rotary evaporator. The residue was diluted with hexane and concentrated on a rotary evaporator three times to obtain the desired product (6.2 g, of 54.8 mmol, 59,0% yield) as a clear oil.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 4,55 (t, J=3,32 Hz, 1H), of 4.04 (DDD, J=of 12.59, 9,27, to 2.73 Hz, 1H), a 3.87 (d, J=3,12 Hz, 2H), of 3.77-3,84 (m, 1H), 3,70-of 3.77 (m, 2H).

B. 1,4-Dioxane-2-carboxylic acid. A solution of sodium hydroxide (5.0 g, 125 mmol) in distilled water (45 ml) was added to 1,4-dioxane-2-carbonitrile (6.5 g, 57 mmol). The mixture was heated at boiling with reflux for four hours, acidified with 6 n sulfuric acid (15 ml) and was extracted with simple ether (3×30 ml). The aqueous solution was evaporated under reduced pressure and was extracted with simple ether. The ethereal solution was dried over anhydrous sodium sulfate, was evaporated, to give a clear oil which crystallized upon cooling. Recrystallization from carbon tetrachloride gave 1,4-dioxane-2-carboxylic acid (4.1 g, of 31.0 mmol, 54% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,88 (lat.s, 1H), 4,32 (DD, J=8,59, 3,12 Hz, 1H), 4,07 (DD, J=11,52, 3,32 Hz, 1H), 4,00 (dt, J=11,71, 2,93 Hz, 1H), 3,64-3,83 (m, 4H).

C. N-Methoxy-N-methyl-1,4-dioxane-2-carboxamide. Oxaliplatin (1,093 ml, 12,49 mmol) was added dropwise to a stirred solution of 1,4-dioxane-2-carboxylic acid (1.5 g, to 11.35 mmol) and N,N-dimethylformamide (0,018 ml, 0,227 mmol) in dichloromethane (50 ml). The obtained colorless solution was stirred at room temperature in a nitrogen atmosphere for 2 hours. The mixture was cooled to 0°C in an atmosphere of nitrogen, was then added the hydrochloride of N,O-dimethylhydroxylamine (1.7 g, to control an additional 17.03 mmol). The mixture in the form of a thick suspension was stirred at room temperature in a nitrogen atmosphere for 10 minutes. The resulting mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layers were washed with saturated brine and then dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified using flash chromatography (30-70% ethyl acetate in hexane) obtaining specified in the title compound (1.5 g, of 8.56 mmol, 75%) as a clear oil. MS (ESI) m/z 176,4 [M+1]+.

Intermediate compounds 136 and 137: 6-Bromo-1,4-dimethylindoline-2,3-dione and 4-bromo-1,6-dimethylindoline-2,3-dione

A. 3-Bromo-N,N,5-trimethylaniline. To races�thief hydrochloride salt of 3-bromo-5-methylaniline (0,419 g, 2,25 mmol) in 1,2-dimethoxyethane (6 ml) was added sodium hydride (0,162 g, of 6.75 mmol) and the reaction mixture stirred at room temperature for 15 minutes. Added itmean (0.7 ml, of 11.25 mmol) and the reaction mixture stirred at room temperature for 17 hours. Added water and the reaction mixture was extracted with ethyl acetate (3×50 ml). The organic layers were washed with saturated solution of ammonium chloride (100 ml) and saturated brine, dried over magnesium sulfate, filtered and concentrated. The crude substance was purified using column chromatography (elwira using 0-40% ethyl acetate in hexane) to give 3-bromo-N,N,5-trimethylaniline (0.31 g, 66.4 per cent yield) as a yellow liquid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 6,62 (d, J=1,95 Hz, 2H), is 6.51 (s, 1H), 2,88 (s, 6H), 2,22 (s, 3H). MS (ESI) m/z RUB 213.9 [M+2]+.

B. 6-Bromo-1,4-dimethylindoline-2,3-dione and 4-bromo-1,6-dimethylindoline-2,3-dione. A solution of 1,4-diazabicyclo[2,2,2]octane (DABCO) (1,912 g, 17,05 mmol) in chloroform (5 ml) was cooled to 0°C in an atmosphere of nitrogen was added dropwise oxalicacid (1,492 ml 17,05 mmol) to give pale yellow solids. This solid substance was slowly added 3-bromo-N,N,5-trimethylaniline (0.73 g, to 3.41 mmol) in chloroform (3 ml) at 0°C. the Reaction mixture from yellow suspension became a brown suspension. The reaction mixture then was warmed to room �of emperature, was transferred into a sealed tube and heated to 90°C for 3 hours. The reaction mixture was neutralized using 10% sodium hydroxide solution to pH 8-9. The aqueous layer was extracted with ethyl acetate (3×100 ml), washed with saturated solution of ammonium chloride and saturated brine, dried over magnesium sulfate, filtered and concentrated to give a mixture of regioisomers in the form of a red-brown solid. Regioisomer were separated using column chromatography (elwira using 0-100% ethyl acetate in hexane). Less polar compound was identified as 6-bromo-1,4-dimethylindoline-2,3-dione (0,34 g, 39.2 percent).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,27 (s, 1H), 7,21 (s, 1H), 3,12 (s, 3H), 2,44 (s, 3H). MS (ESI) m/z 256,1 [M+2]+.

Regioniniu confirmed using NOE (NOE-NMR (400 MHz, DMSO-d6) δ (M. D.) 2,44 (peak emitted suppressed one main peak at 7,21 M. D.). The most polar compound was identified as 4-bromo-1,6-dimethylindoline-2,3-dione, and optionally purified by grinding into powder with methanol (of 0.146 g, 17%).1H NMR (400 MHz, DMSO-d6) δ (M. D.) made 7.16 interest (s, 1H), 7,02 (s, 1H), 3,11 (s, 3H), of 2.38 (s, 3H). MS (ESI) m/z 256,1 [M+2]+.

Regioniniu confirmed using NOE (NOE-NMR (400 MHz, DMSO-d6) δ (M. D.) 2,38 (peak emitted suppressed two major peak at 7,02 and made 7.16 interest of M. D.).

EXAMPLES

Example 1: N,5-Diphenyl-[1,2,4]Tria�olo[1,5-α]pyridin-2-amine

A. 2-(3-Ethoxycarbonyl-2-touraid)-6-bromopyridin. To a solution of 2-amino-6-bromopyridine (8 g, a 46.5 mmol) in dioxane (160 ml) was added dropwise ethoxycarbonylmethylene (6,09 g, a 46.5 mmol) in a nitrogen atmosphere at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored using TLC (petroleum ether:ethyl acetate=5:1). When the starting material was consumed, the dioxane was removed under reduced pressure to obtain crude 2-(3-ethoxycarbonyl-2-touraid)-6-bromopyridine (14,81 g) in the form of solids.1H NMR (300 MHz, DMSO-d6) δ (M. D.) 12,16 (lat.s, 1H), 11,65 (lat.s, 1H), 8,65 (d, J=8,1 Hz, 1H), 7,84 (DD, J1=8,1, J2=12 Hz, 1H), 7,49 (d, J=7,2 Hz, 1H), 4,24 (sq, J=7.2 Hz, 2H), 1.27 mm (t, J=7,2 Hz, 3H); MS (ESI): m/z 303,9 [M+1]+.

B. 5-Bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To a solution of hydroxylaminopurine (16,16 g, to 232.5 mmol) and N,N-diisopropylethylamine (23,89 ml, 139.5 mmol) in a mixture of methanol and ethanol (V/V, 1:1, 95 ml) was added 2-(3-ethoxycarbonyl-2-touraid)-6-bromopyridin (14,81 g, a 46.5 mmol) in one portion at room temperature. After stirring at room temperature for 2 hours the reaction mixture was heated at 60°C over night. TLC analysis (ethyl acetate:methanol=20:1) showed that the starting material consumed. Volatiles were removed under reduced pressure� and the residue treated with water. The precipitate was collected by filtration, washed with a mixture of methanol and diethyl ether (4:1, 18,5 ml). After drying in a high vacuum of 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (7,29 g, total yield of 74% for two steps) was obtained as an off-white solid.1H NMR (300 MHz, DMSO-d6) δ (M. D.) 7,34 (m, 2H), 7,20 (m, 1H), for 6.24 (lat.s, 2H); MS (ESI): m/z 213,0 [M+1]+.

C. 5-Phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (2.5 g of 11.8 mmol), phenylboronic acid (2,88 g, the 23.6 mmol), triphenylphosphine (618 mg, 2.36 mmol) and potassium phosphate (5,00 g, the 23.6 mmol) in 1,2-dimethoxyethane (35 ml) was degassed and added palladium acetate (0.5 g, 1,77 mmol) in a nitrogen atmosphere. The reaction mixture was heated at boiling with reflux in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was distributed between ethyl acetate (50 ml) and water (50 ml) and the aqueous layer was extracted with ethyl acetate (30 ml ×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated. The residue was purified on a column of silica gel (elwira using 15-25% ethyl acetate in petroleum ether) to give 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (1.7 g, up 68.5% yield) as solid.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) a 7.92 (m, 2H), members, 7.59-7,34 (m, 5H), 7,40 (d, J=7,2, 1H); MS (ESI): m/z 211,0 [M+1 +.

D. N,5-Diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (200 mg, 0,94 mmol), panelbased (163 mg, of 1.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (54 mg, 0,094 mmol) and cesium carbonate (430 mg, 1,32 mmol) in dioxane (8 ml) was degassed and added Tris(dibenzylideneacetone)dipalladium (0) (43 mg, 0,047 mmol) in a nitrogen atmosphere. The reaction mixture was heated at 120°C with stirring overnight. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate (25 ml ×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate, concentrated. The residue was purified using preparative TLC (elwira using 25% ethyl acetate in petroleum ether) to give N,5-diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (130 mg, 48% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,62 (s, 1H), 8,04 (d, J=8.4 Hz, 2H), 7,68-7,51 (m, 6H), 7,22 (t, J=7,6 Hz, 2H), 7,18 (d, J=8.4 Hz, 1H), 6,83 (t, J=7,6 Hz, 1H); MS (ESI): m/z 286,9 [M+1]+.

Iodides or chlorides can be used instead of the bromide to the reaction combination.

Example 2: N-(4-Morpholinomethyl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. N-(4-Morpholinomethyl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. After a mixture of 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (100 mg, 0.47 mmol), 4-(4-bromo-phenyl)morpholine (137 mg, 0,57 mmol), 4,-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0,047 mmol) and tert-butoxide potassium (105 mg, 0,94 mmol) in dioxane (6 ml) was degassed, was added Tris(dibenzylideneacetone)dipalladium (0) (21.6 mg, 0,024 mmol) in a nitrogen atmosphere and the reaction mixture was heated at 80°C with stirring in a nitrogen atmosphere over night. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate (15 ml ×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified using preparative TLC (elwira using 25% ethyl acetate in petroleum ether) to give N-(4-morpholinomethyl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine in free base form, which was converted into the corresponding hydrochloride salt using methanolic solution of hydrochloride (28 mg, 15.8% of output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,91 (lat.s, 1H), 8,02 (d, J=8,0 Hz, 2H), 7,75-7,52 (m, 9H), 7,20 (d, J=6,8 Hz, 1H), 3,97 (s, 4H), 3.45 points (s, 4H); MS (ESI): m/z 372,2 [M+1]+.

Example 3: 5-(Furan-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-a] pyridin-2-amine

Example 4: 5-(2-Fluorophenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-(2-Fluorophenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. 5-(2-Fluorophenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine was obtained from 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine and 2-ftorhinolonovy acid,following the procedure described for the synthesis of 5-(furan-3-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. Degassed mixture of 5-(2-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (73 mg, 0.3 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 0,064 mmol), Tris(dibenzylideneacetone)diplegia(0) (29 mg, to 0.032 mmol), brombenzene (47 mg, 0.3 mmol) and tert-butoxide potassium (72 mg, 0.64 mmol) in dioxane (5 ml) was heated at 120°C in a nitrogen atmosphere over night. After cooling to room temperature, was added ethyl acetate (30 ml) and water (30 ml). The organic layer was separated and then the aqueous phase was extracted with ethyl acetate (30 ml ×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using reverse-phase preparative HPLC (40-70% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to give 5-(2-fluorophenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine in the form of the trifluoroacetic acid salt which was converted to the corresponding hydrochloride salt using methanolic solution of hydrochloride (23 mg, 24% yield).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,10 (t, J=8,0 Hz, 1H), 7,81 (m, 2H), 7,71 (m, 1H), 7,58 (m, 1H), 7,50 (m, 2H), of 7.42 (m, 2H), 7,32 (m, 2H), 7,07 (m, 1H); MS (ESI): m/z 305,1 [M+1]+.

Example 5: N-(5-Methoxypyridine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α] pyridin-2-amine

A. N-(5-Methoxypyridine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (303 mg, 1.44 mmol), 3-bromo-5-methoxy-pyridine (245 mg, 1,31 mmol), (R)-(+)-2,2'-bis(diphenylphosphino) 1,1'-binaphthyl (162 mg, 0,26 mmol) and tert-butoxide sodium (252 mg, is 2.88 mmol) in toluene (10 ml) was degassed and added Tris(dibenzylideneacetone)dipalladium(0) (119 mg, 0,13 mmol). The reaction mixture was heated at 80°C in a nitrogen atmosphere with stirring overnight. The toluene was removed under reduced pressure and the residue was purified on a column of silica gel (elwira using 5-30% ethyl acetate in petroleum ether) to give crude product that was recrystallized from methanol to obtain N-(5-methoxypyridine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (170 mg, to 41.0% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,94 (s, 1H), 8,30 (d, J=2,0 Hz, 1H), 8,01 (d, J=2,0 Hz, 2H), 7,94 (s, 1H), 7,78 (d, J=2.4 Hz, 1H), 7,65 (m, 1H), 7,61 (s, 1H), 7,55 (m, 3H), 7,28 (d, 1H), 3,76 (s, 3H); MS (ESI): m/z 318,1 [M+1]+.

Example 6: N2-(2-Aminoethyl)-N4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)pyridine-2,4-diamine

A. N-(2-Chloropyridin-4-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. Degassed mixture of 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (420 mg, 2.0 mmol), 2-chloro-4-iodo-pyridine (478 mg, 2.0 mmol), Tris(�dibenzylideneacetone)diplegia(0)(180 mg, 0,2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg, 0.4 mmol) and cesium carbonate (1.3 g, 4.0 mmol) in dioxane (5 ml) was heated at 80°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product was washed with water (10 ml) and methanol (20 ml) and dried in vacuum to give N-(2-chloropyridin-4-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (502 mg, 78% yield) as solid which was used without further purification. MS (ESI): m/z 321,9 [M+H]+.

B. N2-(2-aminoethyl)-N4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)pyridine-2,4-diamine. A mixture of N-(2-chloropyridin-4-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (160 mg, 0.5 mmol), ethane-1,2-diamine (5 ml) and copper iodide (I) (10 mg, 0.05 mmol) in a sealed tube was subjected to irradiation in a microwave (150 W) at 150°C in a nitrogen atmosphere for 45 minutes. Added water and the mixture was extracted with dichloromethane. The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse-phase preparative HPLC (24-54%: acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 20 min) to give N2-(2-aminoethyl)-N4-(5-phenyl-[1,2,4]�triazolo[1,5-α]pyridin-2-yl)pyridine-2,4-diamine in the form of trifluoroacetic acid salt, which was converted into hydrochloride salt, using a methanol solution of hydrochloride,(35 mg, 20% yield) in the form of solids.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) a 7.92 (m, 2H), 7,71 (m, 2H), members, 7.59 (m, 1H), 7,51 (m, 4H), 7,21 (DD, J1=M Hz, J2=7,6 Hz, 1H), 6,9 (d, J=1.2 Hz, 1H), 3,55 (t, J=6,0 Hz, 2H), 3,02 (t, J=6,0, 2H); MS (ESI): m/z 346,1 [M+1].

Example 7: 3-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol

A. 5-Bromo-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. To a solution of 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (2 g, 9,39 mmol) in 100 ml of dioxane was added iadanza (3,83 g, 18,78 mmol), tert-butoxide sodium (1,804 g, 18,78 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1,086 g, 1,878 mmol) and Tris(dibenzylideneacetone)palladium (0,903 g, 0,986 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture was heated at 100°C for 2 hours. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was poured into water/saturated salt solution and was extracted with ethyl acetate several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified column chromatography on silica gel (elwira using 0-80% ethyl acetate in hexane) obtaining specified in the header connection in the form of a brown solid (1.3 g, 48% yield).1H NMR (400 MHz, DMSO-d6 ) δ (M. D.) 9,84 (s, 1H), 7,74-7,71 (m, 2H), 7,62-to 7.60 (m, 1H), 7,52-of 7.48 (m, 1H), 7,40-7,38 (m, 1H), 7,32-7,28 (m, 2H), at 6.92-to 6.88 (m, 1H); MS (ESI) m/z 290,13 [M+1]+.

B. 3-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol. Degassed solution of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (60 mg, 0,286 mmol), 3-hydroxy-phenylboronic acid (43 mg, 0,312 mmol), 1-1'-bis(diphenylphosphino)ferienparadies (15 mg, 0,020 mmol) and aqueous sodium carbonate solution (2 M, 1 ml) in dioxane (3 ml) was heated at boiling with reflux for 2 hours in a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organics were combined, dried using sodium sulfate and evaporated in vacuum. The residue was purified using preparative TLC (elwira using 15-20% ethyl acetate in petroleum ether) to give 3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol (45 mg, 52% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,81 (lat.s, 1H), 9,62 (lat.s, 1H), 7,68-7,56 (m, 4H), of 7.42-7,35 (m, 3H), 7,24 (t, J=8,0 Hz, 2H), 7,11 (d, J=6,8 Hz, 1H), 6,93 (m, 1H), 6,83 (m, 1H); MS (ESI): m/z 303,0 [M+1]+.

Example 8: 5-(1H-Indazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-(1H-indazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (180 mg, of 0.625 mm�l), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-carboxylate (258 mg, 0,72 mmol), tetrakis(triphenylphosphine)palladium(0) (72 mg, 0,06 mmol) and an aqueous solution of potassium phosphate (2 M, of 0.625 ml, 1.3 mmol) in dimethyl sulfoxide (5 ml) in a test tube was heated at 85°C with stirring in a nitrogen atmosphere over night. Was added a saturated aqueous solution of sodium chloride and the precipitated substance was collected by filtration. Pale yellow solid was dissolved in ethyl acetate (5 ml) and added dropwise a methanolic hydrochloride solution (2 M, 2 ml). The mixture was concentrated in vacuo and the residue was washed with ethyl acetate to obtain 5-(1H-indazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (82 mg, 41% yield) in the form hydrochloride salt.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,65 (lat.s, 1H), 8,49 (s, 1H), 8,23 (s, 1H), 7,98 (d, J=8,8 Hz, 1H), 7,68 (m, 4H), 7,56 (d, J=8,8 Hz, 1H), 7,22 (m, 3H), 6,83 (t, J=7,2 Hz, 1H); MS (ESI): m/z 327,1 [M+1]+.

Alternatively, this reaction can be carried out in N,N-dimethylformamide as the solvent and at a temperature of 100°C.

Example 9: 5-(2-((Methylamino)methyl)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-(4-Amino-3-nitrophenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. Degassed mixture of 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.5 g mg, 1,89 mmol), 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-AMI�a (0.54 g, 1,89 mmol), sodium carbonate (0.4 g, of 3.78 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (50 mg, 0,043 mmol) in 1,2-dimethoxyethane and water (V/V, 3:1, 12 ml) was heated to 85°C over night. The reaction mixture was extracted with ethyl acetate and the organic layer was evaporated. The crude product was purified on a column of silica gel (elwira using 15% ethyl acetate in petroleum ether) to give 5-(4-amino-3-nitrophenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,39 g, 60% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,63 (lat.s, 1H), 9,23 (lat.s, 1H), 8,08-8,06 (DD, J1=9,2 Hz, J2=2.4 Hz, 1H), 7,82 (s, 2H), 7,73 (d, J=7,6 Hz, 2H), 7,63 (d, J=8,8 Hz, 1H), 7,51 (d, J=8,8 Hz, 1H), 7,29-7.23 percent (m, 3H), 7,18 (d, J=8,8 Hz, 1H), of 6.85 (t, J=7,2 Hz, 1H); MS (ESI): m/z 347,0 [M+1]+.

B. 4-(2-Phenylamino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-benzene-1,2-diamine. A mixture of 5-(4-amino-3-nitrophenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.59 g, 1,72 mmol), zinc dust (1.12 g, and 17.2 mmol) and ammonium chloride (0.92 g, and 17.2 mmol) in a mixture of tetrahydrofuran and methanol (1:1, 30 ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was distributed between water and ethyl acetate and the aqueous solution was extracted with ethyl acetate three times. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuum to give 4-(2-phenylamino-[12,4]triazolo[1,5-α]pyridin-5-yl)-benzene-1,2-diamine (0.36 g, 61% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,54 (lat.s, 1H), of 7.70 (m, 2H), 7,55 (m, 1H), 7,39 (m, 1H), 7,25-7,21 (m, 4H), 6,95 (d, J=7,2 Hz, 1H), 6,84 (m, 1H), 6,63 (d, J=6,8 Hz, 1H), 4,99 (lat.s, 2H), 4,63 (lat.s, 2H); MS (ESI): m/z 317,0 [M+1]+.

C. 5-(2-(Chloromethyl)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 4-(2-phenylamino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-benzene-1,2-diamine (0,34 g, 1.1 mmol) and hydrochloride of ethyl 2-chloracetamide (0.17 g, 1.1 mol) in anhydrous ethanol (50 ml) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was poured into water. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuum to give 5-(2-(chloromethyl)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,34 g, 84% yield).1H NMR (400 MHz, δ (M. D.) 13,03 (lat.s, 1H), 9,61 (lat.s, 1H), of 8.33-of 8.25 (m, 1H), of 7.88-7,51 (m, 6H), 7,39-7,21 (m, 3H), only 6.64 (d, J=7,6 Hz, 1H), 4,97 (s, 2H); MS (ESI): m/z 375,0 [M+1]+.

D. 5-(2-((Methylamino)methyl)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-(2-(chloromethyl)-1H-benzo[ύ(]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.18 g, 0.4 mmol) and an aqueous solution of methylamine(0.24 g, 2.0 mmol) in acetonitrile (25 ml) was stirred at room temperature over night. The solvent was removed under reduced pressure � obtain crude product, which was purified using reverse-phase preparative HPLC (20 to 54% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min), to obtain 5-(2-((methylamino)methyl)-1H-benzo[fif]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt using methanolic solution of hydrochloride (0.65 g, 37% output).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,53 (s, 1H), 8,21-8,13 (m, 2H), 8,03 (d, J=8.4 Hz, 1H), a 7.85 (d, J=8.4 Hz, 1H), 7,78 (d, J=7,6 Hz, 1H), EUR 7.57 (d, J=7,6 Hz, 2H), 7,40 (t, J=8,0 Hz, 2H), 7,14 (t, J=7,6 Hz, 1H), 4,69 (s, 2H), Of 2.97 (s, 3H); MS (ESI): m/z 370,1 [M+1]+.

Example 10: 7-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)isoquinoline-1-amine

A. 5-(1-Chloroisoquinoline-7-yl)-N-phenyl-[1,2,4]triazolo[1,5-α] pyridin-2-amine. Degassed mixture of 1-chloroisoquinoline-7-Voronovo acid (288 mg, 1.38 mmol), 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (400 mg, 1.38 mmol), potassium phosphate (296 mg, to 2.76 mmol) and tetrakis(triphenylphosphine)palladium(0)(160 mg, was 0.138 mmol) in dimethylsulfoxide (10 ml) was heated at 90°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was washed with ethyl acetate to obtain 5-(1-chloroisoquinoline-7-yl)-N-phenyl-[,2,4]triazolo[1,5-α]pyridin-2-amine (200 mg, 38.7% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,68 (lat.s, 1H), 9,23 (s, 1H), 8,45 (d, J=8.4 Hz, 1H), to 8.41 (d, J=5,2 Hz, 1H), 8,27 (d, J=8,8 Hz, 1H), 8,01 (d, J=5.6 Hz, 1H), 7,69 (m, 4H)3 7,44 (d, J=6,0 Hz, 1H), 7.23 percent (t, J=7,6 Hz, 2H), of 6.85 (t, J=7,2 Hz, 1H); MS (ESI) m/z: 372,1 [M+1]+.

B. N-(4-Methoxybenzyl)-7-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoquinoline-1-amine. A mixture of 5-(1-chloroisoquinoline-7-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (200 mg, 0,54 mmol) and (4-methoxyphenyl)-methanamine (20 ml) was heated at 180°C for 6 hours. Then the reaction mixture was concentrated in vacuum to give crude product, which was purified using reverse-phase preparative HPLC (34-54%: acetonitrile + 0,1% trifluoroacetic acid in water, over 15 min) to give N-(4-methoxybenzyl)-7-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)isoquinoline-1-amine in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt using methanolic solution of hydrochloride (120 mg, 47% output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,67 (lat.s, 1H), 9,19 (s, 1H), 8,65 (m, 1H), to 8.14 (m, 1H), 7,72 (m, 5H), 7,35 (m, 4H), 7,21 (t, J=7,6 Hz, 2H), 6,89 (m, 2H), 6,83 (t, J=6,8 Hz, 1H), 4,76 (d, J=5,2 Hz, 2H), 3,70 (s, 3H); MS (ESI): m/z to 473.1 [M+1]+.

C. 7-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)isoquinoline-1-amine. A solution of N-(4-methoxybenzyl)-7-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)isoquinoline-1-amine (120 mg, 0.25 mmol) in trifluoroacetic Ki�lot (20 ml) was heated at boiling with reflux for 6 hours. The reaction mixture was concentrated in vacuum to give crude product, which was purified using reverse-phase preparative HPLC (30-50%: acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 12 min) to give 7-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoquinoline-1-amine in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt using methanolic solution of hydrochloride (28 mg, 31.5% of the output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,18 (lat.s, 1H), 8,67 (d, J=6,8 Hz, 1H), 8,15 (d, J=8.4 Hz, 1H), 7,96 (m, 1H), 7,71 (m, 2H), 7,58 (m, 3H), of 7.36 (d, J=7,2 Hz, 1H), 7,31 (m, 2H), 7,01 (m, 1H); MS (ESI): m/z 353,1 [M+1]+.

Example 11: 5-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzo[d]izocsazol-3-amine

A. 2-Fluoro-5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzonitrile.

To a degassed mixture of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (700 mg, 2.8 mmol), 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (400 mg, 1.4 mmol) and potassium acetate (317 mg, 9,51 mmol) in dioxane (10 ml) was added 1,1'-bis(diphenylphosphino)ferienparadies (104 mg, 0.14 mmol) and the mixture was heated at 100°C in a nitrogen atmosphere over night. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain 2-fluoro-5-(-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzonitrile (300 mg, 65% yield) in the form of solids.1H NMR (400 MHz, δ (M. D.) 9,70 (s, 1H), of 8.34 (d, J=1.2 Hz, 1H), 8,16 (m, 2H), 7,69 (m, 3H), value of 7, 37 (t, J=4.4 Hz, 1H), 7,25 (m, 2H), 6,86 (m, 1H); MS (ESI): m/z 330,0 [M+1]+.

B. 5-(2-(Phenylamino[1,2,4]triazolo[1,5-α]pyridin-5-yl)-2-(propane-2-ylideneamino)benzonitrile. Propane-2-on oxime (131 mg, 1.8 mmol) was added to a solution of tert-butoxide potassium (202 mg, 1.8 mmol) in tetrahydrofuran (15 ml) and the mixture was stirred for 1 hour at room temperature. Was added 2-fluoro-5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzonitrile (300 mg, 0.9 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using reverse-phase preparative HPLC (30-60%: acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid over 25 min) to give 5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-2-(propane-2-ylideneamino)-benzonitrile in the form of a trifluoroacetic acid salt (150 mg, 43.7% of the output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 9.52 (s, 1H), to 8.19 (s, 1H), 7,81 (d, J=8,0 Hz, 1H), 7,56 (d, J=8.4 Hz, 1H), 7,51 (m, 4H), 7,12 (DD, J1=6,4 Hz, J2=2,0 Hz, 1H), 7,05 (t, J=8,0 Hz, 2H), 6,68 (t, J=7,2 Hz, 1H), 1,98 (s, 3H), of 1.80 (s, 3H); MS (ESI): m/z RR 383.0 [M+1]+.

C. 5-(2-(Phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)�-[d]izocsazol-3-amine. A solution of 5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-2-(propane-2-ylideneamino)benzonitrile (150 mg, 0,39 mmol) in trifluoroacetic acid and 5 n hydrochloric acid (4:1, 50 ml) was stirred at room temperature in a nitrogen atmosphere over night. The solvent was concentrated in vacuum to give crude product, which was purified using reverse-phase preparative HPLC (27-57%: acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min), to obtain 5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzo[d]izocsazol-3-amine in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt (67 mg, 47,0% output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) to 9.67 (s, 1H), 8,18 (s, 1H), 8,00 (d, J=8,0 Hz, 1H), to 7.89 (d, J=8.4 Hz, 1H), 7,65 (m, 4H), 7,31 (d, J=7,2 Hz, 1H), 7,24 (t, J=8,0 Hz, 2H), 6,86 (t, J=7,6 Hz, 1H); MS (ESI): m/z 343,0 [M+1]+.

Example 12: 4-(5-(3-Hydroxyphenyl)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamide

A. 4-(5-Bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile. To the orange solution of 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (2.00 g, 9,39 mmol) in dioxane (100 ml) was added 4-iodobenzonitrile (4,30 g, 18,78 mmol), cesium carbonate (6.12 g, 18,78 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1,086 g, 1,878 mmol) and Tris(dibenzylideneacetone)palladium (0,903 g, 0,986 mmol at room temperature in a nitrogen atmosphere. The reaction mixture was heated at 100°C for 18 hours in a nitrogen atmosphere. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was poured into water/saturated salt solution and was extracted with ethyl acetate several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was ground into powder with ethyl acetate receive specified in the header connection in the form of a brownish-yellow solid (0,565 g, 20% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,55 (s, 1H), to 7.89-7.87 ft (m, 2H), to 7.77-of 7.75 (m, 2H), 7,71-7,69 (m, 1H), 7,58-7,54 (m, 1H), 7,49-of 7.46 (m, 1H); MS (ESI) m/z 315,14[M+1]+.

B. 4-(5-Bromo-[1,2,4]triazole[1,5-α]pyridine-2-ylamino)benzamide. Pale yellow solution of 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (0,909 g 2,89 mmol) in 85% phosphoric acid (15 ml) was heated at 100°C for 2 hours. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was poured in a minimum amount of water and neutralized with 1 n sodium hydroxide solution (pH 6-7). The mixture was extracted using 20% isopropanol in chloroform several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified using chromatography on silica gel using a gradient of 0-8% of a saturated methanolic solution of ammonia in chloroform with n�the receiving specified in the header connection in the form of a pale yellow solid (0,677 g, 71% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,20 (s, 1H), 7,84 (d, 2H, J=8 Hz), 7,78-of 7.75 (m, 3H), 7,66 (d, 1H, J=8 Hz), 7,53 (t, 1H, J=8 Hz), 7,45-of 7.42 (m, 1H), made 7.16 interest (the Shire.s, 1H); MS (ESI) m/z 332,16 and 334,16 [M]+and [M+2]+.

C. 4-(5-(3-Hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzamide.

To a colorless solution of 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamide derivative (0,150 g, 0,452 mmol) in dioxane (10 ml) was added 3-oxyphenylbutazone acid (0,069 g, 0,497 mmol), sodium carbonate (0,020 g, 0,189 mmol) dissolved in minimum amount of water, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0,026 g, to 0.032 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture was heated at 100°C for 18 hours in a nitrogen atmosphere. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was poured into water/saturated salt solution and was extracted with ethyl acetate several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified using chromatography on silica gel using a gradient of 0-15% of a saturated methanolic solution of ammonia in chloroform to obtain a pale yellow solid. This solid substance was washed with methanol and the filtrate concentrated to give a net specified in the header connection in the form of a brownish solid (92.1% of purity, 0.036 g, 23 output). 1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,01 (s, 1H), 9,78 (s, 1H), 7,82-7,76 (m, 3H), 7,74-7,71 (m, 2H), 7,69-7,61 (m, 2H), 7,43-value of 7, 37 (m, 3H), 7,17 (d, 1H, J=8 Hz), 7,12 (lat.s, 1H), 6,97-to 6.95 (m, 1H); MS (ESI) m/z 346,35[M+1]+.

Example 13: N5-Isopropyl-N2-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine

A. N5-Isopropyl-N2-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine. A mixture of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (60 mg, 0,286 mmol) and Isopropylamine (5 ml) in a sealed vessel was heated at 120°C overnight. The solvent was removed under reduced pressure and the crude product was purified using preparative TLC (elwira using 15-20% ethyl acetate in petroleum ether) to give N5-isopropyl-N2-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine (20 mg, 35.9 percent) in the form of solids.1H NMR (300 MHz, METHANOL-d4) δ (M. D.) 7,63 (m, 2H), of 7.46 (m, 1H), 7,32-7,27 (m, 2H), 6,95 (m, 1H), 6,71 (m, 1H), 6,15 (d, J=7,8 Hz, 1H), 3,86 (m, 1H), 1,38 (d, J=6,6 Hz, 6H); MS (ESI): m/z 268,2 [M+1]+.

Example 14: CIS-4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol

A. 5-Bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To the orange solution of 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (1.00 g, 4,69 mmol) in dioxane (40 ml) was added 1-iodo-4-(trifluoromethyl)benzene (2.55 g, 1.3 ml, 9,39 mmol), tert-butoxide (0,902 g, 9,39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0,543 g, 0,939 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0,451 g, 0,492 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture was heated at 100°C for 1 hour in a nitrogen atmosphere. When the reaction was completed, as shown by the LC/MS analysis, the reaction mixture was poured into water/saturated salt solution and was extracted with ethyl acetate several times. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified column chromatography on silica gel (elwira using 0-50% ethyl acetate in hexane) to give 5-bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine as yellowish brown solid (0,306 g, 18% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) will be 10.39 (s, 1H), 7.87 ft-of 7.93 (m, 2H), of 7.64-7,72 (m, 3H), 7,52-7,58 (m, 1H), 7,44-7,49 (m, 1H); MS (ESI) m/z 358,13 [M+1]+.

B. CIS-4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol. To the orange solution of 5-bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.300 g, 0,840 mmol) in dioxane (15 ml) was added CIS-4-aminocyclohexanecarboxylic (0,255 g, 1,680 mmol), tert-butoxide sodium (0,242 g, 2,52 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0,097 g, 0,168 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0,081 g, 0,088 mmol) at room temperature in the atmosphere is�re nitrogen. The reaction mixture was heated at 100°C for 1 hour in a nitrogen atmosphere. When the reaction was completed, as shown by the LC/MS analysis, the reaction mixture was poured into water/saturated salt solution and was extracted with ethyl acetate several times. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified column chromatography on silica gel (elwira using 0-100% ethyl acetate in hexane) obtaining specified in the header connection in the form of a brownish-yellow solid (100% purity, 0,078 g, 24% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,03 (s, 1H), 7,90-7,98 (m, 2H), 7,58-7,66 (m, 2H), 7,44 (t, J=8,27 Hz, 1H), was 6.77 (DD, J=1,00, to 8.57 Hz, 1H), 6,19-of 6.26 (m, 2H), 4,51 (d, J=3,17 Hz, 1H), 3,80 (d, J=to 2.54 Hz, 1H), 3,55-3,66 (m, 1H), 1,83-of 1.96 (m, 2H), 1.56 to 1,78 (m, 6H); MS (ESI) m/z 392,39[M+1]+.

Example 15: (S)-4-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-α] pyridine-2-ylamino)benzamide

A. (S)-tert-Butyl 3-(2-(4-cyanovinylene)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)piperidine-1-carboxylate. To the orange solution of 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (0,250 g, 0,796 mmol) in dioxane (10 ml) was added (S)-tert-butyl 3-aminopiperidine-1-carboxylate (0,319 g, 1,592 mmol), cesium carbonate (0,519 g, 1,592 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0,092 g, 0,159 mmol) and Tris(dibenzylideneacetone)palladium (0,077 g, 0,084 mmol) at room�th temperature in a nitrogen atmosphere. The reaction mixture was heated at 100°C for 1.5 hours in a nitrogen atmosphere. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was poured into a saturated saline solution and was extracted with ethyl acetate several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified using column chromatography (elwira using 0-80% ethyl acetate in hexane) obtaining specified in the header connection in the form of a rusty-brown solid (0,122 g, 35% yield). MS (ESI) m/z 434,51[M+1]+.

B. (S)-4-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamide. Pale yellow solution of (S)-tert-butyl 3-(2-(4-cyanovinylene)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)piperidine-1-carboxylate (amount of 0.118 g, 0,272 mmol) in 85% phosphoric acid (7 ml) was heated at 100°C for 4 hours. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was passed through 5 g stratta column for removal of phosphoric acid to obtain a pale yellow foamy substance, which was purified using chromatography on silica gel (elwira using 0-20% of a saturated methanolic solution of ammonia in chloroform), to obtain specified in the title compound as a white solid (92.1% of purity, 100% ei, 0,053 g, 55% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) for 9.88 (s, 1H), 780-7,85 (m, 2H), 7,73-7,79 (m, 3H), 7,44 (t, J=8,27 Hz, 1H), 7,12 (lat.s, 1H), 6,78 (DD, J=0,63, 8,49 Hz, 1H), 6,45 (d, J=8,78 Hz, 1H), 6,21 (d, J=7,71 Hz, 1H), 3,65-3,73 (m, 1H), 3,03 (d, J=14,40 Hz, 1H), 2,71-2,79 (m, 2H), 2,62-2,70 (m, 1H), 1,80-1,89 (m, 1H), 1,70-1,80 (m, 1H), 1,59 by 1.68 (m, 1H), 1,42-of 1.53 (m, 1H); MS (ESI) m/z 352,41 [M+1]+.

Example 16: CIS-4-(5-(4-Aminocyclohexane)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamide

A. tert-Butyl CIS-4-(2-(4-cyanovinylene)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexylcarbamate. To the orange solution of 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (0,200 g, 0,637 mmol) in dioxane (10 ml) was added tert-butyl CIS-4-aminocyclohexanol (0,273 g, 1,273 mmol), cesium carbonate (0,415 g, 1,273 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (to 0.074 g, are 0.127 mmol) and Tris(dibenzylideneacetone)palladium (0,061 g, 0,0669 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture was heated at 100°C for 1 hour in a nitrogen atmosphere. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was poured into a saturated saline solution and was extracted with ethyl acetate several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified using column chromatography (elwira using 0-80% ethyl acetate in hexane) obtaining specified in the header connection in the form of a rusty-brown solid substances�VA (0,082 g, 29% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,22 (s, 1H), to 7.89 (d, 2H, J=8 Hz), 7,73 (d, 2H, J=8 Hz), of 7.46 (t, 1H, J=8 Hz), is 6.81 (d, 1H, J=8 Hz), of 6.25 (d, 1H, J=8 Hz), of 6.02 (d, 1H, J=8 Hz), 3,71-to 3.64 (m, 1H), 3,56-to 3.34 (m, 1H), 1,90-of 1.73 (m, 4H), 1,66-to 1.61 (m, 4H), of 1.40 (s, 9H); MS (ESI) m/z 448,53 [M+1]+.

B. tert-Butyl CIS-4-(2-(4-carbamoylpiperidino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexylcarbamate. To pale yellow solution of tert-butyl CIS-4-(2-(4-cyanovinylene)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexylcarbamate (0,078 g, 0.174 were revealed mmol) in ethanol (10 ml) (heated by using the apparatus for heating a stream of warm air to obtain the original substance in the solution) was added 3 n sodium carbonate solution (4 ml) and 30% mass/mass of hydrogen peroxide (4 ml) at room temperature. The reaction mixture was stirred over night at room temperature. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was poured into a saturated saline solution and was extracted with ethyl acetate several times. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified using column chromatography (elwira using 0-10% of a saturated methanolic solution of ammonia in chloroform) to give specified in the header connection in the form of a pale pink solid (0,066 g, 81% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) was 9.86 (s, 1H), 7,84 (�, 2H, J=8 Hz), 7,76 (d, 3H, J=8 Hz), 7,44 (t, 1H, J=8 Hz), 7,12 (s, 1H), 6,78 (d, 1H, J=8 Hz), from 6.22 (d, 1H, J=8 Hz), 5,96 (d, 1H, J=8 Hz), 3,73-3,65 (m, 1H), 3,58-3,51 (m, 1H), 1,91-to 1.82 (m, 2H), 1,81-of 1.73 (m, 2H), 1,69-1,58 (m, 4H), of 1.40 (s, 9H); MS (ESI) m/z 466,55 [M+1]+.

C. CIS-4-(5-(4-Aminocyclohexane)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamide. The clear orange solution of tert-butyl CIS-4-(2-(4-carbamoylpiperidino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexylcarbamate (0,057 g, 0,122 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml) at room temperature. The reaction mixture was stirred at room temperature over night. After completion of the reaction, as shown by the LC/MS analysis, the reaction mixture was concentrated and the residue was purified using chromatography on silica gel (elwira using 0-25% of a saturated methanolic solution of ammonia in chloroform) to give specified in the header connection in the form of a pale yellow solid. This solid was passed through stratta column with the receipt of the form of the free base of the desired product as a pale yellow solid (98.7% of purity, 0,026 g, 58% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) was 9.86 (s, 1H), 7,84 (d, 2H, J=8 Hz), to 7.77 (d, 3H, J=8 Hz), 7,44 (t, 1H, J=8 Hz), 7,12 (s, 1H), 6,78 (d, 1H, J=8 Hz), 6,21 (d, 1H, J=8 Hz), 6,07 (d, 1H, J=8 Hz), 3,71-3,63 (m, 1H), 2,95-2,92 (m, 1H), 1,95-of 1.85 (m, 2H), 1,74-to 1.63 (m, 4H), 1,50-of 1.43 (m, 2H); MS (ESI) m/z 366,43 [M+1]+.

Example 17: N2-phenyl-N 5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine

A. N2-Phenyl-N5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine. Degassed mixture of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (200 mg, 0,868 mmol) and pyridine-2-amine (1.5 g, 15,96 mmol) was subjected to irradiation in a microwave (150 W) at 220°C for 1 hour in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using reverse-phase preparative HPLC (30-50% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to give N2-phenyl-N5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine (65 mg, 31% yield) as an oil.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,35 (d, J=6,4 Hz, 1H), 8,17 (m, 1H), 8,03 (t, J=8.4 Hz, 1H), 7,91 (d, J=8.4 Hz, 1H), 7,54 (m, 3H), 7,47 (d, J=8.4 Hz, 1H), of 7.36 (m, 3H), 7,12 (t, J=7,6 Hz, 1H); MS (ESI): m/z 303,0 [M+1]+.

Other examples were obtained by following a similar procedure, by changing the temperature and reaction time.

Example 18: N5-Methyl-N2N5-diphenyl-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine

A. N5-Methyl-N2N5-diphenyl-[1,2,4]triazolo[1,5-α]�of iridin-2,5-diamine. A mixture of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (150 mg, 0,521 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60 mg, 0.104 mmol), cesium carbonate (338 mg,1,04 mmol), tert-butoxide sodium (120 mg, 1.04 mmol), methyl-phenylamine (111 mg, 1.04 mmol) and Tris(dibenzylideneacetone)diplegia(0) (48 mg, 0,052 mmol) in dioxane (5 ml) was heated at 100°C for 1 hour in a nitrogen atmosphere with shaking. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified using reverse-phase preparative HPLC (28-58% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 20 min) to give N5-Methyl-N2N5-diphenyl-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt (30 mg, 18.3 per cent) using methanolic solution of the hydrochloride.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 7,99 (m, 1H), 7,43 (m, 2H), 7,26 (m, 2H), 7,15 (m, 5H), 7,03 (m, 3H), 3,62 (s, 3H); MS (ESI): m/z was 316.0 [M+1]+.

The synthesis of some examples in the present application, may require removal of one or more protective groups such as Boc, SEM or THP group. The removal of protection was carried out using standard� procedures such as the procedure described below.

Example 19: N-(Isoindoline-5-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A. N-(Isoindoline-5-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. tert-Butyl 5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)isoindoline-2-carboxylate was obtained from tert-butyl 5-promisingly-2-carboxylate and 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine, following the procedure described for the synthesis of N-(4-morpholinomethyl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A solution of tert-butyl 5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)isoindoline-2-carboxylate (120 mg, 0.28 mmol) in methanolic hydrochloride solution (2 M, 2 ml) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to obtain N-(isoindoline-5-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (110 mg, 100% yield) in the form hydrochloride salt.1H NMR (300 MHz, METHANOL-d4) δ (M. D.) 8,24 (m, 1H), 8,03 (m, 2H), 7,80 (m, 2H), to 7.77 (m, 5H), of 7.64 (m, 1H), 4,60 (d, J=4.5 Hz, 4H); MS (ESI): m/z 328,1 [M+1]+.

Example 20: 5-(3-Dapsone base)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-(3-Dapsone base)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. 5-(3-Nitrophenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine was obtained from 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine, 3-nitro-phenylboronic acid and panelbased in accordance with the procedure of�vannoy for the synthesis of 5-(furan-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-(3-nitrophenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (170 mg, 0.51 mmol), zinc dust (338 mg, 5.1 mmol) and ammonium chloride (270 mg, 5.1 mmol) in a mixture of methanol and tetrahydrofuran (V/V, 1:1, 8 ml) was stirred at room temperature over night. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuum to give crude product, which was washed with ethyl ether to obtain 5-(3-Dapsone base)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (79 mg, 51% yield).1H NMR (400 MHz, METHANOL-d4) δ (M. D.), a 7.62 members, 7.59 (m, 3H), 7,44 (m, 1H), value of 7, 37 (m, 1H), 7,30-of 7.24 (m, 4H), was 7.08 (m, 1H), 6,89 (m, 2H); MS (ESI): m/z 302,1 [M+1]+.

Example 21: 5-Cyclohexyl-N-phenyl-[1,2,4]triazolo[1,5-α] pyridin-2-amine

A. 5-Cyclohexyl-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. 5-Cyclohexenyl-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine was obtained from 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine, cyclohexanedione acid and panelbased in accordance with the procedure described for the synthesis of 5-(furan-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-cyclohexenyl-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (350 mg, to 1.21 mmol) and palladium hydroxide (10% mass/mass, 100 mg) was gidrirovanie under the pressure of the hydrogen gas at 1 atmosphere over night. The catalyst was filtered and the filtrate concentrated. The residue was purified column of chromatographie� on silica gel (elwira using 15-20% ethyl acetate in petroleum ether) to give 5-cyclohexyl-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (40 mg, 11% yield).1H NMR (300 MHz, METHANOL-d4) δ (M. D.) 7,67 (d, J=6,9 Hz, 2H), 7,55 (m, 1H), to 7.33-7,26 (m, 3H), 6,94 (t, J=7,2 Hz, 1H), 6,86 (m, 1H), of 3.45 (m, 1H), 2,23 (m, 2H), 1,94-of 1.65 (m, 3H), of 1.65 and 1.28 (m, 5H); MS (ESI): m/z 293,2 [M+1]+.

Other catalysts (such as palladium on carbon) can also be used for such conversion.

Example 22: 5-(3-Amino-1H-indazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α] pyridin-2-amine

A. 5-(3-Amino-1H-indazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α] pyridin-2-amine. 2-Fluoro-5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzonitrile was obtained from 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine, 3-cyano-4-ftorhinolonovy acid and odensala, according to the procedure described for the synthesis of N,5-diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A suspension of 2-fluoro-5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzonitrile (0,274 g, 0,832 mmol) in water (1.5 ml) and hydrazinoacetate (0,522 ml, 4.99 mmol) was heated to 105°C. Since the reaction was not completed after 3 hours, was added undiluted hydrazinoacetate (1.5 ml), and kept heating at 105°C for 3 hours. Was added water (20 ml) and the obtained black solid was collected by filtration and washed with methanol. This solid was purified using reverse-phase semi-preparative HPLC (20-100% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid in t�within 30 minutes, 4 injection). The desired fractions were combined, neutralized with the help of a 1.75 M aqueous solution of potassium carbonate. The product which has precipitated in the form of a white solid by evaporation of the acetonitrile, collected by filtration and washed with water until neutral pH and dried in a vacuum oven over night. 5-(3-Amino-1H-indazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,092 g, 0,270 mmol, 32.4% of yield) was collected as white solid (97.2% of net).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,70 (lat.s, 1H), 9,62 (s, 1H), 8,44 (s, 1H), 7,91 (d, J=8,78 Hz, 1H), 7,71 (d, J=8,00 Hz, 2H), 7,65 (t, J=8,00 Hz, 1H), 7,54 (d, J=8,64 Hz, 1H), 7,40 (d, J=is 8.74 Hz, 1H), 7,25 (t, J=7,78 Hz, 2H), 7,13 (d, J=7,17 Hz, 1H), of 6.85 (d, J=7,22 Hz, 1H), 5,61 (lat.s, 1H); MS (ESI) m/z 342 [M+1]+.

Example 23: N-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)benzo[d]izocsazol-6-amine

A. N-(5-Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzo[d]izocsazol-6-amine. 2-Fluoro-4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzaldehyde was obtained from 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine and 4-bromo-2-fluoro-benzaldehyde according to the procedure described for the synthesis of N,5-diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A solution of sodium hydride (60% in mineral oil, 640 mg, 16 mmol) in N,N-dimethylformamide (5 ml) was added in portions to a mixture of hydroxylaminopurine (556 mg, 8 mmol) in N,N-dimethylformamide (5 ml) at 0°C. After one hour was added a solution of 2-fluoro-4-(5-�enyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzaldehyde (260 mg, 0.8 mmol) in N,N-dimethylformamide (5 ml) and the resulting mixture was stirred at 80°C for about 20 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude product, which was purified using reverse-phase preparative HPLC (20 50%: acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min), to obtain N-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)benzo[d]izocsazol-6-amine in the form of the trifluoroacetic acid salt which was converted to the form of the free base (80 mg, 30% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,15 (lat.s, 1H), 7,98 (m, 2H), 7,65 (m, 2H), members, 7.59 (m, 3H), 7,41 (m, 2H), members, 7.59 (m, 2H); MS (ESI): m/z 328,1 [M+1]+.

Example 24: 2-Fluoro-5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamide

A. 2-Fluoro-5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamide. 2-Fluoro-5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile was obtained from 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine and 5-bromo-2-perbenzoate, according to the procedure described for the synthesis of N,5-diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 2-fluoro-5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (100 mg, 0.3 mmol), aqueous solution of hydrogen peroxide (30%, 1 ml) and potassium carbonate (123 mg, 0.9 mmol) in dimethyl sulfoxide (5 ml) was stirred at room temperature for but�I. The mixture was poured into ice water and the precipitate was collected, washed with water, dried in vacuum to give 2-fluoro-5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamide derivative (60 mg, 57% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,80 (lat.s, 1H), with 8.05 (m, 2H), 7,60 (m, 6H), of 7.19 (m, 2H); MS (ESI): m/z 348,1 [M+1]+.

For some examples, used sodium hydroxide instead of potassium carbonate.

Example 25: (S)-N2-(3-Amino-1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine

A. 4-(5-Bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-2-perbenzoate. Degassed mixture of 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (800 mg, of 3.78 mmol), 2-fluoro-4-iodobenzonitrile (1.3 g, of 5.29 mmol), tert-butoxide sodium (720 mg, was 7.56 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (432 mg, 0,756 mmol) and Tris(dibenzylideneacetone)diplegia(0) (352 mg, 0,378 mmol) in dioxane (20 ml) was heated at 100°C in a nitrogen atmosphere for 2 hours. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude substance was purified on a column of silica gel (elwira using 0-25% ethyl acetate in petroleum ether) to give 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-2-perbenzoate in the form of cor�cinefogo solid (600 mg, 48.4% of output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,83 (s, 1H), 7,94 (DD, J=12,8 Hz, J2=1.6 Hz, 1H), 7,78 (t, J=8,0 Hz, 1H), of 7.70 (d, J=8,8 Hz, 1H), 7,54 (t, J=7,6 Hz, 1H), of 7.48 (t, J=6,4 Hz, 2H); MS (ESI): m/z 331,9 [M+1]+.

B. (S)-tert-Butyl 3-(2-(4-cyano-3-forgenerating)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)piperidine-1-carboxylate. Degassed mixture of 4-(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-2-perbenzoate (300 mg, 0.9 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (272 mg, 1.4 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (105 mg, 0.18 mmol), Tris(dibenzylideneacetone)diplegia(0) (83 mg, 0,09 mmol) and cesium carbonate (590 mg, 1.8 mmol) in dioxane (10 ml) was heated at 100°C in a nitrogen atmosphere over night. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude substance was purified using column chromatography on silica gel (elwira using 0-25% ethyl acetate in petroleum ether) to give (S)-tert-butyl-3-(2-(4-cyano-3-forgenerating)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)piperidine-1-carboxylate in the form of a solid (200 mg, 49.4 per cent of the output).

C. (S)-2-Fluoro-4-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile. A solution of (S)-tert-butyl 3-(2-(4-cyano-3-forgenerating)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)piperidine-1-carboxylate (200 �g, 0,44 mmol) in methanolic hydrochloride solution (15 ml, 2 M) was stirred for 30 minutes at room temperature. The solvent was removed under reduced pressure and the residue was washed with ethyl acetate, dried in vacuum to give (S)-2-fluoro-4-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (150 mg, 96.2 per cent) in the form hydrochloride salt.

D. (S)-N2-(3-Amino-1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine. A solution of (S)-2-fluoro-4-(5-(piperidine-3-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (150 mg, 0.43 mmol) and hydrazine hydrate (0.50 ml) in n-butanol (10 ml) was stirred at 120°C in a nitrogen atmosphere over night. The solvent was concentrated in vacuum to give crude product, which was purified using reverse-phase preparative HPLC (7-37%: acetonitrile + 0,1% trifluoroacetic acid in water, over 15 min) to give (S)-N2-(3-amino-1H-indazol-6-yl)-N5-(piperidine-3-yl)-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt using methanolic hydrochloride solution (99,14% ei, 70 mg and 44.9% yield) as solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 12.46 (s, 1H), 10,15 (s, 1H), 9,27 (m, 2H), 8,17 (s, 1H), a 7.87 (d, J=8,8 Hz, 1H), 7,50 (t, J=8,0 Hz, 1H), 7,32 (d, J=2,0 Hz, 1H), at 6.84 (d, J=8,8 Hz, 1H), 6,74 (d, J=8,8 Hz, 1H), system 6.34 (d, J=8,0 Hz, 1H), 4,05 (�, 1H), 3,42 (m, 1H), 3,23 (m, 1H), is 3.08 (m, 1H) 2,80 (m, 1H), 2,05 (m, 1H), 1,88 (m, 3H); MS (ESI): m/z 364,0 [M+1]+.

Example 26: 5-(3-(Aminomethyl)phenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-(3-(Aminomethyl)phenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of (3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzonitrile)and (70 mg, 0,225 mmol) and Raney Ni (100 mg) in a mixture of methanol (10 ml) and aqueous ammonia solution (0.5 ml) was gidrirovanie under a hydrogen pressure of 1 ATM at room temperature for 2 hours. After the starting material was consumed (the reaction was monitored through TLC), the reaction mixture was filtered and the filtrate was evaporated. The residue was purified using reverse-phase preparative HPLC (35-65% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to give 5-(3-(aminomethyl)phenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine in the form of the trifluoroacetic acid salt which was converted to the corresponding hydrochloride salt with a methanolic solution of hydrochloride (35 mg, 49% yield).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,18 (m, 1H), 8,01 (s, 1H), 8,07 (m, 1H), 7,76-7,72 (m, 3H), members, 7.59 and 7.55 (m, 3H), of 7.36-7,32 (m, 2H), was 7.08 (m, 1H), 4,27 (s, 2H); MS (ESI): m/z 316,1 [M+H]+.

Example 27: N-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)acetamide

A. N-(6-Aminopyridin-2-yl)acetami�. To a mixture of pyridine-2,6-diamine (1.5 g, of 13.7 mmol) and triethylamine (1.4 g, of 13.8 mmol) in dichloromethane (30 ml) was added dropwise acetyl chloride (1,39 g of 13.7 mmol) at room temperature. Upon completion of addition the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water, dried over sodium sulfate and was evaporated to obtain N-(6-aminopyridin-2-yl)acetamide (0.95 g, 46% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,84 (s, 1H), 7,31 (t, J=7,6 Hz, 1H), 7,26 (lat.s, 1H), 6,15 (d, J=8,0 Hz, 1H), 5,70 (lat.s, 2H).

B. N-(6-(3-(ethoxycarbonyl)touraid)pyridin-2-yl)acetamide. A solution of N-(6-amino-pyridin-2-yl)acetamide (0.9 g, 5,96 mmol) and ethoxycarbonyl the isothiocyanate (0,94 g, 5,96 mmol) in dioxane (10 ml) was stirred at room temperature for 5 hours. The solvent was removed to give N-(6-(3-(ethoxycarbonyl)touraid)pyridin-2-yl)acetamide (1.4 g, 83,3% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 12,10 (lat.s, 1H), 11,52 (lat.s, 1H), is 10.51 (lat.s, 1H), 8,37 (m, 1H), 7,91 (d, J=8,0 Hz, 1H), 7,91 (t, J=8,0 Hz, 1H), 4,25 (sq, J=7.2 Hz, 2H), 2,1 (s, 3H), of 1.28 (t, J=7,2 Hz, 3H).

C. N-(2-Amino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)acetamide. To a solution of hydroxylaminopurine (1.22 g, 17.7 mmol) and N,N-ethyldiethanolamine (1.37 g, 10.6 mmol) in a mixture of ethanol and methanol (1:1, 20 ml) was added N-(6-(3-(ethoxycarbonyl)touraid)pyridin-2-yl)acetamide (1.00 g, 3,54 MMO�ü). The mixture was stirred at room temperature for 2 hours and at 70°C for 5 hours. Volatiles were removed under reduced pressure and the residue treated with water. The resulting precipitate was washed with 20% solution of diethyl ether in methanol (10 ml) and diethyl ether (10 ml). After drying under high vacuum gave not quite white crystals of N-(2-amino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)acetamide) (0.50 g, 62%).1H NMR: (400 MHz, DMSO-d6) δ (M. D.) 10,2 (lat.s, 1H), 7,41 (m, 2H), 7,05 (DD, J1=7,2, J2=I,6 Hz, 1H), 5,94 (lat.s, 2H), 2,19 (s, 3H).

D. N-(2-(Phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)acetamide. To a degassed mixture of N-(2-amino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)acetamide)and (300 mg 1,58 mmol), panelbased (270 mg, of 1.74 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (91 mg, 0,158 mmol) and cesium carbonate (1.03 g, 3,16 mmol) in dioxane (15 ml) was added Tris(dibenzylideneacetone)dipalladium(0) (45 mg, 0,079 mmol) in a nitrogen atmosphere and the mixture was heated at 80°C in a nitrogen atmosphere over night. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate (15 ml ×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified using reverse-phase preparative HPLC (35-68% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min with a production of N-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)acetamide in the form of trifluoroacetic acid salt, which was converted into the corresponding free base (50 mg, 12% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,24 (lat.s, 1H), 9,53 (lat.s, 1H), 7,76 (d, J=7,6 Hz, 2H), 7,55 (m, 2H), 7,30 (m, 3H), to 6.88 (t, J=7,2 Hz, 1H), 2,27 (s, 3H); MS (ESI): m/z 267,9 [M+1]+.

Example 28: N-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)isobutyramide

A. N2-Phenyl-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine. To a suspension of copper iodide (10 mg, 0,053 mmol) in liquid ammonia (10 ml) in an autoclave at -40°C was added 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (50 mg, 0.174 were revealed mmol). The autoclave was then hermetically closed and heated at 180°C for 4 hours. The reaction mixture was cooled, the autoclave was washed with ethyl acetate three times and the combined organic layer was dried and evaporated. The residue was purified by column chromatography on silica gel (elwira using 10-15% ethyl acetate in petroleum ether) to give N2-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine (30 mg, 77% yield) as a solid substance. MS (ESI): m/z 226,1 [M+1]+.

B. N-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-isobutyramide. To a solution of N2-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2,5-diamine (30 mg, 0,13 mmol) and triethylamine (26 mg, 0,26 mmol) in dichloromethane (5 ml) was added isobutylene (14 mg, 0,13 mmol) at 0°C and the mixture was stirred at room temperature over night. The reaction mixture was poured into �edanww water and was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to dryness. The residue was purified using preparative TLC (elwira using 15-20% ethyl acetate in petroleum ether) to give N-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)isobutyramide (15 mg, 38% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,67 (m, 3H), of 7.48 (m, 1H), 7,30 (m, 3H), 6,95 (m, 1H), 2,93 (m, 1H), 1,31 (t, J=6,8 Hz, 6H); MS (ESI): m/z 296,1 [M+1]+.

Example 29: N-(3-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenyl)acetamide

A. N-(3-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenyl)acetamide. A mixture of 5-(3-Dapsone base)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (50 mg, 0,17 mmol), pyridine (26,9 mg, 0,34 mmol), acetic anhydride (33,8 mg, 0,34 mmol) in dichloromethane (5 ml) was stirred at room temperature over night. The precipitate was collected by filtration and the filter cake was washed with water and ethyl ether to obtain N-[3-(2-phenylamino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenyl]acetamide (40 mg, 70% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,15 (lat.s, 1H), 9,61 (lat.s, 1H), of 8.26 (s, 1H), 7,70-of 7.46 (m, 7H), 7,21 (m, 2H), 7,10 (m, 1H), about 6,82 (m, 1H), of 2.06 (s, 3H); MS (ESI): m/z 344,1 [M+1]+.

Example 30: 4-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-(piperidine-4-yl)benzamide

A. 4-(5-Hairdryer�l-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoic acid. A suspension of methyl 4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoate (260 mg, 0,76 mmol) (obtained from 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine and methyl 4-bromobenzoate, according to the procedure described for the synthesis of N,5-diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine) in 10% aqueous sodium hydroxide solution (5 ml) was heated at boiling with reflux during the night. After cooling to room temperature the reaction mixture was neutralized with 3% aqueous hydrochloric acid solution to pH=3. The precipitate was collected by filtration and washed with water to obtain 4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoic acid (220 mg, 88% yield) in the form of solids. MS (ESI): m/z 331,1 [M+1]+.

B. tert-Butyl 4-(4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamido)piperidine-1-carboxylate. A mixture of 4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoic acid (200 mg, 0.6 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (121 mg, 0.6 mmol), hexaflurophosphate 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylthiourea(V) (460 mg, 1.2 mmol) and N-methylmorpholine (306 mg, 3.0 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature over night. Was added water (5 ml) and the precipitate was collected by filtration and washed with water to obtain tert-butyl 4-(4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamido)piperidine-1-carboxylate (220 mg, 2% yield) as a solid substance. MS (ESI): m/z 535,1 [M+23]+.

C. 4-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-(piperidine-4-yl)benzamide. A solution of tert-butyl 4-(4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzamido)piperidine-1-carboxylate (50 mg, 0.1 mmol) in methanolic hydrochloride solution (10 ml) was stirred at room temperature over night. The reaction mixture was concentrated in vacuum to give 4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-(piperidine-4-yl)benzamide derivative (25 mg, 60% yield) in the form hydrochloride salt.1H NMR (300 MHz, DMSO-d6) δ (M. D.) 9,99 (lat.s, 1H), 8,65 (lat.s, 2H), 8,22 (d, J=7.5 Hz, 1H), 8,03 (d, J=6,9 Hz, 2H), 7,81-7,58 (m, 8H), 7,21 (d, J=6,9 Hz, 1H), 4,01 (m, 1H), 3,30 (m, 2H), 2,99 (m, 2H), 1,96 (m, 2H), 1,74 (m, 2H); MS (ESI): m/z 413,2 [M+1]+.

Example 31: 5-(5-Phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)pyridin-2-ol

A. 5-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)pyridin-2-ol. A mixture of N-(6-methoxypyridine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (100 mg, 0,31 mmol) (obtained according to the procedure described for the synthesis of N-(4-morpholinomethyl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine) in a solution of methyl hydrogen in acetic acid (6 ml, 35%) was heated at 120°C in a tightly closed container for 0.5 hours. After cooling to room temperature the mixture was podslushivaet saturated aqueous sodium bicarbonate solution to pH=7. The resulting mixture was extracted with atilas�tat and the combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using reverse-phase preparative HPLC (40-70% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid over 25 min) to give 5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)pyridin-2-ol in the form of the trifluoroacetic acid salt which was converted to the corresponding hydrochloride salt using methanolic solution of the hydrochloride (40 mg, 38% yield).1H NMR (300 MHz, METHANOL-d4) δ (M. D.) of 8.56 (m, 1H), 8,18 (m, 1H), 8,00 (m, 2H), 8,83 (m, 1H), 7,63-EUR 7.57 (m, 4H), 7,32 (DD, J1=7,2 Hz, J2=1,8 Hz, 1H), to 7.09 (m, 1H); MS (ESI): m/z 304,1 [M+1]+.

Example 32: 4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)pyridin-2-ol

A. 4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)pyridin-2-ol. The initial substance in a total quantity of 60 mg has Demetrashvili two batches (20 mg and 40 mg) according to the procedure described below. The crude substance was then combined for purification. A suspension of 5-(2-methoxypyridine-4-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,040 g, 0,126 mmol) (obtained according to the procedure described for the synthesis of N,5-diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine) in dichloromethane (3 ml) at room temperature was treated with tribromide boron (0,555 ml 0,555 mmol) and stirred at room temperature for 2 days. Pic�ol'ku conversion was not complete, used additional quantity of tribromide boron (0,555 ml 0,555 mmol) and the reaction mixture was stirred at room temperature for 12 hours. Although he remained unreacted starting substance, the reaction was quenched with water (1 ml) and was extracted with ethyl acetate (3 times, 25 ml), then dichloromethane (3×15 ml). The combined extracts were dried over sodium sulfate and the residue obtained after evaporation of the solvent, was dissolved in a mixture of 10:1 DMSO:MeOH and purified using semi-preparative HPLC (20-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 30 minutes - 5 injections). The desired fractions were combined and neutralized using a 1.75 M aqueous solution of potassium carbonate. As a result of removal of acetonitrile under reduced pressure there was a formation of white solid which was collected by filtration, washed with water until neutral pH and dried in a vacuum oven at low heat. 4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)pyridin-2-ol (7 mg, 12% yield overall yield) was isolated as a white solid (99.6% purity).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,53 (lat.s, 1H), 8,14 (d, J=9,47 Hz, 1H), 7,56-to 7.77 (m, 2H), 7,45-to 7.55 (m, 1H), 7,17-of 7.36 (m, 2H), to 6.88 (m, 1H), a 6.53 (d, J=9,52, 1H); MS (ESI) m/z 304 [M+1]+.

Example 33: 5-(3-(1H-1,2,4-Triazole-5-yl)phenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

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A. the Hydrochloride of ethyl 3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzimidate. Through a suspension of 3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzonitrile (0,115 g, 0,369 mmol) (obtained according to the procedure described for the synthesis of N,5-diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine) in ethanol (10 ml) were barbotirovany gaseous HCl for 10 minutes at 0°C. the Suspension became transparent immediately after the administration of HCl (gas) and after a while was partially delaminated. After 6 hours the solvent was removed under reduced pressure and used in the next stage without additional purification. MS (ESI) m/z 358 [M+1]+.

B. 5-(3-(1H-1,2,4-Triazole-5-yl)phenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To a suspension of ethyl hydrochloride 3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzimidate (0,145 g, 0,369 mmol) in ethanol (10 ml) was added formoderate (0,111 g, 1,845 mmol) and diisopropylethylamine (0,226 ml, 1,292 mmol). The reaction mixture was heated overnight to 120°C in a sealed tube. The reaction mixture was cooled to room temperature and the solvent evaporated. The residue was purified using semi-preparative HPLC (20-100% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 30 minutes, 4 injection). The desired fractions were combined and neutralized using a 1.75 M aqueous solution of potassium carbonate. After vol�experiences of acetonitrile was formed gel-like precipitate, which was collected by filtration and washed with water until neutral pH leaching. 5-(3-(1H-1,2,4-Triazole-5-yl)phenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.033 g, 0,093 mmol, 25.3% yield) was isolated as an off-white solid (99.8% purity).1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 9.65 (s, 1H), 8,87 (lat.s, 1H), of 8.71 (lat.s, 1H), 8,16-compared to 8.26 (m, 1H), 7,58-of 7.82 (m, 6H), 7,32 (d, J=6,39 Hz, 1H), made 7.16 interest-7,25 (m, 2H), of 6.79-6,89 (m, 1H); MS (ESI) m/z 354 [M+1]+.

Example 34: (S)-2-(Phenylamino)-N-(piperidine-3-yl)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxamide

A. 2-Amino-[1,2,4]triazolo[1,5-α]pyridine-5-carbonitrile. A mixture of 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (4.26 g, 20 mmol), zinc dust (0,97 g, 15 mmol), Tris(dibenzylideneacetone)diplegia(0) (1.1 g, 1.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1,32 g, 2,4 mmol) and zinc cyanide (4.3 g, 39 mmol) in N,N-dimethylacetamide (60 ml) in a 250-ml round-bottom flask are degassed. In a nitrogen atmosphere the reaction mixture was heated at 100°C overnight. When the main quantity of the solvent was removed under vacuum, was added a saturated aqueous solution of sodium chloride and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (elwira using 10-30% ethyl acetate in petroleum ether) on silica gel with obtaining 2-�eno-[1,2,4]triazolo[1,5-α]pyridine-5-carbonitrile (910 mg, 28% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (MD), 7,69 (DD, J=8,8 Hz, 1H), of 7.64 (DD, J=8,8 Hz, 1H), 7,51 (t, J=8,2 Hz, 1H), 6,47 (lat.s, 1H).

B. 2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbonitrile. Degassed solution of 2-amino-[1,2,4]triazolo[1,5-α]pyridine-5-carbonitrile (0.9 g, 5.7 mmol), 1-brombenzene (0.89 g, 5,7 mmol), Tris(dibenzylideneacetone)diplegia(0) (326 mg, 0.35 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (526 mg, of 0.91 mmol) and cesium carbonate (3.68 g, 12 mmol) in dioxane (20 ml) was heated at 100°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified column chromatography on silica gel (elwira using 10-30% ethyl acetate in petroleum ether), to obtain 2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbonitrile (0.7 g, 52% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,96 (lat.s, 1H), 7,93 (DD, J1=8,8, J2=0.8 Hz, 1H), 7,82 (DD, J1=7,6, J2=0.8 Hz, 1H), of 7.75 (m, 3H), 7,29 (t, J=8,0 Hz, 2H), 6,90 (t, J=7,6 Hz, 1H); MS (ESI): m/z 236,1 [M+1]+.

C. 2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxylic acid. A solution of 2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbonitrile (700 mg, 3 mmol) and sodium hydroxide (1.2 g, 30 mmol) in a mixture of ethanol (30 ml) and water (15 ml) was heated at 80°C until Ana�from TLC did not show, that the starting material was consumed. The solvent was removed in vacuo and water was added. The mixture was washed with ethyl acetate twice. The aqueous layer was acidified with by adding aqueous hydrochloric acid to pH=3 and then the mixture was extracted with ethyl acetate. The combined organic layer was dried and concentrated to give 2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxylic acid (560 mg, 73% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,77 (lat.s, 1H), 7,72 (m, 3H), 7,60 (t, J=7,2 Hz, 1H), 7,44 (d, J=7,2 Hz, 1H), 7,25 (t, J=7,6 Hz, 2H), 6,86 (t, J=7,6 Hz, 1H); MS (ESI): m/z 255,3 [M+1]+.

D. (S)-tert-Butyl 3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxamido)piperidine-1-carboxylate. A mixture of 2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxylic acid (70 mg, 0.27 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (55 mg, 0.27 mmol), hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (106 mg, 0,55 mmol), hydroxybenzotriazole (74 mg, 0,55 mmol) and N-methylmorpholine (75 mg, 0,55 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature over night. The reaction mixture was diluted with saturated brine. The precipitate that formed was collected, washed with water and petroleum ether to obtain (S)-tert-butyl 3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxamido)piperidine-1-carboxylate (102 mg, 85% o�d) in the form of solids, which was used for next step without further purification.

E. (S)-2-(Phenylamino)-N-(piperidine-3-yl)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxamide. A solution of (S)-tert-butyl 3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxamido)piperidine-1-carboxylate (102 mg, 0,24 mmol) in methanolic hydrochloride solution (2 ml, 2 M) was stirred at room temperature until TLC analysis showed the starting material was consumed. The solvent was evaporated under reduced pressure to obtain crude product, which was purified using reverse-phase preparative HPLC (35-65% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min), to obtain (S)-2-(phenylamino)-N-(piperidine-3-yl)-[1,2,4]triazolo[1,5-α]pyridine-5-carboxamide in the form of the trifluoroacetic acid salt which was converted to the corresponding hydrochloride salt (69 mg, 88% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) and 9.95 (d, J=6,8 Hz, 1H), 9,87 (lat.s, 1H), 9,13 (lat.s, 2H), 7,78 (DD, J1=8,4, J2=1.2 Hz, 1H), 7,72-760 (m, 4H), 7,32 (t, J=8,0 Hz, 2H), 6,94 (t, J=7,6 Hz, 1H), to 4.26 (m, 1H), 3,40 (m, 1H), 3,14 (m, 1H), 2,90 (m, 2H), 2,10 (m, 1H), 1,79 (m, 1H), of 1.75 (m, 2H); MS (ESI): m/z 337,4 [M+1]+.

Example 35: N-Phenyl-5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 2,2'-Bipyridine 1-oxide. To a solution of 2,2'-bipyridine (10 g, 64 mmol) in dichloromethane (250 ml) was added 3-CL�benzoperoxide (33 g, 192 mmol) in portions at room temperature. The mixture was stirred at room temperature for 1 hour. After the starting material was consumed, was added a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to obtain 2,2'-bipyridine 1-oxide (5.5 g, 50% yield) in the form of solids.1H NMR (300 MHz, METHANOL-d4) δ (MD), 8,73 (d, J=5.1 Hz, 1H), and 8.50 (d, J=5.7 Hz, 1H), to 8.42 (d, J=6.3 Hz, 1H), 8,06 (DD, J1=2,1 Hz, J2=5.1 Hz, 1H), 7,96 (DD, J1=7,2 Hz, J2=9,0 Hz, 1H), of 7.70 (t, J=7.5 Hz, 1H), 7,58-of 7.48 (m, 2H).

B. 6-Chloro-2,2'-bipyridine. A mixture of 2,2'-bipyridine 1-oxide (5.5 g, 32 mmol) and phosphorylchloride (20 ml) was heated at boiling with reflux for 4 hours. Phosphorylchloride was distilled and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 6-chloro-2,2'-bipyridine (3.5 g, 57% yield) in the form of solids.

C. N-(4-Methoxybenzyl)-2,2'-bipyridine-6-amine. A solution of 6-chloro-2,2'-bipyridine (1 g, 5.2 mmol) (4-methoxyphenyl)methanamine (5 ml) re�shivali at 180°C for 4 hours. The mixture was purified on a column of silica gel (elwira using 10-80% ethyl acetate in petroleum ether) to give N-(4-methoxybenzyl)-2,2'-bipyridine-6-amine (1.2 g, 80% yield). MS (ESI): m/z 291,9 [M+1]+.

D. 2,2'-Bipyridine-6-amine. A solution of N-(4-methoxybenzyl)-6-(pyridin-2-yl)pyridin-2-amine (600 mg, 2 mmol) in trifluoroacetic acid (10 ml) was stirred at 80°C over night. When TLC analysis (3% dichloromethane in methanol) showed that the starting material was consumed, the mixture was adjusted to pH=7 with an aqueous sodium carbonate solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give crude product, which was purified on a column of silica gel (elwira using 0.5-1% methanol in dichloromethane), to obtain 2,2'-bipyridine-6-amine (280 mg, 79% yield). MS (ESI): m/z 172,1 [M+1]+.

E. Ethyl 6-(pyridin-2-yl)pyridin-2-incarnationally. To a solution of 2,2'-bipyridine-6-amine (280 mg, 1,63 mmol) in dioxane (10 ml) was added ethoxycarbonylmethylene (213 mg, 1,63 mmol) dropwise in a nitrogen atmosphere at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored using TLC (50% ethyl acetate in petroleum ether) and when the starting material was consumed, the solvent was removed under reduced pressure with a semi�the group of crude ethyl 6-(pyridin-2-yl)pyridin-2-incarnationally (340 mg) in the form of solids. MS (ESI): m/z 303,1 [M+1]+.

F. 5-(Pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To a solution of hydroxylamine hydrochloride (388 mg, 5.5 mmol) and N,N-diisopropylethylamine (435 mg, 3.3 mmol) in a mixture of methanol and ethanol (V/V, 1:1, 6 ml) was added ethyl 6-(pyridin-2-yl)pyridin-2-incarnationally (340 mg, 1.1 mmol) in one portion at room temperature. After stirring at room temperature for 2 hours the reaction mixture was heated at 60°C over night. When TLC analysis (10% ethyl acetate in methanol) showed that the starting material consumed, the solvent was removed under reduced pressure and the residue treated with water. The precipitate was collected and washed with a mixture of methanol and ethyl ether (V/V, 4:1, 8 ml), to obtain 5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (100 mg, 51% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,77 (d, J=8,0 Hz, 2H), 7,99 (t, J=7,6 Hz, 1H), 7,50 (m, 2H), of 7.46 (m, 2H), 6,21 (lat.s, 2H); MS (ESI): m/z 211,9 [M+1]+.

G. N-Phenyl-5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. Degassed solution of 5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (100 mg, 0.47 mmol), brombenzene (81 mg, 0.52 mmol), Tris(dibenzylideneacetone)diplegia(0) (27 mg, 0,047 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (43 mg, 0.09 mmol) and tert-butoxide potassium (100 mg, 0.9 mmol) in dioxane (5 ml) was heated at 80°C in a nitrogen atmosphere within but�I. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified on a column of silica gel (elwira using 2% methanol in dichloromethane), to obtain N-phenyl-5-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (52 mg, 38% yield).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) is 8.81 (m, 2H), 8,16 (t, J=8,0 Hz, 1H), 7,76 (m, 2H), of 7.64 (m, 4H), 7,31 (t, J=7,6 Hz, 2H), 6,97 (t, J-7.2 Hz, 1H); MS (ESI): m/z 288,1 [M+1]+.

Example 36: N-(lH-Indazol-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 2-Bromo-5-phenyl-[1,2,4]triazolo[1,5-α]pyridine. To a solution of 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (2 g, 9.5 mmol) in a mixture branovacki acid (40% in water) and acetic acid (V/V, 2:1, 20 ml) was added sodium nitrite (3.2 g, of 47.5 mmol) at room temperature and the mixture was stirred at this temperature for 0.5 hours, then stirred at 50°C for another 0.5 hours. The mixture was cooled and podslushivaet with sodium carbonate to pH>9 and was extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude mixture was purified using column chromatography (elwira using 0-25% ethyl acetate in petroleum ether) to give 2-bromo-5-phenyl-[1,2,4]triazolo[1,5-α]pyridine (1.5 g, yield 57.7 per cent) in the form of firmly�about substance. 1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 7.82 (m, 2H), 7,71 (m, 2H), 7,47 (m, 3H), 7,29 (m, 1H); MS (ESI): m/z of 274.1 [M+1]+.

B. 5-Phenyl-N-(1-(tetrahydro-2H-pyraii-2-yl)-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. Degassed solution of 1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-6-amine (365 mg, 1.7 mmol), 2-bromo-5-phenyl-[1,2,4]triazolo[1,5-α]pyridine (460 mg, 1.7 mmol), 4,5-bis(diphenyl phosphino)-9,9-dimethylxanthene (156 mg, 0.34 mmol), Tris(dibenzylideneacetone)diplegia(0) (96 mg, 0,17 mmol) and cesium carbonate (1 g, 3,4 mmol) in dioxane (10 ml) was heated at 80°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified on a column of silica gel (elwira using 1% methanol in dichloromethane), to obtain 5-phenyl-N-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (100 mg, 15% yield). MS (ESI): m/z 411,0 [M+1]+.

C. N-(lH-Indazol-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-phenyl-N-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (100 mg, 0,24 mmol) and methanolic hydrochloride solution (2 M, 5 ml) was stirred at room temperature over night. The solvent was evaporated under reduced pressure to obtain N-(1H-indazol-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (75 mg, 86% yield) in the form hydrochlorides with�Lee. 1H NMR (300 MHz, DMSO-d6) δ (M. D.) 9,91 (lat.s, 1H), 8,14 (s, 1H), 8,07 (d, J=7,2 Hz, 2H), 7,73 (s, 1H), 7,72-7,54 (m, 7H), 7,25-7,21 (m, 2H); MS (ESI): m/z 327,1 [M+1]+.

Example 37: 5-Phenoxy-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 2-Chloro-6-phenoxypyridine. Degassed mixture of 2,6-dichloropyridine (2.9 g, 20 mmol) (1.72 g, 10 mmol), phenol (12 g, 0,13 mmol) and sodium hydroxide (4.8 g, 0.12 mmol) in water (20 ml) was heated at 140°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and the organic phase was washed with water twice. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 2-chloro-6-phenoxypyridine (1.7 g, 41% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 7,78 (t, J=8,0 Hz, 1H), 7,43 (t, J=8,0 Hz, 2H), 7,25 (t, J=7,6 Hz, 1H), 7,13 (m, 3H), 6,83 (d, J=8,0 Hz, 1H).

B. N-(4-Methoxybenzyl)-6-phenoxypyridine-2-amine. Degassed mixture of (4-methoxyphenyl)methanamine (10 ml) and 2-chloro-6-phenoxypyridine (1.7 g, 8,29 mmol) was heated at 180°C in a nitrogen atmosphere with stirring for 5 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and the mixture was washed with saturated brine twice. Organicheskoi dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give N-(4-methoxybenzyl)-6-phenoxypyridine-2-amine (1.5 g, 29% yield) as a white solid. MS (ESI): m/z 306,9 [M+1]+.

C. 6-Phenoxypyridine-2-amine. A solution of N-(4-methoxybenzyl)-6-phenoxypyridine-2-amine (700 mg, 2,61 mmol) in a mixture of 2,2,2-trifluoroacetic acid and dichloromethane (V/V, 1/2) was heated at boiling with reflux for 2 hours. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (10% ethyl acetate in petroleum ether) to give pure 6-phenoxypyridine-2-amine (260 mg, 53% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) value of 7, 37 (m, 3H), made 7.16 interest (t, J=7,2 Hz, 1H), to 7.04 (m, 2H), for 6.24 (d, J=8,0 Hz, 1H), 5,93 (d, J=7,8 Hz, 1H); MS (ESI): m/z 186,9 [M+1]+.

D. 5-Phenoxy-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 6-phenoxypyridine-2-amine (260 mg, 1.4 mmol) and ethoxycarbonylmethylene (183 mg, 1.4 mmol) in dioxane (10 ml) was stirred at room temperature for 5 hours. The solvent was evaporated to obtain the intermediate teoretico-compound (440 mg, 99% yield) as a white solid which was used in next step without further purification.

To a solution of hydroxylamine hydrochloride (486 mg, 7.0 mmol) and N,N-diisopropylethylamine (541 mg, 4.2 mmol) � mixture of ethanol and methanol (20 ml, 1:1) was added intermediate teoretico-compound (440 mg, 1.4 mmol) and the reaction mixture was stirred at room temperature for 2 hours and at 70°C for 5 hours. Volatiles were removed under reduced pressure and the residue was diluted with water. The precipitate was collected by filtration, washed with methanol (10 ml) and ethyl ether (10 ml). After drying under vacuum gave 5-phenoxy-[1,2,4]triazolo[1,5-α]pyridin-2-amine (280 mg, 88% yield) as an off white crystalline solid. MS (ESI): m/z 226,9 [M+1]+.

E. 5-Phenoxy-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. Degassed mixture of 5-phenoxy-[1,2,4]triazolo[1,5-α]pyridin-2-amine (226 mg, 1.00 mmol), brombenzene (156 mg, 1.00 mmol), Tris(dibenzylideneacetone)diplegia(0) (20 mg, 0,022 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0,044 mmol) and tert-butoxide potassium (244 mg, 2.00 mmol) in dioxane (5 ml) was heated at 80°C in a nitrogen atmosphere over night. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using reverse-phase preparative HPLC (38-68% acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid over 20 minutes) to give 5-phenoxy-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine in the form of the trifluoroacetic salt sour�s, which was converted into hydrochloride salt using methanolic solution of the hydrochloride, (60 mg, 20% yield) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) a 7.92 (t, J=8.4 Hz, 1H), EUR 7.57 (m, 4H), of 7.42 (m, 6H), 7,12 (t, J=7,2 Hz, 1H), to 6.67 (d, J=8.4 Hz, 1H); MS (ESI): m/z 303,1 [M+1]+.

Example 38: 5-(Cyclohexyloxy)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A. 2-Chloro-6-(cyclohexyloxy)pyridine. To a solution of cyclohexanol (26 g, 26 mmol) in toluene (300 ml) was added sodium (624 mg, 26 mmol) in portions and the mixture was heated at boiling with reflux during the night. After cooling to room temperature was added 2,6-dichloropyridine (29 g, 20 mmol) and the mixture was heated at boiling with reflux during the night. The reaction mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified on a column of silica gel (elwira using 20% ethyl acetate in petroleum ether) to give 2-chloro-6-(cyclohexyloxy)pyridine (30 g, 71% yield).1H NMR (300 MHz, CHLOROFORM-d) δ (M. D.) of 7.46 (t, J=7,6 Hz, 1H), at 6.84 (d, J=7.5 Hz, 1H), 6,59 (d, J=8,1 Hz, 1H), 5,01 (m, 1H), 1,94 (m, 2H), of 1.77 (m, 2H), 1,20 (m, 6H).

B. 6-(Cyclohexyloxy)-N-(4-methoxybenzyl)pyridin-2-amine. Degassed mixture of (4-methoxyphenyl)methanamine (10 ml) and 2-chloro-6-(cyclohexyloxy)pyridine (1.0 g, 4,73 mmol) was stirred and heated at 180°C in a nitrogen atmosphere in those�Linux 5 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and the mixture was washed with saturated brine twice. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 6-(cyclohexyloxy)-N-(4-methoxybenzyl)pyridin-2-amine (800 mg, 54% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,17 (m, 3H), 6,94 (t, J=6,0 Hz, 1H), is 6.81 (d, J=8.4 Hz, 2H), 5,93 (d, J=8,0 Hz, 1H), of 5.72 (d, J=8,0 Hz, 1H), 4,76 (m, 1H), 4,28 (d, J=6,0 Hz, 2H), to 3.67 (s, 3H), of 1.81 (m, 2H), 1,64 (m, 2H), 1,50 (m, 1H), 1,24 (m, 5H); MS (ESI): m/z 313,4 [M+1]+.

C. 6-(Cyclohexyloxy)pyridin-2-amine. A solution of 6-(cyclohexyloxy)-N-(4-methoxybenzyl)pyridin-2-amine (800 mg, 2.68 mmol) in a mixture of 2,2,2-trifluoroacetic acid and dichloromethane (V/V, 1:2, 10 ml) was heated at boiling with reflux for 2 hours. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (elwira using 10% ethyl acetate in petroleum ether) to give 6-(cyclohexyloxy)pyridin-2-amine (500 mg, 97% yield) as a white solid. MS (ESI): m/z 193,2 [M+1]+.

D. 5-(Cyclohexyloxy)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 6-(cyclohexyloxy)pyridin-2-amine (500 mg, 2.6 mmol) and ethoxycarbonylmethylene (341 mg, 2.6 mmol) in dioxane (15 �l) was stirred at room temperature for 5 hours. The mixture was evaporated to obtain the intermediate teoretico-compound (800 mg, 90% yield), which was used for next step without further purification.

To a solution of hydroxylamine hydrochloride (903 mg, 7.0 mmol) and N,N-diisopropylethylamine (1,00 mg, 7.8 mmol) in a mixture of ethanol and methanol (20 ml, 1:1) was added intermediate teoretico-compound (800 mg, 2.6 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was heated at 70°C for 5 hours and the volatiles removed under reduced pressure. The residue was diluted with water. The precipitate was washed with methanol (10 ml) and ethyl ether (10 ml). After drying under high vacuum gave 5-(cyclohexyloxy)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (500 mg, 83% yield) as an off white crystalline solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) value of 7, 37 (t, J=8,0 Hz, 1H), 6,86 (d, J=8.4 Hz, 1H), 6,40 (d, J=7,6 Hz, 1H), of 5.92 (lat.s, 2H), a 4.64 (m, 1H), 1,95 (m, 2H), 1,72 (m, 2H), of 1.52 (m, 3H), 1.26 in (m, 3H); MS (ESI): m/z to 233.1 [M+1]+.

E. 5-(Cyclohexyloxy)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. Degassed mixture of 5-(cyclohexyloxy)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (150 mg, 0.64 mmol), brombenzene (100 mg, 0.64 mmol), Tris(dibenzylideneacetone)diplegia(0) (118 mg, 0,129 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (149 mg, 0,256 mmol) and tert-butoxide potassium (144 mg, 1,28 mmol) in dioxane (10 ml) was heated at 80°C in ATM�the sphere of nitrogen over night. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using reverse-phase preparative HPLC (53-67%: acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid over 20 minutes) to give 5-(cyclohexyloxy)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt using methanolic solution of the hydrochloride, (130 mg, 65.9 per cent of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,62 (lat.s, 1H), 7,65 (d, J=8,0 Hz, 2H), 7,47 (t, J=8,0 Hz, 1H), 7,21 (t, J=8,0 Hz, 2H), 7,10 (d, J=8,0 Hz, 1H), to 6.58 (d, J=8,0 Hz, 1H), 4.75 in (m, 1H), 2,01 (m, 2H), 1,73 (m, 2H), 1,23 (m, 6H); MS (ESI): m/z 309,2 [M+1]+.

Example 39: Phenyl(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methanon

A. Phenyl(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methanon. To a solution of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.1 g, 0,346 mmol) in tetrahydrofuran (1,729 ml) (colorless) at -78°C was added dropwise n-butyllithium (2.5 M, 0,291 ml, 0,726 mmol). The reaction mixture became bright yellow, and it was maintained at low temperature for 1 hour. Was then added undiluted benzonitrile (0,039 g, 0,380 mmol). The reaction mixture immediately mills�was orange, and she gave to slowly warm to room temperature over night. According to LC/MS, all the starting material was converted to obtain the desired product (main) and deponirovano kernels (by-product).

Dark orange/brown solution was cooled to 0°C and treated using 2.5 ml of 3 n aqueous HCl. The reaction mixture was stirred at 0°C for 20 minutes, then the layers were separated. The aqueous phase was then extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate and evaporated to dryness (bright yellow). The residue was suspended in methanol and the resulting yellow precipitate was collected by filtration. The obtained solid substance was purified using semi-preparative HPLC (20-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid - 1 injection, for 30 min). The desired fraction was neutralized using a 1.75 M aqueous solution of potassium carbonate and acetonitrile was removed under reduced pressure. The bright yellow solid was collected by filtration, washed with water until neutral pH and dried in vacuum over night. Phenyl(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methanon (0,021 g, 0,067 mmol, for 19.32% yield) was collected as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,67 (lat.s, 1H) 7,69-7,90 (m, 2H) 7,53-of 7.64 (m, 1H) 7,44 (d, 1H) 7,32 (d, 1H) 7,15 (t, 1H) about 6,82 (1H) of 2.50(d, J=1,90 Hz, 22H); MS (ESI): m/z 315,3 [M+1]+.

Example 40: 5-Benzyl-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-Benzyl-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To a mixture of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.1 g, 0,346 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,020 g, 0,017 mmol) at room temperature under a nitrogen atmosphere was added anhydrous tetrahydrofuran (at 6.92 ml). The mixture immediately became transparent. Was added a 0.5 M solution of benzylchloride zinc(II) in tetrahydrofuran (1,383 ml, 0,692 mmol) and the reaction mixture was stirred at 65°C for 20 hours. After 2.5 hours was observed conversion of about 25%, with a slight recovery kernel. In order to bring the reaction to completion, added additional reagents at room temperature (solution of benzylchloride zinc(II) (1,383 ml, 0,692 mmol) and heating was resumed for 4 hours. The reaction was quenched with ice and the crude product was extracted with ethyl acetate. The extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified using semi-preparative HPLC (30-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 30 minutes, 4 injection). The desired fractions were combined and neutralized by the addition of a 1.75 M aqueous solution of potassium carbonate. After removal of acetonitrile was formed a white precipitate, which�, were taken to pieces by filtration and washed with water until while the pH of the washings became neutral. This solid was dried overnight in a vacuum oven under low heat. 5-Benzyl-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,090 g, 0,300 mmol, 87% yield) was collected as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,60 (lat.s, 1H), 7,69 (d, J=7,96 Hz, 3H), 7,49-EUR 7.57 (m, 2H), 7,44-7,49 (m, 1H), 7,38-the 7.43 (m, 3H), 7,32-value of 7, 37 (m, 3H), 7,20-7,30 (m, 4H), 6,84-6,91 (m, 1H), was 6.77-6,83 (m, 1H), of 4.44 (lat.s, 3H); MS (ESI): m/z 301,1 [M+1]+.

Example 41: 5-(4-Aminobutyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbaldehyde. To the colorless solution/suspension of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.2 g, 0,692 mmol) in tetrahydrofuran (3,46 ml) at -78°C was added n-butyllithium (2.5 M, 0,581 ml 1,453 mmol) dropwise. The reaction mixture became bright yellow, and maintained at this temperature for 1 hour. Was then added undiluted N,N-dimethylformamide (0,106 g, 1,453 mmol). The reaction mixture gave to slowly warm to room temperature and stirred over night. The reaction was quenched by adding at 0°C acetic acid (1 ml) and water (10 ml). The crude product was extracted with ethyl acetate. The extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified using column chromatography on silica gel (elwira when POMOSHHI% ethyl acetate in hexane) to give 2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbaldehyde (0.125 g, 0,525 mmol, 76% yield) as a bright yellow solid.1H NMR (400 MHz, METHANOL-d4) δ (MD), 7,66-of 7.70 (m, 2H), 7,60 (DD, J=7,27, 8,83 Hz, 1H), 7,47 (DD, J=1,27, 8,83 Hz, 1H), 7,27-to 7.33 (m, 2H), 7,22 (DD, J=1,17, 7,32 Hz, 1H), 6,91-of 6.96 (m, 1H), 6,16 (lat.s, 1H).

B. (E)-4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)but-3-enitel. To a suspension of 2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbaldehyde (0.125 g, 0,525 mmol) in tetrahydrofuran (1,049 ml) was added diethyl 2-cyanomethylphosphonate (0,092 ml, 0,525 mmol) followed by the addition of 100 mg of a 50% aqueous solution of sodium hydroxide (0.050 g, 0,630 mmol). Suspension immediately became transparent-yellow, then yellow precipitate appeared. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water and the product extracted in ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to dryness. (E)-4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)but-3-enitel was isolated as a yellow solid (0,145 g, quantitative yield). MS (ΕSI): m/z 276,1 [M+1]+.

C. 4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)Botanical. A suspension of (E)-4-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)but-3-onitrile (0,145 g, 0,527 mmol) in ethanol (20 ml) was purged with nitrogen. Was added an excess amount of palladium on carbon (10 wt%) (0,056 g, 0,527 mmol) and the mixture was placed in a hydrogen atmosphere. The reaction mixture premesis�whether at room temperature for 48 hours with the addition of the catalyst and purging the reaction flask with additional quantity of hydrogen over night. After completion of the reaction the catalyst was removed by filtration and washed copiously with methanol. The filtrate was evaporated to dryness. The residue was purified on a column of silica gel (elwira using 50% ethyl acetate in hexane). 4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)Botanical (0.07 g, 0,252 mmol, 47.9% of yield) was collected as white solids. MS (ESI): m/z 278,1 [M+1]+.

D. 5-(4-Aminobutyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A solution of 4-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)Botanical (0.07 g, 0,252 mmol) in tetrahydrofuran (2,52 ml) was cooled to 0°C and treated with the help of a 1.0 M solution of hydride (0,505 ml 0,505 mmol) in tetrahydrofuran. The solution became yellow-green as soon as I started adding. The reaction mixture was stirred at 0°C for 2.5 hours. The reaction mixture became bright yellow, and a precipitate formed. The reaction was quenched at 0°C with saturated sodium sulfate solution and 10% aqueous sodium hydroxide solution. The supernatant solution was collected by filtration, and evaporated to dryness. The residue was taken for absorption in methanol and purified using semi-preparative HPLC (20-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid - 3 injection). The desired fractions were combined and the acetonitrile was removed under reduced pressure. The product was neutralized using an ion-exchange column. �luat was evaporated in a tared vessel. After drying in a vacuum oven 5-(4-aminobutyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.045 g, 0,160 mmol, 63.4% of yield) was isolated as an oil that hardens on drying (not quite white solid).1H NMR (400 MHz, METHANOL-d4) δ (MD), 7,63-to 7.67 per (m, 2H), 7,52 (DD, J=7,17, 9,03 Hz, 1H), 7,38 (DD, J=1,22, 8,83 Hz, 1H), 7,27-to 7.33 (m, 2H), 6,94 (DD, J=1,12, value of 7, 37 Hz, 1H), 6,89 (DD, J=1,12, up 7.17 Hz, 1H), 3,24-3,29 (m, 1H), 2,99 (DD, J=7,61, 13,71 Hz, 1H), 2,59-2,73 (m, 2H), 2,31-2,40 (m, 1H), was 1.04 (d, J=6,78 Hz, 3H); MS (ESI): m/z 282,3 [M+1]+.

Example 42: 5-(3-Aminopropyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 3-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)Acrylonitrile. To a solution of 2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbaldehyde (0,108 g, 0,453 mmol) in tetrahydrofuran (4.0 ml) was added dieticiansupervised (0,080 g, 0,453 mmol) followed by the addition of 100 mg of a 50% aqueous solution of sodium hydroxide (0,044 g, 0,544 mmol). Added additional amount of the base in 30 minutes (a total of 0.5 ml with 0.1 ml increments) and the reaction mixture was stirred for 24 hours. The reaction was quenched with water and the product extracted in ethyl acetate. The extracts were dried over sodium sulfate and evaporated to dryness. The resulting oil was purified using column chromatography (elwira using 25% ethyl acetate in hexane). Although they were shared, both isomers were collected and combined (0,070 g, 84% yield). MS (ESI): m/z 62,0 [M+1] +.

B. 5-(3-Aminopropyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. A solution of 3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)Acrylonitrile (0.05 g, 0,191 mmol) in tetrahydrofuran (2,52 ml) was cooled to 0°C and treated with a solution of hydride in tetrahydrofuran (the 0.383 ml, the 0.383 mmol). The solution became orange, then brown after heating to room temperature. The reaction mixture was then heated to 35-40°C during the night. Was added 2 equivalent of hydride and heated to 50°C was continued for 9 hours. The reaction was quenched at 0°C with saturated sodium sulfate solution and 10% aqueous sodium hydroxide solution. The crude substance was extracted in ethyl acetate. The extracts were dried over sodium sulfate and evaporated to dryness. Carried out the absorption of the residue in methanol and purified using semi-preparative HPLC (10-50% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 30 minutes, 2 injection). The desired fraction was neutralized using an ion-exchange column. The eluate was evaporated in a tared vessel. 5-(3-Aminopropyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.006 g, 0,022 mmol, 11,73% yield) was isolated as an oil that hardens on drying (not quite white solid).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) of 7.64-7,69 (m, 2H), 7,54 (DD, J=7,22, 8,83 Hz, 1H), 7,38 (DD, J=1,22, 8,83 G�, 1H), 7,28-to 7.33 (m, 2H), 6,89-6,97 (m, 2H), 3,22-3,27 (m, 2H), 2,82-2,89 (m, 2H), 2,08-to 2.18 (m, 2H). MS (ESI): m/z 268,0 [M+1]+.

Example 43: (1-Benzylpiperidine-4-yl)(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methanol

A. (1-Benzylpiperidine-4-yl)(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methanol. To a solution of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,270 g, 0,934 mmol) in tetrahydrofuran (4,67 ml), cooled to -78°C was added a 2.5 M solution of n-utility in hexane (0,784 ml 1,961 mmol). The yellow solution was stirred at low temperature for 30 minutes, then was added neat 1-benzylpiperidine-4-carbaldehyde (0,389 ml 1,961 mmol). The reaction mixture was stirred at low temperature for 1.5 hours. The reaction mixture is then poured into the containing ice-ammonium chloride. The crude substance was extracted with ethyl acetate and the extracts were dried over magnesium sulfate. The residue was purified on a column of silica gel (elwira using 0-10% methanol in ethyl acetate). (1-Benzylpiperidine-4-yl)(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methanol mixed with N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,321 g, 0,592 mmol, 63.4% of yield) was collected as a light yellow oil which partially hardens in a vacuum.

Part of the residue then was purified using semi-preparative HPLC (20-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of triperoxonane�th acid, 30 minutes, 2 injection). The desired fractions were combined and neutralized through a column of cation exchange resin. (1-Benzylpiperidine-4-yl)(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methanol (0,076 g) was isolated as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) a 9.64 (lat.s, 1H), 1,69-of 1.15 (m, 2H), members, 7.59 (DD, J=7,32, 8,78 Hz, 1H), 7,47 (DD, J=1,32, is 8.74 Hz, 1H), 7,18-to 7.33 (m, 7H), 7,01-7,06 (m, 1H), 6,84-6,90 (m, 1H), of 5.75 (d, J=5.08 mm Hz, 1H), 5,16 (t, J=4,78 Hz, 1H), 3,36-3,44 (m, 2H), 2,74-2,87 (m, 2H), 1,92-2,04 (m, 1H), 1,61-1,89 (m, 3H), of 1.33 to 1.55 (m, 3H). MS (ESI): m/z of 414.2 [M+1]+.

Example 44: (2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)(piperidine-4-yl)methanol

A. (2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)(piperidine-4-yl)methanol. To a degassed solution of (1-benzylpiperidine-4-yl)(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methanol (ends 0.245 g, 0,592 mmol) in ethanol (25 ml) was added an excess amount of palladium on carbon (10 wt%) and the reaction mixture was stirred under hydrogen atmosphere overnight. Added additional amount of catalyst and used fresh atmosphere of hydrogen and the reaction mixture stirred at room temperature for 24 hours. To complete the reaction required the addition of acetic acid (10 drops) and stirring at room temperature. The catalyst was removed under reduced pressure and washed liberally with methanol and ethyl acetate. F�ltrate was evaporated to dryness. The obtained pale yellow oil was purified using semi-preparative HPLC (10-50% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 30 minutes to 4 injection). The desired fractions were combined and the acetonitrile was removed under reduced pressure. The desired product was converted into the form of its free base by elution of an aqueous solution of the salt through a column of ion-exchange resin STRATA-XC. (2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)(piperidine-4-yl)methanol (0,056 g, 0,173 mmol, 29.2% of yield) was isolated as an oil that hardens in a vacuum.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) of 7.58-7.67 per (m, 3H), 7,40 (DD, J=1,17, the 8.88 Hz, 1H), 7,27-to 7.33 (m, 2H), 7,12 (DD, J=0,68, 7,27 Hz, 1H), 6,91-of 6.96 (m, 1H), and 5.30 (d, J=a 4.64 Hz, 1H), 3,09-3,21 (m, 2H), 2,63-2,73 (m, 1H), 2,54-2,63 (m, 1H), 2,29-2,39 (m, 1H), 1,72-of 1.84 (m, 1H), 1.56 to to 1.68 (m, 3H); MS (ESI): m/z 324,0 [M+1]+.

Example 45: N-Phenyl-5-(piperidine-4-ylmethyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. tert-Butyl 4-((2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperidine-1-carboxylate. A solution of tert-butyl 4-methyleneimine-1-carboxylate (0,154 g, 0,778 mmol) of (1S,5S)-9-borabicyclo[3.3.1]nonane (1,038 ml, 0,519 mmol) (0.5 n in tetrahydrofuran) was heated to boiling temperature with reflux for 3 hours in a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and cooperated � complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)•dichloro methane (0.030 g, 0,036 mmol), potassium carbonate (0,072 g, 0,519 mmol) and 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,150 g, 0,519 mmol) in N,N-dimethylformamide (2 ml). The reaction mixture was heated to 90°C for 36 hours. In order to bring the reaction to completion had 4 additional equivalent boranova reagent and heated for 3 hours to 90°C. the Reaction was quenched with water and the mixture was stirred at room temperature over night. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel (elwira using 50% ethyl acetate in hexane). tert-Butyl 4-((2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperidine-1-carboxylate with an admixture of N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine was isolated as an oil (yield not calculated). The mixture was used without further purification in the subsequent reaction of removing the protection. MS (ESI): m/z 408,5 [M+1]+.

B. N-Phenyl-5-(piperidine-4-ylmethyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. tert-Butyl 4-((2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperidine-1-carboxylate was dissolved in dichloromethane (5 ml) and treated with neat trifluoroacetic acid (1.5 ml, 19,47 mmol). After 15 minutes at room temperature the reaction was completed. The solvent was removed under reduced pressure and the residue neutralized using kationoobmena�th resin. Substance in the form of the free base was dissolved in methanol and purified using semi-preparative HPLC (20-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 30 min, 2 injections). The desired fraction was neutralized with the use of cation-exchange resin and was dried in vacuum at low heat. N-Phenyl-5-(piperidine-4-ylmethyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,038 g, 0,124 mmol, 15.9% of yield) was collected as oil that hardens at room temperature after drying.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,62 (s, 1H), 7,73 (DD, J=1.02 mm, 8,64 Hz, 2H), of 7.42-7,54 (m, 2H), 7.24 to 7,31 (m, 2H), 6,83-at 6.92 (m, 2H), 2,99 (d, J=7,22 Hz, 2H), 2,90 (d, J=12,05 Hz, 2H), 2,34 is 2.43 (m, 2H), 2,01-of 2.15 (m, 1H), 1,51 (d, J=11,66 Hz, 2H), 1,12-1,25 (m, 2H); MS (ESI): m/z 308,3 [M+1]+.

Example 46: (S)-2-Methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propan-1-ol

A. (S)-Methyl 2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propanoate. To a mixture of 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,200 g, 0,692 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,200 g, 0,173 mmol) at room temperature under a nitrogen atmosphere was added anhydrous tetrahydrofuran (at 6.92 ml). The mixture immediately became transparent. Then was added a 0.5 M solution of bromide (R)-(3-ethoxy-2-methyl-3-oxopropyl)zinc(II) in tetrahydrofuran (0,901 g, and 3.46 mmol) and the reaction mixture was stirred at 65°C for 2 hours. The reaction� was quenched with ice and the crude product was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel using 50% ethyl acetate in hexane. Fractions were combined and evaporated to dryness. (S)-Methyl 2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propanoate (0,21 g, 0,677 mmol, 98% yield) was isolated as a yellow solid. MS (ESI): m/z 311,1 [M+1]+.

B. (S)-2-Methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-1-ol. To a solution of (S)-methyl 2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propanoate (0.05 g, 0,161 mmol) in tetrahydrofuran (0,895 ml) at -78°C was added a 1.0 M solution of hydride in tetrahydrofuran (0,322 ml, 0,322 mmol). The reaction mixture was then warmed to room temperature after 30 minutes and stirred for 30 minutes. The reaction mixture was then quenched by adding saturated aqueous solution of ammonium chloride and the product was extracted in ethyl acetate. The obtained pale-brown oil was purified using semi-preparative HPLC (20-70% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 30 min, 2 injections). The desired fraction was neutralized with the help of 1.75 n aqueous solution of potassium carbonate and acetonitrile was removed under reduced pressure. The substance is extracted in ethyl acetate and the extracts were washed with water. The extracts were dried in a vacuum oven for overnight�. (S)-2-Methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-1-ol (0,034 g, 0,120 mmol, 74.7 percent yield) was collected as white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,61 (s, 1H), 7,73 (d, J=7,66 Hz, 2H), of 7.48-to 7.55 (m, 1H), 7,41-of 7.46 (m, 1H), 7.24 to 7,31 (m, 2H), 6,83-at 6.92 (m, 2H), 4,61-the 4.67 (m, 1H), 3,35-of 3.42 (m, 2H), 3,18 (DD, J=6,25, 13,81 Hz, 1H), 2,85 (DD, J=8,05, 14,01 Hz, 1H), 2,24-of 2.35 (m, 1H), of 0.90 (d, J=6,74 Hz, 3H); MS (ESI): m/z 283,2 [M+1]+.

Example 47: (S)-2-Methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propanamide

A. (S)-2-Methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propane acid. A solution of (S)-methyl 2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propanoate (0.11 g, 0,354 mmol) in methanol (5 ml) were processed using a 4.0 n aqueous solution of sodium hydroxide (ml 3,90, 15,60 mmol) and heated at boiling with reflux. After 1 hour the reaction mixture was cooled to room temperature and the pH was lowered to 2-3 with a 4 n aqueous solution of HCl. Besieged not quite white solid substance was collected by filtration and washed with water and dried in vacuum. (S)-2-Methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propane acid (0,096 g, 0,324 mmol, 91% yield) was isolated as an off-white solid. MS (ESI): m/z 297,1 [M+1]+.

B. (S)-2-Methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propanamide. A solution of (S)-2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyrid�n-5-yl)propane acid (0,096 g, 0,324 mmol), ammonium chloride (0,026 g, 0,486 mmol), N-methylmorpholine (0,053 ml, 0,486 mmol) in N,N-dimethylformamide (1,296 ml) was obtained at room temperature and treated with hexaflurophosphate the benzotriazole-1-yloxy-Tris(dimethylamino)phosphonium (0,215 g, 0,486 mmol). The reaction mixture was stirred at room temperature over night. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution and the crude substance was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness. The residue was purified using semi-preparative HPLC (20-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 30 min, 4 injection). The desired fraction was neutralized using a 1.75 M aqueous solution of potassium carbonate, which led to the formation of sludge. The acetonitrile was removed under reduced pressure and the obtained white solid substance was collected by filtration and washed with water until the pH of the washings became neutral. (S)-2-Methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propanamide (0,071 g, 0,240 mmol, 74.2% of yield) was collected in the form of cotton-like white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) a 9.64 (s, 1H), 7,74 (d, J=7,76 Hz, 2H), of 7.42-7,54 (m, 2H), of 7.36 (s, 1H), 7.24 to 7,31 (m, 2H), 6,78-6,91 (m, 3H), 3,26-of 3.33 (m, 1H), 2,94-3,09 (m, 2H), of 1.15 (d, 3H); MS (ESI): m/z 296,1 [M+1]+.

Example 48: (S)-5-(3-amino-2-methylpropyl�)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. (S)-5-(3-amino-2-methylpropyl")-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of (S)-2-methyl-3-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)propan-1-ol (0.045 g, 0,161 mmol), phthalimide (0,047 g, 0,322 mmol), polymer-bonded triphenylphosphine (3 mmol/g, 0,107 g, 0,322 mmol) in tetrahydrofuran (1,610 ml) was treated with diisopropylcarbodiimide (0,063 ml, 0,322 mmol) and stirred at room temperature for 1 hour. The resin was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in ethanol (2 ml) and treated with hydrazinoacetate (0,025 ml, 0,805 mmol). The reaction mixture was heated to 40°C during the night. The reaction mixture was evaporated to dryness and suspended in methanol. The filtrate was evaporated to dryness and dissolved in dimethyl sulfoxide (2 ml) for purification using semi-preparative HPLC (20-100% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 30 min, 2 injections). The desired fractions were combined and neutralized using a column with a cation exchange resin (STRATA column). The residue was evaporated in a tared flask and dried in a vacuum oven. (S)-5-(3-amino-2-methylpropyl")-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,023 g, 0,082 mmol, 50.8 per cent yield) was isolated as a clear oil, which hardens when dried.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,61 (s, 1H), 7,69-to 7.77 (m, 2H), 7,47-7,53(m, 1H), 7,41-of 7.46 (m, 1H), 7.23 percent-7,31 (m, 2H), 6,83-at 6.92 (m, 2H), 3,20 (d, J=6,30, 13,71 Hz, 1H), 2,84 (DD, J=8,00, 13,91 Hz, 1H), 2,52-of 2.58 (m, 2H), 2,11-of 2.21 (m, 1H), of 0.88 (d, J=6,74 Hz, 3H); MS (ESI): m/z 282,2 [M+1]+.

Example 49: N-(6-Morpholinopropan-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. N-(6-Chloropyridin-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. In a nitrogen atmosphere to a mixture of 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.3 g, 1,43 mmol), 2-chloro-5-iodopyridine (0,402 g, 1.68 mmol), palladium acetate(II) (8 mg 0,035 mmol), 2,2'-bis(diphenylphosphino)1-1'-binaphthyl (0,021 g, 0,034 mmol), cesium carbonate (2,73 g, of 8.39 mmol) was added toluene. The solution was purged with nitrogen, stirred at room temperature for 30 minutes and heated to 120°C over night. The reaction was quenched with water and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated to dryness (yellow oil). The residue was purified using column chromatography using 50% ethyl acetate in hexane. N-(6-Chloropyridin-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.08 g, 0,249 mmol, 14,81% yield) was isolated as a yellow solid. MS (ESI): m/z 322,0 [M+1]+.

B. N-(6-Morpholinopropan-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A solution of N-(6-chloropyridin-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.08 g, 0,249 mmol) in morpholine (5 ml, 57,4 mmol) was heated to 150°C for 6 days, with daily monitoring of converse� (55% conversion). The reaction mixture was cooled to room temperature and the morpholine was removed under reduced pressure. The residue was suspended in methanol, and the filtrate was purified using semi-preparative HPLC (20-100% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 2 injection, 30 min). The desired fraction was neutralized with the use of cation-exchange resin, was evaporated to dryness and dried overnight in a vacuum oven. N-(6-Morpholinopropan-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,021 g, 0,056 mmol, 22.7% of yield) was collected as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,41 (s, 1H), is 8.46 (d, J=2,39 Hz, 1H), 8,00-8,06 (m, 2H), 7,92 (DD, J=2,78, remaining 9.08 Hz, 1H), 7,52-to 7.68 (m, 5H), made 7.16 interest (DD, J=1,32, 7,22 Hz, 1H), 6,83 (d, J=remaining 9.08 Hz, 1H), 3,67-3,74 (m, 4H), 3,27-of 3.33 (m, 4H); MS (ESI): m/z 373,3 [M+1]+.

Example 50: 5-(5-Methylisoxazol-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. N-(6-Bromopyridin-2-yl)pivalate. To a mixture of 6-bromo-pyridin-2-ylamine (100 g, 0.6 mole) and triethylamine (70,5 g, to 0.72 mol) in dichloromethane (200 ml) was added dropwise pualeilani (83,5 g, to 0.72 mol) at room temperature and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water, dried over sodium sulfate and was evaporated to obtain N-(6-bromopyridin-2-yl)palamida (120 g, yield of 80.5%) as a white solid.1 H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,11 (s, 1H), 8,04 (d, J=8,0 Hz, 1H), 7,68 (t, J=8,0 Hz, 1H), 7,28 (d, J=7,6 Hz, 1H), 1,19 (s, 9H); MS (ESI): m/z 257,1 [M+1]+.

B. N-(6-Formylpyridine-2-yl)pivalate. A solution of N-(6-bromopyridin-2-yl)palamida (40 g, 0.16 mole) in toluene was cooled to 3-5°C and added dropwise a solution of isopropylacrylamide in tetrahydrofuran (200 ml, 2 M) for 1 hour at a temperature below 5°C. the resulting mixture was stirred at 5°C for 12 hours and was added anhydrous N,N-dimethylformamide (58,4 g, 0.8 mole) for 20 minutes at 10~15°C and the mixture was stirred for 30 minutes at 10~15°C. the Reaction was quenched with water and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate and concentrated to give N-(6-formylpyridine-2-yl)palamida (22 g, 68.8 per cent of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,16 (s, 1H), of 9.90 (s, 1H), 8,29 (d, J=8,0 Hz, 1H), 7,99 (t, J=8,0 Hz, 1H), of 7.64 (d, J=7,6 Hz, 1H), 1,25 (s, 9H); MS (ESI): m/z 207,1 [M+1]+.

C. N-(6-((Hydroxyimino)methyl)pyridin-2-yl)pivalate. To a solution of sodium hydroxide (3.2 g, 0.08 mole) in a mixture of ethanol / water (V/V, 5:1) was added hydroxylamine hydrochloride (5.6 g, 0,08 mol) and a solution of N-(6-formylpyridine-2-yl)palamida (15 g, 0,073 mol) in ethanol (50 ml) at 0°C. the Mixture was stirred at 0°C for 4 hours and at room temperature for 1 hour. The precipitate was collected �altropane, was washed with water and ethanol to obtain N-(6-((hydroxyimino)methyl)pyridin-2-yl)palamida (15 g, 93.7% of output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,68 (s, 1H), 9,84 (s, 1H), 7,98 (m, 1H), to 7.77 (t, J=8,0 Hz, 1H), of 7.46 (d, J=7,6 Hz, 1H), 1,21 (s, 9H); MS (ESI): m/z 222,1 [M+1]+.

D. N-(6-(5-Methylisoxazol-3-yl)pyridin-2-yl)pivalate. N-Chlorosuccinimide (3.3 g, 0,015 mol) was added dropwise to a solution of N-(6-((hydroxyimino)methyl)pyridin-2-yl)palamida (5 g, 0.02 mmol) in N,N-dimethylformamide (40 ml) and the mixture was heated to 50°C for 1 hour. Was slowly added a mixture of prop-1-EN-2-ilaclama (11 g, 0.1 mol) and triethylamine (5.7 g, of 0.056 mol) and the reaction mixture was stirred at 50°C over night. The reaction was quenched by adding water, the mixture was extracted with ethyl acetate (15 ml ×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified using column chromatography on silica gel (elwira using 20% ethyl acetate in petroleum ether) to give N-(6-(5-methylisoxazol-3-yl)pyridin-2-yl)palamida (1.5 g, 25.8% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 8,15 (d, J=8.4 Hz, 1H), 7,93 (t, J=8,0 Hz, 1H), of 7.70 (d, J=7,6 Hz, 1H), 6,72 (s, 1H), 2,51 (s, 1H), of 1.34 (s, 9H); MS (ESI): m/z of 260.1 [M+1]+.

E. 6-(5-Methylisoxazol-3-yl)pyridin-2-amine. A mixture of N-(6-(5-methylisoxazol-3-yl)pyridin-2-yl)palamida (1.5 g, 5.8 mmol) and an aqueous solution of hydroxide Kal�I (10 ml, 2 M) was stirred at 100°C for 12 hours. The reaction mixture was extracted with ethyl acetate and the combined organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (elwira using 50% ethyl acetate in petroleum ether) to give 6-(5-methylisoxazol-3-yl)pyridin-2-amine (450 mg, 47% yield) as a white solid.

F. 5-(5-Methylisoxazol-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. A solution of 6-(5-methylisoxazol-3-yl)pyridin-2-amine (450 mg, 2.57 mmol) and ethoxycarbonylmethylene (337 mg, 2.57 mmol) in dioxane (10 ml) was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure obtaining intermediate touraid connection in the form of a solid which was used directly without further purification.

To a solution of hydroxylamine hydrochloride (900 mg, of 12.85 mmol) and N,N-ethyldiethanolamine (994 mg, 7,71 mmol) in a mixture of ethanol and methanol (V/V, 1:1, 20 ml) was added touraid connection (786 mg, 2.57 mmol) and the mixture was stirred at room temperature for 2 hours and at 70°C overnight. Volatiles were removed under reduced pressure and the residue was purified on a column of silica gel (elwira using 50% ethyl acetate in petroleum� ether) to give 5-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (200 mg, 36.2% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,54 (m, 2H), 7,39 (d, J=8,8 Hz, 1H), 7,13 (s, 1H), 6.18 of (s, 2H), 2,52 (s, 3H); MS (ESI): m/z 216,2 [M+1]+.

G. 5-(5-Methylisoxazol-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To a degassed mixture of 5-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (200 mg, 0.93 mmol), odensala (190 mg, 0.93 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (108 mg, 0,186 mmol) and tert-butoxide sodium (108 mg, 1.1 mmol) in dioxane (20 ml) was added Tris(dibenzylideneacetone)dipalladium(0) (84 mg, 0,093 mmol) in a nitrogen atmosphere and the mixture was heated at 100°C in a nitrogen atmosphere for 2 hours. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate (15 ml ×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified using reverse-phase preparative HPLC (48-68% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to give 5-(5-methylisoxazol-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt using methanolic solution of hydrochloride (75 mg, 27.8% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) the 9.73 (s, 1H), 7,71 (m, 4H), 7,56 (d, J=8,8, 1H), 7,29 (t, J=8,0, 2H), 7,22 (s, 1H), to 6.88 (t, J=7,2, 1H), of 2.57 (s, 3H); MS (ESI): m/z 291,9 [+1] +.

Example 51: N4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)pyridine-2,4-diamine

A. N-(4-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)pyridin-2-yl)pivalate. To a degassed mixture of 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (200 mg, 0.95 mmol), N-(4-chloropyridin-2-yl)palamida (244 mg, 1.15 mmol), tert-butoxide sodium (184 mg, 1.92 mmol) and (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (120 mg, 0,19 mmol) in toluene (8 ml) was added Tris(dibenzylideneacetone) dipalladium(0)(88 mg, 0.10 mmol) in a nitrogen atmosphere and the reaction mixture was subjected to irradiation in a microwave (150 W) at 150°C in a nitrogen atmosphere for 1 hour. After filtration the solvent of the filtrate was removed using a rotary evaporator and the residue was purified using reverse-phase preparative HPLC (30-60%: acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 17.2 minutes) to give N-(4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)pyridin-2-yl)palamida (52 mg, 14.2% of yield) as a white solid. MS (ESI): m/z 387,1 [M+1]+.

B. N4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)pyridine-2,4-diamine. N-(4-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)pyridin-2-yl)pivalate (52 mg, is 0.135 mmol) was dissolved in a solution of potassium hydroxide in ethanol (2 M, 5 ml) and the mixture was stirred at 90°C in a nitrogen atmosphere over night. Ethanol prowess of�and using a rotary evaporator and the residue was diluted with water. The aqueous layer was extracted with ethyl acetate five times. The organic layer was combined, dried over anhydrous sodium sulfate, concentrated under high vacuum to yield N4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)pyridine-2,4-diamine (30 mg, 75% yield) in the form of solids.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) 8,02 (m, 2H), 7,91 (d, J=6,0 Hz, 1H), 7,58 (m, 6H), 7,07 (m, 2H), 6,68 (m, 1H); MS (ESI): m/z 303,1 [M+1]+.

Example 52: 4-(5-(3-Hydroxyphenyl)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide

A. 4-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methylbenzamide. To a degassed mixture of 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (2,12 g, 10 mmol), 4-iodo-N-methylbenzamide (2,87 g, 11 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.15 g, 2.0 mmol) and tert-butoxide sodium (1.92 g, 20 mmol) in dioxane (30 ml) was added Tris(dibenzylideneacetone)dipalladium (0) (913 mg, 1 mmol) and the reaction mixture was heated at 90°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified on a column of silica gel (elwira using 10-80% ethyl acetate in petroleum ether) to give 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide (2.2 g, 64% yield). MS (ESI): m/z 347,7 [M+1]+.

B. 4-(5-(3-Hydroxyben�l)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide. A mixture of 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide (104 mg, 0.3 mmol), 3-hydroxy-phenylboronic acid (82 mg, 0.6 mmol), triphenylphosphine (16 mg, 0,06 mmol) and potassium phosphate (127 mg, 0.6 mmol) in 1,2-dimethoxyethane (5 ml) was degassed and added palladium acetate (7 mg, 0,03 mmol) in a nitrogen atmosphere. The reaction mixture was heated to boiling temperature with reflux at 80°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was distributed between ethyl acetate (20 ml) and water (20 ml) and the aqueous layer was extracted with ethyl acetate (20 ml ×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate and evaporated. The crude product was purified using reverse-phase preparative HPLC (20-55%: acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to give 4-(5-(3-hydroxyphenyl)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt (30 mg, 30% yield).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) compared to 7.97 (t, J=8,8 Hz, 1H), of 7.75 (m, 2H), of 7.64 (DD, J1=1.2 Hz, J2=8,8 Hz, 1H), 7,61 (m, 2H), of 7.46 (DD, J1=0.8 Hz, J2=7,6 Hz, 1H), 7,38 (m, 3H), of 6.96 (m, 1H), 2,81 (s, 3H). MS (ESI): m/z 360,1 [M+1]+.

Example 53: 2-(2-(4-Forgenerating)-[1,2,4]triazolo[1,5-α]pyridine-5-and�)-1-phenylethanol

A. 2-(3-Ethoxycarbonyl-2-touraid)-6-methylpyridine. To a solution of 6-methylpyridine-2-amine (5.0 g, or 46.2 mmol) in 1,4-dioxane (185 ml) cooled to 0°C, was added undiluted ethoxycarbonylmethylene (5,23 ml of 46.2 mmol) dropwise. The bath gave Rosstat and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was maintained at room temperature for 48 hours. The solvent was removed under reduced pressure. 2-(3-Ethoxycarbonyl-2-touraid)-6-methylpyridine was isolated as a light yellow solid with a quantitative yield and was used without any further purification (residual solvent/reagent). MS (ESI): m/z 240,1 [M+1]+.

B. 5-Methyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To a solution of hydroxylamine hydrochloride (16,05 g, 231 mmol) and N,N-diisopropylethylamine (24,21 ml, 139 mmol) in a mixture of methanol (50,0 ml) and ethanol (50 ml) was added 2-(3-ethoxycarbonyl-2-touraid)-6-methylpyridine (11,06 g, or 46.2 mmol). The reaction mixture was stirred at room temperature over night. The solvent was removed under reduced pressure, was added water (50 ml) and the light yellow suspension was stirred at room temperature for 30 minutes. When all the substance is passed into the solution, the crude substance was extracted in ethyl acetate. The extracts were dried over sulfate� magnesium and evaporated to dryness. The extracts were suspended in ethyl acetate (5 ml) and the white suspension obtained was collected by filtration. The aqueous phase also contained a certain amount of product mixed with N,N-diisopropylethylamine, but attempts additional extraction of the aqueous phase with diethyl ether or a mixture of methanol in diethyl ether or ethyl acetate to obtain any material amount of substance, failed. 5-Methyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (4,05 g, 27,3 mmol, 59.2% of yield) was isolated as a white solid.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) of 7.42 (t, 1H), 7.23 percent (d, J=8,20 Hz, 1H), 6,80 (d, J=of 7.42 Hz, 1H), 2,63 (s, 3H); MS (ESI): m/z 149,4 [M+1]+.

C. N-(4-Fluorophenyl)-5-methyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To a suspension of 5-methyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (1 g, of 6.75 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0,781 g, 1,350 mmol), tert-butoxide sodium (1,297 g 13,50 mmol) and Tris(dibenzylideneacetone)diplegia(0) (0,451 g, 0,492 mmol) in 1,4-dioxane (40 ml) under a nitrogen atmosphere was added 1-fluoro-4-iodobenzoyl (1,557 ml 13,50 mmol). The reaction mixture (white suspension) was stirred at room temperature for 30 minutes, then at 40°C for 30 minutes. Heating was stopped after 2 hours and the reaction was quenched with water. The crude substance was extracted with ethyl acetate and dried over magnesium sulfate. The extracts were evaporated to dryness (brown solid). OST�OK suspended in dichloromethane and the obtained pale grey solid was collected by filtration and washed with dichloromethane. The filtrate was concentrated and the obtained brown residue was suspended in minimum volume of methanol (5 ml). The suspension was collected by filtration and quickly washed with methanol. N-(4-Fluorophenyl)-5-methyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,839 g, and 3.46 mmol, 51.3% of output), with an admixture of about 10% detoriating product was isolated as an off-white solid which was dried under vacuum and used without further purification.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) members, 7.59-7,73 (m, 2H), 7,43-7,54 (m, 1H), 7,20-7,39 (m, 2H), 7,02 (t, J=8,59 Hz, 2H), 6,86 (d, J=of 7.42 Hz, 1H), 2,73 (lat.s, 3H);19F NMR (400 MHz, DMSO-d6) δ (M. D.) -125,97; MS (ESI): m/z of 243.3 [M+1]+.

D. 2-(2-(4-Forgenerating)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1-phenylethanol. A suspension of N-(4-fluorophenyl)-5-methyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.15 g, 0,619 mmol) in diethyl ether (6.0 ml) was cooled to 0°C. Then was added dropwise a solution of n-utility in hexane (0,508 ml of 1.269 mmol, 2.5 M). The reaction mixture turned into a brown more thick slurry. The reaction mixture was stirred at 0°C for 30 minutes, then 30 minutes at room temperature. The reaction mixture was again cooled to 0°C, was then added benzaldehyde (0.075 ml, 0,743 mmol) as a solution in diethyl ether (6.0 ml). After 1 hour at 0°C temperature gave to rise slowly to room temperature and the reaction mixture was stirred for n�Chi. Not seen any further conversion after the addition of 1.1 equivalents of benzaldehyde. The reaction was quenched with water and the crude substance was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness. The yellow residue (2/3 substances) was purified using semi-preparative HPLC (20-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 39 minutes, 2 injection). The desired fraction was neutralized using a 1.75 M aqueous solution of potassium carbonate and acetonitrile was removed under reduced pressure, resulting in precipitation of the product. 2-(2-(4-Forgenerating)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1-phenylethanol (0,021 g, is 0.060 mmol, 9,74% yield) was isolated as a white solid which was dried in a vacuum oven over night. Unreacted starting substance was isolated (0.030 g).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9.66 as per (s, 1H), 7,72-of 7.82 (m, 2H), 7,41-to 7.55 (m, 4H), 7,34-7,40 (m, 2H), 7,28 (d, J=of 7.42 Hz, 1H), 7,11-7,20 (m, 2H), of 6.87 (DD, J=1,56, only 6.64 Hz, 1H), 5,52 (d, J=4,69 Hz, 1H), 5.25 in-of 5.34 (m, 1H), 3,38-3,48 (m, 1H), 3,23-of 3.31 (m, 1H);19F NMR (376 MHz, DMSO-d6) δ (M. D.) -124,4; MS (ESI): m/z 349,2 [M+1]+.

Example 54: 4-((2-(4-Forgenerating)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperidine-4-ol

A. tert-Butyl 4-((2-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate. A suspension of N-(4-fluorophenyl)-5-methyl-[1,2,4]Tr�azolo[1,5-α]pyridin-2-amine (0.15 g, 0,619 mmol) in diethyl ether (2,064 ml) was cooled to 0°C. Then was added dropwise a solution of n-utility in hexane (0,508 ml of 1.269 mmol). The reaction mixture turned into a thick brown slurry. The reaction mixture was stirred at 0°C for 30 minutes, then 30 minutes at room temperature. The temperature was again lowered to 0°C, was then added tert-butyl 4-oxopiperidine-1-carboxylate (0,123 g, 0,619 mmol) as a solution in diethyl ether (2,064 ml). After 30 minutes at 0°C temperature gave to rise slowly to room temperature and the reaction mixture was stirred over night. The reaction was quenched with water and the crude product was extracted with ethyl acetate. The extracts were dried over sodium sulfate and evaporated to dryness. The green oily residue was purified column chromatography on silica gel (elwira using 0-50% ethyl acetate in hexane). The desired fractions were combined and evaporated to dryness to obtain tert-butyl 4-((2-(4-forgenerating)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate (0,109 g, 0,247 mmol, 39.9% of yield) as a white solid which was dried in vacuum.1H NMR (400 MHz, METHANOL-d4) δ (MD), EUR 7.57-of 7.64 (m, 2H), of 7.48-7,54 (m, 1H), of 7.36 (d, J=of 7.42 Hz, 1H), 6,98-7,06 (m, 2H), 6,93 (d, J=of 7.03 Hz, 1H), 3,74-3,83 (m, 2H), 3,37-of 3.43 (m, 2H), 3,05-3,21 (m, 2H), 1,63-of 1.74 (m, 2H), 1,49-1,60 (m, 2H), 1,38-of 1.44 (m, 8H), 1,31-of 1.34 (m, 1H), 1,26-1,30 (m, 1H); MS (ESI): m/z 442,5 [M+1]+.

B. 4-((2(4-Forgenerating)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperidine-4-ol. tert-Butyl 4-((2-(4-forgenerating)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate (0,109 g, 0,247 mmol) was dissolved in dichloromethane (5 ml) and treated at room temperature neat trifluoroacetic acid (1.5 ml, 19,47 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to obtain yellow oil. The substance was purified using semi-preparative HPLC (1 injection using 20-80 and 3 injection using a 10-50% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 30 min). The desired fractions were combined and neutralized using the column with ion-exchange resin. 4-((2-(4-Forgenerating)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperidine-4-ol (0,073 g, 0,214 mmol, 87% yield) was isolated as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,61 (s, 1H), 7,67-to 7.77 (m, 2H), 7,47-7,56 (m, 1H), 7,39-7,47 (m, 1H), 7,08-to 7.18 (m, 2H), of 6.96 (d, J=5,86 Hz, 1H), a 4.64 (s, 1H), 3,29 (s, 2H), 2,69-2,79 (m, 2H), 2,57-2,69 (m, 2H), 1,42-of 1.55 (m, 2H), 1,32-of 1.42 (m, 2H);19F NMR (376 MHz, DMSO-d6) δ (M. D.) -124,5; MS (ESI): m/z 342,2 [M+1]+.

Example 55: N1-(4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)pyridin-2-yl)ethane-1,2-diamine

A. 5-(2-Herperidin-4-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. 5-Bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine(0,44 g, 1,522 mmol), 2-herperidin-4-Voronovo acid (0,257 g, 1,826 mmol), a 1M solution of sodium carbonate (45.7 ml, up 4.57 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) adduct of accession with dichloromethane (0,037 g, 0.046 mmol) and dioxane (10 ml) was heated to 100°C for 5 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and then filtered. This solid substance was washed with methanol to obtain 5-(2-herperidin-4-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.29 g, 62% yield) as a green solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,76 (s, 1H), and 8.50 (d, J=5.1 Hz, 1H), 8,09 (d, J=5.1 Hz, 1H), 8,00 (s, 1H), 7.67 per-7,78 (m, 4H), of 7.48 (DD, J=6,2, 2,3 Hz, 1H), 7,28 (t, J=8,0 Hz, 2H), 6,89 (t, J=7,2 Hz, 1H). MS (ESI) m/z 306,1 [M+1]+.

B. N1-(4-(2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)pyridin-2-yl)ethane-1,2-diamine. 5-(2-Herperidin-4-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (90 mg, 0,295 mmol), N,N-dimethylformamide (1.5 ml) and ethane-1,2-diamine (0,030 ml 0,442 mmol) was heated to 80°C for 16 hours in a nitrogen atmosphere. The reaction mixture was purified using reverse-phase HPLC (10-70% acetonitrile + 0.1% of trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 30 min). The fractions containing the product, was passed through a Strata column to remove trifluoroacetic acid and then was extracted using 2M ammonia solution in methanol to obtain N -(4-(2-(phenylamino)-[1,2,4]triazolo[1,5-ύi]pyridin-5-yl)pyridin-2-yl)ethane-1,2-diamine (96 mg, 32% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,69 (s, 1H), 8,15 (d, J=5,5 Hz, 1H), 7,69 (DD, J=8,6, 1,2 Hz, 2H), 7,60-7,67 (m, 2H), 7,27 (t, J=7,8 Hz, 2H), 7,20 (DD, J=6,4, and 2.1 Hz, 1H), 7,10 (s, 1H), 6,99-to 7.04 (m, 1H), 6,87 (t, J=7,2 Hz, 1H), 6,80 (t, J=5,5 Hz, 1H), 3,30 (d, J=6,4 Hz, 2H), 2,73 (t, J=6,4 Hz, 2H). MS (ESI) m/z 346,0 [M+1]+.

Example 56: 3-((2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)benzamide

A. 3-((2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)benzonitrile. Getting organozinc slurry: in a nitrogen atmosphere, zinc powder (of 0.654 g, 10,000 mmol) was suspended in tetrahydrofuran (3 ml) and treated with 1,2-dibromoethane (0,080 ml, 0,865 mmol). The mixture was heated to boiling temperature to reflux for 5 minutes and cooled to room temperature. Was then added undiluted trimethylsilane (0,120 ml 0,940 mmol) followed by addition of a solution of 3-(methyl bromide)benzonitrile (0,980 g, 5,000 mmol) in tetrahydrofuran (20 ml) for 15 minutes. The reaction mixture was stirred at room temperature for 20 minutes. In an atmosphere of nitrogen was weighed palladium tetranitroaniline (0.5 g, 0,433 mmol) and 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.25 g, 0,865 mmol). Was added tetrahydrofuran (10 ml) followed by the addition of 20 ml of organozinc�solution, described above. The reaction mixture was stirred at 65°C for 1 hour, resulting in the conversion of about 50% according to LC/MS. Then added the remainder organozinc suspension and the reaction mixture was stirred at the boiling temperature of the solvent during the night. Since the conversion was complete, the reaction was quenched with a saturated solution of sodium bicarbonate and was extracted with ethyl acetate. The extracts were dried over sodium sulfate and evaporated to dryness. Purification was performed using column chromatography on silica gel using 50% ethyl acetate in hexane. 3-((2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)benzonitrile (0,150 g, 0,461 mmol, 53,3% yield) with an admixture of the product recovered in trace amounts allocated in the form of a yellow oil which was used without further purification. MS (ESI): m/z to 326.1 [M+1]+.

B. 3-((2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)benzamide. To a suspension of 3-((2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)benzonitrile (0,150 g, 0,461 mmol) in ethanol (3.0 ml) was added dropwise at room temperature hydrogen peroxide (3.0 ml, 98 mmol) and 6.0 n aqueous sodium hydroxide solution (0.03 ml, 0,180 mmol). The suspension was then heated to 45°C for 2 hours. The reaction mixture was cooled to room temperature and were processed using 0.05 ml of 6.0 n aqueous HCl. Added �ode (20 ml) and the precipitate that formed was collected and washed with water. The product is dissolved in 6 ml of dimethyl sulfoxide, was purified using semi-preparative HPLC (20-80% then 30-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 30 min, 4 injection). The desired fraction was neutralized using a 1.75 M aqueous solution of potassium carbonate. The product precipitated after removal of acetonitrile. The precipitate was collected by filtration and washed with water until the pH of the washings became neutral. 3-((2-(Phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)benzamide (0.055 g, 0,160 mmol, 34.7 percent yield) was isolated as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,60 (lat.s, 1H), 7,95 (d, J=16,40 Hz, 2H), 7,62-7,81 (m, 3H), 7,08-members, 7.59 (m, 7H), to 6.88 (d, J=6,64 Hz, 2H), 3,35 (s, 2H); MS (ESI): m/z 344,3 [M+1]+.

Example 57: 3-(2-(1-methyl-1H-benzo[d][1,2,3]triazole-6-ylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol

A. N-(5-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-6-amine. To a degassed mixture of 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole (126 mg, 0.6 mmol), 5-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (144 mg, 0.6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol) and cesium carbonate (390 mg, 1.2 mmol) in dioxane (3 ml) was added Tris(dibenzylideneacetone)palladium(0) (55 mg, 0,06 mmol) in a nitrogen atmosphere and the mixture was heated at 100°C with stirring in a nitrogen atmosphere during the night. The mixture was filtered and washed with water (20 ml), then washed with methanol (20 ml) to give crude N-(5-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-6-amine (80 mg, 36% yield), which was used for next step without further purification. MS (ESI): m/z 372,0 [M+1]+.

B. 3-(2-(1-methyl-1H-benzo[d][1,2,3]triazole-6-ylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol. A mixture of N-(5-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-6-amine (80 mg, 0.21 mmol) and sodium iodide (65 mg, 0,42 mmol) in a solution of methyl hydrogen (6 ml, 48%) was heated at 80°C in a tightly closed container overnight. After cooling to room temperature the solution was neutralized to pΗ=7~8 with saturated sodium bicarbonate solution. The precipitate was collected by filtration, was purified using reverse-phase preparative HPLC (28-58%: acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to give 3-(2-(1-methyl-1H-benzo[d][1,2,3]triazole-6-ylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt. (30 mg, 39% yield).1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,32 (d, J=2,0 Hz, 1H), 8,04 (t, J=8,0 Hz, 1H), 7,86 (d, J=9,2 Hz, 1H), 7,72 (d, J=8,8 Hz, 1H), 7,55 (m, 2H), 7,40 (m, 3H), 7,01 (d, J=7,2 Hz, 1H), 4,19 (s, 3H); MS (ESI): m/z 358,1 [M+1]+.

Example 58: 5-(2-((Methylamino)methyl)Ben�about[d]oxazol-6-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A. the Hydrochloride of 5-(4-amino-3-methoxyphenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. 5-Bromo-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,631 g, 2.184 mmol), 4-(tert-butoxycarbonylamino)-3-methoxyphenylalanine acid (0.7 g, 2,62 mmol), a 1M solution of sodium carbonate (6,55 ml, 6.55 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) in the form of product adherence with dichloromethane (0,054 g, 0,066 mmol) and dioxane (20 ml) was heated to 80°C for 5 hours in a nitrogen atmosphere. The reaction mixture was concentrated and was purified on a column of silica gel (0-70% ethyl acetate in hexane). The fractions containing the product were concentrated and then stirred with 4n solution of hydrogen chloride in dioxane (4 ml) for 4 hours at room temperature. The reaction mixture was concentrated and then triturated to powder with a 10% solution of methanol in a simple ether to obtain a light yellow solid (0.56 g, 1,522 mmol, 69.7% of output). MS (ESI) m/z 332,3 [M+1]+.

B. 2-Amino-5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol. Hydrochloride 5-(4-amino-3-methoxyphenyl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,43 g, 1,169 mmol), dichloro methane (10 ml) and 1M solution of tribromide boron (3,51 ml, 3,51 mmol in dichloromethane) was stirred at room temperature for 20 hours. The reaction was quenched with methanol and then concentrated. The residue was ground into powder in 10% RA�creators of ethyl acetate in hexane to obtain a dark solid. MS (ESI) m/z 318,3 [M+1]+.

C. 5-(2-((Methylamino)methyl)benzo[d]oxazol-6-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. 2-(tert-Butoxycarbonyl(methyl)amino)acetic acid (0,143 g, 0,756 mmol), triethylamine (0,316 ml 2,269 mmol), O-benzotriazole-N,N,N',N'-tetramethyl-urani-hexaflurophosphate (0,574 g, 1,513 mmol) and N,N-dimethylformamide (3 ml) was stirred together for 15 minutes then to the reaction mixture were added 2-amino-5-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol (0.24 g, 0,756 mmol). The reaction mixture was stirred at room temperature for 16 hours to obtain the desired product with removed protection. The reaction mixture was concentrated and then purified on a column of silica gel (0-100% ethyl acetate in hexane). The mixture containing the product was concentrated and then triturated to powder in a minimal amount of methanol and then filtered to obtain the desired product as a white solid (0.015 g, 0.040 mmol, 5.35% of the output).1H NMR (400 MHz, DMSO-d6) δ (M. D.) of 9.65 (s, 1H), 8,22 (d, J=1.6 Hz, 1H), of 7.88 (DD, J=8,2, 1.6 Hz, 1H), 7,71 (d, J=7,8 Hz, 2H), 7,63 (d, J=7,0 Hz, 1H), 7,50-members, 7.59 (m, 1H), 7,43 (d, J=8,2 Hz, 1H), 7,17-7,31 (m, 3H), 6,86 (t, J=7,2 Hz, 1H), 3,20 (s, 6H). MS (ESI) m/z 371,4 [M+1]+.

Example 59: CIS-2-(4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexyl)propan-2-ol

A. CIS-Ethyl 4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]PI�idin-5-ylamino)cyclohexanecarboxylate. 5-Bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.1 g, 0,280 mmol), CIS-ethyl 4-aminocyclohexanecarboxylic hydrochloride (0,076 g, 0,364 mmol), cesium carbonate (0,274 g, 0,840 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0,032 g, 0,056 mmol), Tris(dibenzylideneacetone)palladium(0) (0,026 g, 0,028 mmol) and dioxane (5 ml) was heated to 90°C in a nitrogen atmosphere for 16 hours. The reaction mixture was filtered and then concentrated. The residue was purified using chromatography on silica gel (0-50% ethyl acetate in hexane) to give a white solid (0.1 g, 0,223 mmol, 80% yield). MS (ESI) m/z 448,3 [M+1]+.

B. CIS-2-(4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexyl)propan-2-ol. CIS-Ethyl 4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanecarboxylate (0.1 g, 0,223 mmol) was dissolved in tetrahydrofuran (1 ml) and then cooled to -78°C in a nitrogen atmosphere. Added methylmagnesium (0,745 ml, was 2,235 mmol, 3M in diethyl ether) and the reaction mixture was allowed to warm to room temperature for 18 hours. The reaction was quenched with a saturated solution of ammonium chloride and then was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and then concentrated. The residue was purified using reverse-phase HPLC (10-100% acetonitrile and water with 0.1% trifluoroacetic acid). Fractions with�holding the product, passed through the ion exchange column and then were isolated using 2M ammonia in methanol. Eluent was concentrated and then triturated to powder in hexane to give a white solid (0.045 g, 0.104 mmol, 46.5% of the output).1H (400 MHz, DMSO-d6) δ (M. D.) 10,12 (s, 1H), to 7.89 (m, J=8,6 Hz, 2H), 7,60 (m, J=8,6 Hz, 2H), of 7.48 (t, J=8.4 Hz, 1H), 6,83 (d, J=8,6 Hz, 1H), of 6.25 (d, J=7,8 Hz, 1H), of 5.89 (d, J=8,2 Hz, 1H), 4,16 (s, 1H), 3,97 (lat.s, 1H), 1,98 (d, J=12.9 Hz, 2H), 1,71 (d, J=12.9 Hz, 2H), 1,62 (t, J=13,1 Hz, 2H), 1,18-of 1.40 (m, 3H), of 1.08 (s, 6H). MS (ESI) m/z 434,5 [M+1]+.

Example 60: N6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-N3-(piperidine-4-yl)-1H-indazole-3,6-diamine

A. 2-Fluoro-4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile. A mixture of 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine (300 mg, 1,43 mmol), 4-bromo-2-perbenzoate (314 mg, 1,57 mmol), cesium carbonate (928 mg, 2,86 mmol), Tris(dibenzylideneacetone)diplegia(0) (240 mg, 0.28 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (324 mg, 0,56 mmol) in dioxane (10 ml) was heated at 120°C in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using preparative TLC to obtain 2-fluoro-4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (38 mg, 8% yield) in the form of solids.1H NMR (300 MHz, DMSO-d6) � (M. D.) 10,66 (C, 1H), 8,00 (d, J=3,9 Hz, 2H), 7,92 (m, 1H), 7,74 (m, 3H), EUR 7.57 (m, 3H), of 7.46 (d, J=9,0 Hz, 1H), 7,27 (m, 1H); MS (ESI): m/z 330,1 [M+1]+.

B. N6-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-1H-indazole-3,6-diamine. A mixture of 2-fluoro-4-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (200 mg, 0.61 mmol) and hydrazine hydrate (0.10 ml) in n-butanol (4 ml) was stirred at 120°C in a nitrogen atmosphere over night. After cooling to room temperature, the precipitate was collected by filtration, washed with methanol and dried in vacuum to yield N6-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-1H-indazole-3,6-diamine (60 mg, 29% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) to 11.11 (lat.s, 1H), 9,67 (lat.s, 1H), 8,04 (d, J=7,2 Hz, 2H), 7,81 (s, 1H), 7.62 mm (m, 5H), of 7.46 (d, J=6,8 Hz, 1H), 7,18 (d, J=6,8 Hz, 1H), 6,98 (d, J=8.4 Hz, 1H), 5,15 (lat.s, 2H); MS (ESI): m/z 341,9 [M+1]+.

C. tert-Butyl 4-(6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-1H-indazol-3-ylamino)piperidine-1-carboxylate. To a mixture of N6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-1H-indazole-3,6-diamine (350 mg, 1.02 mmol) in a mixture of acetic acid and methanol (1:20, 40 ml) was added tert-butyl 4-oxopiperidine-1-carboxylate (300 mg, 1.5 mmol) and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0°C and added cyanoborohydride sodium (130 mg, a 2.01 mmol). The reaction mixture was stirred at room temperature overnight, concentrated under reduced Yes�lenny and was purified on a column of silica gel (elwira using 30% ethyl acetate in petroleum ether) and using reverse-phase preparative HPLC (30-60% acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid) to give the desired tert-butyl 4-(6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-1H-indazol-3-ylamino)piperidine-1-carboxylate (70 mg, 13% yield) as a solid substance. MS (ESI): m/z RUB 525.1 [M+1]+.

D. N6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-N3-(piperidine-4-yl)-1H-indazole-3,6-diamine. A solution of tert-butyl 4-(6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-1H-indazol-3-ylamino)piperidine-1-carboxylate (70 mg, 0.13 mmol) in methanolic hydrochloride solution (2 M, 5 ml) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain N6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-N3-(piperidine-4-yl)-1H-indazole-3,6-diamine in the form hydrochloride salt (55 mg, 98% yield).1H NMR (300 MHz, DMSO-d6) δ (M. D.) 12.84 per (lat.s, 1H), 10,31 (s, 1H), 9,16 (lat.s, 2H), 8,07 (m, 4H), 7,73 (m, 5H), 7,28 (m, 2H), 3,41 (m, 2H), 3,03 (m, 2H), 2,19 (m, 2H), 1,73 (m, 2H); MS (ESI): m/z 425,1 [M+1]+.

Example 61: N6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)quinoline-2,6-diamine

A. N6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)quinoline-2,6-diamine. N2-(4-methoxy-benzyl)-N5-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-quinoline-2,6-diamine was obtained by following the same procedure used to obtain 5-phenyl-N-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-6-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine from 2-bro�-5-phenyl-[1,2,4]triazolo[1,5-α]pyridine and N 2-(4-methoxybenzyl)quinoline-2,6-diamine, using tert-butoxide potassium as a base and heating to 100°C. a Solution of N2-(4-methoxy-benzyl)-N6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)-quinoline-2,6-diamine (40 mg, 0,085 mmol) in trifluoroacetic acid (10 ml) was stirred at 50°C for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was purified using reverse-phase preparative HPLC (elwira using 31-61% acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 10 min) to give N6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)quinoline-2,6-diamine (28 mg, 93% yield) which was converted into hydrochloride salt, as a yellow solid.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,22 (s, 1H), 8,16 (m, 4H), 7,91 (d, J=8,8 Hz, 1H), 7,81 (d, J=8,8 Hz, 1H), 7,69 (m, 5H), 7,11 (d, J=9,2 Hz, 1H); MS (ESI): m/z 353,1 [M+1]+.

Example 62: CIS-4-(2-(4-Forgenerating)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)cyclohexanol

A. 2.5-Dibrom-[1,2,4]triazolo[1,5-α]pyridine. To 5-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (2 g, 9,39 mmol) was added a 48% solution of Hydrobromic acid (20 ml). The white suspension was stirred for 5 minutes and cooled to 0°C. was Slowly added sodium nitrate (1,943 g, 28.2 mmol) in water (9 ml) was generating brown gas). Upon completion DOB�ing brown suspension was stirred at 0°C for 30 minutes and then allowed to warm to room temperature. Added copper bromide(I) (2,69 g, 18,78 mmol) in 48% solution of Hydrobromic acid (10 ml) and the reaction mixture turned into a black suspension. The suspension was stirred at room temperature for 3 hours and water was added (100 ml). The reaction mixture was filtered through celite and the aqueous layer was extracted with ethyl acetate (3×100 ml). The combined Organic layers were washed with sodium bicarbonate (100 ml, saturated solution) and saturated brine (100 ml), dried over magnesium sulfate, filtered and concentrated to give 2,5-dibrom-[1,2,4]triazolo[1,5-α]pyridine (1.8 g, 69.2 per cent yield) as a light yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ (M. D.) of 7.70 (d, J=8,59 Hz, 1H), of 7.42-7,53 (m, 1H), to 7.33 (d, J=of 7.03 Hz, 1H). MS (ESI): m/z 278,2 [M+1]+.

B. CIS-2-Bromo-5-(4-(tert-butyldimethylsilyloxy)cyclohexyloxy)-[1,2,4]triazolo[1,5-α]pyridine. To a solution of CIS-4-(tert-butyldimethylsilyloxy)cyclohexanol (200 mg, 0.87 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydride (52 mg, 1,31 mmol) in portions at 0°C. Upon completion of addition the mixture was stirred at room temperature for 1 hour. Added 2,5-dibrom-[1,2,4]triazolo[1,5-α]pyridine (239 mg, 0.87 mmol) and the resulting mixture was stirred at room temperature over night. Added water and the solution was extracted with ethyl acetate. The combined organic layer was concentrated, washed with d�and times with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified using preparative TLC (elwira using 30% ethyl acetate in petroleum ether) to give CIS-2-bromo-5-(4-(tert-butyldimethylsilyloxy)cyclohexyloxy)-[1,2,4]triazolo[1,5-α]pyridine (115 mg, 31.1% for output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) to 7.68 (t, J=8.4 Hz, 1H), to 7.33 (d, J=8,8 Hz, 1H), is 6.81 (d, J=8,0 Hz, 1H), 4,84 (m, 1H), 3,88 (m, 1H), 1,92 (m, 4H), 1,64 (m, 4H), of 0.87 (s, 1H), of 0.04 (s, 6H); MS (ESI): m/z 426,0 [M+1]+.

C. CIS-5-(4-(tert-butyldimethylsilyloxy)cyclohexyloxy)-N-(4-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of CIS-2-Bromo-5-(4-(tert-butyldimethylsilyloxy)cyclohexyloxy)-[1,2,4]triazolo[1,5-α]pyridine (110 mg, 0,26 mmol), 4-fluoro-phenylamine (35 mg, 0,31 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg, 0,052 mmol) and tert-butoxide potassium (58 mg, 0.52 mmol) in dioxane (10 ml) was degassed and added Tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) in a nitrogen atmosphere. The mixture was stirred at 100°C in a nitrogen atmosphere over night. After concentrating, the residue was diluted with methanol and filtered. The filtrate was concentrated under reduced pressure and was purified using preparative TLC (elwira using 30% ethyl acetate in petroleum ether) to give CIS-5-(4-(tert-butyldimethylsilyloxy)cyclohexyloxy)-N-(4-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (110 mg, 93.2% in yield) � the form of solids. MS (ESI): m/z 457,3 [M+1]+.

D. CIS-4-(2-(4-Forgenerating)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)cyclohexanol. A solution of CIS-5-(4-(tert-butyldimethylsilyloxy)cyclohexyloxy)-N-(4-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (100 mg, 0,22 mmol) in methanolic hydrochloride solution (2 M, 20 ml) was stirred at 50°C for 10 minutes. The solution was concentrated under reduced pressure and the residue was purified using reverse-phase preparative HPLC (30-60% acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 10 min) to give CIS-4-(2-(4-forgenerating)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)of cyclohexanol in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt (58 mg, 77,3% yield).1H NMR (400 MHz, METHANOL-d4) δ (MD), 7,99 (t, J=8.4 Hz, 1H), 7,66 (m, 2H), 7,29 (d, J=8.4 Hz, 1H), 7,17 (t, J=8,8 Hz, 2H), 7,06 (d, J=8.4 Hz, 1H), of 5.03 (m, 1H), 3,82 (m, 1H), 2,19 (m, 2H), 1.91 a (m, 6H); MS (ESI): m/z 343,1 [M+1]+.

Example 63: 3-(2-(4-(Aminomethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol

A. 4-(5-(3-Hydroxyphenyl)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile. To a degassed mixture of 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (160 mg, 0.51 mmol) and 3-hydroxyphenylpropionic acid (99 mg, 0,72 mmol) in dimethylsulfoxide (5 ml) was added tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol) and phosphate Kal�I (0.5 ml, 2 M). The mixture was heated at boiling with reflux in a nitrogen atmosphere over night. After cooling to room temperature the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to obtain crude product, which was purified using preparative TLC (elwira using 2% methanol in dichloromethane), to obtain 4-(5-(3-hydroxyphenyl)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (60 mg, 36% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,22 (s, 1H), 9,68 (s, 1H), 7,73 (m, 1H), 7,537 (m, 6H), 7,27 (m, 2H), 7,06 (m, 1H), of 6.85 (m, 1H); MS (ESI): m/z 328,1 [M+1]+.

B. 3-(2-(4-(Aminomethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol. A mixture of 4-(5-(3-hydroxyphenyl)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzonitrile (60 mg, 0.18 mmol) and Raney Nickel (20 mg) in methanol (10 ml) were gidrirovanie under a hydrogen pressure of 1 ATM for 1 hour. The catalyst was filtered and the filtrate concentrated. The residue was purified using reverse-phase preparative HPLC (10-65% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to give 3-(2-(4-(aminomethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)phenol in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt (45 mg, 74% yield) using methanolic solution of the hydrochloride.1H NMR (40 MHz, DMSO-d6) δ (M. D.) 9,78 (s, 1H), 8,14 (lat.s, 2H), of 7.70 (m, 2H), EUR 7.57 (m, 1H), 7,63 (m, 1H), 7,39 (m, 5H), 7,13 (m, 1H), 6,95 (m, 1H), of 3.91 (s, 2H); MS (ESI): m/z 332,1 [M+1]+.

Example 64: N-Phenyl-5-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 2-(Pyrrolidin-1-yl)acetic acid. 2-Chloroacetic acid (3,66 g, of 38.7 mmol), a 1M solution of sodium hydroxide (77 ml, 77 mmol) and pyrrolidine (3,20 ml, of 38.7 mmol) was stirred together at room temperature for 3 days. The reaction mixture was concentrated and the residue was filtered with hot ethanol. The filtrate was concentrated and then triturated to powder with ethyl acetate to obtain 2-(pyrrolidin-1-yl)acetic acid (4.4 g, 88% yield) as a white solid. MS (ESI) m/z of 130.1 [M+1]+.

B. N-Phenyl-5-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. 2-(Pyrrolidin-1-yl)acetic acid (0,104 g, 0,806 mmol), O-benzotriazole-N,N,N',N'-tetramethyl-urani-hexaflurophosphate (0,224 g, 0,591 mmol), triethylamine (0,225 ml, 1,612 mmol) and acetonitrile (3 ml) was stirred at room temperature for 10 minutes. To the reaction mixture were added 4-(2-(phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzene-1,2-diamine (0.17 g, 0,537 mmol) and then stirred at room temperature for 16 hours. The solid was filtered from the reaction mixture and the filtrate was concentrated�. To the residue from the filtrate was added a 50% solution of trifluoroacetic acid in glacial acetic acid and then heated in a microwave oven (200°C, 20 min). The reaction mixture was concentrated and then purified using reverse-phase HPLC (elwira using 5-40% acetonitrile and water +0,1% trifluoroacetic acid). The fractions containing the product, was passed through a Strata column to remove trifluoroacetic acid. The main product was isolated from the column using 2M ammonia in methanol to obtain N-phenyl-5-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,027 g, 12% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 9,63 (s, 1H), of 7.70 (DD, J=8,6, 1,2 Hz, 2H), 7,67 (d, J=7,4 Hz, 1H), of 7.64 (d, J=7,0 Hz, 1H), 7,52-7,58 (m, 1H), 7,25 (t, J=7,8 Hz, 2H), 7,20 (DD, J=7,4 Hz, 1,2, 1H), of 6.85 (t, J=7,2 Hz, 1H), 3,89 (s, 2H), 2,53-2,62 (m, 4H), of 1.76 (DDD, J=6,4 Hz, 3,1, 2,9, 4H). MS (ESI) m/z 410,4 [M+1]+.

Example 65: 6-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)quinoline-2-ol

A. 6-(5-Phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)quinoline-2-ol. 2-Methoxy-N-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)quinolin-6-amine was synthesized from 5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine and 6-bromo-2-methoxy-quinoline according to the procedure described to obtain N,5-diphenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 2-methoxy-N-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-yl)Hino�in-6-amine (90 mg, 0,24 mmol) in concentrated hydrochloric acid (12 M, 20 ml) was stirred at 100°C overnight. The mixture was evaporated in vacuum to give 6-(5-phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)quinoline-2-ol in the form hydrochloride salt (66 mg, 78% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 11,62 (lat.s, 1H), 9,72 (s, 1H), 8,06 (m, 3H), 7,73 (d, J=9,2 Hz, 1H), 7,60 (m, 6H), 7,21 (m, 2H), 6,47 (d, J=9,2 Hz, 1H); MS (ESI): m/z 354,0 [M+1]+.

Example 66: 4-(5-(3-carbamoylphenoxy)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide

A. 4-(5-(3-Carbamoylphenoxy)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide. A mixture of 4-(5-bromo-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide (200 mg, of 0.58 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (102 mg, 0.69 mmol), tetrakis(triphenylphosphine) palladium (100 mg, 0,09 mmol) and aqueous sodium carbonate solution (2 M, of 0.625 ml, 1.3 mmol) in 1,2-dimethoxyethane (5 ml) degassed three times and stirred at 80°C in a nitrogen atmosphere over night. The solvent was removed under reduced pressure and the residue was washed with ethyl acetate. The solid was dissolved in dimethylsulfoxide (3 ml), followed by the addition of hydrogen peroxide (1.0 ml, 30%) and potassium carbonate (160 mg, of 1.16 mmol). The mixture was stirred at room temperature overnight, poured into water (20 ml) and was extracted with ethyl acetate (15×3). The combined organic �Loy was dried over sodium sulfate, concentrated in vacuum to give crude product, which was washed with ethyl acetate and was purified using reverse-phase preparative HPLC (35-65% acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 10 minutes), to obtain 4-(5-(3-carbamoylphenoxy)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt (45 mg, 20,0% yield) using methanolic solution of the hydrochloride.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,01 (s, 1H), of 8.56 (s, 1H), 8,21 (d, J=6,4 Hz, 2H), 8,14 (s, 1H), 8,06 (d, J=7,6 Hz, 1H), to 7.77 (m, 7H), 7,54 (s, 1H), 7,32 (d, J=6,8 Hz, 1H), to 2.76 (d, J=3.2 Hz, 3H); MS (ESI): m/z 387,16 [M+1]+.

Example 67: trance-4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)cyclohexanecarboxylic

A. the TRANS-4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yloxy)cyclohexanecarbonyl acid. TRANS-Ethyl 4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)cyclohexanecarboxylate synthesized from 2,5-dibrom-[1,2,4]triazolo[1,5-α]pyridine, TRANS-ethyl 4-hydroxycyclohexanecarboxylate and 4-(trifluoromethyl)aniline by following the procedure described to obtain CIS-4-(2-(4-forgenerating)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)of cyclohexanol. To a solution of TRANS-ethyl 4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4 triazolo[1,5-α]pyridine-5-yloxy)cyclohexanecarboxylate (10 mg, 0,022 mmol) in methanol (5 ml) was added lithium hydroxide (5 mg, 0,2 mmol) and the mixture was heated to boiling temperature with reflux for 2 hours. The reaction mixture was neutralized and concentrated in vacuo. The residue was diluted with water and was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and was evaporated to obtain TRANS-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)cyclohexanecarboxylic acid (6 mg, 70% yield). MS (ESI): m/z 420,9 [M+1]+.

B. TRANS-4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)cyclohexanecarboxylic. A mixture of TRANS-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)cyclohexanecarboxylic acid (6 mg, of 0.014 mmol), ammonium chloride (1.5 mg, 0,03 mmol), hexaflurophosphate [dimethylamino-([1,2,3]triazolo[4,5-b]pyridine-3-yloxy)-methylene]-dimethyl-ammonium (11 mg, 0,03 mmol), N-methylmorpholine (2 mg, 0.02 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature over night. The reaction mixture was concentrated and the residue was purified using preparative TLC (elwira using 75% ethyl acetate in petroleum ether) to give the TRANS-4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)cyclohexanecarboxylate (3 mg, 50% yield) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,16 (s, 1H), 7,84 (�, J=8.4 Hz, 2H), 7,61 (d, J=8.4 Hz, 2H), 7,55 (t, J=8.4 Hz, 1H), 7,27 (d, J=8.4 Hz, 1H), 7,27 (s, 1H), of 7.19 (d, J=8.4 Hz, 1H), 6,74 (s, 1H), 4,71 (m, 1H), 2,22 (m, 3H), of 1.86 (m, 2H), 1,53 (m, 4H); MS (ESI): m/z 420,1 [M+1]+.

Example 68: 5-((1-Ethylpiperazin-4-yl)methyl)-Ν-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-((1-Ethylpiperazin-4-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. 5-((1-Benzylpiperidine-4-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine was synthesized from 1-benzyl-4-methyleneimine and 5-bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine, following the procedure described to obtain N-phenyl-5-(piperidine-4-ylmethyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. 5-((1-Benzylpiperidine-4-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,165 g, 0,354 mmol) was dissolved in ethanol (30 ml) and treated with a catalytic amount of palladium on carbon (10% wt.). The reaction mixture was stirred in an atmosphere of hydrogen gas overnight at room temperature. Because observed only trace conversion, added a drop of acetic acid and the reaction mixture was stirred at room temperature over night. The main quantity of the original substance was converted to the specified in the title compound mixed with a small amount of 5-(piperidine-4-ylmethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,]triazolo[1,5-α]pyridin-2-amine. The catalyst was removed by filtration, washed with methanol and the filtrate was concentrated under reduced pressure. The residue was purified using semi-preparative HPLC (20-70% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 3 injection, 30 minutes). The desired fractions were combined and neutralized using a column with a cation exchange resin STRATA. The eluate was concentrated under reduced pressure and dried in a vacuum oven for 5 hours. 5-((1-Ethylpiperazin-4-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine is 0.019 g, 0,047 mmol, 13,29% yield) was isolated as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) is 10.18 (s, 1H), 7,91 (d, J=8,59 Hz, 2H), of 7.64 (d, J=8,59 Hz, 2H), of 7.48-members, 7.59 (m, 2H), 6,95 (s, 1H), 3,03 (d, J=6,64 Hz, 2H), 2,82 (lat.s, 2H), and 2.26 (s, 2H), 1,99 (lat.s, 1H), 1,78 (lat.s, 2H), 1,55 (lat.s, 2H), 1,33 (lat.s, 2H), 0,89-1,02 (m, 3H);19F NMR (400 MHz, DMSO-d6) δ (M. D.) -59,9 M. D.; MS (ESI): m/z 404,2 [M+1]+.

Example 69: 5-(Piperazine-1-ylmethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbaldehyde. To a suspension of 5-bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.2 g, 0,560 mmol) in tetrahydrofuran (2.80 ml) (colorless) at -78°C was added n-butyllithium in hexane (0,470 ml, 1,176 mmol, 2.5 M solution in hexane) dropwise. Reaction�I mixture became bright yellow, and maintained at low temperature for 1 hour. Was then added undiluted N,N-dimethylformamide (0,086 g, 1,176 mmol) and the reaction mixture gave to slowly warm to room temperature. After 2 hours the reaction was completed, it was quenched at 0°C by adding 1 ml acetic acid and 10 ml of water. The crude product was extracted with ethyl acetate and the extracts were dried over sodium sulfate and evaporated to dryness. The residue was suspended in a few ml of ethyl acetate and collected by filtration. 2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbaldehyde (0.13 g, 0,424 mmol, 76% yield) was collected as a bright yellow solid and used without further purification.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,58 (s, 1H), 10,41 (s, 1H), 7.87 ft-with 8.05 (m, 3H), 7,72-7,84 (m, 1H), 7,53-of 7.70 (m, 3H).

B. tert-Butyl 4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperazine-1-carboxylate. To a suspension of 2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-carbaldehyde (0,150 g, 0,490 mmol) in dichloroethane (2,449 ml) was added tert-butylpiperazine-1-carboxylate (0,100 g, 0,539 mmol). The mixture was stirred at room temperature for 30 minutes, then added triacetoxyborohydride sodium (0,114 g, 0,539 mmol). The reaction mixture was stirred at room temperature over night. The reaction was quenched with water and the crude product extraheavy�and ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness. The residue was purified using column chromatography on biotage AB using 5-100% ethyl acetate in hexane. The desired fractions were combined and evaporated to dryness. tert-Butyl 4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperazine-1-carboxylate (0,142 g, 0,298 mmol, 60,8% yield) was isolated as a light yellow solid which was dried under vacuum and used without further purification. MS (ESI): m/z 477,1 [M+1]+.

C. 5-(Piperazine-1-ylmethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A suspension of tert-butyl 4-((2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)methyl)piperazine-1-carboxylate (0,233 g, 0,490 mmol) in dichloromethane (3 ml) was treated at room temperature with trifluoroacetic acid (1 ml, 12,98 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was purified using preparative HPLC (10-80% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 30 min, 1 injection). The desired fractions were combined and neutralized with the use of STRATA column with ion-exchange resin. 5-(Piperazine-1-ylmethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,066 g, 0,175 mmol, 35.8% of yield) was collected as white solid.1H NMR (40 MHz, DMSO-d6) δ (M. D.) 10,19 (s, 1H), 7,91 (d, J=8,59 Hz, 2H), members, 7.59-of 7.70 (m, 3H), 7,51-members, 7.59 (m, 1H), 7,11 (d, J=of 7.03 Hz, 1H), 3,95 (s, 2H), 3,34 (lat.s, 4H), 2,70-2,82 (m, 4H);19F NMR (376 MHz, δ (M. D.) -60,01 M. D.; MS (ESI): m/z 377,2 [M+1]+.

Example 70: CIS-3-(5-(4-Hydroxycyclohexanone)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide

A. CIS-4-(2-Bromo-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol. 2,5-Dibrom-[1,2,4]triazolo[1,5-α]pyridine (4,15 g, 14,99 mmol), CIS-4-aminocyclohexanecarboxylic (3.12 g, 20,58 mmol) and potassium carbonate (4,93 g, to 35.7 mmol) was added to 200-ml flask. Was added DMSO (15 ml) and the reaction mixture was placed for thorough mixing in a 100°C oil bath for 3 hours. The reaction mixture was cooled to room temperature and added water (~50 ml). The mixture was stirred for 15 minutes, then filtered through a glass filter with an average pore size, collecting not quite white solid, which was dried in vacuo at 60°C for 2 hours, to obtain the desired CIS-4-(2-bromo-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol (4,0438 g, 13,00 mmol, 87% yield).1H NMR (300 MHz, DMSO-d6) δ (M. D.) of 7.88 (d, J=compared to 7.97 Hz, 1H), 7,66 (s, 1H), 7,56 (t, J=to 8.38 Hz, 1H), at 6.92 (d, J=8,52 Hz, 1H), about 6,82 (l, J=compared to 7.97 Hz, 1H), 6.35 mm (d, J=compared to 7.97 Hz, 1H), 4,39 (lat.s, 1H), of 3.78 (lat.s, 1H), 3.45 points-to 3.64 (m, 1H), 1,76-of 1.98 (m, 2H), 1,45-of 1.76 (m, 7H), (ESI): m/z 311,3 [M+1]+.

B. Ethyl CIS-3-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamine�)benzoate. CIS-4-(2-Bromo-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol (976,7 mg, 3,14 mmol), ethyl 3-aminobenzoate (734,9 mg, of 4.45 mmol), Tris(dibenzylideneacetone)dipalladium(0) (268,0 mg, 0,293 mmol), (9,9-dimethyl-9H-Xanten-4,5-diyl)bis(diphenylphosphine) (489,5 mg, 0,846 mmol) and 2-methylpropan-2-Olathe potassium (352 mg, 3,14 mmol) was weighed into 25-ml flask. The flask was closed by a membranous septum, and purged with nitrogen. Added dioxane (4 ml), svezhezakachannyh by 5 min bubbling of nitrogen through a syringe and the reaction mixture was placed for thorough mixing in a 95°C oil bath. After 3 hours the reaction mixture was cooled to room temperature, filtered through celite using THF and then concentrated. The crude product was dissolved again in dichloromethane/methanol and loaded in column (biotage AB. Flash chromatography in methanol:dichloromethane (0-7%) gave the desired ethyl CIS-3-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzoate (0,719 g, 1,818 mmol, 57.9% of output). (ESI): m/z 396,2 [M+1]+.

C. CIS-3-(5-(4-Hydroxycyclohexanone)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoic acid. Ethyl CIS-3-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoate (0,719 g, 1,818 mmol) was treated with a tetrahydrofuran (5 ml) and 1.0 M sodium hydroxide solution (2.5 ml, 2.5 mmol). The reaction mixture was heated to 60°C for 2 hours, by which time LC/M� analysis showed what was left of the original substance. Was added ethanol (2 ml) and heating was continued for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and dichloromethane, and washed with 1 n sodium hydroxide solution. The aqueous layer was acidified with using a 10% solution of potassium dihydrogen phosphate, was extracted with ethyl acetate and the organic solution was dried over magnesium sulfate, filtered and concentrated to give CIS-3-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoic acid (299,4 mg, 0,815 mmol, 44.8% of output).1H NMR (300 MHz, DMSO-d6) δ (M. D.) case 9.83 (s, 1H), 8,35 (lat.s, 1H), 8,21 (d, J=6,59 Hz, 1H), 7,41-7,67 (m, 4H), 6,86 (d, J=8,52 Hz, 1H), of 6.31 (d, J=compared to 7.97 Hz, 1H), 6,12 (l, J=compared to 7.97 Hz, 1H), 4.61 record (lat.s, 1H), a 3.87 (lat.s, 1H), and 3.72 (lat.s, 1H), 1,59-2,07 (m, 15H), (ESI): m/z 368,5 [M+1]+.

D. CIS-3-(5-(4-Hydroxycyclohexanone)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide. CIS-3-(5-(4-Hydroxycyclohexanone)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoic acid (299,4 mg, 0,815 mmol) and methylaminopropane (357,6 mg, and 5.30 mmol) was treated with N,N-dimethylformamide (2 ml) in a 20-ml scintillation vessel. Added diisopropylethylamine (0.9 ml, 5,15 mmol) followed by the addition of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N)N',N'-tetramethylurea (HATU) (1.74 g, 4,58 mmol) and the reaction mixture is thoroughly stirred at 50°C aluminum block. After 1 hour R�promotional mixture was cooled to room temperature, was diluted with ethyl acetate and tetrahydrofuran and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The sample was dissolved in minimum amount of a mixture of 1:1 DMSO:water and purified using semi-preparative reversed-phase HPLC (0-100% acetonitrile:water with 0.1% TFA). The product was isolated as free base by dissolving in ethyl acetate, washing with saturated sodium bicarbonate solution, drying over magnesium sulfate, followed by filtration and concentration to obtain CIS-3-(5-(4-hydroxycyclohexanone)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)-N-methylbenzamide (77,7 mg, 0,204 mmol, 25,06% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ (M. D.) 9.66 as per (s, 1H), to 8.42 (d, J=4,40 Hz, 1H), to 8.19 (s, 1H), 7,90 (d, J=7,69 Hz, 1H), of 7.19-7,54 (m, 3H), 6,74 (d, J=8,52 Hz, 1H), 6,08-between 6.30 (m, 2H), a 4.53 (lat.s, 1H), of 3.77 (lat.s, 1H), 3,63 (d, J=7,69 Hz, 1H), 2,79 (d, J=4,12 Hz, 3H), 1,49-of 2.01 (m, 8H), (ESI): m/z of 381.1 [M+1]+.

Example 71: CIS-4-(2-(3-Methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol

A. CIS-4-(2-(3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol. Degassed mixture of CIS-4-(2-bromo-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol (160 mg, 0.5 mmol), 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (138 mg, 0.50 mmol), �rice(dibenzylideneacetone)diplegia(0) (46 mg, Of 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57 mg, 0.1 mmol) and tert-butoxide potassium (112 mg, 1.0 mmol) in dioxane (5 ml) was heated at 100°C in a nitrogen atmosphere over night. The reaction mixture was poured into water (20 ml), was extracted with ethyl acetate (15 ml ×3). The combined organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified on a column of silica gel (elwira using 5-50% ethyl acetate in petroleum ether) to give CIS-4-(2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol (180 mg, 72% yield). MS (ESI): m/z 508,2 [M+1]+.

B. CIS-4-(2-(3-Methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol. A mixture of CIS-4-(2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)cyclohexanol (180 mg, 0.36 mmol) and methanolic hydrochloride solution (2 M, 5 ml) was stirred at 55°C over night. The solvent was evaporated under reduced pressure to obtain crude product, which was purified using reverse-phase preparative HPLC (17-43%: acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid for 20 minutes), to obtain CIS-4-(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-silts�o)cyclohexanol (80 mg, 60% of output) in the form hydrochloride salt.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,06 (d, J=1.6 Hz, 1H), 7,78 (t, J=8,8 Hz, 2H), 7,24 (DD, J1=8,8 Hz, J2=2,0 Hz, 1H), 6,86 (d, J=8.4 Hz, 1H), 6,62 (d, J=8,0 Hz, 1H), 3,98 (m, 1H), 3,76 (m, 1H), 2,59 (s, 3H), 2,00 (m, 8H); MS (ESI): m/z 377,1 [M+1]+.

Example 72: (6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)methanol

A.(6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)methanol. 4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzene-1,2-diamine was synthesized according to the procedure similar to that described to obtain 4-(2-phenylamino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-benzene-1,2-diamine. A mixture of 4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzene-1,2-diamine (250 mg, of 0.65 mmol) and 2-hydroxiacetic (198 mg, 2.6 mmol) in hydrochloric acid (4n, 30 ml) was heated at boiling with reflux for 3 days. The mixture was evaporated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (20-50% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to obtain(6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)methanol in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride with�l (65 mg, 23.6% of output) using a methanolic solution of the hydrochloride.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,21 (s, 1H), and 8.50 (s, 1H), 8,08 (DD, J1=8.4 Hz, J2=1.2 Hz, 1H), 7,95 (d, J=8,8 Hz, 1H), 7,83 (d, J=8.4 Hz, 2H), 7,73-to 7.60 (m, 4H), 7,31 (d, J=6,0, 1H), 5,07 (s, 2H); MS (ESI): m/z 425,1 [M+1]+.

Example 73: 1-(6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)ethanol

A. 1-(6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)ethanol. 4-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzene-1,2-diamine was synthesized according to the procedure similar to that described to obtain 4-(2-phenylamino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-benzene-1,2-diamine. A mixture of 4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzene-1,2-diamine (700 mg, 1.82 mmol) and 2-hydroxypropanoic acid (328 mg, 3.65 mmol) in hydrochloric acid (4n, 30 ml) was heated at boiling with reflux for 48 hours. The mixture was evaporated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (20-50% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to obtain 1-(6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)ethanol (330 mg, 41.4% of output) in the form of trifluoroacetic acid salt, which changes�asavali in hydrochloride salt using methanolic solution of the hydrochloride. 1H NMR (400 MHz, METHANOL-d4) δ (M. D.) 8,53 (s, 1H), 8,24 (d, J=8,8 Hz, 1H), 8,08 (m, 2H), 7,82 (d, J=8,8 Hz, 1H), to 7.77 (d, J=8.4 Hz, 2H), 7,66 (m, 3H), 5,42 (m, 1H), 1,78 (d, J=6,8 Hz, 3H); MS (ESI): m/z 439,1 [M+1]+.

Example 74: 2-(6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol

A. 1-(6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)alanon. The mixture 1-(6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)ethanol (200 mg, 0,457 mmol) and manganese oxide (IV) (398 mg, up 4.57 mmol) in chloroform (30 ml) was heated at boiling with reflux for 72 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using preparative TLC with obtaining 1-(6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)ethanone (100 mg, 50.3% of output) in the form of solids.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 13,66 (s, 1H), 10,19 (s, 1H), 8,55 (s, 1H), 8,32 (s, 1H), 8,04 (m, 1H), of 7.88 (m, 2H), 7,76-members, 7.59 (m, 4H), 7,31 (d, J=7,2 Hz, 1H), 2,74 (s, 3H); MS (ESI): m/z 437,1 [MH+1]+.

B. 2-(6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol. The mixture 1-(6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)ethanone (100 mg, 0,23 mmol) in anhydrous tetrahydrofuran (10 ml) was stirred at 0°C for 0,5 hours. Then slowly added methylmagnesium (0.5 ml, 1.6 M in diethyl ether) and motility (2.0 ml, 3.0 M in diethyl ether) and the resulting mixture was stirred at 0°C for 2 hours, warmed to room temperature and stirred over night. Was added a saturated aqueous solution of ammonium chloride (15 ml) and the mixture was extracted with ethyl acetate (10 ml ×3). The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The residue was purified using preparative TLC with obtaining 2-(6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol (28 mg, 26.9% of output) in the form of solids.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) of 8.34 (s, 1H), 7,90 (lat.s, 1H), 7,81 (d, J=8,8 Hz, 2H), 7,72 (m, 2H), 7,55 (m, 3H), 7.23 percent (d, J=7,2 Hz, 1H), of 1.74 (s, 6H); MS (ESI): m/z to $ 453.1 [M+1]+.

Example 75: 6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazole-2-carboxamide

A. 5-(2-(Trichloromethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 4-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)benzene-1,2-diamine (300 mg, 0,78 mmol) and methyltrichlorosilane (165 mg, 0,94 mmol) in acetic acid (10 ml) was stirred at room temperature for 3 hours. To the mixture was added water (15 ml) and the precipitate collected by filtration. Solid �raavali water and dried in vacuum to give 5-(2-(trichloromethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (380 mg, 95,5% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) is 10.18 (s, 1H), to 8.38 (s, 1H), 7,98 (d, J=8,0 Hz, 1H), 7,86 (d, J=8.4 Hz, 3H), 7,74-members, 7.59 (m, 4H), 7,30 (DD, J1=1.2 Hz, J2=1.2 Hz, 1H); MS (ESI): m/z 511,0 [M+1]+.

B. 6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-carbonitrile. A solution of 5-(2-(trichloromethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (380 mg, 0,745 mmol) in methanolic ammonia solution (20 ml) was stirred at 0°C to room temperature for 2 hours. The solvent was removed under reduced pressure to obtain crude 6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-carbonitrile (300 mg, 96.1% of output). MS (ESI): m/z 420,1 [M+1]+.

C. 6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazole-2-carboxamide. A mixture of 6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-carbonitrile (300 mg, 0.5 mmol), hydrogen peroxide (30%, 1.0 ml) and sodium hydroxide (40 mg, 1.0 mmol) in dimethylsulfoxide (5 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water (15 ml) and the mixture was extracted with ethyl acetate (15 ml ×3). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified using reverse-phase preparative HPLC(35-65% acetonitrile + 0,1% trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, within 15 minutes) to give 6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-1H-benzo[d]imidazol-2-carboxamide (65 mg, 29.7% of output) in the form of a salt of trifluoroacetic acid, which was converted into hydrochloride salt using methanolic solution of the hydrochloride.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,19 (s, 1H), 8,37 (s, 1H), 7,95 (m, 5H), 7,73 (m, 4H), 7,29 (d, J=7,2 Hz, 1H); MS (ESI): m/z 438,1 [M+1]+.

Example 76: 5-(2-(Methoxymethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-(2-(Methoxymethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. 5-(2-(Chloromethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine was synthesized according to the procedure similar to the one used to obtain 5-(2-(chloromethyl)-1H-benzo[d]imidazol-5-yl)-N-phenyl-[1,2,4]triazolo[1,5-α]pyridin-2-amine. A mixture of 5-(2-(chloromethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (150 mg, 0,339 mmol) and methanolate sodium (55 mg, 1.02 mmol) in methanol (10 ml) was heated at boiling with reflux for 1 hour. The solvent was removed under reduced pressure and the residue was poured into water (10 ml). The aqueous layer was extracted with ethyl acetate (10 ml ×3). The organic layer was dried over sodium sulfate, filtered� and the filtrate concentrated. The residue was purified using reverse-phase preparative HPLC (25-55% acetonitrile + 0,1% trifluoroacetic acid in water + 0,1% trifluoroacetic acid, over 15 min) to obtain 5-(2-(methoxymethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (55 mg, 37% yield) in the form of trifluoroacetic acid salt, which was converted into hydrochloride salt using methanolic solution of the hydrochloride.1H NMR (400 MHz, METHANOL-d4) δ (M. D.) to 8.57 (s, 1H), 8,24 (d, J=8,8 Hz, 1H), 8,13-with 8.05 (m, 2H), 7,84 (d, J=8,8 Hz, 1H), 7,76 (d, J=8.4 Hz, 2H), 7,69 (d, J=7,2 Hz, 1H), 7,63 (d, J=8.4 Hz, 2H), 5,12 (s, 2H), 3,69 (s, 3H); MS (ESI): m/z 385,1 [M+1]+.

Example 77: 1-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)piperidine-4-ol

A. 1-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridin-5-yl)piperidine-4-ol. 5-Bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,200 g, 0,549 mmol) and piperidine-4-ol (0,170 g, 1,680 mmol) was dissolved in N,N-dimethylformamide (2 ml) and stirred at 80°C for 20 hours. The solution was cooled to room temperature and diluted with water (8 ml) and received no white precipitate was collected and washed with water (2 ml). The substance was purified using column flash chromatography on silica gel (5-100% ethyl acetate in hexane) to give product as a white solid (0,152 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ (M. D.) for 10.08 (s, 1H), 7,92 (d, J=8,59 Hz, 2H), 7,63 (d, J=is 8.74 Hz, 2H), 7,52 (t, J=8,20 Hz, 1H), 7,17 (d, J=8,54 Hz, 1H), 6,47 (d, J=7,76 Hz, 1H), to 4.81 (d, J=4.20 Hz, 1H), 3,71-of 3.85 (m, 3H), 3,10 (t, J=9,59 Hz, 2H), of 1.97 (d, J=of 11.08 Hz, 2H), 1,59-of 1.74 (m, 2H). MS (ESI) m/z 378,2 [M+1]+.

Example 78: (S)-2-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)propan-1-ol

A. (S)-2-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)propan-1-ol. 5-Bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0,250 g, 0,700 mmol) was suspended in (S)-2-aminopropan-1-Ola (3.0 ml, of 38.5 mmol) and stirred at 110°C for 24 hours. The orange solution was cooled to room temperature and added to water (20 ml) and triturated into a powder. Received no white precipitate was collected, washed with water (20 ml) and dried in vacuo at 60°C for 12 hours to give product as an off-white solid (0,210 g, 85% yield).1H NMR (300 MHz, DMSO-d6) δ (M. D.) 10,13 (s, 1H), 8,02 (d, J=8,58 Hz, 2H), 7,72 (d, J=8,72 Hz, 2H), 7,55 (t, J=of 8.28 Hz, 1H), to 6.88 (d, J=to 8.41 Hz, 1H), 6,28-6,38 (m, 2H), 5,13 (t, J=of 5.29 Hz, 1H), 3,83-3,95 (m, 1H), 3,65-and 3.72 (m, 2H), To 1.37 (d, J=of 6.46 Hz, 3H). MS (ESI) m/z 352,2 [M+1]+.

(R)-2-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]pyridine-5-ylamino)propan-1-ol was obtained by following the same procedure using (R)-2-aminopropan-1-ol as the starting material.

Example 79: (S)-5-(piperidine-3-yloxy)-N-(-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. ((S)-tert-Butyl 3-(2-bromo-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)piperidine-1-carboxylate. To a clear colorless solution of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0,262 g, 1.3 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (is 0.102 g, 2,52 mmol, 60% in mineral oil) slowly in portions at 0°C in an atmosphere of nitrogen. The reaction mixture was stirred at 0°C for 1 hour followed by the addition of 2,5-dibrom-[1,2,4]triazolo[1,5-α]pyridine (0.300 g, distributed among 1.083 mmol) at 0°C. the Reaction mixture was stirred at room temperature overnight in a nitrogen atmosphere. When the reaction was completed, as shown by the LC/MS analysis, the reaction mixture was poured into water/saturated salt solution and was extracted with ethyl acetate several times. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified by chromatography (elwira using 0-100% ethyl acetate in hexane) to give (S)-tert-butyl 3-(2-bromo-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)piperidine-1-carboxylate as a white solid (0,273 g, 63% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 7,74 (m, 1H), 7,40 (d, J=8,69 Hz, 1H), about 6,82-6,89 (m, 1H), 4.95 points (the Shire.s, 1H), 4,06-4,16 (m, 1H), 3,78-3,88 (m, 1H), 3,29 (d, J=be 13.42 Hz, 1H), 1,92-of 2.08 (m, 2H), 1,79-of 1.92 (m, 1H), 1,48-1,58 (m, 1H), 1,33 (lat.s, 2H), of 0.91 (lat.s, 6H); MS (ESI) m/z 398,27 [M+1]+.

B. (S)-tert-Butyl 3-(2-(4-(trifluoromethyl)phenyl�Mino)-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)piperidine-1-carboxylate. To a solution of (S)-tert-butyl 3-(2-bromo-[1,2,4]triazolo[1,5-α]pyridine-5-yloxy)piperidine-1-carboxylate (0,270 g, 0,680 mmol) in dioxane (10 ml) was added 4-(trifluoromethyl)aniline (0.219 g, 1,359 mmol), tert-butoxide sodium (0,131 g, 1,359 mmol), (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0,079 g, 0,136 mmol) and Tris(dibenzylideneacetone)palladium (0,065 g, 0,071 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture was heated at 100°C for 1.5 hours. When the reaction was completed, as shown by the LC/MS analysis, the reaction mixture was poured into water/saturated salt solution and was extracted with ethyl acetate several times. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified by chromatography (elwira using 0-100% ethyl acetate in hexane) to give (S)-tert-butyl 3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yloxy)piperidine-1-carboxylate as a yellow solid (0,280 g, 86% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,19 (s, 1H), 7,84-a 7.92 (m, 2H), 7,56-7,66 (m, 3H), of 7.19-7,27 (m, 1H), 6,70 (d, J=of 7.86 Hz, 1H), to 4.92 (lat.s, 1H), of 4.09-4,18 (m, 1H), 3,29 (lat.s, 1H), 2,93-3,05 (m, 1H), 1,88-of 2.09 (m, 1H), 1,45-to 1.60 (m, 1H), 1,21-of 1.40 (m, 4H), of 0.82 to 0.99 (m, 6H); MS (ESI) m/z 478,48 [M+1]+.

C. (S)-5-(piperidine-3-yloxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. The clear orange solution of (S)-tert-butyl 3-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-α]�of iridin-5-yloxy)piperidine-1-carboxylate (0,275 g, 0,576 mmol) in methylene chloride (10 ml) was added trifluoroacetic acid (5 ml) at room temperature. The reaction mixture was stirred at room temperature over night. When the reaction was completed, as shown by the LC/MS analysis, the reaction mixture was concentrated and the residue was purified column chromatography on silica gel (elwira using 0-15% methanol solution of ammonia in chloroform) and the desired fraction was passed through a STRATA column with the receipt of the form of the free base specified in the title compounds as a pale yellow solid (99.8% purity, 0,176 g, 81% yield).1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,23 (s, 1H), a 7.87 (d, J=8,49 Hz, 2H), 7,63 (d, J=8,54 Hz, 2H), EUR 7.57 (t, J=8,32 Hz, 1H), 7,22 (d, J=8,69 Hz, 1H), 6,69 (d, J=of 7.86 Hz, 1H), 4,63-4.72 in (m, 1H), 3,20 (d, J=13,47 Hz, 1H), 2,76-2,84 (m, 1H), 2,69 (DD, J=7,98, 12,23 Hz, 1H), 2,57 (lat.s, 1H), 2,13-of 2.21 (m, 1H), 1,63-to 1.79 (m, 2H), 1,46-of 1.57 (m, 1H); MS (ESI) m/z 378,36 [M+1]+.

(R)-5-(piperidine-3-yloxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine was obtained by following the same procedure using (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate as the starting material.

Example 80: 5-(Morpholinomethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

A. 5-(Morpholinomethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine. To a solution/suspension of 5-bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]�triazolo[1,5-α]pyridin-2-amine (300 mg, 0,8400 mmol) in dioxane (2 ml) and water (1 ml) was added trifter(morpholinomethyl)borate potassium (348 mg, 1,680 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24,3 mg, 0,042 mmol), palladium acetate(II) (9,43 mg, 0,042 mmol), Tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0,042 mmol) and potassium carbonate (348 mg, 2,52 mmol) under an inert atmosphere. After the reaction mixture was barbotirovany nitrogen for 5 minutes and then the reaction mixture was heated to 100°C for 3 hours. The development of the reaction was monitored using LC/MS analysis. After the starting material was consumed, the reaction mixture was filtered through the filter cartridge and the solvent was removed in vacuum. The crude substance was again dissolved in dimethylsulfoxide and purified using semi-preparative HPLC (20-100% acetonitrile + 0.1% of trifluoroacetic acid in water + 0.1% of trifluoroacetic acid, 20 min). The fractions containing the product were loaded into strata-X column to remove trifluoroacetic acid and then the methanol was evaporated in vacuum. The solid is dried in vacuum. 5-(Morpholinomethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (20.7 mg, 0,055 mmol, a 6.53% yield) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ (M. D.) 10,19 (s, 1H), 7,91 (d, J=8,59 Hz, 2H), of 7.48-7,73 (m, 4H), 7,12 (s, 1H), 4,00 (s, 5H), 3,58-3,74 (m, 4H), 2,59 (d, J=8,98 Hz, 4H). MS (ESI): m/z 378,2 [M+1]+.

Example 81: CIS-6-(5-(4-Hydr