5-anilinoimidazopyridines and methods for using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazopyridines of formula I

and to their pharmaceutically acceptable salts where Z1 represents CR1; R1 represents H; R1' represents H; Z2 represents CR2; Z3 represents CR3 or N; R2 and R3 are independently selected from H, halogen; R4 represents H; Y represents W-C(O)-; W represents or , R5 represents H; X1 is selected from R11' and -OR11'; each R11 independently represents H, C1-C12alkyl, C2-C8alkenyl; X4 represents , R6 represents H, halogen, cyclopropyl or -(CR19R20)n-SR16; R6 represents H, halogen; p represents 0, 1, 2 or 3; n represents 0, 1 or 2; where each specified alkyl in R11 is independently substituted by one or two groups independently selected from halogen, -(CR19R20)nOR16 and R21; each R16 independently represents H, C1-C12alkyl; R19 and R20 are independently selected from H, C1-C12alkyl; R21 represents cyclopropyl.

EFFECT: invention refers to a pharmaceutical composition for treating hyperproliferative disorder.

10 cl, 25 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority based on provisional application U.S. No. 61/015129, filed December 19, 2007, and provisional application U.S. No. 61/054014, filed may 16, 2008, the contents of which are incorporated into this description by reference in its entirety.

The SCOPE of the PRESENT INVENTION

The present invention relates to imidazopyridine, which have anticancer activity, and more specifically to imidazopyridines that inhibit the activity of MEK kinase. The present invention also relates to methods of using these compounds forin vitro, in situandin vivodiagnosis or treatment of mammalian cells or associated pathological conditions.

BACKGROUND of the PRESENT INVENTION

In search of understanding of how Ras transmit signals from extracellular growth, it became clear that the road MAP (mitogen-activated protein) kinase (MAPK) is a critical path between associated with membranes Ras and nuclei. The MAPK path includes the cascade acts phosphorylation, involving three key kinases, namely Raf, MEK (MAP kinase kinase) and ERK (MAP kinase). Active GTP-bound Ras leads to activation and indirect phosphorylation of Raf kinase.

Then Raf phosphorylates MEK1 and 2 on two serine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (hn et al., Methods in Enzymology2001, 332, 417-431). Then activated MEK phosphorylates its only known substrate, MAP kinases, ERK1 and 2. ERK phosphorylation through MEK occurs Y204 and T202 for ERK1 and Y185 and T183 for ERK2 (Ahn et al.,Methods in Enzymology2001, 332, 417-431). Phosphorylated ERK dimerizes and then moves to the nucleus where it accumulates (Khokhlatchev et al.,Cell1998, 93, 605-615). In the nuclei of ERK is involved in several important cellular functions, including, but not limited to, nuclear transport, signal transduction, DNA repair, Assembly, and translocation of nucleosomes and the processing and translation of mRNA (Ahn et al., Molecular Cell 2000, 6, 1343-1354). In General, treatment of cells with growth factors leads to activation of ERK1 and 2, resulting in proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res. 1998, 74, 49-139).

There is considerable evidence that genetic mutations in protein kinases and/or overexpression of its protein kinases are involved in the cascade of reactions MAP kinases, eventually leading to uncontrolled cell proliferation and ultimately to the formation of tumors, proliferative diseases. For example, some cancers contain mutations that lead to continuous activation of the cascade of reactions associated with the constant production of growth factors. Other mutations can lead to defects in decontamination GTP-associated Ras complex, which again leads to the activation of a cascade of reactions of MAP kinase. Mutated, oncogenic forms of Ras are found in 50% of cases of colon cancer and more than 90% of cancers of the pancreas, as well as many other types of cancer (Kohl et al., Science 1993, 260, 1834-1837). Recently, skin disease mutations were identified in more than 60% of malignant melanomas (Davies, H. et al., Nature 2002, 417, 949-954). These mutations in skin disease lead to constitutive active cascade reactions of MAP kinase. Samples of primary tumors and cell lines also exhibit constitutive or an overactive cascade reactions of MAP kinase for cancer of the pancreas, colon, lung, ovarian and kidney (Hoshino, R. et al., Oncogene 1999, 18, 813-822).

MEK has proved itself as an attractive therapeutic target in the cascade of reactions MAP kinase. MEK, in the forward direction from Ras and Raf, is highly specific in phosphorylation of MAP kinase; indeed, the only known substrates for phosphorylation of MEK are the MAP kinases, ERK1 and 2. In some studies it has been shown that inhibition of MEK provides potential therapeutic benefits. For example, it was shown that small molecule MEK inhibitors inhibit the growth of human tumors in Nude mice with xenografts (Sebolt-Leopold et al.,Nature Medicine1999 5 (7), 810-816; Trachet et al., AACR Apr. 6-10, 2002, Poster #5426; Tecle, H. IBC 2.sup.nd International Conference of Protein Kinases, Sep. 9-10, 2002), block static allodynia in animals (WO 01/05390 published Jan. 25, 2001) and inhibit the growth of cells in acute myeloid leukemia (Milella et al.,J. Clin. Invest.2001, 108 (6), 851-859).

They also discussed some small molecule MEK inhibitors, for example, in WO 02/06213, WO 03/077855 and WO 03/077914. Therefore, there is still a need in the creation of MEK inhibitors as an effective and safe therapeutic agents for the treatment of various proliferative disease conditions, such as conditions associated with hyperactivity of MEK, as well as diseases modulated by the MEK cascade of reactions.

The INVENTION

The present invention generally relates to imidazopyridine formula I (and/or their solvate, hydrates and/or salts)that have anticancer and/or anti-inflammatory activity and more specifically the activity of inhibition of MEK kinase. Some of hyperproliferative and inflammatory disorders are characterized by a modulation function MEK kinase, for example, due to mutations or overexpression of proteins. Accordingly, the compounds of the present invention and their compositions can be used for the treatment of hyperproliferative disorders such as cancer or inflammatory diseases such as rheumatoid arthritis.

and its salts, where

Z1represents CR1or N;

R1represents H, C1-C3alkyl, halogen, CF3, CHF2CN, ORAor NRARA;

R1'represents H, C1-C3alkyl, halogen, CF3, CHF2CN, ORAor NRARA;

where each RAindependently represents N or C1-C3alkyl;

Z2represents CR2or N;

Z3represents CR3or N; provided that only one of the Z1, Z2and Z3can simultaneously represent N;

R2and R3independently selected from H, halogen, CN, CF3, -OCF3, -NO2, -(CR14R15)nC(=Y')R11, -(CR14R15)nC(=Y')OR11, -(CR14R15)nC(=Y')NR11R12, -(CR14R15)nNR11R12, -(CR14R15)nOR11, -(CR14R15)nSR11, -(CR14R15)nNR12C(=Y')R11, -(CR14R15)nNR12C(=Y')OR11, -(CR14R15)nNR13C(=Y')NR11R12, -(CR14R15)nNR12SO2R11, -(CR14R15)nOC(=Y')R11, -(CR14R15)nOC(=Y')OR11, -(CR14R15)nOC(=Y')NR11R12, -(CR14R15)nOS(O) 2(OR11), -(CR14R15)nOP(=Y')(OR11)(OR12), -(CR14R15)nOP(OR11)(OR12), -(CR14R15)nS(O)R11, -(CR14R15)nS(O)2R11, -(CR14R15)nS(O)2NR11R12, -(CR14R15)nS(O)(OR11), -(CR14R15)nS(O)2(OR11), -(CR14R15)nSC(=Y')R11, -(CR14R15)nSC(=Y')OR11, -(CR14R15)nSC(=Y')NR11R12C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, carbocycle, heterocyclyl, aryl and heteroaryl;

R4represents H, C1-C6alkyl or C3-C4carbocyclic;

Y W represents-C(O) -, or W';

W representsor;

R5represents H or C1-C12alkyl;

X1selected from R11'and-OR11'; if X1is an R11'X1optionally taken together with R5and the nitrogen atom to which they are attached, form a 4-7-membered saturated or unsaturated ring containing 0-2 additional heteroatoms selected from O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2 , oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17, -(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21;

each R11'independently represents H, C1-C12alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heterocyclic, aryl or heteroaryl is;

R11, R12and R13independently represent H, C1-C12alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heterocyclic, aryl or heteroaryl,

or R11and R12together with the nitrogen to which they are attached, form a 3-8-membered saturated, unsaturated or aromatic ring containing 0-2 heteroatoms selected from O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2C1-C6alkyl, -OH, -SH, -O(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SO2(C1-C6alkyl), -CO2H, -CO2(C1-C6alkyl), -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHSO2(C1-C6alkyl), -N(C1-C6alkyl)SO2(C1-C6alkyl), -SO2NH2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)NH(C1-C6alkyl), -N(C 1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6alkyl) and-N(C1-C6alkyl)C(O)O(C1-C6alkyl);

R14and R15independently selected from H, C1-C12of alkyl, aryl, carbocycle, heterocyclyl and heteroaryl;

W' represents a

whererepresents a

each X2independently represents O, S or NR9;

each R7independently selected from H, halogen, CN, CF3, -OCF3, -NO2, -(CR14R15)nC(=Y')R11, -(CR14R15)nC(=Y')OR11, -(CR14R15)nC(=Y')NR11R12, -(CR14R15)nNR11R12, -(CR14R15)nOR11, -(CR14R15)nSR11, -(CR14R15)nNR12C(=Y')R11, -(CR14R15)nNR12C(=Y')OR11, -(CR14R15)nNR13C(=Y')NR11R12, -(CR14R15)nNR12SO2R11, -(CR14R15)nOC(=Y')R11, -(CR14R15)nOC(=Y')OR11, -(CR14R15)nOC(=Y')NR11R12, -(CR14R15)nOS(O)2(OR11), (CR 14R15)nOP(=Y')(OR11)(OR12), -(CR14R15)nOP(OR11)(OR12), -(CR14R15)nS(O)R11, -(CR14R15)nS(O)2R11, -(CR14R15)nS(O)2NR11R12, -(CR14R15)nS(O)(OR11), -(CR14R15)nS(O)2(OR11), -(CR14R15)nSC(=Y')R11, -(CR14R15)nSC(=Y')OR11, -(CR14R15)nSC(=Y')NR11R12C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, carbocycle, heterocyclyl, aryl and heteroaryl;

each R8independently selected from C1-C12of alkyl, aryl, carbocycle, heterocyclyl and heteroaryl;

R9selected from H, -(CR14R15)nC(=Y')R11, -(CR14R15)nC(=Y')OR11, -(CR14R15)nC(=Y')NR11R12, -(CR14R15)qNR11R12, -(CR14R15)qOR11, -(CR14R15)qSR11, -(CR14R15)qNR12C(=Y')R11, -(CR14R15)qNR12C(=Y')OR11, -(CR14R15)qNR13C(=Y')NR11R12, -(CR14R15)qNR12SO2R11, -(CR14R15)qOC(=Y')R11, -(CR14R15)qOC(=Y')OR11, -(CR14R15)q OC(=Y')NR11R12, -(CR14R15)qOS(O)2(OR11), -(CR14R15)qOP(=Y')(OR11)(OR12), -(CR14R15)qOP(OR11)(OR12), -(CR14R15)nS(O)R11, -(CR14R15)nS(O)2R11, -(CR14R15)nS(O)2NR11R12C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, carbocycle, heterocyclyl, aryl and heteroaryl;

R10represents H, C1-C6alkyl or C3-C4carbocyclic;

X4represents a

R6represents H, halogen, C1-C6alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heteroaryl, heterocyclyl, -OCF3, -NO2, -Si(C1-C6alkyl)3, -(CR19R20)nNR16R17, -(CR19R20)nOR16or -(CR19R20)n-SR16;

R6'represents H, halogen, C1-C6alkyl, carbocyclic, CF3, -OCF3, -NO2, -Si(C1-C6alkyl)3, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16C2-C8alkenyl, C2-C8quinil, heterocyclyl, aryl or heteroaryl;

p not only is em a 0, 1, 2 or 3;

n represents 0, 1, 2 or 3;

q represents 2 or 3;

where each specified alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl in R1, R2, R3, R4, R5, R6, R6', R7, R8, R9, R10, R11, R11', R12, R13, R14, R15and RAindependently optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl)3, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -(CR19 R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17, -(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21;

each R16, R17and R18independently represents H, C1-C12alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heterocyclic, aryl or heteroaryl where the specified alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl or heteroaryl optionally substituted by one or more groups selected from halogen, CN, -OCF3, CF3, -NO2C1-C6of alkyl, -OH, -SH, -O(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SO2(C1-C6alkyl), -CO2H, -CO2(C1-C6alkyl), -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHSO2(C1-C6alkyl), -N(C1-C6alkyl)SO2(C1-C6alkyl), -SO2NH2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -OC(O)NH2, -OC(O)NH(C -C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)NH(C1-C6alkyl), -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6alkyl) and-N(C1-C6alkyl)C(O)O(C1-C6alkyl);

or R16and R17together with the nitrogen to which they are attached, form a 3-8-membered saturated, unsaturated or aromatic ring containing 0-2 heteroatoms selected from O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN, -OCF3, CF3, -NO2C1-C6of alkyl, -OH, -SH, -O(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SO2(C1-C6alkyl), -CO2H, -CO2(C1-C6alkyl), -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHSO2(C1-C6alkyl), -N(C1-C6alkyl)SO2(C1-C6alkyl), -SO2NH2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)NH(C1-C6alkyl), -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6alkyl) and-N(C1-C6alkyl)C(O)O(C1-C6alkyl);

R19and R20independently selected from H, C1-C12of alkyl, -(CH2)n-aryl, -(CH2)n-carbocycle, -(CH2)n-heterocyclyl and -(CH2)n-heteroaryl;

R21represents a C1-C12alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heterocyclic, aryl or heteroaryl, where each member of R21optionally substituted by one or more groups selected from halogen, oxo, CN, -OCF3, CF3, -NO2C1-C6of alkyl, -OH, -SH, -O(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SO2(C1-C6alkyl), -CO2H, -CO2(C1-C6alkyl), -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHSO2(Csub> 1-C6alkyl), -N(C1-C6alkyl)SO2(C1-C6alkyl), -SO2NH2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)NH(C1-C6alkyl), -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6alkyl) and-N(C1-C6alkyl)C(O)O(C1-C6alkyl);

each Y' independently represents O, NR22or S; and

R22represents H or C1-C12alkyl.

The present invention includes a composition (e.g., pharmaceutical composition)comprising a compound of formula I (and/or its solvate, hydrates and/or salts) and a carrier (a pharmaceutically acceptable carrier). The present invention also includes a composition (e.g., pharmaceutical composition)comprising a compound of formula I (and/or its solvate, hydrates and/or salts) and a carrier (a pharmaceutically acceptable carrier), further comprising a second chemotherapeutic and/or second anti-inflammatory agent. Compositions of the present invention can be used is La inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (for example, in humans). Compositions of the present invention can also be used for the treatment of inflammatory diseases in mammals (e.g. humans).

The present invention includes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof, alone or in combination with a second chemotherapeutic agent.

The present invention includes a method of treating inflammatory disease in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof, alone or in combination with a second anti-inflammatory agent.

The present invention includes a method of using compounds of the present invention for in vitro, in situ and in vivo diagnosis or treatment of cells, organisms, mammals, or associated pathological conditions.

A DETAILED description of the PREFERRED OPTIONS

The following is a detailed description of some preferred variants of the present invention, examples of which are illustrated by the use of the accompanying structures and formulas. Although the present invention is disclosed in connection with the above options, it should be understood that they in no way limit the present invention the specified options. On the contrary, the present invention includes all alternatives, modifications and equivalents that may be included in the scope of the present invention, which is defined by the claims. Specialists will be apparent many methods and materials similar or equivalent to those disclosed in the present description, which can be used in the practice of the present invention. The present invention is in no way limited to the disclosed here are methods and materials. If one or more of the incorporated references, patents and similar materials differ or contradict the description, including, but not limited to, definitions of terms, use of terms, description of methods, or the like, then consider the description has the preference.

DEFINITION

The term "alkyl" in the sense used here, refers to saturated linear or branched-chain monovalent hydrocarbon radical containing from one to twelve carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1 pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 1-heptyl, 1-octyl etc.

The term "alkenyl" refers to linear or branched apostolopoulou hydrocarbon radical, consisting of two to twelve carbon atoms, with at least one site of unsaturation, i.e. a carbon-carbon, sp2a double bond where indicated alkanniny radical includes radicals having "CIS" and "TRANS" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylenic or vinyl (-CH=CH2), allyl (-CH2CH=CH2and so on

The term "quinil" refers to a linear or branched monovalent hydrocarbon radical, consisting of two to twelve carbon atoms, with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to, ethinyl (-C≡CH), PROPYNYL (propargyl, -CH2C≡CH), etc.

The terms "carbocycle", "carbocyclic", "carbocyclic ring" and "cycloalkyl" refers to a monovalent non-aromatic, saturated or partially unsaturated ring containing from 3 to 12 carbon atoms in the case of a monocyclic ring or 7 to 12 carbon atoms in the case of the bicyclic ring. Bicyclic carbocycle containing from 7 to 12 atoms can be, for example, bicyclo[4.5], [5.5], [5.6] or [6.6] system, and bicyclic carbocycle containing 9 or 10 ring atoms, may represent a bicyclo[5,6] or [6,6] system, or can be bridged systems, so the mi as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonan. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl, cyclododecyl etc.

The term "aryl" means a monovalent aromatic hydrocarbon radical containing 6 to 18 carbon atoms obtained by removing one hydrogen atom from a single carbon atom of the original aromatic ring system. Some aryl group designated in the examples as "Ar". Aryl includes bicyclic radicals comprising an aromatic ring condensed with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzene, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl etc.

The terms "heterocycle", "heterocyclyl" and "heterocyclic ring" are used here interchangeably, and they refer to a saturated or partially unsaturated (i.e. containing one or more double and/or triple with the ides in the ring) the carbocyclic radical, containing from 3 to 18 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulphur and the remaining ring atoms are C, where one or more of the ring atoms optionally substituted independently one or more of the substituents disclosed hereinafter. A heterocycle may be a monocycle containing from 3 to 7 ring members (2 to 6 carbon atoms and from 1 to 4 heteroatoms selected from N, O, P and S), or bicyclo containing from 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), e.g., bicyclo[4.5], [5.5], [5.6] or [6.6] system. Heterocycles disclosed in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.(1960) 82:5566. The term "heterocyclyl" also includes radicals where heterocyclic radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, tetrahydropyranyl, dihydropyran, tetrahydrothiopyran, piperidine, morpholine, timehole the sludge, dioxane, piperazinil, homopiperazine, azetidine, oxetane, titanyl, homopiperazine, oxetanyl, tepanil, oxazepines, diazepines, thiazepines, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, dithienyl, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolopyrimidines, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes and azabicyclo[2.2.2]hexanal. Spiroergometry also included in the scope of the specified definition. Examples of heterocyclic groups, where the ring atoms is substituted by an oxo (=O) fragments, are pyrimidinones and 1,1-dioxothiazolidine.

The term "heteroaryl" refers to a monovalent aromatic radical consisting of 5 - or 6-membered rings, and includes a condensed ring systems (at least one of which is aromatic), consisting of 5-18 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridine), imidazolyl, imidazopyridines, pyrimidinyl (including, for example, 4-hydroxypyrimidine), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolin, pyrrolyl, chinoline, ethenolysis, indolyl, be imidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, triazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properidine.

These heterocyclic or heteroaryl group may be attached via carbon (uglerodsesola) or nitrogen (ottsvetaniya), where possible. So, for example (but not limitation), linked through a carbon heterocycles or heteroaryl can be connected at positions 2, 3, 4, 5, or 6 of a pyridine, in positions 3, 4, 5 or 6 pyridazine, in positions 2, 4, 5, or 6 of a pyrimidine, in positions 2, 3, 5 or 6 pyrazine, in positions 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, in positions 2, 4, or 5 oxazole, imidazole or thiazole, positions 3, 4 or 5 isoxazol, pyrazole or isothiazole, in positions 2 or 3 of aziridine, in positions 2, 3 or 4 azetidine, the provisions 2, 3, 4, 5, 6, 7 or 8 of a quinoline or provisions 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

So, for example (but not limitation), linked through nitrogen heterocycles or heteroaryl can be connected to position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, Piras is Lina, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, in position 2 of a isoindole, or isoindoline in position 4 of the research and in position 9 carbazole or β-carboline.

The term “halogen” refers to F, Cl, Br or I. the Heteroatoms present in heteroaryl or heterocyclyl include their oxidized forms, such as the N+→ O-, S(O), and S(O)2.

The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, when a subject to prevent or reduce (reduce undesired physiological disorders or diseases, such as development or metastasis of the cancer. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviating symptoms, reducing the extent of disease, stabilization (i.e., the absence of worsening) state of disease, delay or slowing of disease progression, relief or temporary relief of painful conditions and remission (whether partial or total), whether noticeable or not noticeable. The term "treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Those in need of treatment subjects include those that have already been painful the status or violation of, as well as those who are predisposed to such painful conditions or disorders, or those in respect of which the necessary prevention of these illnesses or disorders.

The phrase "therapeutically effective amount" means such amount of the compounds of the present invention that (i) treats or prevention of a specific disease, condition or violation of, (ii) relaxes, improves or eliminates one or more symptoms of the particular disease, condition or violation, or (iii) prevents or slows down the occurrence of one or more of the symptoms described here, specific diseases, conditions or disorders. In the case of cancer a therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., to slow to some extent and preferably stop) infiltration of cancer cells into peripheral organs; inhibit (i.e., to slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or reducing to some extent one or more symptoms associated with cancer. With regard to the extent to which specified the drug may prevent growth and/or kill existing cancer cells and, this degree may be cytostatic and/or cytotoxic. For cancer therapy efficacy can be measured, for example, assessing the time to disease progression (TTP) and/or determining the extent of reaction (RR).

The term "abnormal cell growth" and "hyperproliferative violation" is used in this application interchangeably. "Abnormal cell growth", in the sense as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This growth includes, for example, an abnormal growth of: (1) tumor cells (tumors)that proliferate at the expense of the expression of the mutated tyrosine kinase or overexpression of the receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant activation of tyrosine kinase; (3) any tumors that proliferate at the expense of receptor tyrosine kinase; (4) any tumors that proliferate due to aberrant activation of the serine/trionychinae; and (5) benign and malignant cells of other proliferative diseases in which aberrant activation of the serine/trionychinae.

The terms "cancer" and "cancerous" refer to or describe the physiological condition of mlekovita them, that is typically characterized by a misaligned cell growth. The term "tumor" includes one or more of the cancer cells. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid leukemia. More specific examples of cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneal cavity, hepatocellular cancer, stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver cancer, hepatoma, breast cancer, colorectal cancer, rectal cancer, colorectal cancer, endometrial carcinoma or carcinoma of the cervix, carcinoma of the salivary glands, kidney cancer or renal cell cancer, prostate cancer, cancer of the vagina, thyroid cancer, liver carcinoma, anal carcinoma, carcinoma of the penis, acute leukemia, as well as cancers of the head/brain and neck cancer.

The term "chemotherapeutic agent" refers to a compound that can be used for cancer treatment. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX is, AstraZeneca), sutent (SU11248, Pfizer), letrozole (FEMARA®, Novartis), machinemessiah (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fu), leucovorin, rapamycin (Sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs) and gefitinib (IRESSA®, AstraZeneca), AG1478 effect, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® (cyclophosphamide; alkyl sulphonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodepa, carboquone, matureup and uredepa; ethylenimines and methylmelamine, including altretamin, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylaniline; acetogenins (especially bullatacin, bullatacin); camptothecin (including the synthetic analogue topotecan); bryostatin; callistemon; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (especially cryptophycin 1 and 8 cryptophycin); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorpropamide, estramustine, ifosfamide, mechlorethamine, hydrochloride mechlorethamine, melphalan, novemberin, finasterin, prednimustine, trofosfamide, uracil mustard; microsociety, such as carmustine, chlorozotocin, fotemustine, lomonte is, nimustine and ranimustine; antibiotics such as andinavia antibiotics (for example, calicheamicin, especially calicheamicin gammalI and calicheamicin omegaIl (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; spiramycin; as well as the chromophore of neocarzinostatin and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, autralian, azaserine, bleomycin, actinomycin, carubicin, karminomitsin, calcination, chromomycin, dactinomycin, daunorubicin, demoralizing, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino doxorubicin, cyanomethane doxorubicin, 2-pyrroline doxorubicin and desoxidation), epirubicin, zorubicin, idarubitsin, marsellaise, mitomycin, such as mitomycin C, mikofenolna acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, colomycin, radiobeacon, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); analogs of folic acid, such as deeperin, methotrexate, peripherin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, timipre, tioguanin; pyrimidine analogues such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine dideoxyuridine, doxifluridine, enocitabine, Flo is sorigin; androgens, such as calusterone, dromostanolone, epitiostanol, mepitiostane, testolactone; antegradely, such as aminoglutetimid, mitotane, trilostane; auxiliary agents folic acid, such as prolinnova acid; Eagleton; glycoside aldophosphamide; aminolevulinic acid; eniluracil; amsacrine; astroball; bisantrene; edatrexate; defaming; demecolcine; diazide; alternity; the acetate slipline; epothilone; etoposide; gallium nitrate; hydroxyurea; lentinan; londini; maytansinoid, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitrean; pentostatin; penomet; pirarubicin; losoxantrone; podophylline acid; 2-acylhydrazides; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trihlortrietilamin; trichothecenes (especially T-2 toxin, verrucarin a, roridin A and unguided); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; Galitsin; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoid, such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ (Cremophor-free, designed on the basis of albumin nanoparticle composition of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® (docetaxel; Rhône-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® (gemcitabine is); 6-tioguanin; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinova acid; and pharmaceutically acceptable salts, acids and derivatives of any of these compounds.

In the definition of "chemotherapeutic agent" also includes (i) protivokomarinye agents, the action of which is to regulate or inhibit the effects of hormones on tumor, such as antiestrogens and selective modulators of estrogen receptors (SERM), including, for example, tamoxifen (including NOLVADEX®; tamoxifenside), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifene); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutetimid, MEGASE® (magistralata), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bikalutamid, leuprolide, and goserelin; as well as rockcity (similar to 1,3-deoxyanthocyanins); (iv) inhibitors of protein kinases; (v) inhibitors of the lipid kinase; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling circuits involved in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as inhibitors of the expression of VEGF (e.g., ANGIOZYME®) and inhibitors of HER2 expression; (viii) vaccines such as vaccines, used in gene therapy, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; inhibitors of topoisomerase 1, such as LURTOTECAN®; ABARELIX® rmRH; (ix) antiangiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above compounds. Other antiangiogenic agents include inhibitors of MMP-2 (matrix metalloproteinase 2)inhibitors, MMP-9 (matrix metalloproteinase 9)inhibitors, COX-II (cyclooxygenase II) inhibitors of VEGF receptor tyrosine kinase. Examples of suitable inhibitors of matrix metalloproteinases, which can be used in combination with the compounds/compositions of the present invention (such as any of the compounds in the headlines examples 5-25) are disclosed in WO 96/33172, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606046, EP 931788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, U.S. patent No. 5863949, U.S. patent No. 5861510, and EP 780386, and all of them are included here for reference in their entirety. Examples of inhibitors of VEGF receptor tyrosine kinase include 4-(4-bromo-2-foronline)-6-methoxy-7-(1-methylpiperidin-4-ylethoxy)hinzelin (ZD6474; example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1 ipropose)hinzelin (AZD2171; example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds such as those disclosed in PCT publication no WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354.

Other examples of chemotherapeutic agents that can be used in combination with the compounds of the present invention (such as any of these compounds in the headlines examples 5-25)include inhibitors of PI3K (phosphoinositide-3 kinase), such that reported in the footsteps of Yaguchi et al. (2006) Jour. of the Nat. Cancer Inst. 98(8):545-556; US 7173029; US 7037915; US 6608056; US 6608053; US 6838457; US 6770641; US 6653320; US 6403588; US 2008/0242665; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO 2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; US 2003/158212; EP 1417976; US 2004/053946; JP 2001247477; JP 08175990; JP 08176070; US 6703414; and WO 97/15658, all they are included here for reference in its entirety. Specific examples of such inhibitors include PI3K SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.) and GDC-0941 (PI3K inhibitor, Genentech, Inc.).

The term "inflammatory disease" in the sense as used in this application includes, but is not limited to, rheumatoid, Arti is, atherosclerosis, congestive heart failure, inflammatory bowel disease (including, but not limited to, Crohn's disease and ulcerative colitis), chronic obstructive pulmonary disease, fibrotic liver disease and kidney disease, Crohn's disease, lupus, skin diseases such as psoriasis, eczema and scleroderma, osteoarthritis, multiple sclerosis, asthma, diseases and disorders associated with diabetic complications, fibrous failure in organs such as lungs, liver, kidneys, and inflammatory complications of the cardiovascular system, such as acute coronary syndrome.

The term "anti-inflammatory agent" means a compound that can be used to treat inflammation. Examples of anti-inflammatory drugs include protein therapeutic drugs for injection, such as Enbrel®, Remicade®, Humira®, Kineret®. Other examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory agents (NSAID)such as ibuprofen or aspirin (which reduces swelling and relieves pain); modifying the disease protivorevmaticalkie drugs (DMARDs)such as methotrexate; 5-aminosalicylate (sulfasalazin and does not contain sulfonamides agents; corticosteroids; immunomodulators such as 6-mercaptopurine ("6-MP"), azathioprine ("AZA"), cyclosporine, and option is Katori biological reactions, such as Remicade.RTM. (infliximab) and Enbrel.RTM. (etanercept); fibroblast growth factors; obtained from platelet growth factors; blockers of enzymes, such as Arava.RTM. (Leflunomide); and/or agents, protecting cartilage, such as hyaluronic acid, glucosamine and chondroitin.

The term "prodrug" in the sense as used in this application refers to a precursor or to the form derived compounds of the present invention, which is capable of being enzymatically or hydrolytically activated or converted into the more active its original form. See, for example, Wilman, "Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery,"Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press (1985). Prodrugs of the present invention include, but are not limited to containing esters prodrugs, phosphate-containing prodrugs, thiophosphoramide prodrugs, sulfadimidine prodrugs, peptideatlas prodrugs, modified D-amino acid prodrugs, glycosylated prodrugs, β-lactosidase prodrugs, optionally substituted phenoxyacetamide prodrugs, optionally substituted phenylacetamides prodrugs, 5-fortitudinous and other 5-ptoluidine prodrugs which can be converted into the more active the e recitations medicines. Examples of cytotoxic drugs that can be turned into proletarienne forms for use in the present invention include, but are not limited to, compounds of the present invention and chemotherapeutic agents, such as disclosed above.

The term "metabolite" refers to a product produced through metabolism in the body of specific compounds or salts thereof. Metabolites of compounds can be identified using routine techniques known in the art, and to determine their activity, using the disclosed here tests. Such products can be obtained, for example, as a result of oxidation, hydroxylation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic degradation, etc. of the input connections. Accordingly, the present invention includes metabolites of compounds of the present invention, including the compounds obtained using the method, including the implementation of contacting compounds of the present invention with the body of a mammal for a period of time sufficient to obtain its metabolic product.

The term "liposome" refers to a small vesicle composed of various types of lipids, phospholipids and/or surface-active agent, which can use the TB for delivery to the mammal medicines (such as inhibitors of MEK, disclosed here, and optionally, a chemotherapeutic agent). Components of liposomes are typically arranged in a bilayer formation, similar to the lipid structure of biological membranes.

The term "liner in the package have a relatively instructions, which usually invest in commercial packages of therapeutic products and which contain information about the indications, application methods, doses, routes of administration, contraindications and/or warnings concerning the use of such therapeutic products.

The term "chiral" refers to molecules that do not possess the property of vzaimovlijanie mirror images of each other, while the term "achiral" refers to molecules which have the property vzaimovlijanie mirror images of each other.

The term "stereoisomer" refers to compounds that have the same chemical composition, but different orientation of their atoms in space and which is not vzaimoprevrascheny while rotating around simple links.

The term "diastereoisomer" refers to a stereoisomer with two or more centers of chirality, and such molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, the key points is to be placed, spectral characteristics and reactive abilities. A mixture of diastereoisomers can be separated using the analytical technique of high resolution, such as crystallization, electrophoresis and chromatography.

The term "enantiomers" refers to two stereoisomers of compounds that are not vzaimovliianie mirror images of each other.

Stereochemical definitions and conventions used in the description correspond mainly S. P. Parker, Ed.,McGraw-Hill Dictionary of Chemical Terms(1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. Assumes that all stereoisomeric forms of these compounds of the present invention, including, but not limited to, the diastereomers, the enantiomers and tropically, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compounds of the prefixes D and L, orRandSuse to denote the absolute configuration of the molecule otnositel is its chiral center (chiral centers). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the specified connection, and (-) or l meaning that the specified connection is levogyrate. The symbols (+) or d before connecting means that it is Pervouralsk. For specific chemical structure of these stereoisomers are identical, except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. The mixture of enantiomers of 50:50 is called a racemic mixture or a racemate, which does not show stereoselectivity or stereospecificity in chemical reactions or processes. The terms "racemic mixture" and "racemate" refers to an equimolar mixture of two enantiomeric samples, devoid of optical activity.

The terms "tautomer or tautomeric form" refers to the structural isomers with different energies, which can vzaimoprevrascheny due to the low energy barrier. For example, proton tautomers (also known as prototroph the tautomers) perform interconversion due to the migration of a proton, such as keto-enol and Imin-enamino isomerization. Valence tautomers include interconversion by reorganizing necatoriasis electrons.

The phrase "pharmaceutically acceptable salt" in the sense used here, refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Examples of salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannat, Pantothenate, bitartrate, ascorbate, succinate, maleate, genticin, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate “mesilate”, aconsultant, bansilalpet, a pair of-toluensulfonate, pamoate (i.e. 1,1'-methylene-bis(2-hydroxy-3-aftout)), alkali metal salts (e.g. sodium and potassium), salts of alkaline earth metals (e.g. magnesium), and ammonium salts. Pharmaceutically acceptable salt may contain inclusions of other molecules, such as ions, acetate, succinate ions or other counterions. The specified counterion can be any organic or inorganic fragment, which stabilizes the charge on the source connection. In addition, pharmaceutically acceptable salt may contain more than one charged atom in its structure. In cases when several of charged atoms are part of a pharmaceutically acceptable salt, this salt may be a few who motivaional. Consequently, the pharmaceutically acceptable salt may contain one or more of the charged atoms and/or one or more of the counterions.

If the compound of the present invention is a base, the desired pharmaceutically acceptable salt may be obtained in any appropriate way known to specialists in this field, for example by treatment of the free base of an inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesulfonate acid, phosphoric acid, etc. or organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, paranoidly acid, such as glucuronic acid or galacturonic acid alpha-hydroxy acid, such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as para-toluensulfonate acid or econsultancy acid or the like

If the compound of the present invention is an acid, it takes the Yu pharmaceutically acceptable salt can be obtained in any suitable way, for example, treating the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkali earth metal hydroxide, or the like, Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The phrase "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients contained in the composition, and/or with the body of a mammal, which they treat.

The term "MES" refers to an Association or complex of molecules of one or more of the solvents and compounds of the present invention. Examples of solvents that form the solvate include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to a complex in which the solvent is water.

The term "protective group" refers to the Deputy, to the which is normally used to block or protect a particular functionality, during the reaction of other functional groups of the specified connection. For example, the term "aminosidine group" means the Deputy attached to the amino group that blocks or protects amidofunctional in the specified connection. Suitable aminosidine groups include acetyl, TRIFLUOROACETYL, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, the term "hidroxizina group" refers to the Deputy hydroxy-group that blocks or protects hydroxyquinolinato. Suitable protective groups include acetyl and trialkylsilyl. The term "carboxyamide group" refers to the Deputy at the carboxyl group that blocks or protects carboxypenicillins. Normal carboxyamide group include phenylsulfonyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(para-toluensulfonyl)ethyl, 2-(para-nitrobenzylidene)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl etc. For a General description of the protective groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms "compound of the present invention", "compounds of the present invention", "compounds of formula I", "imidazopyridine and imidazopyridine formula I, unless otherwise indicated, include compounds/imidazopyridine fo the formula I and the stereoisomers, geometric isomers, tautomers, solvate, metabolites, salts (e.g., pharmaceutically acceptable salts) and their proletarienne form.

In the present invention proposed imidazopyridine formula I, above, which you can use as kinase inhibitors, in particular can be used as inhibitors of MEK kinase. In one embodiment of the present invention, if R3represents -(CR14R15)nC(=O)R11, -(CR14R15)nNR11R12, -(CR14R15)nOR11, -(CR14R15)nSR11, -(CR14R15)nS(O)R11or -(CR14R15)nS(O)2R11; n is 0; and Z1represents N, then the specified R11or R12not represent aryl;

if Z1represents N, then R3does not represent a CH2-aryl; and all other variables are defined in formula I.

In one embodiment of the present invention the compounds have the formula I-a or I-b; and all other variables have the meanings defined in formula I or as defined in the open higher version.

In one embodiment of the present invention R2represents H, halogen, CF3or C1-C3alkyl; and all other PE is b defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R2represents H, methyl, CF3, F, or Cl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R2represents H, F or Cl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention R3represents H, halogen, CF3or C1-C3alkyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R3represents H, methyl, CF3, F or Cl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R3represents H, F or Cl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention R1'represents H or C1-C3alkyl; and all the rest of the s variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options. In another embodiment, R1'represents H, and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention Z1represents CR1and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention Z1represents N, and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention Z1represents CR1and R1represents H or C1-C3alkyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options. In another embodiment, R1represents H, and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options. In another embodiment, R1represents methyl, and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment, n is standing the invention R 4represents H or C1-C6alkyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R4represents H or methyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options. In another embodiment of the present invention R4represents H; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention R5represents H or C1-C6alkyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R5represents H or methyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R5represents H; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R5represents methyl, and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention X1is a OR11'; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X1is a OR11'where R11'represents H or C1-C12alkyl (for example, C1-C6alkyl), substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(O 16)(OR17), -(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17, -(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X1is a OR11'where R11'represents heterocyclyl (e.g., 4-6-membered heterocyclyl), optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R 16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17, -(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X1is a OR11'where R11'is a 4-6-membered heterocyclyl containing 1 ring nitrogen atom, where the specified heterocyclyl optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20 )nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17, -(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X1represents a

and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment, altoadige invention X 1represents a

and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X1is an R11'; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X1is an R11'where R11'represents H or C1-C12alkyl (for example, C1-C6alkyl), substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl)3, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16 17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17, -(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X1represents a

and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R5represents H and X1represents a

and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X1represents a

and all other variables are defined is received in the formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R5represents methyl and X1represents a

and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention X1is an R11'and X1taken together with R5and the nitrogen atom to which they are attached, form a 4-to 5-membered saturated cyclic ring containing 0-2 additional heteroatoms selected from O, S and N, where the specified cyclic ring optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(Y')OR 16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17, -(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention W is a

and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention W is a OR11'where R11'represents H or C1-C12alkyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention W is a OR11'where R11'not only is em a H; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention W is a OR11'where R11'represents a C1-C6alkyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention W' represents-NHSO2R8; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention R6represents halogen, C2-C8quinil, carbocyclic, or-SR16; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention R6represents halogen, C2-C3quinil, C3-carbocycle, or-SR16where R16represents a C1-C2alkyl; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention R6'represents H, halogen, or C1-C3alkyl; and the all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention p represents 1 or 2; and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In one embodiment of the present invention X4represents a

and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

In another embodiment of the present invention X4represents a

and all other variables are defined in formula I, I-a or I-b or have the values listed in any of the disclosed above options.

Another variant of the present invention includes compounds disclosed in the examples 5-25, and presents further connections

Obtaining compounds of formula I

Imidazopyridine formula I receive in accordance with the disclosed hereinafter schemes and examples or known to specialists in this field means. For example, the compounds of formula (I), where Y = W-C(O)-, can be obtained in accordance with scheme 1.

Scheme 1

Nicotinic acid of formula (II) can be obtained from commercial history is nicks or receive, using disclosed in the literature methods. Acid (II) can be subjected to interaction with aniline (by introducing appropriate substituents R1), in the presence of a base, such as LiHMDS in a solvent such as THF, at temperatures from -78°C to 25°C, receiving acid of formula (III). Esters of nicotinic acid (IV) can be obtained from nicotinic acid (III), interacting with an alkylating agent such as trimethylsilyldiazomethane, in a solvent such as toluene, at a temperature from 0°C to 50°C. 2-aniline-6-cyanopyridines of the formula (V) can be obtained from 6-halogenopyrimidines (IV), interacting with an inorganic cyanide, such as cyanide zinc, in the presence of a transition metal catalyst such as Pd(PPh3)4in a solvent such as DMF, at a temperature from 50°C to the boiling temperature under reflux or under microwave irradiation at a temperature from 70°C to 200°C. Cyanopyridines (V) can be restored by receiving 2-aminomethylpyridine (VI), A = CH2restoring hydrogen at a pressure of from 1 to 5 atmospheres, in the presence of a catalyst such as palladium-on-charcoal, in a solvent such as methanol or acetic acid, with or without adding a strong acid such as concentrated hydrochloric acid. Alternatively, the cyanopyridines (V) can be converted into 2-am is nomailplease, interacting with inorganic metal hydride such as sodium borohydride, in the presence of a metal salt such as cobalt chloride, in a solvent such as methanol, at temperatures from 0°C to room temperature. Alternative compounds of formula (VI), A = NH, can be obtained from compounds of formula (IV), interacting with hydrazinehydrate in a solvent such as ethanol, at temperatures from 0°C to the boiling temperature under reflux.

Compounds (VII) can be obtained from the compounds (VI), interacting with an anhydride such as acetic anhydride or a mixed anhydride, such as formic-acetic anhydride, in a solvent such as tetrahydrofuran, at temperatures from 0°C to the boiling temperature under reflux. The compounds of formula (VIII) can be obtained from compounds of formula (VII), interacting gloriouse agent such as phosphorus oxychloride in a solvent such as toluene, at a temperature from 25°C to the boiling temperature under reflux. Alternatively, the compounds of formula (VIII) can be obtained from compounds of formula (VII), interacting with acid, such as formic acid, pure or in a solvent such as dioxane, at temperatures from 50°C to the boiling temperature under reflux. The compounds of formula (IX) mozhnopoluchit of the compounds of the formula (VIII), interacting with a base such as sodium hydroxide, in a solvent such as ethanol or methanol, at temperatures from room temperature up to the boiling temperature under reflux.

The compounds of formula (IX) can be subjected to interaction with functionalized hydroxylamine of the formula (XII) (commercially available or can be obtained in accordance with schemes 5, 6 and 7) or an amine and a suitable crosslinking agent such as O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate, hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or N,N'-dicyclohexylcarbodiimide, in the presence of N-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base such as diisopropylethylamine or triethylamine in an inert solvent, such as tetrahydrofuran, N,N-dimethylformamide or dichloromethane, at a temperature of about room temperature, obtaining the compounds of formula (X). The compounds of formula (X) can be obtained directly from compounds of formula (VIII), interacting with an amine or hydroxylamine DNHR in the presence of a Lewis acid such as trimethylaluminum in a solvent such as DCM, at a temperature of from room temperature to the boiling temperature under reflux. Alternatively, the compounds of formula (X) can be obtained from compounds of formula (VIII) by treatment with NGF is tonalizowana hydroxylamine in the presence of a base, such as letibit(trimethylsilyl)amide, in a solvent such as THF, at temperatures from -78°C to 25°C.

In addition, the compounds of formula (I), where Y is W-C(O)-, can be obtained in accordance with scheme 2.

Scheme 2

The compounds of formula (XV) can be obtained from commercial sources or obtained using disclosed in the literature methods. The compounds of formula (XVI) can be obtained from compounds of formula (XV), interacting with a halogenation agent such as succinimide or 1,3-dibromo-5,5-dimethylhydantoin, in the presence of a catalyst, such as AIBN or benzoyl peroxide, in a solvent such as dichloroethane or carbon tetrachloride, using activation by light or by heating at a temperature from room temperature up to the boiling temperature under reflux. Alternatively, the compounds of formula (XVI) can be obtained from compounds of formula (XV) in two stages, first forming an N-oxide of pyridine, using an oxidizing agent such as 3-chloroperoxybenzoic acid, in a solvent such as DCM, at a temperature of about room temperature. The intermediate N-oxides can be transformed into halogenopyrimidines formula (XVI), interacting with gloriouse agent such as phosphorus oxychloride. The compounds of formula (XVII) can be obtained from compounds of formula (XVI), while in aimogasta with a protected form of ammonia, such as phthalimide potassium or deformylated sodium in a solvent such as DMF, at a temperature from -5°C to 50°C. If R'"= H and R"= C(=O)H, the compounds of formula (XVII) can be converted into esters formelementname acid of formula (XVIII) by treatment with acid, such as formic acid or hydrochloric acid, in a solvent such as methanol, at temperatures from room temperature to the boiling temperature under reflux. The compounds of formula (XVIII) can be cilitate to imidazopyridines formula (XIX), interacting with oxyhalogenation phosphorus, such as phosphorus oxychloride in a solvent such as toluene, at a temperature from 50°C to the boiling temperature under reflux. Alternatively, the cyclization can be carried out using an acid, such as formic acid or acetic acid, pure, at temperatures from 25°C to the boiling temperature under reflux. Esters of imidazopyridine-5-aniline of the formula (XX) can be obtained from halides of the formula (XIX), interacting with aniline (by introducing appropriate substituents R1), in the presence of a base, such as letibit(trimethylsilyl)amide, in a solvent such as THF, at temperatures from -78°C to room temperature. Alternatively, the compounds of formula (XX) can be obtained from compounds of formula (XIX), carried the interaction with aniline (by introducing appropriate substituents R1), in the presence of a catalyst such as Tris(dibenzylideneacetone)dipalladium(0), bases such as potassium phosphate, ligand, such as 2-dicyclohexylphosphino-2',6'-(diisopropoxide)biphenyl, in a suitable solvent, such as toluene, at a temperature of from room temperature to the boiling temperature under reflux of the solvent, or under microwave irradiation at a temperature from 70°C to 150°C. the Acid of formula (XXI) can be obtained from the esters of formula (XX)using the methods disclosed for the conversion of compounds of formula (VIII) in the compounds of formula (IX) in scheme 1. Alternatively, the acid of formula (XXI) can be obtained from compounds of formula (XIX), first by saponification using the methods disclosed for the conversion of compounds of formula (VIII) in the compounds of formula (IX), followed by treatment of the aniline (including appropriate substituents Rl), in the presence of a base, such as lithium(bestemmelser)amide, in a solvent such as THF, at temperatures from -78°C to room temperature.

Aniline acid of formula (XXI) can be converted into compounds of formula (X), using the methods disclosed for the conversion of compounds of formula (IX) in the compounds of formula (X) in scheme 1. In addition, esters of the formula (XX) can be converted into compounds of formula (X), using the methods disclosed for the conversion of compounds of formula (VII) in the compounds of formula (X) in scheme 1.

The compounds of formula (XVI) and (XVII) can be obtained in accordance with scheme 3.

Scheme 3

The compounds of formula (XXIII) can be obtained from compounds of formula (XXII). The compounds of formula (XXII) in the beginning atrificial due to the formation of chloride bis-acid, using oxalicacid with catalytic DMF in a solvent such as DCM, at a temperature of about room temperature, then quenched with an alcohol, such as methanol. The obtained bis-ester intermediate compound can then oxidize to the compounds of formula (XXIII), interacting with an oxidizing agent such as metallocarboxypeptidase acid, in a solvent such as DCM, at a temperature from 0°C to room temperature. The compounds of formula (XXV) can be obtained from compounds of formula (XXIV) by restoring metalhydrides, such as sodium borohydride, in the presence of additives, such as calcium chloride, in a solvent such as ethanol, at temperatures from 0°C to room temperature. The compounds of formula (XXV) can be converted into compounds of formula (XXVI), where R = Cl by halogenation using sulphonylchloride, such as thionyl chloride, in a solvent such as dichloromethane, at a temperature from -5°C to room temperature. The compounds of formula (XXVI), where R= N3can be obtained from compounds of formula (XXV), interacting the azide, such as diphenylphosphoryl, in the presence of diazocarbonyl, such as diisopropylethylamine, in the presence of a base, such as triethylamine, in a solvent such as THF, at a temperature of about room temperature. The compounds of formula (XXVI), where R = N3can be converted into compounds of formula (XXVI), where R = NH2by processing regenerating agent such as triphenylphosphine, in a solvent such as THF, at a temperature of from room temperature to the boiling temperature under reflux.

The compounds of formula (I)in which Y = R8SO2NH-, can be obtained in accordance with scheme 4.

Scheme 4

The compounds of formula (XXVII) can be obtained from compounds of formula (IX) by treatment with diphenylphosphorylacetate in a solvent such as toluene, in the presence of a base such as triethylamine. The compounds of formula (XXVIII) can be obtained from compounds of formula (XXVII) by treatment with base such as sodium hydride, in a solvent such as DMF, then through reaction with sulphonylchloride (appropriately substituted). The compounds of formula (XXIX) can be obtained from compounds of formula (XXVIII), removing the protective group using a base such as sodium hydroxide, in a solvent such as DMF, at a temperature from 50°C to 150°C.

Hydrox lamina formula (XII) can be obtained using the methods disclosed in the literature, or the method of synthesis presented in figure 5.

Scheme 5

Primary or secondary alcohols of General formula (XXXVII) can be obtained using the methods disclosed in the literature. The alcohols can be subjected to the interaction with N-hydroxyphthalimide using phosphine and binding agent, such as diethylazodicarboxylate, to obtain compounds of General formula (XXXVIII). The compounds of General formula (XXXVIII) can remove the protective group using hydrazine, methylhydrazine, or acid, such as hydrochloric acid, or base, such as aqueous ammonia, getting hydroxylamine General formula (XII-a).

The compounds of formula (XII-a) can be further modified using the reductive amination of aldehydes or ketones using a reducing agent such as triacetoxyborohydride sodium, cyanoborohydride sodium or borane-pyridine, in a solvent such as dichloroethane at a temperature of from room temperature to the boiling temperature under reflux, getting hydroxylamine General formula (XII-b). In addition, the compounds of formula (XII-a) can be further modified by alkylation with alkylhalogenide in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, getting hydroxylamine General form is s (XII-b).

Alternatively, hydroxylamine formula (XII-a) can be obtained according to scheme 6.

Scheme 6

Alkylhalogenide formula (XL) can be subjected to the interaction with N-hydroxyphthalimide in the presence of a base such as potassium carbonate, in a solvent such as dimethyl sulfoxide, at a temperature from 10°C to 50°C. the compounds of formula (XLI) can be converted into compounds of formula (XII), using the methods disclosed for the conversion of compounds of formula (XXXVIII) in the compounds of formula (XII) in scheme 5.

Alternatively, the compounds of formula (XII-a) can be obtained in accordance with scheme 7.

Scheme 7

The compounds of formula (XLII) can be subjected to the interaction with N-hydroxyphthalimide in the presence of catalytic amounts of a base, such as DIPEA, and socializaton, such as tetrabutylammonium, in a solvent such as toluene, at a temperature from 50°C to the boiling temperature under reflux. The compounds of formula (XLIII) can be converted into compounds of formula (XII), using the methods disclosed for the conversion of compounds of formula (XXXVIII) in the compounds of formula (XII) in scheme 5.

Anilines of General formula (XXXI), used in disclosed above reactions cross combinations can be obtained using disclosed in the literature methods or with the availa able scientific C to scheme 8.

Scheme 8

Substituted 1-chloro-4-nitrobenzene can be subjected to the interaction with the metal R"'MXn, such as cyclopropylboronic acid or hexamethyldisilazane, in a solvent such as xylene, using a catalyst, such as tetrakis(triphenylphosphine)palladium, at a temperature of from room temperature to the boiling temperature under reflux, obtaining the compounds of formula (XXX). The nitro-group can be recovered using disclosed in the literature methods, such as the reaction takes place in an atmosphere of hydrogen at a pressure of from 1 to 5 atmospheres, in the presence of a catalyst such as palladium-on-charcoal, in a solvent such as ethanol or ethyl acetate, at room temperature, obtaining the compounds of formula (XXXI).

Alternatively, anilines of the formula (LV) can be obtained in accordance with scheme 9.

Scheme 9

4-Bromo - or itanyone formula (LIV) can be subjected to interaction with at least 2 equivalents of a strong ORGANOMETALLIC base such as n-utility, in a solvent such as THF, at a temperature from -100°C to -20°C, followed by quenching the intermediate abilities compounds of the electrophile, such as trimethylsilane, to obtain compounds of formula (LV).

It should be clear that in those cases when the relevant functional groups, you can find the derivatives of the compounds of formula (I) or we can further derive any intermediates used in their obtaining, using one or more of the standard synthesis methods, using substitution reaction, oxidation, recovery, or splitting. Specific schemes to introduce substituents include conventional methods of alkylation, arilirovaniya, heteroarylboronic, acylation, sulfonylamine, halogenation, nitration, formirovanie and combinations.

For example, groups of arilbred or artilharia can be turned into arisitide using the Finkelstein reaction, using a source of iodide such as sodium iodide, and a catalyst such as copper iodide, a ligand such as TRANS-N,N'-dimethyl-1,2-cyclohexanediamine, in a solvent such as 1,4-dioxane, and heating the reaction mixture at the boiling point under reflux. Aryldialkyl can be turned into arisitide, treating the silane source of iodide such as monochloride iodine, in a solvent such as dichloromethane, with a Lewis acid, such as tetrafluoroborate silver, or without, at a temperature from -40°C up to the boiling temperature under reflux.

In another example, groups of primary amine (-NH2) you can alkilirovanii through a process of restorative alkylation, using the aldehyde or ketone and borohydride, for example triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as halogenated hydrocarbon such as 1,2-dichloroethane, or an alcohol, such as ethanol, and optionally in the presence of acid, such as acetic acid, at ambient temperature. Groups, secondary amine (-NH-) you can alkilirovanii similar way, using the aldehyde.

The following example groups, primary amine or secondary amine can be converted into amide group (-NHCOR', or-NRCOR') by acylation. The acylation can be carried out using a reaction with a suitable acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reaction with an appropriate carboxylic acid in the presence of a suitable binding agent, such as HATU (O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine), in a suitable solvent such as dichloromethane. Similarly, the amine group can be converted into sulfonamidnuyu group (-NHSO2R' or-NR"SO2R'), by reaction with the corresponding sulphonylchloride in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane. The group's primary or secondary amine can be converted into the urea group (-NHCONR'R" or-NRCONR'R"), through which eakly with the appropriate isocyanate in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane.

Amine (-NH2) can be obtained by restoring the nitro group (-NO2), for example, catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a substrate, such as coal, in a solvent such as ethyl acetate or an alcohol, for example methanol. Alternatively, the above transformation can be accomplished using chemical recovery, using, for example, metal, such as tin or iron, in the presence of acid, such as hydrochloric acid.

In the following example, the amine group (-CH2NH2) can be obtained by the reduction of NITRILES (-CN), for example, by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a substrate, as charcoal or Raney Nickel, in a solvent such as a simple ether, e.g. a cyclic simple ether, such as tetrahydrofuran, at temperatures from -78°C to the boiling temperature under reflux of the solvent.

In the following example, the amine group (-NH2) can be obtained from carboxylic acid groups (-CO2H)using the transformation into the corresponding acylated (-CON3), Curtis rearrangement and hydrolysis of the resulting isocyanate (-N=C=O.

Aldehyde group (-CHO) can be converted into amine groups (-CH2NR'r R") by reductive amination, using amine and a borohydride, for example triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as a halogenated hydrocarbon, for example dichloromethane or an alcohol, such as ethanol, optionally in the presence of acid, such as acetic acid, at ambient temperature.

In the following example, the aldehyde group can be converted into alkeneamine group (-CH=CHR')using the Wittig reaction or the reaction of Wordsworth-Emmons (Wadsworth-Emmons), using the appropriate fosfory or phosphonate under standard conditions known to specialists in this field.

Aldehyde groups can be obtained by recovery of the ester groups (such as CO2Et) or NITRILES (-CN), using diisobutylaluminium in a suitable solvent, such as toluene. Alternatively, the aldehyde group can be obtained by oxidation of the alcohol groups using any suitable oxidizing agent, known to specialists in this field.

Ester group (-CO2R') can be transformed into the corresponding acid group (-CO2H)using acid catalyzed hydrolysis or base catalyzed hydrolysis, depending on the nature of R. If R is tertbutyl, acid catalyzed hydrolysis can be accomplished, for example, by treatment with an organic acid, such as triperoxonane acid, in an aqueous solvent or by treatment with an inorganic acid, such as hydrochloric acid, in an aqueous solvent.

The carboxylic acid group (-CO2H) can be converted into amides (CONHR' or-CONR'R"), by reaction with an appropriate amine in the presence of a suitable binding agent, such as HATU, in a suitable solvent such as dichloromethane.

In the following example, you can get homologues carboxylic acid one carbon (i.e.- CO2H to the-CH2CO2H) by conversion into the corresponding acid chloride (-COCl) with subsequent synthesis of the Arndt-Eistert.

In the following example, the-OH group can be obtained from the corresponding complex ether (for example, -CO2R') or aldehyde (-CHO) by restoring, using, for example, metal hydride complex such as sociallyengaged, diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol. Alternatively, the alcohol can be obtained by restoring the appropriate acid (-CO2H)using, for example, sociallyengaged in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.

Sportowy the group can be turned into otsepleniya group, such as halogen atoms or sulfonyloxy, such as alkylsulfonate, for example, tripterocalyx or arylsulfonate, for example para-toluensulfonate, using conditions well known to the experts in this field. For example, the alcohol can be subjected to interaction with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane)to give the corresponding chloride. In this reaction can also use a base (e.g. triethylamine).

In another example, an alcohol, phenol or amide groups can be alkilirovanii, carrying out the reaction mix phenol or amide with an alcohol in a solvent such as tetrahydrofuran, in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, aminobutiramida or diethylazodicarboxylate. Alternatively, the alkylation can be accomplished by deprotonation using a suitable base, for example sodium hydride, followed by addition of an alkylating agent, such as alkylhalogenide.

Aromatic halogenated substituents in the compounds can be subjected to the exchange of the halogen-metal by treatment with base, for example a lithium base such as n-butyl or tert-utility, optionally at a low temperature, for example at a temperature of about -78°C, in a solvent such as tet is hydrofuran, and then extinguish electrophilic reagent for introducing the desired substituent. For example, the formyl group can be entered using N,N-dimethylformamide as the electrophile. Aromatic halogenated substituents can, alternatively, be subjected to a catalyzed metal reactions (for example, using a palladium or copper) for injection, for example, acid, ester, cyano, amide, aryl, heteroaryl, alkenyl, etkinlik, thio - or aminosalicyclic. Suitable procedures that can be used include those disclosed heck, Suzuki, Stille, Buchwald or Hardwick.

Aromatic halogenated substituents may also undergo a nucleophilic substitution reaction, followed by reaction with an appropriate nucleophile such as an amine or alcohol. It is advantageous to conduct this reaction at a high temperature under the action of microwave radiation.

Compounds of the present invention are tested for their ability to inhibit MEK activity and activation (primary analysis) and their biological effects on growing cells (secondary analyses), as disclosed hereinafter. These compounds of the present invention that has value IR50less than 5 μm (more preferably less than 0.1 μm, most preferably less than 0.01 μm) in the analysis of MEK asset the spine of example 1, IR50less than 5 μm (more preferably less than 1 μm, even more preferably less than 0.1 μm, most preferably less than 0.01 μm) in the analysis of activation of MEK example 2, EC50less than 10 microns (more preferably less than 1 μm, even more preferably less than 0.5 μm, most preferably less than 0.1 μm) in cell proliferative analysis of example 3 and/or EC50less than 10 microns (more preferably less than 1 μm, even more preferably less than 0.5 μm, most preferably less than 0.1 μm) in the analysis of the phosphorylation of ERK example 4, can be used as inhibitors of MEK.

The present invention includes a composition (e.g., pharmaceutical composition)comprising a compound of formula I (and/or solvate and/or salt) and the media (pharmaceutically acceptable carrier). The present invention also includes a composition (e.g., pharmaceutical composition)comprising a compound of formula I (and/or solvate and/or salt) and the media (pharmaceutically acceptable carrier), further comprising a second chemotherapeutic and/or second anti-inflammatory agent, such as disclosed in the present description. Compositions of the present invention can be used for inhibiting abnormal cell growth or treating hyperproliferative the disorders in a mammal (for example, in humans). Compositions of the present invention can also be used for the treatment of inflammatory diseases in a mammal (e.g. human).

Compounds of the present invention (such as any of the compounds listed in the headers of examples 5-25) and compositions can also be used to treat autoimmune diseases, destructive bone destruction, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (e.g. human). Examples of such diseases/disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retinopathy of prematurity, age-related muscular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis, and atopic dermatitis, kidney disease and renal failure, polycystic kidney disease, heart failure with congestion, neurofibromatosis, rejection of transplanted organs, cachexia, shock, septic shock, heart failure, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis (B) (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr (EBV). The term "chronic pain" for the purposes of this is part II of the invention includes, but they are not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, hypothyroidism, inflammation, arthritis, and post-operative pain. Neuropathic pain associated with many conditions that include, but are not limited to, inflammation, postoperative pain, phantom limb pain, pain caused by burns, gout, trigeminal neuralgia, acute herpetic and post herpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, damage to razmozjenie tissues, compressive lesions, tissue damage, amputation, pain from arthritis and nerve lesions between the peripheral nervous system and Central nervous system.

Compounds of the present invention (such as any of the compounds listed in the headers of examples 5-25) and compositions can also be used for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and kidney disease caused by diabetes) in a mammal (e.g. human).

Compounds of the present invention (such as any of the compounds listed in the headers of examples 5-25) and compositions can also be used to prevent blastocyte implantation in a mammal (e.g. human).

The present image is the buy includes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (for example, in humans, including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or solvate and/or salt or composition thereof. Also included in the present invention a method of treating inflammatory disease in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or solvate and/or salt or composition thereof.

The present invention includes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or solvate and/or salt or composition thereof, in combination with a second chemotherapeutic agent such as those disclosed in the present description. The present invention also includes a method of treating inflammatory disease in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or solvate and/or salt or composition thereof, in combination with a second anti-inflammatory agent, such as those disclosed in the present description.

Infusion is her invention includes a method of treating an autoimmune disease, destructive destruction of the bone, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof, and optionally additionally comprising the introduction of a second therapeutic agent. Examples of such diseases/disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retinopathy of prematurity, age-related muscular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis, and atopic dermatitis, kidney disease and renal failure, polycystic kidney disease, heart failure with congestion, neurofibromatosis, rejection of transplanted organs, cachexia, shock, septic shock, heart failure, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis (B) (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr (EBV).

The present invention includes a method of treating pancreatitis or kidney disease (including proliferative glomerulonephritis and caused the diabetes kidney disease) in a mammal (for example, in humans, including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof, and optionally including additional introduction of a second therapeutic agent.

The present invention includes a method of preventing blastocyte implantation in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate, or salt or composition thereof, and optionally additionally comprising the introduction of a second therapeutic agent.

The present invention includes a method of using compounds of the present invention forin vitro, in situ and in vivodiagnosis or treatment of cells or organisms mammals or associated pathological conditions.

Consider also that the compounds of the present invention can make abnormal cells more susceptible to treatment using radiation to destroy such cells and/or inhibiting the growth of such cells. Accordingly, the present invention also relates to a method of sensitizing abnormal cells in a mammal (e.g. human) for the treatment of radiation, which includes the introduction of the specified mammal such number is and the compounds of formula I (and/or its solvate, or salt or composition thereof, which effectively sencibilisiruet abnormal cells for further treatment of their exposure.

Introduction compounds of the present invention (hereinafter "the active connection active connection)") can be done in any way that will ensure the delivery of such compounds to the site of their action. These methods include oral, intraduodenal, parenteral (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion), external rectal routes of administration or inhalation.

The amount of active compound will depend on the subject to the treatment of the subject, the severity of the violation or condition, the speed of introduction, the proposed actions specified connection and choice of physician. However, the effective dose is in the range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day in one dose or in divided doses. For a person weighing 70 kg, this amount will be from about 0.05 to 7 g/day, preferably from about 0.05 to about 2.5 g/day. In some cases, could be suitable dose levels above or below these limits, while in other cases still larger doses may be used without harmful side effect, provided that such larger doses are first pre share who and several small doses for administration throughout the day.

The active compound can be used as the sole therapy or in combination with one or more chemotherapeutic or anti-inflammatory drugs, such as those disclosed in the present description. Such joint treatment can be achieved by simultaneous, sequential or separate introduction of the individual components of the treatment.

Mentioned pharmaceutical composition can be, for example, in a form suitable for oral administration such as tablets, capsules, pills, powders, compositions with delayed allocation, solutions, suspensions, in the form of preparations for parenteral injection in the form of sterile solutions, suspensions or emulsions, preparations for external use in the form of ointments or creams or medicines for rectal administration in the form of suppositories. The pharmaceutical composition may be in unit dose forms for a single administration of a precise dose. The pharmaceutical compositions will include a conventional pharmaceutical carrier or excipient and connection in accordance with the present invention as an active ingredient. In addition, they may include other medicinal or pharmaceutical agents, carriers, excipients, etc.

Examples of forms for parenteral administration include solutions or suspensions of the active compounds in tellnig aqueous solutions, for example, in aqueous solutions of propylene glycol or dextrose. These dose forms can be appropriately bufferirana.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. These pharmaceutical compositions may optionally contain additional ingredients, such as flavoring agents, binders, excipients, etc. for oral administration can be used tablets containing various excipients such as citric acid, together with various leavening agents, such as starch, alginic acid and certain complex silicates, and a binding agent, such as sucrose, gelatin and acacia. For the purposes of tabletting often you can use the additional lubricating agents such as magnesium stearate, nutriceuticals and talc. Solid compositions of a similar type can also be used, filling them soft or hard gelatin capsules. Therefore, preferred materials include lactose or milk sugar and high molecular weight glycols. If oral administration is desired aqueous suspensions or elixirs, the active compound can be combined with various sweetening or flavoring agents, coloring agents or dye is s and if desired, emulsifying agents or suspendresume agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of obtaining various pharmaceutical compositions containing specific amounts of active compounds, known or will be clear to experts in this field. Examples can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

EXAMPLES

Reduction

The sodium sulfate
nBuLin-utility
CDCl3Deuterated chloroform
CD3ODDeuterated methanol
CH2Cl2Dichloromethane
DCMDichloromethane
DIPEADiisopropylethylamine
DMFDimethylformamide
DMSOThe sulfoxide
Dppf1,1'-bis(diphenylphosphino)ferrocene
EDI 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
Et3NThe triethylamine
Et2ODiethyl ether
HATUAbout-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine
HClHydrochloric acid
Hyflo®Diatomaceous earth
HOBt1-hydroxybenzotriazole
H2SO4Sulfuric acid
IClMonochloride iodine
IMSIndustrial methylated spirits
LHMDSLetibit(trimethylsilyl)amide
MeOHMethanol
MgSO4Magnesium sulfate
NaHCO3Sodium bicarbonate
Na2SO4
NBSN-bromosuccinimide
Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)
Pd2dba3Tris-(dibenzylideneacetone)dipalladium(0)
Pd(dppf)Cl2[1,1']-bis(diphenylphosphino)ferrocene]dichloropalladium(0)
Si-PPCPre-filled cartridge for flash chromatography on silica gel: Isolute® SPE, Biotage SNAP ® or ISCO Redisep®
SCX-2Isolute ® sorbent based on silica with chemically bound to functional groups propylsulfonyl acid
THFTetrahydrofuran

General terms experimentation

1H NMR spectra were recorded at room temperature on the spectrometer Varian Unity Inova (400 MHz) with a 5 mm probe with triple resonance. Chemical shifts are expressed in ppm (ppm) relative to tetramethylsilane. We used the following abbreviations: br = broad signal, s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = Quartet, m = multiplet.

Experiments on high is ffektivnoe liquid chromatography - mass spectrometry (GHMC) to determine retention time (RT) and the corresponding ion mass exercise, using one of the following methods.

The way A: the experiments carried out on a mass spectrometer (Waters Micromass ZQ quadrupole connected to the system liquid chromatography on a Hewlett Packard HP1100 LC with diode detector in the form of a matrix. In this system, use column Higgins Clipeus 5 micron C18 100×3.0 mm and a flow rate of 1 ml/min, the Initial solvent system consists of 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) in the first minute, followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system is maintained constant over the next 5 minutes.

Method B: The experiments carried out on a mass spectrometer Waters Platform LC quadrupole connected to the system liquid chromatography on a Hewlett Packard HP1100 LC with diode detector in the form of a matrix and a 100-position auto-sampler, using a column Phenomenex Luna C18(2) 30×4.6 mm, at a flow rate of 2 ml/min, the Initial solvent system consists of 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) during the first 0.5 minute after the ith gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system is maintained constant during the following 0.50 minutes.

The method C: The experiments carried out on a mass spectrometer (PE Sciex API 150 EX quadrupole connected to the system liquid chromatography Shimadzu LC-IOAD LC with diode detector in the form of a matrix and 225-position auto sampler using a column Kromasil C18 50×4.6 mm at a flow rate of 3 ml/min Apply a gradient solvent system starting with 100% water containing 0.05% TFA (solvent A) and 0% acetonitrile, consisting 0,0375% TFA (solvent B), and changing it to 10% solvent A and 90% solvent B for 4 minutes. The final solvent system support constant over the next 0,50 minutes.

Method D: Experiments performed on a liquid chromatograph - mass spectrometer Agilent Technologies, United with system liquid chromatography Agilent Technologies 1200 Series LC with diode detector in the form of a matrix, using a column Bond of 1.8 MK SB-C18 30×2.1 mm at a flow rate of 1.5 ml/minMethod D1: Source system solvent consists of 95% water containing 0.05% triperoxonane acid (solvent A)and 5% acetonitrile containing 0.05% triperoxonane acid (solvent B), with subsequent gradient change system up to 5% solvent A and 95% solvent B over 1.5 minutes. The final solvent system support Kee is Noah in the next 1 minute. Method D2: Source system solvent consists of 95% water containing 0.05% triperoxonane acid (solvent A)and 5% acetonitrile containing 0.05% triperoxonane acid (solvent B), with subsequent gradient change system up to 5% solvent A and 95% solvent B over 3.0 minutes. The final solvent system constant support during the next 1 minute.

The way E:Experiments performed on a liquid chromatograph - mass spectrometer Agilent Technologies, United with system liquid chromatography Agilent Technologies 1200 Series LC with diode detector in the form of a matrix, using a column Bond of 1.8 MK SB-C18 30×2.1 mm at a flow rate of 0.6 ml/minMethod E1: Source system solvent consists of 95% water containing 0.05% triperoxonane acid (solvent A)and 5% acetonitrile containing 0.05% triperoxonane acid (solvent B), with subsequent gradient change system up to 5% solvent A and 95% solvent B over 9.0 minutes. The final solvent system constant support during the next 1 minute.Method E2:The initial solvent system consists of 95% water containing 0.05% triperoxonane acid (solvent A)and 5% acetonitrile containing 0.05% triperoxonane acid (solvent B), with subsequent gradient change system up to 5% solvent A and 95% of rest is ritala B for 20.0 minutes. The final solvent system constant support during the next 1 minute.

Microwave experiments carried out using the device Personal Chemistry Emrys Iniatiator™ or Optimizer™, which uses a single-mode resonator and tuning dynamic field, both provide reproducibility and control. It is possible to change the temperature in the range 40-250ºC and pressure up to 20 bar.

EXAMPLE 1

MEK analysis (analysis of the activity of MEK)

Constitutively activated mutant human MEK1, expressed in insect cells, used as a source of the enzymatic activity of the kinase in the analysis at a final concentration of 15 nm.

The specified analysis is carried out for 30 minutes in the presence of 50 μm ATP, using recombinant GST-ERK1 obtained inE. colias the substrate. Phosphorylation of the substrate is detected and determined quantitatively using HTRF reagents supplied Cisbio. These reagents consist of anti-GST antibodies conjugated with allophycocyanin (XL665) and anti-phospho (Thr202/Tyr204) ERK antibodies conjugated with europium-Cryptocom. Agents are used at a final concentration of 4 μg/ml and 0.84 μg/ml, respectively. Anti-phospho antibodies recognize ERK1, dual phosphorylated at Thr202 and Tyr204. When both antibodies are associated with ERK1 (i.e. when the substrate phosphorylase the Academy of Sciences), the energy transfer from cryptate on allophycocyanin occurs after excitation at a wavelength of 340 nm, which leads to fluorescence, which is proportional to the resultant phosphorylated substrate. Fluorescence determined using advance fluorimeter.

Compounds were diluted in DMSO before adding in analytical buffer, and the final concentration of DMSO in the above analysis is 1%.

The value of IR50defined as the concentration at which the considered connection provides 50% inhibition from control. Values IR50calculated using the software package XLfit (version 2.0.5).

The connections defined in the headers of examples 5-20 and 22-24 demonstrate value IR50less than 0.5 μm in the analysis described in example 1. Some of these compounds demonstrate value IR50less than 0.1 μm in the analysis described in example 1. The connections defined in the headers of examples 21 and 25 demonstrate the value IR50less than 10 microns in the analysis described in example 1.

EXAMPLE 2

skin disease analysis (analysis of activation of MEK)

Constitutively activated skin disease mutants, expressed in insect cells, used as a source of enzyme activity.

The specified analysis is carried out for 30 minutes in Pris is accordance 200 μm ATP, using recombinant GST-MEK1 produced inE. colias the substrate. Phosphorylation of the substrate accurately detect and quantify using HTRF reagents supplied Cisbio. These reagents consist of anti-GST antibodies conjugated with allophycocyanin (XL665), and anti-phospho (Ser217/Ser221) MEK antibodies conjugated with europium-Cryptocom. Anti-phospho antibodies recognize MEK, a dual phosphorylated at Ser217 and Ser221 or single phosphorylated at Ser217. When both antibodies are associated with MEK (i.e. when the substrate is phosphorylated), energy transfer from cryptate on allophycocyanin occurs after excitation at a wavelength of 340 nm, which leads to fluorescence, which is proportional to the resultant phosphorylated substrate. Fluorescence detected using advance fluorimeter.

Compounds were diluted in DMSO before adding to the analytical buffer, and the final concentration of DMSO in the above analysis is 1%.

The value of IR50defined as the concentration at which the considered connection provides 50% inhibition from control. Values IR50calculated using the software package XLfit (version 2.0.5).

EXAMPLE 3

Analysis of cell proliferation

Compounds are tested in cell proliferative Ana is ize, using the following cell lines:

HCT116 colorectal carcinoma person (ATCC),

A375 malignant melanoma of the person (ATCC).

Both cell lines support in DMEM/F12 (1:1) medium (Gibco), supplemented with 10% FCS at 37 degrees C in a humid incubator with 5% CO2.

Cells were seeded in 96-cell-based tablets in the amount of 2000 cells/well and after 24 hours they exhibit various concentrations of compounds in 0,83% DMSO. Cells were cultured for 72 hours in each well add an equal volume of CellTiter-Glo reagent (Promega). This causes lysis of the cells and causes the luminescence signal, which is proportional to the amount of released ATP (and, hence, proportional to the number of cells per well), which can be detected using advance luminometer.

The value of EC50defined as the concentration at which the considered connection provides 50% inhibition from control values. Value IR50calculated using the software package XLfit (version 2.0.5).

In this assay, compounds listed in the headers of examples 5-8, 11-13 and 18-20, demonstrate the value of EC50less than 0.5 μm for both cell lines. Some of the compounds listed in the headers of examples 5-8, 11-13 and 18-20, demonstrate the value of EC50less than 0.1 μm for both cell lines. Connect the tion, specified in the headers of examples 9-10 and 14-17 show the values of EC50less than 0.8 μm for the HCT116 cell line.

EXAMPLE 4

Analysis on the basis of phospho-ERK cell

Compounds are tested using ELISA for phospho-ERK cells, using the following cell lines:

HCT116 colorectal carcinoma person (ATCC),

A375 malignant melanoma of the person (ATCC).

Both cell lines support in DMEM/F12 (1:1) medium (Gibco), supplemented with 10% FCS at 37°C in a humid incubator with 5% CO2.

Cells were seeded in 96-cell-based tablets in the amount of 2000 cells/well and after 24 hours they exhibit various concentrations of compounds in 0,83% DMSO. Cells were cultured for another 2 hours or 24 hours, fixed with formaldehyde (final concentration 2%) and paniceum methanol. After blocking TBST-3% BSA, fixed cells are incubated with the primary antibody (anti-phospho ERK rabbit) overnight at 4°C. Cells incubated with propitiation (fluorescent DNA dye) and the definition of the cellular para-ERK carried out using anti-rabbit secondary antibody conjugated with the fluorescent dye Alexa Fluor 488 dye (Molecular probes). Fluorescence analyzed using the Acumen Explorer (TTP Labtech), laser scanning microplate of zitomer, and obtained using the Alexa Fluor 488 signal to normalize the PI signal (proportional to the number of the notches).

The value of EC50defined as the concentration at which the signal value of the considered connection corresponds to half the distance from the baseline to the maximum value of the reaction. Value EC50calculated using the software package XLfit (version 2.0.5).

In this assay, compounds listed in the headers of examples 5-8, 11-12 and 18-20 show the values of EC50less than 0.02 μm for both cell lines. Some of the compounds listed in the headers of examples 5-8, 11-12 and 18-20 show the values of EC50less than 0.01 μm for both cell lines. The connections defined in the headers of examples 9-10 and 13 to 17 show the values of EC50less than 0.05 microns for the HCT116 cell line.

SYNTHESIS of IMIDAZO[1,5-a]PYRIDINES

2-Fluoro-4-trimethylsilylmethylamine

Method A, step 1: (3-Fluoro-4-nitrophenyl)trimethylsilane

4-Chloro-2-ftorirovannom (97,2 g, 0.55 mol) was dissolved in xylenes (208 ml) and add hexamethyldisilane (306 g, 2,78 mol). Argon is bubbled through the mixture for 20 minutes, then add Pd(PPh3)4(16.2 g, 14 mmol) and the resulting mixture is heated in a continuous flow of argon at 150°C for 1 hour. Then argon cylinder is closed and the resulting mixture is heated at 150°C in the next 60 is aces. After cooling, the mixture was diluted with diethyl ether and filtered through a layer of silicon dioxide. The filter cake was washed with additional diethyl ether and the combined filtrates concentrated in vacuo. In the purification of the obtained residue using flash chromatography (SiO2, 98:1:1 pentane:CH2Cl2:Et2O eluent) get mentioned in the title compound as orange oil (76,7 g). Impure chromatographic fractions are combined and concentrated and then carry out vacuum distillation (so Kip. l10°C, 6 mbar), receiving the next portion specified in the title compound as orange oil (7.2 g, total yield 83.9 g, 71%).

1H NMR δ (DMSO-d6): 0,30 (9H, c), 7,56 (1H, d, J=8,02 Hz), to 7.67 (1H, DD, J=11,49, 1,14 Hz), 8,10 (1H, t, J=7,66 Hz).

Method A, step 2: 2-Fluoro-4-trimethylsilylmethylamine

A suspension of 10 wt.% palladium-on-coal (4.0 g) in IMS (25 ml) was added to a solution of (3-fluoro-4-nitrophenyl)trimethylsilane (62,0 g, 0.29 mol) in IMS (250 ml) and the resulting reaction mixture is blown with nitrogen five times, and then three times with hydrogen. The reaction mixture is then stirred under a pressure of 3 bar of hydrogen at room temperature for 4 hours. The reaction mixture then is blown with nitrogen before filtered through a layer of Celite® washing with ethyl acetate, the Obtained filtrate is concentrated under reduced pressure, getting listed in the title compound in the form of butter, light brown (53,0 g, quantitatively).

1H NMR (CDCl3): 7,16-to 7.09 (1H, m), 7,10 (1H, d, J=7,75 Hz), for 6.81 (1H, t, J=8,16 Hz), of 3.78 (2H, c), of 0.26 (9H, c).

Method B, step 2: 2-Fluoro-4-trimethylsilylmethylamine

To a solution of 4-bromo-2-ftorhinolona (114 g, 0.6 mol) in anhydrous THF (750 ml) at -78°C was added 1,6M solution of nBuLi in hexano (1500 ml, 2.4 mol) dropwise, maintaining the internal temperature below -60°C, in an inert atmosphere. The reaction mixture is treated dropwise TMSCl (256 ml, 2.0 mol), maintaining the internal temperature below -60°C. the resulting reaction mixture is left to warm to 0°C for 1 hour and poured into ice 2M HCl (approximately 1 liter). The resulting mixture was intensively stirred for 10 minutes, then the organic layer is isolated and washed with water and saturated potassium carbonate solution, dried (Na2SO4), filtered and concentrated, obtaining mentioned in the title compound in the form of butter, light brown (89 g, 81%).

4-Cyclopropyl-2-forfinally

Stage 1: 3-Fluoro-4-nitrophenyloctyl ether triftormetilfullerenov acid

To a solution of 3-fluoro-4-NITROPHENOL (12.5 g, 80 mmol) and triftormetilfullerenov anhydride (26,8 ml, 160 mmol) in DCM (300 ml) at 0°C add triethylene the (44,6 ml, 320 mmol) dropwise. The reaction mixture is then stirred at 0°C for 2 hours, then allowed to warm to room temperature and stirred for 18 hours. The reaction is quenched by adding water, and the resulting mixture extracted with DCM. The organic layer emit, washed with water and then dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0 to 40% ethyl acetate in cyclohexane)to give specified in the title compound as yellow oil (12.8 g, 56% yield).

1H NMR (DMSO-d6, 400 MHz): 8,39 (1H, t, J=8,83 Hz)to 8.12 (1H, DD, J=11,09, 2.65 Hz), to 7.67 (1H, DDD, J=9,20, 2,62, of 1.52 Hz).

Stage 2: 4-Cyclopropyl-2-fluoro-1-nitrobenzene

Stir a suspension of 3-fluoro-4-nitrophenylamino ether triftormetilfullerenov acid (5.6 g, 19 mmol), cyclopropylboronic acid (2,09 g, with 23.3 mmol) Pd(dppf)Cl2(1.24 g, 1.5 mmol) and 2M aqueous cesium carbonate (30 ml, 60 mmol) in toluene (20 ml) Tegaserod before heated at 90°C in argon atmosphere for 2.5 hours. The resulting reaction mixture is allowed to cool to room temperature before filtering through a layer of Celite®, washing with ethyl acetate. The obtained filtrate was washed (water, brine) and dried (MgSO4), filtered and concentrated in vacuo the resulting residue is treated, using flash chromatography (Si-PPC, gradient 0-30% ethyl acetate in pentane)to give specified in the title compound in the form of solid yellow (2,79 g, 81%).

1H NMR (DMSO-d6, 400 MHz): 8,03 (1H, t, J=8,39 Hz), 7,28 (1H, DD, J=13,19, 1,91 Hz), 7,16 (1H, DD, J=8,61, 1.90 GHz), 2,14-2,05 (1H, m), 1,21-of 1.05 (2H, m), 0,92-of 0.82 (2H, m).

Stage 3: 4-Cyclopropyl-2-forfinally

A suspension of palladium-on-coal (200 mg, 10%wt.) in IMS added to the degassed solution of 4-cyclopropyl-2-fluoro-1-nitrobenzene (1.45 g, 8 mmol) in IMS (50 ml), air is pumped out, filled with nitrogen, then pumped again and filled with hydrogen. The reaction mixture is then stirred at a pressure of 1 atmosphere of hydrogen at room temperature for 24 hours before filtering through a layer of Celite®, and then washed with ethyl acetate. The obtained filtrate was concentrated in vacuo, obtaining mentioned in the title compound as a residue pale purple (1.19 g, 98%).

1H NMR (CDCl3, 400 MHz): 6,72-6,63 (3H, m), of 3.56 (2H, c), 1,83 is 1.75 (1H, m), 0,93-of 0.82 (2H, m), 0,59-of 0.54 (2H, m).

Methyl ester 2-(2-fluoro-4-trimethylsilylmethylamine)-6-formelementname acid

Stage 1: 6-Chloro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid

To a cold (-78°C) solution of 2-fluoro-4-trimethylsilylmethylamine (64,7 g, 353 the mol) in anhydrous THF (170 ml) add a solution of LHMDS (555 ml, 1M hexano, 555 mmol) dropwise over 45 minutes in nitrogen atmosphere. After 2.5 hours at -78°C, add a solution of 2,6-dichloronicotinic acid (33,8 g, 177 mmol) in anhydrous THF (100 ml). The reaction mixture is then stirred at -78°C for 30 minutes, then allowed to warm to room temperature. After 18 hours stirring at room temperature the reaction is quenched by adding crushed ice and the pH adjusted to pH 1 by adding concentrated HCl (about 90 ml). The resulting solution was extracted with ethyl acetate and the organic layer washed with water, then brine, dried (Na2SO4), filtered and evaporated in vacuum. The resulting residue triturated three times successively with methanol and filtered, obtaining mentioned in the title compound in the form of a solid yellow color in them (46.7 g, 78%). LC-MS (method B): RT= a 4.83 min, M+H+= 339.

Stage 2: Methyl ester of 6-chloro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid

To a suspension of 6-chloro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid (33,7 g of 99.5 mmol) in dichloromethane (500 ml) at 0°C is added DIPEA (17,1 ml of 99.5 mmol). The reaction mixture is then stirred for 10 minutes, then DMF (2 ml) and oxacillin (8,7 ml of 99.5 mmol) is added dropwise (caution: rapid ejecta is gas). The reaction mixture is then stirred at room temperature for 2 hours and then added dropwise to a solution of DIPEA (17,1 ml of 99.5 mmol) in MeOH (500 ml) at 0°C for 45 minutes. Then the resulting reaction mixture was stirred at room temperature for 18 hours before concentrated in vacuo. The resulting residue is dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, then water, then brine, dried (Na2SO4), filtered and evaporated in vacuum, obtaining mentioned in the title compound in the form of a brown foam, which is used without purification in the next stage cases (36.4 g). LC-MS (method B): RT= 5,35 minutes, M+H+= 353.

Stage 3: Methyl ester of 6-cyano-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid

Degassed suspension of methyl ester of 6-chloro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid (4.8 g, 12.4 mmol), cyanide zinc (1.2 g, 10.2 mmol) and Pd(PPh3)4(1.6 g, of 1.36 mmol) in dimethylformamide (14 ml) was subjected to microwave irradiation at 190°C for 20 minutes. This procedure is repeated seven times, and all the resulting reaction mixtures are combined and concentrated in vacuo. The resulting residue is dissolved in ethyl acetate and washed with saturated concrete water is sodium bicarbonate. The aqueous layer was isolated and extracted three times with ethyl acetate. The combined organic extracts washed with water and then brine, dried (Na2SO4), filtered and evaporated in vacuum. The resulting residue is treated using flash chromatography (silica, gradient from 0% to 100%diethyl ether in pentane)to give specified in the title compound in the form of solid yellow (18.2 g). LC-MS (method B): RT= 4,74 minutes, M+H+= 344.

Stage 4: Methyl ester of 6-aminomethyl-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid

To a suspension of methyl ester of 6-cyano-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid (13.1 g, is 38.2 mmol) in methanol (285 ml) was added cobalt chloride(II) (18.2 g, to 76.4 mmol). The reaction mixture is cooled to 0°C and the small portions add sodium borohydride (14.5 g, 382 mmol) in 20 minutes (caution: rapid evolution of gas). The reaction mixture is then stirred at 0°C for 1 hour. The reaction is quenched by adding concentrated hydrochloric acid (50 ml)and the resulting mixture was stirred at 0°C for 10 minutes and at room temperature for 45 minutes. Then add Diethylenetriamine (9 ml) and the resulting mixture is stirred for another 15 minutes. The reaction mixture is shown that the comfort, to remove a white solid, which was washed with dichloromethane. The obtained filtrate was concentrated in vacuo and the resulting residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, then with water and then brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo, obtaining mentioned in the title compound in the form of a solid brown color (13,2 g, 100%). LC-MS (method B): RT= 2,82 minutes, M+H+= 348.

Stage 5: Methyl ester of 2-(2-fluoro-4-trimethylsilylmethylamine)-6-formelementname acid

A solution of methyl ester of 6-aminomethyl-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid (13,2 g of 38.2 mmol) in formic acid (200 ml) and acetic anhydride (40 ml) then stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and carry out azeotropic distillation with toluene. The resulting residue is dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate, then brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo, obtaining mentioned in the title compound in the form of a solid yellow (12.7 g, 89%). LC-MS (method B): RT= 4,17 minutes, M+H+= 376.

p> Methyl ester 5-chloroimidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1, method A: Methyl ester 6-methyl bromide-2-chloronicotinic acid

To a solution of methyl ester of 2-chloro-6-methylnicotinic acid (100 g, 0.54 mol) in DCE (1.0 l) add recrystallized N-bromosuccinimide (124.7 g, 0.70 mol) and benzoyl peroxide (13,1 g, 0.05 mol). The resulting reaction mixture is heated at 70°C for 16 hours, and during this time the reagents are dissolved, forming a dark red solution. The reaction mixture is diluted with saturated aqueous sodium bicarbonate (200 ml), while the red color of the solution brightens to yellow. The aqueous layer was extracted with DCM (2×100 ml). The combined organic fractions washed with brine (100 ml), dried (MgSO4) and concentrated in vacuum to give crude product (<138 g, <0.54 mol) in the form of a yellow oil, which contains approximately 40% of the target product.1H NMR (CDCl3, 400 MHz): 8,18 (1H, d, J=8.0 Hz), of 7.48 (1H, d, J=7.9 Hz), 4,51 (2H, c), of 3.94 (3H, c).

Stage 1, method B: an Alternative way to obtain the methyl ester 6-methyl bromide-2-chloronicotinic acid

To a mechanically stirred solution of methyl ester of 2-chloro-6-methylnicotinic acid (147 g of 0.79 mol) in DCE (1.5 l) add 13-dibromo-5,5-dimethylhydantoin (181,8 g, 0,635 mol) and AIBN (6,35 g, 0.04 mol). The resulting reaction mixture is heated at 65°C for 72 hours, and during this time the reagents are dissolved, forming a solution dark red/brown color. The resulting reaction mixture is cooled and diluted with saturated aqueous sodium bicarbonate (1 l), resulting red solution brightens to yellow. The layers are separated and the aqueous layer was extracted with DCM (2×750 ml). The combined organic fractions washed with water (1 l), saturated brine (1 l), dried (MgSO4) and concentrated in vacuo. The resulting yellow oil (235 g)containing approximately 46% of the desired product, used crude in the next stage without additional purification.1H NMR (CDCl3, 400 MHz): 8,18 (1H, d, J=8.0 Hz), of 7.48 (1H, d, J=7.9 Hz), 4,51 (2H, c), of 3.94 (3H, c).

Stage 2, method A: Methyl ether of 2-chloro-6-determinainternational acid

To a solution of crude methyl ester 6-methyl bromide-2-chloronicotinic acid (<138 g, <0.54 mol) in DMF (400 ml) is added deformed sodium (56,3 g, 0.59 mol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture is quickly darkens and there is a slight evolution of heat. The reaction mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate (200 is l). The resulting solution was washed with water (400 ml) and the aqueous layer was extracted with ethyl acetate (2×200 ml). The combined organic extracts washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue is placed in a dry form on silica (150 g) and the residue is treated using flash chromatography (SiO2400 g, 40% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solid yellow (46 g, 33% over two stages).1H NMR (CDCl3, 400 MHz): 8,46 (2H, user. c), 7,56 (1H, d, J=7,7 Hz), of 6.66 (1H, d, J=7.9 Hz), 4,39 (2H, user. c)to 3.36 (3H, c).

Stage 2, method B: Methyl ester of 2-chloro-6-determinainternational acid

To a solution of crude methyl ester 6-methyl bromide-2-chloronicotinic acid (235 g) in DMF (500 ml) was added in several portions deformed sodium (82 g of 0.878 mol), keeping the temperature below 30°C, and the resulting reaction mixture was stirred at room temperature for 16 hours (N.B.the reaction mixture is quickly darkens, and there is a slight evolution of heat). The reaction mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate (400 ml). The resulting solution was washed with water (2×400 ml) and the aqueous layer was extracted with ethyl acetate (2×300 ml). The combined organic extracts washed with brine (200 ml), dried (MgSO4and Konz is tryout in vacuum. The resulting residue is placed in a dry form on silica (200 g) and the residue is treated using flash chromatography (SiO2300 g, 10-30% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solid yellow (90,2 g, 44% over two stages).1H NMR (CDCl3, 400 MHz): 8,46 (2H, user. c), 7,56 (1H, d, J=7,7 Hz), of 6.66 (1H, d, J=7.9 Hz), 4,39 (2H, user. c)to 3.36 (3H, c).

Stage 3, method A: Methyl ether of 2-chloro-6-formelementname acid

To a solution of methyl ester of 2-chloro-6-determinainternational acid (53,0 g, 0.21 mol) in methanol (300 ml), add water (and 3.72 ml, 0.21 mol) and formic acid (15.6 ml, 0.42 mol) before the reaction mixture is heated at boiling temperature under reflux for 16 hours. The reaction mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate (200 ml). The resulting solution was washed with water (200 ml) and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic extracts washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo, obtaining mentioned in the title compound in the form of an orange oil which solidifies upon standing (42.6 g, 90%).1H NMR (CDCl3, 400 MHz): to 8.34 (1H, c), 8,17 (1H, d, J=8.0 Hz), 7,31 (1H, d, J=7.8 Hz), 6,63 (1H, user. c)4,63 (2H, d, J=5.6 Hz), of 3.96 (3H, c).

u> Stage 3, method B: Methyl ester of 2-chloro-6-formelementname acid

To a solution of methyl ester of 2-chloro-6-determinainternational acid (90,2 g, 0,352 mol) in methanol (530 ml) is added water (8 ml, 0.44 mol) and formic acid (27,6 ml, 0.73 mol) before the resulting reaction mixture is heated at a low boil under reflux for 16 hours. The reaction mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate (400 ml). The resulting solution was washed with water (400 ml) and the aqueous layer was extracted with ethyl acetate (2×200 ml). The combined organic extracts washed with brine (300 ml), dried (MgSO4) and concentrated in vacuo, obtaining mentioned in the title compound as orange oil that solidifies upon standing (79,78 g, 99%).1H NMR (CDCl3, 400 MHz): to 8.34 (1H, c), 8,17 (1H, d, J=8.0 Hz), 7,31 (1H, d, J=7.8 Hz), 6,63 (1H, user. c)4,63 (2H, d, J=5.6 Hz), of 3.96 (3H, c).

Stage 4: Methyl ester 5-chloroimidazo[1,5-a]pyridine-6-carboxylic acid

To a suspension of methyl ester of 2-chloro-6-formelementname acid (42.6 g, to 0.19 mol) in toluene (400 ml) is added phosphorus oxychloride (V) (18.2 ml, 0.20 mol) and the resulting reaction mixture is heated at 65°C for 1.5 hours. The resulting reaction mixture is cooled to room temperature and diluted with ethyl acetate (200 ml) before it is to treated with sodium hydroxide solution (2M), to bring the pH to approximately 8. The layers are separated and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic extracts washed with brine (100 ml), dried (MgSO4), then add activated carbon (~5 g) and the resulting solution was stirred for 5 minutes, and then filtered and concentrated in vacuo, obtaining mentioned in the title compound in the form of a solid yellow-brown (34.4 g, 88%).1H NMR (CDCl3, 400 MHz): charged 8.52 (1H, c), EUR 7.57 (1H, c), was 7.45 (1H, d, J=9.3 Hz), 7,25 (1H, d, J=9.1 Hz), of 3.97 (3H, c).

5-(2-Fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: Methyl ester of 2-(2-fluoro-4-iodoaniline)-6-formelementname acid

To a solution of methyl ester of 2-(2-fluoro-4-trimethylsilylmethylamine)-6-formelementname acid (10.3 g, a 27.4 mmol) in DCM (275 ml) at 0°C is added dropwise to monochloride iodine in the form of a solution in DCM (54.9 ml, 1M, 54,9 mmol). The reaction mixture is then stirred at 0°C for 1 hour. The reaction mixture is washed with an aqueous solution of sodium metabisulfite (100 ml, 0,5M) and the aqueous layer was extracted twice with ethyl acetate (2×50 ml). The combined organic extracts washed with brine (50 ml), dried (MgSO4), filtered and conc is the shape in vacuum, getting listed in the title compound in the form of resin orange (11.6 g, 100%). LC-MS (method B): RT= 3,72 minutes, M+H+= 430.

Stage 2: Methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a suspension of methyl ester of 2-(2-fluoro-4-iodoaniline)-6-formelementname acid (11.6 g, a 27.4 mmol) in toluene (160 ml) is added phosphorus oxychloride (V) (5,1 ml of 54.8 mmol) and the resulting reaction mixture is heated at 95°C for 1 hour. The reaction mixture was concentrated in vacuo and the resulting residue was poured on ice. The resulting mixture was washed with saturated aqueous sodium bicarbonate (40 ml) and the aqueous layer was extracted twice with ethyl acetate (2×30 ml). The combined organic extracts washed with brine (30 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (SiO2gradient of 0-70% ethyl acetate in DCM)to give specified in the title compound as brown oil (5.6 g, 50%). LC-MS (method B): RT= 3,62 minutes, M+H+= 412.

Stage 3: 5-(2-Fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (5.6 g, to 13.6 mmol) in IMS (50 ml) add odny solution of sodium hydroxide (to 27.2 ml, 1M, to 27.2 mmol) and the resulting reaction mixture was stirred at 65°C for 2 hours. The reaction mixture was concentrated in vacuo to remove the IMS. The resulting solution is acidified to pH ~5, adding an aqueous solution of hydrochloric acid (1M), which causes the formation of sludge. The resulting product is collected by filtration and dried in vacuum at 45°C, getting mentioned in the title compound in the form of a solid beige color (5,4 g, 100%). LC-MS (method B): RT= 2,79 minutes, M+H+= 398.

Methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid. The way A

To a solution of letibit(trimethylsilyl)amide (9,98 ml, 1M solution, 9,98 mmol) in THF (20 ml) under nitrogen atmosphere at -70°C is added dropwise over 15 minutes a solution of 2-fluoro-4-iodoaniline (1.01 g, to 4.28 mmol) and methyl ester 5-chloroimidazo[1,5-a]pyridine-6-carboxylic acid (1.0 g, of 4.75 mmol) in THF (20 ml)to give a solution of a bright red colour. After stirring for 30 minutes at -78°C the reaction mixture is left to warm to -30°C and then quenched with a saturated aqueous solution of ammoniaand (200 ml). The resulting mixture was extracted twice with ethyl acetate, then the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is treated, use the I flash chromatography (Si-PPC, the gradient of 0-40% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solid yellow (1,15 g, 65%). LC-MS (method B): RT= 3,54 minutes, M+H+= 412.

Methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid. Method B

To a stirred suspension of 2-fluoro-4-iodoaniline (53,95 g, 0,256 mol) and methyl ester 5-chloroimidazo[1,5-a]pyridine-6-carboxylic acid (62,0 g, 0,253 mol) in THF (500 ml) in a nitrogen atmosphere at -78°C is added dropwise a solution letibit(trimethylsilyl)amide (544 ml, 1M solution, 0,544 mol) over 1 hour, maintaining the temperature below -65°C, resulting in the solution of red-brown color. After stirring for 30 minutes at -78°C the reaction mixture is left to warm to -30°C and then quenched, add water (100 ml). The solvent is removed in vacuum before diluted with water (500 ml)and the resulting mixture is extracted with 2-methyltetrahydrofuran (2×500 ml). The combined organic extracts washed with water, then brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue triturated with tert-butylmethylamine ether (600 ml)to give the product as a solid yellow-brown (87,2 g 83%). LC-MS (method B): RT= 3,54 minutes, [M+H]+= 412.

5-(4-Bromo-2-forgenerating)imidazo[1,5-a]feast the DIN-6-carboxylic acid

Stage 1: Methyl ester of 2-(4-bromo-2-forgenerating)-6-formelementname acid

To a solution of methyl ester of 2-(2-fluoro-4-trimethylsilylmethylamine)-6-formelementname acid (11.6 g, of 30.9 mmol) in DCM (300 ml) at -30°C portions add N-bromosuccinimide (5,56 g of 30.9 mmol). The reaction mixture is then stirred at -30°C for 30 minutes. The reaction mixture was concentrated in vacuo and the residue is divided between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is isolated and washed with water, dried (Na2SO4), filtered and concentrated in vacuo, obtaining specified in the title compound in the form of resin orange (11.8 g, 100%). LC-MS (method B): RT= 3,67 minutes, M+H+= 382/384.

Stage 2: Methyl ester 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester of 2-(4-bromo-2-forgenerating)-6-formelementname acid (11.8 g, of 30.9 mmol) in toluene (550 ml) is added phosphorus oxychloride (V) (3,16 ml, 34 mmol) and the resulting reaction mixture is heated at 95°C for 1 hour. The reaction mixture was concentrated in vacuo and treated with an aqueous saturated solution of sodium bicarbonate, then dailyextended with ethyl acetate. The combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0-30% ethyl acetate in DCM)to give specified in the title compound as brown oil (5.4 g, 49%). LC-MS (method B): RT= 3,56 minutes, M+H+= 364/366.

Stage 3: 5-(4-Bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid (5.4 g, 15 mmol) in IMS (110 ml) is added an aqueous solution of sodium hydroxide (30 ml, 1M, 30 mmol) and the resulting reaction mixture was stirred at 65°C for 1.5 hours. The reaction mixture was concentrated in vacuo to a volume of about 50 ml and the resulting solution is acidified to pH ~2, adding an aqueous solution of hydrochloric acid (1M), which causes the formation of sludge. The precipitate is collected by filtration and dried in vacuum at 35°C, receiving specified in the title compound in the form of solid dark yellow-brown (4,48 g, 85%). LC-MS (method B): RT= 2,81 minutes, M+H+= 350/352.

5-(2-Fluoro-4-cyclopropylamino)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: Methyl ester 5-(2-fluoro-4-cyclopropylamino)imidazo[1,5-a]pyridine-6-carb is new acid

To a solution of 2-fluoro-4-cyclopropylalanine (395 mg, 2,61 mmol) and methyl ester 5-chloroimidazo[1,5-a]pyridine-6-carboxylic acid (500 mg, is 2.37 mmol) in THF under nitrogen atmosphere at -70°C (20 ml) added dropwise letibit(trimethylsilyl)amide (to 4.98 ml, 1M solution, to 4.98 mmol). After stirring for 1 hour at -70°C the reaction mixture is left to warm up and then quenched with a saturated aqueous solution of ameriglide. The resulting mixture was extracted with ethyl acetate (150 ml), the organic extract is dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0-50% ethyl acetate in cyclohexane)to give specified in the title compound (573 mg, 60%). LC-MS (method B): RT= 3,60 minutes, M+H+= 326.

Stage 2: 5-(2-Fluoro-4-cyclopropylamino)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester 5-(2-fluoro-4-cyclopropylamino)imidazo[1,5-a]pyridine-6-carboxylic acid (573 mg, at 1.73 mmol) in methanol (20 ml) is added aqueous sodium hydroxide solution (10 ml, 1M, 10 mmol) and the resulting reaction mixture was stirred at 70°C for 30 minutes. The reaction mixture was concentrated in vacuo to a volume of ~20 ml and the resulting solution was diluted with water (20 ml) and filtered. The obtained filtrate is acidified to pH ~1, d is bawley aqueous solution of hydrochloric acid (1M), what causes the formation of sludge. The precipitate is collected by filtration and dried in vacuum at 45°C, receiving specified in the title compound in the form of solid dark yellow-brown (476 mg, 87%). LC-MS (method B): RT= 2,81 minutes, M+H+= 318.

5-(2-Fluoro-4-methanesulfonanilide)imidazo[1,5-a]pyridine-6-carboxylic acid. The way A

Stage 1: Methyl ester 5-(2-fluoro-4-methylsulfonylamino)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of 2-fluoro-4-methanesulfonanilide (410 mg, 2,61 mmol) and methyl ester 5-chloroimidazo[1,5-a]pyridine-6-carboxylic acid (500 mg, is 2.37 mmol) in THF under nitrogen atmosphere at -70°C (20 ml) added dropwise letibit(trimethylsilyl)amide (to 4.98 ml, 1M solution, to 4.98 mmol). After stirring for 30 minutes at -70°C the reaction mixture is left to warm up, then quenched with a saturated aqueous solution of ameriglide. The resulting mixture was extracted with ethyl acetate (150 ml), the organic extract washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0-50% ethyl acetate in cyclohexane)to give specified in the title compound (471 mg, 73%). LC-MS (method B): RT= 3,39 minutes, M+H+ = 332.

Stage 2: 5-(2-Fluoro-4-methanesulfonanilide)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester 5-(2-fluoro-4-methanesulfonanilide)imidazo[1,5-a]pyridine-6-carboxylic acid (471 mg, 1,45 mmol) in methanol (20 ml) is added aqueous sodium hydroxide solution (10 ml, 1M, 10 mmol) and the resulting reaction mixture was stirred at 70°C for 30 minutes. The reaction mixture was concentrated in vacuo to a volume of ~20 ml and the resulting solution was diluted with water (20 ml) before acidifying to pH ~1, adding an aqueous solution of hydrochloric acid (1M), which causes the formation of sludge. The precipitate is collected by filtration and dried in vacuum at 45°C, receiving specified in the title compound in the form of solid dark yellow-brown (413 mg, 87%). LC-MS (method B): RT= 2,98 minutes, [M+H]+= 312.

5-(2-Fluoro-4-methylsulfonylamino)imidazo[1,5-a]pyridine-6-carboxylic acid. Method B

Step 1: Dimethyl ether, pyridine-2,5-dicarboxylic acid

To a suspension of pyridine-2,5-dicarboxylic acid (20 g, 120 mmol) in dichloromethane (396 ml) and DMF (6.6 ml) added dropwise oxalicacid (60,96 g, 480 mmol) in 20 minutes. After 16 hours at ambient temperature the reaction mixture was concentrated in in the cosmology vacuum and carry out azeotropic distillation of the residue with toluene. The residue is placed in a cold (0°C) methanol (276 ml) and stirred for 15 minutes. The resulting solution was concentrated in vacuo and the residue is transferred in ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate, water and brine. Part of the product collected as a precipitate of white. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo, obtaining mentioned in the title compound in the form of a solid white color (received joint material: 22,93 g, 98%). LC-MS (method B): RT= 2,48 minutes, [M+H]+= 196.

Stage 2: Dimethyl ether 1-oxypyridine-2,5-dicarboxylic acid

To a cold (0°C) solution of dimethyl ether, pyridine-2,5-dicarboxylic acid (22,93 g, 118 mmol) in dichloromethane (472 ml) portions add 3-chloroperbenzoic acid (62.5 g, 278 mmol). The resulting reaction mixture is left to warm to ambient temperature. After stirring for 18 hours the reaction mixture was concentrated in vacuo and the resulting residue adsorb on HMN and processed using flash chromatography (Si-PPC, gradient 0% to 100%ethyl acetate in hexane)to give specified in the title compound in the form of oil, pale yellow (17,08 g, 69%). LC-MS (method B): RT= 1,64 minutes, [M+H]+= 212.

Stage 3: Dimethyl ether 6-chloropyridin-2,5-dicarboxylic acid

To a solution of dimethyl 1-oxypyridine-2,5-dicarboxylic acid (17,08 g, 81 mmol) in toluene (450 ml) is added phosphorus oxychloride (8,3 ml, 89 mmol). The resulting reaction mixture is heated to 95°C and stirred for 1.5 hours. The reaction is quenched by adding water, and the resulting mixture was diluted with ethyl acetate. The resulting solution was washed with saturated aqueous sodium bicarbonate, water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo, obtaining specified in the title compound in the form of solid pale yellow color (of $ 11.97 g, 65%) which was used without purification in the next stage. LC-MS (method B): RT= 2,77 minutes, [M+H]+= 230.

Stage 4: Methyl ether of 2-chloro-6-hydroxymethylamino acid

A cold (0°C) suspension of calcium chloride (19,54 g, 176 mmol) and sodium borohydride (4,18 g, 110 mmol) in anhydrous ethanol (176 ml) and anhydrous THF (88 ml) is stirred for 1 hour, then add dimethyl ether 6-chloropyridin-2,5-dicarboxylic acid (becomes 9.97 g, 44 mmol). After stirring at 0°C for another 6 hours the reaction is quenched by adding H2SO4(35 ml, 5M). The reaction mixture is diluted with et is lacerata and filtered through Celite®. The obtained filtrate was washed with 1M NaOH, water and brine, the organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 100%ethyl acetate in hexane)to give specified in the title compound as yellow oil (6,14 g, 69%). LC-MS (method B): RT= 2,34 minutes, [M+H]+= 202.

Stage 5: Methyl ester of 6-azidomethyl-2-chloronicotinic acid

To a cold (0°C) solution of methyl ester of 2-chloro-6-hydroxymethylamino acid (to 4.98 g of 24.8 mmol) in dichloromethane (161 ml) add methylchloride (2.5 ml, to 29.8 mmol). The resulting reaction mixture is left to warm to room temperature and stirred for 30 minutes. The resulting mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is placed in dimethylformamide (62 ml) and add sodium azide (a 4.03 g, 62 mmol). After stirring at room temperature for 16 hours the reaction mixture is cooled to 0°C, quenched with water (about 50 ml) and extracted three times with ethyl acetate. The combined organic extracts are washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is treated using flash chromatography (Si-PPC, gradient 0% to 50%ethyl acetate in hexane)to give specified in the title compound in the form of oil, pale yellow (4,76 g, 85%). LC-MS (method B): RT= 3,22 minutes, [M+H]+= 227.

Step 6: Methyl ester of 6-aminomethyl-2-chloronicotinic acid

To a solution of methyl ester of 6-azidomethyl-2-chloronicotinic acid and 4.75 g, 21 mmol) in THF (189 ml) and water (3.6 ml) is added triphenylphosphine (11 g, 42 mmol), the reaction mixture is heated at 45°C for 16 hours. The reaction mixture is concentrated under reduced pressure and carry out azeotropic distillation of the residue with methanol. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane)to give specified in the title compound in the form of a solid yellow color. LC-MS (method B): RT= 2,65 minutes, [M+H]+= 201.

Step 7: Methyl ether of 2-chloro-6-formelementname acid

To a solution of methyl ester of 6-aminomethyl-2-chloronicotinic acid (740 mg, 3.7 mmol) in formic acid (18.5 ml) is added acetic anhydride (3,7 ml). The reaction mixture is then stirred at on the th temperature for 1.5 hours. The reaction mixture was concentrated in vacuo three times and carry out azeotropic distillation with toluene, getting mentioned in the title compound as yellow oil (757 mg, 90%), which is used without purification in the next stage. LC-MS (method B): RT= 2,20 minutes, [M+H]+= 229.

Step 8: Methyl ester of 2-(2-fluoro-4-methylsulfonylamino)-6-formelementname acid

To a solution of methyl ester of 2-chloro-6-formelementname acid (123 mg, 0.54 mmol) in toluene (1.6 ml) is added potassium phosphate (119 mg, from 0.76 mmol), 2-fluoro-4-methylsulfinylphenyl (102 mg, of 0.65 mmol), Tris(dibenzylideneacetone)dipalladium (12,8 mg, 0.014 mmol) and DICYCLOHEXYL-(2',6'-diisopropylphenyl-2-yl)Foshan (25 mg, 0,054 mmol). The resulting reaction mixture Tegaserod with argon, then heated at 100°C. After 25 hours the reaction mixture is cooled, diluted with ethyl acetate and washed with saturated aqueous solution of ameriglide, water, then brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with ethyl acetate, getting mentioned in the title compound in the form of a solid bright yellow (43 mg, 23%). LC-MS (method B): RT= 3,53 minutes, [M+H]+= 350.

Step 9: Methyl ester 5-(2-what Thor-4-methylsulfonylamino)imidazo[1,5-a]pyridine-6-carboxylic acid

To a suspension of methyl ester of 2-(2-fluoro-4-methylsulfonylamino)-6-formelementname acid (309 mg, 0.89 mmol) in toluene (15.6 ml) is added phosphorus oxychloride (91 μl, 0.98 mmol) and the resulting reaction mixture is heated to 95°C and stirred for 1 hour. The cooled reaction mixture is quenched by adding water (about 2 ml), then concentrated in vacuo. The resulting residue is placed in ethyl acetate and washed with water, then saturated aqueous sodium bicarbonate and saline. The organic phase is allocated, dried (Na2SO4), filtered, concentrated in vacuo and the residue is treated using flash chromatography (Si-PPC, gradient 0% to 40%ethyl acetate in hexane)to give specified in the title compound in the form of solid yellow (150 mg, 51%). LC-MS (method B): RT= 3,44 minutes, [M+H]+= 332.

Stage 10: 5-(2-Fluoro-4-methylsulfonylamino)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester 5-(2-fluoro-4-methylsulfonylamino)imidazo[1,5-a]pyridine-6-carboxylic acid (150 mg, 0.45 mmol) in IMS (10 ml) is added sodium hydroxide (0.5 ml, 1M aqueous solution, 0.5 mmol), the reaction mixture is heated at 65°C for 1.5 hours. The reaction mixture was concentrated in vacuo, then transferred into the water (about 15 ml, the aqueous solution was washed with diethyl ether before the pH was adjusted to pH 3 using 1M HCl, the resulting precipitate in a solid brown color. The precipitate is extracted using ethyl acetate, the organic phase is isolated and washed with water, then brine, dried (Na2SO4), filtered and concentrated under reduced pressure, obtaining mentioned in the title compound in the form of solid substances like brown (109 mg, 76%).1H NMR (CD3OD): to 7.67 (1H, c), 7,44 (1H, d, J=at 9.53 Hz), 7,39 (1H, d, J=0,83 Hz), 7,24 (1H, DD, J=to 9.57, 0,80 Hz), to 7.15 (1H, DD, J=11,47, 2,12 Hz), 7,02-7,01 (1H, m), 6,76 (1H, t, J=8,49 Hz), 2.49 USD (3H, c).

Methyl ester of 5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)-6-formelementname acid

Stage 1: 6-Chloro-5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid

To a cold (-78°C) solution of 2-fluoro-4-trimethylsilylmethylamine (19.2 g, 105 mmol) in anhydrous THF (50 ml) added dropwise a solution of LHMDS (160 ml, 1M in hexano, 160 mmol) for 45 minutes in a nitrogen atmosphere. After 2 hours at -78°C, add a solution of 2,6-dichloro-5-fornicating acid (10.5 g, 50 mmol) in anhydrous THF (30 ml). The resulting mixture was then stirred at -78°C for 1 hour, then allowed to warm to ambient temperature. After 18 h the in mixing at ambient temperature the reaction is quenched with water and bring the pH to 2, adding concentrated HCl. The resulting solution was extracted with ethyl acetate and the organic layer emit, washed with water, then brine, dried (Na2SO4), filtered and evaporated in vacuum. The resulting residue is triturated with methanol and filtered, obtaining mentioned in the title compound in the form of a solid yellow (8.7 g, 49%). LC-MS (method B): RT= 4,92 minutes, [M+H]+= 357.

Stage 2: Methyl ester of 6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid

To a suspension of 6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid (7.6 g, is 21.3 mmol) in dichloromethane (100 ml) and DMF (1 ml) added dropwise oxalicacid (9.1 ml of 106.4 mmol) in 20 minutes. The reaction mixture is then stirred at the boiling temperature under reflux for 18 hours and then concentrated in vacuo and carry out azeotropic distillation of the residue with toluene. The resulting residue is transferred to a cold (0°C) methanol (100 ml). The resulting solution was heated at boiling temperature under reflux for 1 hour, then cooled to room temperature and filtered. The precipitate was washed with cold methanol and dried in vacuum at 45°C, receiving specified in the title compound in the form of a solid substance W is logo color (7,3 g, 92%). LC-MS (method B): RT= 5,38 minutes, [M+H]+= 371.

Stage 3: Methyl ester of 6-cyano-5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid

Degassed suspension of methyl ester of 6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid (7.8 g, of 21.2 mmol), cyanide zinc(II) (1.84 g, 15.6 mmol) and Pd(PPh3)4(2,43 g, 2,12 mmol) in DMF (40 ml) was subjected to microwave irradiation at 150°C for 15 minutes. The reaction mixture is filtered through Celite® and the resulting filtrate is diluted with ethyl acetate. The organic phase is washed twice with water and once with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue triturated with diethyl ether and pentane and then dried in vacuum, obtaining mentioned in the title compound in the form of a solid yellow (6,9 g, 91%). LC-MS (method B): RT= 4.99 minutes, [M+H]+= 362.

Stage 4: Methyl ester of 6-aminomethyl-5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid

To a suspension of methyl ester of 6-cyano-5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid (5.7 g, 15.8 mmol) in methanol (130 ml) was added cobalt chloride(II) (7.5 g, of 31.6 mmol). The reaction mixture is then stirred during the 10 minutes, then cooled to 0°C and the small portions add sodium borohydride (6.0 g, 158 mmol) for 30 minutes. The reaction mixture is then stirred at 0°C for 15 minutes and then at room temperature for 1 hour. The reaction is quenched by adding concentrated hydrochloric acid (20 ml)and the resulting mixture is stirred for 15 minutes. The resulting reaction mixture is filtered to remove solid white, which was washed with dichloromethane, and the resulting filtrate concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, then water, then brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo, obtaining mentioned in the title compound in the form of a solid brown color (2.0 g, 34%). LC-MS (method B): RT= 2,77 minutes [M+H]+= 366.

Stage 5: Methyl ester of 5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)-6-formelementname acid

To a solution of methyl ester of 6-aminomethyl-5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)nicotinic acid (2.0 g, 5.5 mmol) in formic acid (30 ml) at 0°C, add acetic anhydride (6 ml). The reaction mixture is then stirred at ambient temperature for hours. The reaction mixture was concentrated in vacuo and carry out azeotropic distillation of the obtained residue with toluene, then dissolved in dichloromethane. The obtained organic layer was washed with saturated aqueous sodium bicarbonate, then brine, dried (Na2SO4), filtered and concentrated in vacuo, obtaining mentioned in the title compound in the form of a solid dark brown color (2.1 g, 100%). LC-MS (Method B): RT= 4,36 minutes, [M+H]+= 394.

Methyl ester 5-(4-bromo-2-forgenerating)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: Methyl ester of 2-(4-bromo-2-forgenerating)-5-fluoro-6-formelementname acid

To a solution of methyl ester of 5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)-6-formelementname acid (2.6 g, 6.6 mmol) in dichloromethane (65 ml) at -300C add NBS (1.2 g, 6.6 mmol). The reaction mixture is then stirred at -30°C for 1.5 hours and then concentrated under reduced pressure. The resulting residue is transferred in ethyl acetate and the resulting organic solution was washed with saturated aqueous sodium bicarbonate, then brine, dried (Na2SO4), filtered and evaporated in vacuum, obtaining specified in zag is lowke connection in the form of a solid brown color (2,49 g, 95%). LC-MS (method B): RT= 3,79 minutes, [M+H]+= 400/402.

Stage 2: Methyl ester 5-(4-bromo-2-forgenerating)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylic acid

To a suspension of methyl ester of 2-(4-bromo-2-forgenerating)-5-fluoro-6-formelementname acid (2,49 g, 6.2 mmol) in toluene (60 ml) is added phosphorus oxychloride (0,65 ml, 7.0 mmol). The resulting reaction mixture is heated to 90°C and stirred for 1.5 hours before cooled to room temperature and concentrated in vacuo. The resulting residue is dissolved in ethyl acetate and washed with water, then saturated aqueous sodium bicarbonate and then brine. The organic phase is allocated, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 100%ether in hexane)to give specified in the title compound in the form of solid yellow (692 mg, 29%). LC-MS (method B): RT= 3,97 minutes, [M+H]+= 382/384.

8-Fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: Methyl ester of 5-fluoro-2-(2-fluoro-4-iodoaniline)-6-formelementname acid

To a solution of methyl ester of 5-fluoro-2-(2-fluoro-4-trimethylsilylmethylamine)-6-formylamino technicalinfo acid (2.4 g, 6.1 mmol) in dichloromethane (15 ml) at 0°C add ICl (2.0 g, 12.2 mmol). The resulting mixture was then stirred at 0°C for 0.5 hours, then quenched with water, washed with a saturated solution of sodium sulfite, then brine, dried (Na2SO4), filtered and evaporated in vacuum, obtaining mentioned in the title compound in the form of a solid brown color (2.7 g, 98%). LC-MS (method B): RT= 3,81 minutes, [M+H]+= 448.

Stage 2: Methyl ester of 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a suspension of methyl ester of 5-fluoro-2-(2-fluoro-4-iodoaniline)-6-formelementname acid (2.7 g, 6.2 mmol) in toluene (20 ml) is added phosphorus oxychloride (1.1 ml, 12.2 mmol). The resulting reaction mixture is heated at 95°C for 30 minutes. The resulting reaction mixture is cooled to room temperature and then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate and washed with water, then saturated aqueous sodium bicarbonate, then brine. The organic phase is allocated, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 50%ethyl acetate in hexane)to give specified in the title compound in the form of solids VC the CSOs color (1.0 g, 39%). LC-MS (method B): RT= 3,97 minutes, [M+H]+= 430.

Stage 3: 8-Fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester of 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (500 mg, 1,17 mmol) in IMS (10 ml) is added sodium hydroxide (1.75 ml, 1M aqueous solution of 1.75 mmol), the reaction mixture is heated at 65°C for 45 minutes. The reaction mixture was concentrated in vacuo and the residue is transferred into the water. Add 1H. HCl to bring the pH to 1. The formed precipitate is filtered off and dried in vacuum, obtaining mentioned in the title compound (435 mg, 90%). LC-MS (Method B): RT= 3,47 minutes, [M+H]+= 416.

SYNTHESIS of ASIMILATE[1,5-a]PYRIDINES

Methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid

Stage 1: 3,5-Dichloropyrazine-1-carboxylic acid

To a solution of Diisopropylamine (13,0 ml of 92.6 mmol, 2.3 EQ.) in anhydrous THF (300 ml) at -78°C in an atmosphere of N2add dropwise a solution of 1,6M nBuLi in hexano (57,9 ml of 92.6 mmol, 2.3 EQ.). After 1 hour added dropwise a solution of 2,6-dichloropyrazine in anhydrous THF (6.0 g, of 40.3 mmol) for 30 minutes. After stirring at -78°C for 1 hour the reaction mixture is poured on ismelin the th dry ice (solid carbon dioxide) and the reaction mixture is then stirred at ambient temperature for 16 hours. The resulting mixture was then diluted with water (100 ml) and washed with ethyl acetate (3×100 ml). The aqueous layer was cooled to 0°C, acidified with 2n. HCl to reach pH ~2 and extracted with ethyl acetate (3×100 ml). The combined organic extracts dried (Na2SO4), filtered and evaporated in vacuum. The obtained dry residue is treated using flash chromatography (Si-PPC, gradient 0% to 50%, methanol in dichloromethane)to give the desired product as a solid beige color (3,16 g, 40.6 per cent).1H NMR (CDCl3, 400 MHz), δ ppm: at 8.60 (s, 1H).

Stage 2: 5-Chloro-3-(2-fluoro-4-trimethylsilylmethylamine)pyrazin-2-carboxylic acid

To a solution of 2-fluoro-4-trimethylsilylmethylamine (3.8 g, of 20.7 mmol, 2.0 EQ.) in anhydrous THF (150 ml) at -78°C in an atmosphere of N2add dropwise a solution of 1,0M LHMDS in THF (33,2 ml, 30 mmol, 3.2 EQ.) within 20 minutes. After 1 hour at -78°C, add a solution of 3,5-dichloropyrazine-2-carboxylic acid (2.0 g, of 10.3 mmol) in anhydrous THF (30 ml). The resulting mixture was then stirred at -78°C for 30 minutes and then stirred at ambient temperature for 18 hours. The resulting mixture was quenched with water and the pH adjusted to pH 2 by adding 2n. HCl. The reaction mixture is extracted with ethyl acetate and the organic layer washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuum. The resulting residue is purified through column chromatography (Si-PPC, gradient from 20 to 50% ethyl acetate in hexane, then from 0% to 30%, methanol in dichloromethane)to give the desired compound in the form of solid yellow (2,95 g, 83.8 percent).1H NMR (CDCl3, 400 MHz), δ ppm: 10,41 (c, 1H), 8,28 (t, J=7,79 Hz, 1H), 7,93 (c, 1H), 7,40-of 7.23 (m, 2H), 0,27 (c, 9H).

Stage 3: Methyl ester of 5-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)pyrazin-2-carboxylic acid

To a solution of 5-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)pyrazin-2-carboxylic acid (2,95 g, 8,68 mmol) in methanol (50 ml) and toluene (100 ml) at 0°C in an atmosphere of N2add a solution of 2M trimethylsilyldiazomethane in hexano (of 9.55 ml, 19.0 mmol, 2.2 EQ.) and the reaction mixture is then stirred at ambient temperature for 30 minutes. The reaction mixture is diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuum. The resulting residue is purified using column chromatography (Si-PPC, gradient 0% to 50% ethyl acetate in hexane)to give the desired compound in the form of solid yellow (2,18 g, 71,1%).1H NMR (CDCl3, 400 MHz), δ ppm: 10,54 (c, 1H), at 8.36 (t, J=7,86 Hz, 1H), 8,06 (c, 1H), 7,34-7,26 (m, 2H), 4,05 (c, 3H), 0,28 (c, 9H). LC-MS (method D1) R T= 1,38 minutes, [M+H]+= 354.

Stage 4: Methyl ester of 5-cyano-3-(2-fluoro-4-trimethylsilylmethylamine)pyrazin-2-carboxylic acid

Degassed suspension of methyl ester of 5-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)pyrazin-2-carboxylic acid (1.35 g, is 3.82 mmol), cyanide zinc (II) (492,8 mg, 4.2 mmol, 1.1 EQ.) and Pd(PPh3)4(551,0 mg, 0.48 mmol, 0,12 EQ.) in anhydrous dimethylformamide (30 ml) was subjected to microwave irradiation at 150°C for 18 minutes. The resulting reaction mixture was poured in ethyl acetate and then filtered through a layer of Celite®. Then the filter cake thoroughly washed with ethyl acetate (2×). The combined filtrates washed with 50% brine (2×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue is purified through column chromatography (Si-PPC, gradient 0% to 30% ethyl acetate in hexane)to give a brown oil. In the result of careful grinding with MeOH get the desired compound in the form of solid orange (1.31 g, 99.8 per cent).1H NMR (CDCl3, 400 MHz), δ ppm: 10,56 (c, 1H), at 8.36 (c, 1H), 8,29 (t, J=of 7.82 Hz, 1H), 7,37-7,27 (m, 2H), 4,10 (c, 3H), 0,29 (c, 9H). LC-MS (method D1): RT= 1,28 minutes, [M+H]+= 345.

Stage 5: Methyl ester 5-aminomethyl-3-(2-fluoro-4-trimethylsilylmethylamine)pyrazin-2-carboxylic acid

To a solution of methyl ester of 5-cyano-3-(2-fluoro-4-trimethylsilylmethylamine)pyrazin-2-carboxylic acid (600 mg, of 1.74 mmol) in concentrated glacial acetic acid (12 ml) is added 10% Pd on coal (120 mg). The reaction mixture is vacuum and rinsed H2(3×), then stirred in an atmosphere of H2within 3.5 hours. The reaction mixture is then filtered through a layer of Celite®. The obtained filtrate was concentrated in vacuo, obtaining the desired product as a salt HOAc. LC-MS (method C): RT= of 2.51 min, [M+H]+= 349.

Step 6: Methyl ester 3-(2-fluoro-4-trimethylsilylmethylamine)-5-formalininactivated-2-carboxylic acid

Videolocity a solution of methyl ester 5-aminomethyl-3-(2-fluoro-4-trimethylsilylmethylamine)pyrazin-2-carboxylic acid (800 mg, 2,30 mmol) in formic acid (12 ml) and acetic anhydride (4 ml) then stirred at room temperature in an atmosphere of N2within 1.5 hours. The reaction mixture was concentrated in vacuo and carry out azeotropic distillation of the obtained residue with toluene. The obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo, obtaining specified in is the head of the compound in the form of a yellow foam (850 mg, 98,3%). LC-MS (method D1): RT= 1.09 min, [M+H]+= 377.

Step 7: Methyl ester 3-(2-fluoro-4-iodoaniline)-5-formalininactivated-2-carboxylic acid

To a cold (0°C) solution of methyl ester 3-(2-fluoro-4-trimethylsilylmethylamine)-5-formalininactivated-2-carboxylic acid (480 mg, 1.28 mmol) in dichloromethane (13 ml) in an atmosphere of N2add dropwise a solution of 1M of monochloride iodine in dichloromethane (3.0 ml, 3.0 mmol, 2.4 EQ.) and the resulting mixture is then stirred at 0°C for 1.5 hours. The reaction is quenched by adding saturated aqueous sodium thiosulfate solution (~3 ml). After stirring for 10 minutes the reaction mixture is poured into ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, dried (Na2SO4), filtered and evaporated in vacuum, obtaining the desired product in the form of a solid yellow (548 mg, 99%). LC-MS (method C): RT= 2,65 minutes, [M+H]+= 431.

Step 8: Methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid

To a suspension of methyl ester of 3-(2-fluoro-4-iodoaniline)-5-formalininactivated-2-carboxylic acid (480 mg, 1.12 mmol) in toluene (18 ml) is added phosphorus oxychloride (0,42 ml, 4.4 mmol, 4.0 EQ.) and the reaction mixture is heating the Ute at 95°C for 1 hour. The resulting reaction mixture is cooled to room temperature and then quenched with a saturated aqueous sodium bicarbonate (2 ml). The resulting residue is dissolved in ethyl acetate and washed with water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 20%methanol in ethyl acetate)to give yellow oil. As a result of crystallization from a mixture of dichloromethane-ether-hexane get the desired product in the form of a solid yellow color (190 mg, 41,3%). LC-MS (method C): RT= 2,45 minutes, [M+H]+= 413.

Methyl ester 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyrazin-6-carboxylic acid

Stage 1: Methyl ester of 3-(4-bromo-2-forgenerating)-5-formalininactivated-2-carboxylic acid

To a solution of methyl ester 3-(2-fluoro-4-trimethylsilylmethylamine)-5-formalininactivated-2-carboxylic acid (1.84 g, 4,89 mmol) in dichloromethane (50 ml) at -30°C in an atmosphere of N2add NBS (0.96 g, 5,38 mmol, 1.1 EQ.) and the resulting reaction mixture was then stirred at -30°C for 3 hours. Add NBS (0.96 g, 5,38 mmol, 1.1 EQ.) and the resulting reaction mixture is left to stand at 0°C for 18 hours. According to the scientists, the reaction mixture was diluted with ethyl acetate (250 ml). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material is triturated with methanol, obtaining the desired product in the form of a solid yellow (1.50 g, 80,1%). LC-MS (method C): RT= of 2.51 min, [M+H]+= 383/384.

Stage 2: Methyl ester 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyrazin-6-carboxylic acid

To a suspension of methyl ester of 3-(4-bromo-2-forgenerating)-5-formalininactivated-2-carboxylic acid (1.40 g, 3.65 mmol) in toluene (100 ml) is added phosphorus oxychloride (1.50 ml, at 16.1 mmol, 4.4 EQ.) and the resulting reaction mixture is heated at 95°C in an atmosphere of N2within 1 hour. The resulting reaction mixture is cooled to room temperature and then quenched with a saturated aqueous sodium bicarbonate (20 ml). The resulting residue is dissolved in ethyl acetate and washed with water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient from 70% to 100% ethyl acetate in hexane, then from 0% to 2% methanol in ethyl acetate)to give orange oil. As a result of crystallization from a mixture of ethyl acetate-hexane get the desired product in the form of solid substances is orange (1.26 g, 94,3%). LC-MS (method D1): RT= 0,86 minutes, [M+H]+= 366/367.

5-(2-Fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide

To a solution of 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid (64,0 mg, 0.16 mmol) in anhydrous THF (3.6 ml) is added HOBt (56,5 mg, 0.42 mmol, 2.6 equiv.) DIPEA (0,073 ml, 0.42 mmol, 2.6 mmol) and EDCI (67,8 mg, 0.35 mmol, 2.2 EQ.) and the resulting reaction mixture was then stirred at room temperature in an atmosphere of N2within 2 hours. Add concentrated aqueous ammonium hydroxide solution (0,50 ml) and the reaction mixture is then stirred at room temperature for 20 hours. The reaction mixture is diluted with ethyl acetate (50 ml) and washed with saturated aqueous solution of ameriglide, water and brine. The organic layer is isolated and dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 20% methanol in dichloromethane)to give oil. As a result of crystallization from a mixture of DCM-ether-hexane get mentioned in the title compound in the form of a solid beige color (9,9 mg, 16,0%).1H NMR (MeOD, 400 MHz), δ ppm: a total of 8.74 (c, 1H), 7,86 (c, 1H), 7,79 (c, 1H), 7.62mm (DD, J=10.4 Hz, 2.0 Hz, 1H), of 7.48 (d, J=8,4 Hz, 1H), 6,59 (t, J=8,4 Hz, 1H). LC-MS (method D1): RT= 0,84 minutes, [M+H]+= 398.

EXAMPLE 5

(2 Hydroxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1. Method A: (2-vinyloxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (2.10 g, from 5.29 mmol) and O-(2-vinyloxyethyl)hydroxylamine (0.87 g, 8,46 mmol) in DMF (30 ml) is added EDCI hydrochloride (1.31 g, of 6.90 mmol), HOBt (0,93 g of 6.90 mmol) and DIPEA (1,17 ml of 6.90 mmol). The reaction mixture is then stirred at room temperature for 5 hours before it was concentrated in vacuo. The resulting residue is dissolved in a mixture of 1:1 tert-butyl methyl ether:ethyl acetate (20 ml) and add saturated aqueous sodium bicarbonate solution (20 ml). The resulting mixture is treated with ultrasound before the formation of the precipitate and the precipitate is collected by filtration and dried in vacuum at 45°C, getting mentioned in the title compound in the form of a solid yellow-brown (1.55 g, 60%). LC-MS (method B): RT= 2,80 minutes, M+H+= 483.

Stage 1. Method B: (2-vinyloxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid 1.5 g, of 3.64 mmol) and O-(2-vinyloxyethyl)hydroxylamine (749 mg, 7,28 mmol) in THF (30 ml) at 0°C add letibit(trimethylsilyl)amide in the form of a solution in THF (18 ml, 1M, 18 mmol) for 5 minutes. The reaction mixture is then stirred at ~0°C for 1 h before quenched with a saturated aqueous solution of ameriglide. Volatile solvents are removed in vacuo and then added diethyl ether (10 ml) and ethyl acetate (20 ml). The resulting mixture is treated with ultrasound, which causes the formation of a precipitate, which is filtered off, getting mentioned in the title compound in the form of a solid yellow color (1.07 g, 61%). LC-MS (method B): RT= 2,79 minutes, M+H+= 483.

Stage 1. Method C: (2-vinyloxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a mechanically stirred solution of methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (make 82,17 g, 0.2 mol) and O-(2-vinyloxyethyl)hydroxylamine (by 40.73 g, 0,382 mol) in dry THF (1,27 l) at 5°C in an atmosphere of N2add letibit(trimethylsilyl)amide in the form of a solution in THF (1 l, 1 M, 1 mol) over 1 hour, supported temperature below 10°C. the reaction mixture is then stirred at 0-5°C for 20 minutes, after which it was quenched by adding water (200 ml) and saturated brine (350 ml). Volatile solvents are removed is in vacuum and the residue diluted with water (1.5 l) and extracted with 2-methyltetrahydrofuran (3×1 l). The organic layers washed with water (500 ml), saturated brine (500 ml), dried (Na2CO3and adsorb on silica gel (200 g) and purified on silica gel (400 g), using ethyl acetate as eluent. The obtained crude product is triturated with tert-butylmethylamine ether (400 ml), receiving specified in the title compound in the form of solids brown (58,36 g, 60%). LC-MS (method B): RT= 2,79 minutes, [M+H]+= 483.

Stage 2. Method A: (2-hydroxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a suspension of (2-vinyloxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (2,87 g, 5,95 mmol) in methanol (45 ml) is added aqueous hydrochloric acid solution (11.9 ml, 1M, with 11.9 mmol). The reaction mixture is then stirred at room temperature for 45 minutes, and during this time, the hard part is dissolved. The reaction mixture was concentrated in vacuo to remove the methanol. The resulting solution was diluted with a mixture of 1:1 tert-butyl methyl ether:ethyl acetate (20 ml) and add saturated aqueous sodium bicarbonate solution (20 ml). The resulting mixture is treated with ultrasound until then, until a precipitate, and the precipitate is collected by filtration and dried in vacuum at 45°C, receiving specified in the header is Obedinenie in the form of a solid yellow (2.5 g, 92%).1H NMR (DMSO-d6, 400 MHz): with 8.05 (1H, c), 7,58 (1H, DD, J=10,69, with 1.92 Hz), the 7.43 (1H, c), 7,39 (1H, d, J=was 9.33 Hz), 7,31-7,28 (1H, m), 6.89 in (1H, d, J=9,31 Hz), 6,34 (1H, t, J=8,68 Hz), with 4.64 (1H, c), of 3.64 (2H, t, J=4,78 Hz), of 3.46 (2H,, m). LC-MS (method A): RT= 5,58 minutes, M+H+= 457.

Stage 2. Method B: (2-hydroxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a suspension of (2-vinyloxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (58,36 g, 0.12 mol) in methanol (600 ml) is added an aqueous solution of hydrochloric acid (242 ml, 1M, 0,242 mol). The reaction mixture is then stirred and heated to 45°C for 1 hour, and during this time, the hard part is dissolved. The resulting reaction mixture was then cooled to room temperature and concentrated in vacuo to remove methanol. The resulting residue is treated with saturated aqueous sodium bicarbonate and stirred at room temperature for 1 hour before collecting the crude product by filtration and dried at 55°C over phosphorus oxide (V) in vacuum for 24 hours. The crude product is crystallized from a mixture of IPA:H2O (1:1, vol/about.) (800 ml) with slow cooling and mechanical stirring. The product is collected by filtration and washed with cold mixture of IPA:H2O (1:1, vol/about.) (100 ml) then dried in vacuum at 55°C, receiving specified in sagola the COC connection in the form of a solid light brown color (50.2 g, 90%).1H NMR (DMSO-d6, 400 MHz): with 8.05 (1H, c), 7,58 (1H, DD, J=10,69, with 1.92 Hz), the 7.43 (1H, c), 7,39 (1H, d, J=was 9.33 Hz), 7,31-7,28 (1H, m), 6.89 in (1H, d, J=9,31 Hz), 6,34 (1H, t, J=8,68 Hz), with 4.64 (1H, c), of 3.64 (2H, t, J=4,78 Hz), of 3.46 (2H,, m). LC-MS (method A): RT= 5,58 minutes, [M+H]+= 457.

EXAMPLE 6

((R)-2,3-Dihydroxypropane)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: ((S)-2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (326 mg, 0.82 mmol) in THF (4,1 ml) is added O-((R)-2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)hydroxylamine (362 mg, 2,46 mmol), DIPEA (1.26 in ml, 7.4 mmol), HOBt (327 mg, 2,46 mmol) and EDCI (471 mg, 2,46 mmol), the mixture is stirred for 18 hours at ambient temperature. The reaction mixture is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, then with water and then brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. In the purification of the obtained residue using flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) receive specified in the title compound in the form of solid pale yellow color (364 mg, 84%. LC-MS (method B): RT= 2,58 minutes, [M+H]+= 527.

Stage 2: ((R)-2,3-Dihydroxypropane)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

A solution of ((S)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (364 mg, 0.7 mmol) in methanol (0.5 ml) and dichloromethane (0.5 ml) is injected into SCX-2 cartridge. The cartridge was washed with methanol and the desired product elute using 2M ammonia solution in methanol. The appropriate fractions are combined and concentrated under reduced pressure and carry out azeotropic distillation of the obtained residue with dichloromethane. In the purification of the obtained residue using flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) followed by treatment using preparative HPLC (Gemini column 5 MK, C6-phenyl, 250×21,20 mm, 20 mmol Et3N per liter of solvent, gradient acetonitrile/water, 5 to 98%, the stabilization time of 25 minutes) get mentioned in the title compound in the form of a solid yellow (77,6 mg, 23%).1H NMR (DMSO-d6): 8,01 (1H, c), 7,58 (1H, DD, J=is 10.68, with 1.92 Hz), 7,42 (1H, c), 7,38 (1H, d, J=9,34 Hz), 7,30 (1H, DD, J=8,43, 1,82 Hz)6,91 (1H, d, J=to 9.32 Hz), 6,32 (1H, t, J=8,68 Hz), 3.72 points-to 3.67 (1H, m), 3,60-3,51 (2H, m), 3,30 (2H, d, J=4,94 Hz). LC-MS (method A): RT= 5,13 minutes, [M+H]+= 487.

EXAMPLE 7

((S)-2-Hydroxypropoxy)amide 5-(2-fluoro-4-iodoaniline is about)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (130 mg, 0.33 mmol) in THF (1.7 ml) is added hydrochloride (S)-1-aminocaproyl-2-ol (84 mg, 0.66 mmol), DIPEA (0,23 ml of 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol). After 18 hours stirring at ambient temperature add hydrochloride (S)-1-aminocaproyl-2-ol (84 mg, 0.66 mmol), DIPEA (0,23 ml of 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) and THF (1.7 ml). The reaction mixture is then stirred at ambient temperature for another 5 hours. The reaction mixture is injected into Isolute® SCX-2 cartridge. The cartridge was washed with methanol and the desired product elute using 2M ammonia solution in methanol. The appropriate fractions are combined and concentrated under reduced pressure and carry out azeotropic distillation of the obtained residue with dichloromethane. In the purification of the obtained residue using flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) receive specified in the title compound in the form of solid yellow (17 mg, 11%).1H NMR (DMSO-d6): 8,07 (1H, c), 7,58 (1H, DD, J=10,71, with 1.92 Hz), the 7.43 (1H, c), 7,38 (1H, d, J=9,31 Hz), 7,31-7,28 (1H, m), 6.89 in (1H, d, J=9,31 Hz), 6.35mm (1H, t, J=8,68 Hz), 3,69-of 3.60 (1H, m), 3.45 points-to 3.38 (2H, m)to 0.96 (3H, d, J=6,35 Hz). LC-MS (method A): RT= 6,01 minutes, [M+H]+= 471.

EXAMPLE 8

2 Hydroxyethoxy)amide 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: (2-Vinyloxyethoxy)amide 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid (2.0 g, 5.7 mmol) and O-(2-vinyloxyethyl)hydroxylamine (0.71 g, 6.8 mmol) in DMF (44 ml) is added EDCI hydrochloride (1.42 g, 7.41 mmol), HOBt (1.0 g, 7.41 mmol) and DIPEA (0,97 ml, 5,69 mmol). The reaction mixture is then stirred at room temperature for 3 hours before concentrated in vacuo. The resulting residue is dissolved in a mixture of 1:1 diethyl ether:ethyl acetate (30 ml) and add saturated aqueous sodium bicarbonate solution (30 ml). The resulting mixture is treated with ultrasound until then, until a precipitate. The precipitate is collected by filtration and washed with a mixture of 1:1 diethyl ether:ethyl acetate, getting mentioned in the title compound in the form of a solid yellow-brown (1,33 g, 53%). LC-MS (method B): RT= 2,78 minutes, M+H+= 435/437.

Stage 2: (2-Hydroxyethoxy)amide 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

To a suspension of (2-vinyloxyethoxy)amide 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid (1,33 g, 3,mol) in methanol (40 ml) is added an aqueous solution of hydrochloric acid (6,7 ml, 1M, 6.7 mmol). The reaction mixture is then stirred at room temperature for 30 minutes, then concentrated in vacuo to remove methanol. The resulting residue is dissolved in a mixture of 1:1 diethyl ether:ethyl acetate (30 ml) and add saturated aqueous sodium bicarbonate solution (30 ml). The resulting mixture is treated with ultrasound before the formation of the precipitate, the precipitate is collected by filtration and washed with water, then diethyl ether, obtaining mentioned in the title compound in the form of a solid yellow (1.12 g, 90%).1H NMR (DMSO-d6, 400 MHz): 9,20 (1H, c), 8,07 (1H, c), 7,51 (1H, DD, J=10,86, 2,22 Hz), 7,44 (1H, c), 7,40 (1H, d, J=was 9.33 Hz), 7,16 (1H, DDD, J=8,61, 2,20, 1.07 Hz), 6.89 in (1H, d, J=9,31 Hz), 6,50 (1H, t, J=8,84 Hz), 4,63 (1H, c), 3,65 (2H, t, J=4,79 Hz), of 3.46 (3H, c). LC-MS (method A): RT= 5,22 minutes, [M+H]+= 409/411.

EXAMPLE 9

((S)-2-Hydroxypropoxy)amide 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid (271 mg, 0.77 mmol) in dioxane (3.9 ml) is added HOBT (306 mg, 2.3 mmol) and EDCI (442 mg, 2.3 mmol). The reaction mixture is then stirred at room temperature for 30 minutes, then add hydrochloride (S)-1-aminocaproyl-2-ol (294 mg, 2.3 mmol) and DIPEA (1.2 ml, 6,9 mmol), the resulting mixture is then stirred during the course the e 60 hours at ambient temperature. The reaction mixture is diluted with ethyl acetate, then washed with saturated aqueous sodium bicarbonate, then water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 100%ethyl acetate in dichloromethane, then a gradient from 0% to 10%methanol in dichloromethane)to give specified in the title compound in the form of solid green-yellow (80 mg, 25%).1H NMR (DMSO-d6): 8,10 (1H, c), 7,51 (1H, DD, J=10,87, 2,22 Hz), the 7.43 (1H, c), 7,39 (1H, d, J=9,31 Hz), 7.18 in-7,14 (1H, m), to 6.88 (1H, d, J=9,31 Hz), 6,51 (1H, t, J=cent to 8.85 Hz), 4,69 (1H, c), 3,68-3,59 (1H, m), 3,42 (2H, d, J=5,81 Hz), of 0.95 (3H, d, J=6,35 Hz). LC-MS (method A): RT= 5,71 minutes, [M+H]+= 423/425.

EXAMPLE 10

((S)-2-Hydroxypropoxy)amide 5-(4-bromo-2-forgenerating)-8-torymidae[1,5-a]pyridine-6-carboxylic acid

To a solution of methyl ester 5-(4-bromo-2-forgenerating)-8-torymidae[1,5-a]pyridine-6-carboxylic acid (351 mg, of 0.92 mmol) in IMS (10 ml) is added sodium hydroxide (1.0 ml, 1M aqueous solution, 1.0 mmol). The resulting reaction mixture is heated at 65°C for 1 hour and then concentrated in vacuo. Carry out azeotropic distillation of the obtained residue with toluene and then suspended in dioxane. Added EDCI (353 mg, of 1.84 mmol) and HOBt (248 m is, of 1.84 mmol) and the resulting mixture was then stirred at room temperature for 20 minutes. Add hydrochloride (S)-1-aminocaproyl-2-ol (235 mg, of 1.84 mmol) and DIPEA (0.63 ml, 3,68 mmol) and the resulting mixture is then stirred for 18 hours before concentrating under reduced pressure. The resulting residue is transferred into ethyl acetate, then washed with saturated aqueous sodium bicarbonate, then water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0 to 10%methanol in dichloromethane)to give a solid pale yellow color (124 mg), which was then purified using preparative HPLC (Gemini column 5 MK, C18, 250×21,20 mm, with 0.1% formic acid, gradient acetonitrile/water, 5 to 85%, the stabilization time of 15 minutes), getting mentioned in the title compound in the form of solids not quite white (70 mg, 17%).1H NMR (CDCl3): to 9.45 (1H, c), 8,99 (1H, c), 7,76 (1H, d, J=2,95 Hz), to 7.59 (1H, c), 7,29 (1H, DD, J=10,10, 2,16 Hz), 7,12 (1H, d, J=charged 8.52 Hz), 6,50 (1H, d, J=10,18 Hz), 6,41 (1H, t, J=8.54 in Hz), a 4.03 (1H, t, J=7,52 Hz), 3,94 (1H, d, J=11,57 Hz), 3,70 (1H, t, J=10,24 Hz)to 1.14 (3H, d, J=6,46 Hz). LC-MS (method A): RT= 7,83 minutes, [M+H]+= 441/443.

EXAMPLE 11

(2 Hydroxyethoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carbon is Oh acid

Stage 1: (2-Vinyloxyethoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

8-Fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (0.20 g, 0.48 mmol), O-(2-vinyloxyethyl)hydroxylamine (55 mg, of 0.53 mmol), EDCI (102 mg, of 0.53 mmol), HOBt (72 mg, of 0.53 mmol) and DIPEA (90 μl, of 0.53 mmol) dissolved in DMF (10 ml) and the resulting reaction mixture was stirred at room temperature for 16 hours before concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2×10 ml). The combined organic fractions washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue is treated using flash chromatography (SiO2, gradient 0-10% methanol in DCM)to give specified in the title compound in the form of solid pale yellow color (200 mg, 83%). LC-MS (method B): RT= 3,41 minutes, [M+H]+= 501.

Stage 2: (2-Hydroxyethoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

A solution of (2-vinyloxyethoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (200 mg, 0,39 mmol) in methanol (1 m is) enter in column SCX-2. The column is washed with methanol (10 ml) then elute the product with ammonia in methanol (20 ml, 2M), the appropriate fraction was concentrated in vacuo. The resulting residue is treated using preparative HPLC with a reversed phase (10-90% acetonitrile/water with 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The obtained product is dissolved in ethyl acetate (5 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The aqueous fraction extracted twice with ethyl acetate (2×10 ml) and the combined organic fractions washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo, obtaining specified in the title compound in the form of solid white (88 mg, 39%).1H NMR (DMSO-d6): to 8.20 (1H, c), 7,60 (1H, c), EUR 7.57 (1H, DD, J=of 10.73, a 1.96 Hz), 7,26 (1H, DD, J=8,43, 1,82 Hz), PC 6.82 (1H, d, J=11,14 Hz), 6,30 (1H, t, J=8,71 Hz), the 3.65 (2H, t, J=4,77 Hz), of 3.45 (2H, t, J=4,68 Hz). LC-MS (method A): RT= 7,71 minutes, [M+H]+= 475.

EXAMPLE 12

((R)-2,3-Dihydroxypropane)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: ((R)-2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

8-Fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (235 mg, or 0.57 mmol), O-((R)-2,2-dimethyl-[1,3]dioxolane-4-ILM is Teal)hydroxylamine (92 mg, of 0.62 mmol), EDCI (120 mg, of 0.62 mmol), HOBt (84 mg, of 0.62 mmol) and DIPEA (0.1 ml, of 0.62 mmol) dissolved in DMF (10 ml) and the resulting reaction mixture was stirred at room temperature for 72 hours before concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2×10 ml). The combined organic fractions washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue is treated using flash chromatography (SiO2, gradient 0-10% methanol in DCM)to give specified in the title compound in the form of solid pale yellow color (298 mg, 97%). LC-MS (method B): RT= 3,34 minutes, [M+H]+= 545.

Stage 2: ((R)-2,3-Dihydroxypropane)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of ((R)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (298 mg, 0.55 mmol) in methanol (5 ml) was added hydrochloric acid in dioxane (2 ml, 4n., 8.0 mmol). The reaction mixture is then stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (5 ml), washed with saturated aqueous Rast is or sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2×5 ml). The combined organic fractions washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue is treated using preparative HPLC with a reversed phase (10-90% acetonitrile/water with 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The obtained product is dissolved in ethyl acetate (5 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The aqueous fraction extracted twice with ethyl acetate (2×10 ml) and the combined organic extracts washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo, obtaining specified in the title compound in the form of solid white (83 mg, 30%).1H NMR (DMSO-d6): 11,63 (1H, c), 8,97 (1H, c), by 8.22 (1H, d, J=3,06 Hz), to 7.61 (1H, c), EUR 7.57 (1H, DD, J=a 10.74, 1,93 Hz), 7,26 (1H, d, J=8,50 Hz), PC 6.82 (1H, d, J=11,09 Hz), 6,32 (1H, t, J=total of 8.74 Hz), 3.72 points-of 3.65 (1H, m), 3,59-3,50 (2H, m), 3,29 (2H, m). LC-MS (method A): RT= 7,11 minutes, [M+H]+= 505.

EXAMPLE 13

((S)-2-Hydroxypropoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid

A suspension of 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid (100 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol), DIPEA (0.06 ml, 0.34 mmol) and hydrochloride (S)-2-hydroxypropionate (44 mg, 0.34 mmol) in THF (1 ml) then stirred at room temperature for 18 hours. The resulting reaction is th divide the mixture between ethyl acetate (5 ml) and 1M HCl, the organic layer is isolated and washed with saturated aqueous NaHCO3(2×5 ml) and brine (2×5 ml), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue is treated using preparative HPLC with a reversed phase column (Gemini 5 MK, C18, 250×21,20 mm, with 0.1% formic acid, gradient acetonitrile/water 5 to 98%, the stabilization time of 20 minutes), getting mentioned in the title compound in the form of a solid yellow (13 mg, 8%).1H NMR (DMSO-d6): 11,51 (1H, usher.), of 8.95 (1H, usher.), of 8.25 (1H, c), 7,60 (1H, c), of 7.55 (1H, d, J=10,7 Hz), 7,27 (1H, d, J=8,4 Hz), PC 6.82 (1H, d, J=11,1 Hz), 6,32 (1H, t, J=8,8 Hz), of 4.66 (1H, usher.), of 3.64 (1H, m), 3.43 points (2H, d, J=5.8 Hz), were 0.94 (3H, d, J=6.3 Hz). LC-MS (method A): RT= 8,13 minutes, [M+H]+= 489.

EXAMPLE 14

(2 Hydroxyethoxy)amide 5-(2-permituserenvironment)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: (2-Vinyloxyethoxy)amide 5-(2-fluoro-4-methanesulfonanilide)imidazo[1,5-a]pyridine-6-carboxylic acid

To a mixture of 5-(2-fluoro-4-methanesulfonanilide)imidazo[1,5-a]pyridine-6-carboxylic acid (400 mg, of 1.26 mmol), O-(2-vinyloxyethyl)hydroxylamine (260 mg, 2,52 mmol) and HOBt (221 mg, of 1.64 mmol) in DMF (5 ml) is added EDCI hydrochloride (312 mg, of 1.64 mmol) and DIPEA (0,285 ml of 1.64 mmol) and the resulting mixture was stirred at room temperature techenie hours. The products are divided between ethyl acetate and saturated aqueous NaHCO3. The organic layer is isolated and washed with brine, then dried (Na2SO4), filtered and concentrated in vacuo, obtaining mentioned in the title compound (263 mg, 52%). LC-MS (method B): RT=2,64 minutes, [M+H]+=403.

Stage 2: (2-Hydroxyethoxy)amide 5-(2-fluoro-4-methanesulfonanilide)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of (2-vinyloxyethoxy)amide 5-(2-fluoro-4-methanesulfonanilide)imidazo[1,5-a]pyridine-6-carboxylic acid (263 mg, of 0.65 mmol) in methanol (10 ml) is added 1M hydrochloric acid (1 ml, 1 mmol) and the resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo before divided between saturated aqueous NaHCO3and ethyl acetate. The organic layer emit, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is triturated with ethyl acetate and the solid part is collected by filtration, treated using flash chromatography (Si-PPC, gradient 0 to 10%methanol in DCM)to give specified in the title compound in the form of solid yellow-brown color (123 mg, 50%).1H NMR (DMSO-d6, 400 MHz): 11,54 (1H, c), 9,39 (1H, c), to 7.93 (1H, c), 7,39 (1H, c), 7,32 (1H, d, J=9,36 Hz), 7,16 (1H, DD, J=up 11,86 by 2.13 Hz), 6,93-to 6.88 (2H, m), 6,57 1H, t, J=8,65 Hz), to 4.62 (1H, c), 3,66 (2H, t, J=4,85 Hz), of 3.45 (2H, t, J=4,77 Hz), is 2.40 (3H, c). LC-MS (method A): RT= 5.15 min, [M+H]+= 377.

EXAMPLE 15

(2 Hydroxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid

Stage 1: 5-(2-Fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid

To a solution of methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid (140 mg, 0.34 mmol) in anhydrous 1,2-dichloroethane (2.5 ml) is added hydroxide trimethylurea (215 mg, 1,19 mmol, 3.5 EQ.). The resulting reaction mixture is heated at 85°C for 1 hour and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the crude residue is diluted with ethyl acetate. The organic layer was washed with HCl (3×), water and brine, dried (Na2SO4), filtered and concentrated in vacuo. As a result of crystallization from a mixture of dichloromethane-ether-hexane get mentioned in the title compound in the form of a solid yellow (132,1 mg, 97.7 per cent).1H NMR (MeOD, 400 MHz), δ ppm: 8,76 (c, 1H), 7,92 (c, 1H), 7,86 (c, 1H), to 7.64 (DD, J=10,13, of 1.84 Hz, 1H), 7,55 is 7.50 (m, 1H), 6,72 (t, J=8,49 Hz, 1H). LC-MS (method D1): RT= 0.77 min, [M+H]+= 399.

Stage 2: (2-Vinyloxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid

A mixture of 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid (110 mg, 0.28 mmol), O-(2-vinyloxyethyl)hydroxylamine (of 45.6 mg, 0.44 mmol, 1.6 equiv.) HATU (157,6 mg, 0.41 mmol, 1.5 EQ.) and DIPEA (96,0 μl, 0.55 mmol, 2.0 EQ.) in anhydrous DMF (4,2 ml) is stirred for 18 hours in an atmosphere of N2when the ambient temperature. The reaction mixture is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, then water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 15%, methanol in dichloromethane)to give the desired product as a solid yellow color (24 mg, 18%). LC-MS (method D1): RT= 1.00 min, [M+H]+= 484.

Stage 3: (2-Hydroxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid

To a solution of (2-vinyloxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid (24,0 mg, 0.05 mmol) in methanol (0.5 ml) and dichloromethane (1.0 ml) is added 4M HCl in 1,4-dioxane (30 μl, 0.1 mmol, 2.5 EQ.) and then the reaction mixture was stirred at ambient temperature in an atmosphere of N2within 2 hours. The reaction mixture was concentrated in vacuo, then howled the up in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 25%, methanol in dichloromethane)to give specified in the title compound in the form of solid yellow (11.6 mg, 51%).1H NMR (MeOD, 400 MHz), δ ppm: a total of 8.74 (c, 1H), 7,87 (c, 1H), 7,84 (c, 1H), 7.62mm (DD, J=10,20, 1,82 Hz, 1H), of 7.48 (d, J=to 8.41 Hz, 1H), 6,61 (t, J=8.53 Hz, 1H), of 4.05 (t, J=4,80 Hz, 2H), 3,78 (t, J=4,80 Hz, 2H). LC-MS (method E1): RT= 4,33 minutes, [M+H]+= 458.

EXAMPLE 16

((S)-2-Hydroxypropoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid

To a solution of 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid (85 mg, 0.21 mmol) in anhydrous DMF (1.0 ml) is added hydrochloride (S)-1-aminocaproyl-2-ol (32.7 mg, 0.26 mmol, 1.2 EQ.), DIPEA (of 0.13 ml, 0.77 mmol, 3.6 equiv.) HOBt (36,0 mg, 0.26 mmol, 1.2 EQ.) and EDCI (51,2 mg, 0.26 mmol, 1.2 EQ.) and the resulting reaction mixture was then stirred at room temperature in an atmosphere of N2for 16 hours. The resulting reaction mixture was poured into ethyl acetate and the organic layer washed with saturated sodium bicarbonate solution, 50% saline and saline. The organic phase is allocated, su is at (Na 2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 40%methanol in ethyl acetate)to give oil. As a result of crystallization from a mixture of dichloromethane-ether-hexane get mentioned in the title compound in the form of a solid yellow (10,7 mg, 10.6%), and1H NMR (MeOD, 400 MHz), δ ppm: 8,76 (c, 1H), 7,92 (c, 1H), 7,86 (c, 1H), to 7.64 (DD, J=10,13, of 1.84 Hz, 1H), 7,55 is 7.50 (m, 1H), 6,72 (t, J=8,49 Hz, 1H). LC-MS (method E1): RT= 5,14 minutes, [M+H]+= 472.

EXAMPLE 17

(2 Hydroxyethoxy)amide 5-(4-cyclopropyl-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

Stage 1: (2-Vinyloxyethoxy)amide 5-(4-cyclopropyl-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

To a mixture of 5-(4-cyclopropyl-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid (400 mg, 1,29 mmol), O-(2-vinyloxyethyl)hydroxylamine (265 mg, 2.57 mmol) and HOBt (225 mg, 1,67 mmol) in DMF (5 ml) is added EDCI hydrochloride (320 mg, 1,67 mmol) and DIPEA (0,290 ml, 1,67 mmol) before the reaction mixture is stirred at room temperature for 18 hours. The products are divided between ethyl acetate and saturated aqueous NaHCO3, the organic layer is isolated and washed with brine, then dried (Na2SO4), filtered and conc is the shape in a vacuum. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0-35% ethyl acetate in cyclohexane)to give specified in the title compound (270 mg, 53%). LC-MS (method B): RT=2,79 minutes, [M+H]+=397.

Stage 2: (2-Hydroxyethoxy)amide 5-(4-cyclopropyl-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid

To a solution of (2-vinyloxyethoxy)amide 5-(4-cyclopropyl-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid (270 mg, 0,681 mmol) in methanol (10 ml) is added 1M hydrochloric acid (2 ml, 2 mmol) and the resulting mixture was stirred at room temperature for 2 hours. The solvent is removed in vacuum, and then add saturated aqueous NaHCO3and the resulting mixture extracted with ethyl acetate. The organic layer emit, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue triturated with TBME and the hard part is collected by filtration, getting mentioned in the title compound in the form of solids not quite white (103 mg, 41%).1H NMR (DMSO-d6, 400 MHz): 7,81 (1H, c), 7,37-7,34 (1H, m), 7,27 (1H, d, J=9,37 Hz), to 6.95 (1H, d, J=9,34 Hz)6,91 (1H, DD, J=12,49, with 1.92 Hz), to 6.75 (1H, DD, J=8,27, a 1.96 Hz), 6,56-6,46 (1H, m), 3,71-the 3.65 (2H, m), 3,48-of 3.43 (2H, m), 1,89 and 1.80 (1H, m), 0,91-0,85 (2H, m), 0,65-0,57 (2H, m). LC-MS (method A): RT=5,68 minutes, [M+H]+=371.

EXAMPLE 18

(R)-N-(2,3-Dihydroxypropane)-5-(2-fluoro-4-iodoaniline)is imidazo[1,5-a]pyrazin-6-carboxamide

Stage 1: (R)-N-((2,2-Dimethyl-1,3-dioxolane-4-yl)methoxy)-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide

To a solution of 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid (100.0 mg, 0.25 mmol) in anhydrous DMF (2.5 ml) is added, in order, (R)-O-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)hydroxylamine (40,7 mg, 0.28 mmol, 1.1 equiv.) HOBt (37,3 mg, 0.27 mmol, 1.1 EQ.), EDCI (53,0 mg, 0.27 mmol, 1.1 EQ.) and N-methylmorpholine (0.1 ml, of 0.91 mmol, 3.6 mmol). The reaction mixture is then stirred at room temperature in an atmosphere of N2within 3 days. The reaction mixture is diluted with ethyl acetate and the organic layer washed with saturated sodium bicarbonate solution, water and brine. The organic phase is allocated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient from 80% to 100%ethyl acetate in hexane, then gradient elution from 0% to 20% methanol in ethyl acetate)to give a solid yellow (72,6 mg, 54.8 per cent). LC-MS (method D1): RT= 0.97 min, [M+H]+= 528.

Stage 2: (R)-N-(2,3-Dihydroxypropane)-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide

To a heterogeneous mixture of (R)-N-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-5-(2-FPO is-4-iodobenzylamine)imidazo[1,5-a]pyrazin-6-carboxamide (69,5 mg, 0.13 mmol) in anhydrous methanol (1.6 ml) is added 4M HCl in 1,4-dioxane (0,13 ml, 0.5 mmol, 4.0 EQ.). The reaction mixture is then stirred at room temperature for 10 minutes. Then add solid sodium sulfate (200 mg). The resulting reaction mixture adsorb on silica gel and then treated using flash chromatography (Si-PPC, gradient 0% to 40% methanol in dichloromethane)to give specified in the title compound as yellow foam (to 43.2 mg, 67.3 per cent).1H NMR (DMSO-d6, 400 MHz), δ ppm: 11,90 (c, 1H), 10.30 a.m. (c, 1H), 8,82 (c, 1H), 7,95 (c, 1H), to $ 7.91 (c, 1H), 7,74 (d, J=9.6 Hz, 1H), 7,44 (d, 8,4 Hz, 1H), 6,60 (t, J=8,4 Hz, 1H), a 4.86 (d, J=4.4 Hz, 1H), 4,55 (user. c, 1H), 3,99-3,91 (m, 1H), 3,79 at 3.69 (m, 2H), 3,39 (user. c, 2H). LC-MS (method E2): RT= 8,40 minutes, [M+H]+= 488.

EXAMPLE 19

N-Ethoxy-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide

To a solution of methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid (165,0 mg, 0.40 mmol) and hydrochlorideO-ethylhydroxylamine (78,1 mg, 0.80 mmol, 2.0 EQ.) in anhydrous THF (9.4 ml) at 0°C add litigationrelated (1M in THF, 1.2 ml, 1.2 mmol, 3.0 EQ.). After stirring at room temperature for 16 hours add an additional hydrochlorideO-ethylhydroxylamine (234,3 mg of 2.40 mmol, 3.0 EQ.) and litigationrelated (1M in THF, 3.6 ml, 3.6 mmol, 9,0 EQ.) when 0 is C and the reaction mixture is then stirred at room temperature for 3 days. The reaction mixture is then quenched with a saturated aqueous sodium bicarbonate (5 ml) and diluted with ethyl acetate (50 ml). The organic layer is isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 45% to 100%ethyl acetate in hexane, then a gradient from 0 to 15% methanol in ethyl acetate)to give oil. As a result of crystallization from a mixture of DCM-ether-hexane get mentioned in the title compound in the form of solid yellow solid (33,7 mg, 19.1 percent).1H NMR (DMSO-d6, 400 MHz), δ ppm: up 11,86 (c, 1H), 10,38 (c, 1H), 8,82 (c, 1H), 7,94 (c, 1H), 7,92 (c, 1H), 7,73 (d, J=10.4 Hz, 1H), 7,44 (d, 8,4 Hz, 1H), to 6.57 (t, J=8,4 Hz, 1H), 3,90 (kV, J=7.2 Hz, 2H), of 1.18 (t, J=6.8 Hz, 3H). LC-MS (method D2): RT= 1,24 minutes, [M+H]+= 442.

EXAMPLE 20

N-(Cyclopropylmethoxy)-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide

Specified in the header of the connection receives the same way as the receive N-ethoxy-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide, hydrochloride using O-(cyclopropylmethyl)hydroxylamine as starting material.1H NMR (DMSO-d6, 400 MHz), δ ppm: 11,82 (c, 1H), 10,36 (c, 1H), 8,82 (c, 1H), 7,95 (c, 1H), to $ 7.91 (c, 1H), 7,73 (DD, J=10.4 Hz, 1.8 Hz, 1H), 7,44 (d, 8,4 Hz, 1H), return of 6.58 (t, J=8,4 Hz, 1H), to 3.67 (d, J=7.2 Hz, 2H), 1,12-a 1.01 (m, 1H) 0,54-of 0.48 (m, 2H), 0,28-0,23 (m, 2H). LC-MS (method D2): RT= 1,33 minutes, [M+H]+= 468.

EXAMPLE 21

5-(2-Fluoro-4-iodoaniline)-N-methylimidazo[1,5-a]pyrazin-6-

carboxamid

To a solution of methyl ester 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid (108 mg, 0.26 mmol) in anhydrous methanol (0.5 ml) is added 2M methylamine in THF (1.3 ml, 2.6 mmol, 10 EQ.) and the resulting reaction mixture was then stirred at room temperature in an atmosphere of N2within 3 days. The reaction mixture is diluted with ethyl acetate (50 ml). The organic layer is washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using preparative VIEH with reversed phase [Gemini-NX (100×30 mm, l0 MK), of 0.1% FA in a mixture of water/acetonitrile, 5-85%, the stabilization time of 10 minutes, flow rate 60 ml/min], getting mentioned in the title compound in the form of a solid white color (to 48.3 mg, 44.8 percent).1H NMR (DMSO-d6, 400 MHz), δ ppm: 10,89 (c, 1H), 8,95-8,91 (m, 1H), 8,86 (c, 1H), 7,92 (c, 1H), 7,88 (c, 1H), 7,76 (DD, J=8,4 Hz, 1.2 Hz, 1H), 7,44 (d, J=6,8 Hz, 1H), 6,51 (t, J=6,8 Hz, 1H), 2,81 (d, 4.0 Hz, 3H). LC-MS (method E2): RT= 12,23 minutes, [M+H]+= 412.

EXAMPLE 22

5-(4-Bromo-2-forgenerating)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyrazin-6-carboxamide

One hundred who ia 1: 5-(4-Bromo-2-forgenerating)-N-(2-(vinyloxy)ethoxy)imidazo[1,5-a]pyrazin-6-carboxamide

To a stirred solution of methyl ester 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyrazin-6-carboxylic acid (150 mg, 0.41 mmol) and O-(2-vinyloxyethyl)hydroxylamine (127 mg, of 1.23 mmol, 3.0 EQ.) in anhydrous THF (7.5 ml) at 0°C add litigationrelated (1M in THF, 1.2 ml, of 1.23 mmol, 3.0 EQ.) and the resulting reaction mixture was then stirred at room temperature. After 1 hour the reaction mixture is quenched with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer is isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0 to 5% methanol in dichloromethane)to give oil. As a result of crystallization from a mixture of DCM-ether-hexane get the desired product in the form of a solid pale orange (160,2 mg, 89.4 per cent). LC-MS (method C): RT= 2,53 minutes, [M+H]+= 437/439.

Stage 2: 5-(4-Bromo-2-forgenerating)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyrazin-6-carboxamide

To a solution of 5-(4-bromo-2-forgenerating)-N-(2-(vinyloxy)ethoxy)imidazo[1,5-a]pyrazin-6-carboxamide (150 mg, 0.34 mmol) in methanol (4.5 ml) and dichloromethane (8,9 ml) is added 4M HCl in 1,4-dioxane (0,13 ml, 0.5 mmol, 1.5 EQ.) and the reaction mixture is then stirred pikantnoi temperature in an atmosphere of N 2within 1 hour. To the obtained reaction mixture was added solid sodium carbonate (50 mg). The resulting reaction mixture to absorb the silicon dioxide and then treated using flash chromatography (Si-PPC, gradient 0% to 15%, methanol in dichloromethane)to give specified in the title compound in the form of solid white (112,1 mg, 79,5%).1H NMR (DMSO-d6, 400 MHz), δ ppm: 11,85 (user. c, 1H), 10,32 (user. c, 1H), 8,83 (c, 1H), 7,97 (c, 1H), 7,92 (c, 1H), to 7.64 (DD, J=10.4 Hz, 2.6 Hz, 1H), 7,30 (d, J=8,8 Hz, 1H), 6,77 (t, J=8,8 Hz, 1H), and 4.68 (t, J=5.6 Hz, 1H), 3,89 (t, 4,8 Hz, 2H)and 3.59 (q, J=5.4 Hz, 2H). LC-MS (method D1): RT= of 0.786 minutes, [M+H]+= 410/412.

EXAMPLE 23

(S)-5-(4-Bromo-2-forgenerating)-N-(2-hydroxypropoxy)imidazo[1,5-a]pyrazin-6-carboxamide

Stage 1: 5-(4-Bromo-2-forgenerating)imidazo[1,5-a]pyrazin-6-carboxylic acid

The desired compound is obtained by the method similar to the method for producing a 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid using methyl ester 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyrazin-6-carboxylic acid as starting material. LC-MS (method D1): RT= 0,713 minutes, [M+H]+= 351/353.

Stage 2: (S)-5-(4-Bromo-2-forgenerating)-N-(2-hydroxypropoxy)imidazo[1,5-a]pyrazin-6-carboxamide

To a solution of 5-(4-bromo-2-forgenerating)imidazo[1,5-a]is irisin-6-carboxylic acid (100 mg, 0.28 mmol) in anhydrous DMF (1.5 ml) is added, in order, hydrochloride, (S)-1-aminocaproyl-2-ol (or 37.4 mg, 0.29 mmol, 1.03 equiv.) HOBt (40,4 mg, 0.30 mmol, of 1.05 equiv.) EDCI (57,3 mg, 0.30 mmol, of 1.05 equiv.) and 4 methylmorpholine (0.15 ml, of 1.36 mmol, 4.8 EQ.). The reaction mixture is then stirred at room temperature in an atmosphere of N2within 7 hours and then diluted with ether (25 ml) and ethyl acetate (25 ml). The organic layer is washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is treated using flash chromatography (Si-PPC, gradient 0% to 40% methanol in ethyl acetate)to give oil. As a result of crystallization from a mixture of DCM-ether-hexane get the desired product in the form of a solid white color (30,3 mg, 25,0%).1H NMR (DMSO-d6, 400 MHz), δ ppm: 11,88 (user. c, 1H), 10,29 (user. c, 1H), 8,82 (c, 1H), 7,98 (c, 1H), 7,92 (c, 1H), 7,65 (DD, J=10,6 Hz, 2.2 Hz, 1H), 7,30 (d, J=8.6 Hz, 1H), 6,78 (t, J=8,4 Hz, 1H), 4,80 (d, J=4.0 Hz, 1H), 3,90-3,81 (m, 1H), 3.75 to 3,62 (m, 2H), of 1.05 (d, J=6,4 Hz, 3H). LC-MS (method D2): RT= 1,516 minutes, [M+H]+= 424/426.

EXAMPLE 24

(R)-5-(4-Bromo-2-forgenerating)-N-(2,3-dihydroxypropane)imidazo[1,5-a]pyrazin-6-carboxamide

Stage 1: (R)-5-(4-Bromo-2-forgenerating)-N-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)imidazo[1,5-a]pyrazin-6-carboxamide

Need to connect the group of receiving means, similar to the way to obtain 5-(4-bromo-2-forgenerating)-N-(2-(vinyloxy)ethoxy)imidazo[1,5-a]pyrazin-6-carboxamide, using (R)-O-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)hydroxylamine as starting material. LC-MS (method D1): RT= 0,954 minutes, [M+H]+= 480/482.

Stage 2: 5-(4-Bromo-2-forgenerating)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyrazin-6-carboxamide

The desired compound is obtained by the method similar to the method for producing a 5-(4-bromo-2-forgenerating)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyrazin-6-carboxamide, using (R)-5-(4-bromo-2-forgenerating)-N-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)imidazo[1,5-a]pyrazin-6-carboxamide as source material.1H NMR (DMSO-d6, 400 MHz), δ ppm: 11,90 (user. c, 1H), 10,38 (user. c, 1H), 8,81 (c, 1H), of 7.96 (c, 1H), to $ 7.91 (c, 1H), 7,65 (d, J=10.4 Hz, 1H), 7,30 (d, J=8,4 Hz, 1H), 6,77 (t, J=8,8 Hz, 1H), 4,87 (c, 1H), 4,56 (user. c, 1H), 3,93 (DD, J=9.6 Hz, 3.2 Hz, 1H), 3,79 at 3.69 (m, 2H), 3.43 points-to 3.35 (m, 2H). LC-MS (method D1): RT= 0,724 minutes, [M+H]+= 440/442.

EXAMPLE 25

5-(4-Bromo-2-forgenerating)-N-(cyclopropylmethoxy)imidazo[1,5-a]pyrazin-6-carboxamide

Specified in the header of the connection receives a manner analogous to the method of obtaining N-(cyclopropylmethoxy)-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide using methyl ester 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyrazin-6-carboxylic acid as the similar material. 1H NMR (MeOD, 400 MHz), δ ppm: a total of 8.74 (c, 1H), 7,87 (c, 1H), 7,84 (c, 1H), of 7.48 (DD, J=10.4 Hz, 3.2 Hz, 1H), 7,30 (d, 8,4 Hz, 1H), 6.75 in (t, J=8,4 Hz, 1H), 3,79 (d, J=7.2 Hz, 2H), 1,26-of 1.13 (m, 1H), 0,62 is 0.55 (m, 2H), 0,36-0,30 (m, 2H). LC-MS (method D1): RT= 0,985 minutes, [M+H]+= 420/422.

1. The compound of formula I:

and its pharmaceutically acceptable salts, where
Z1represents CR1;
R1represents H;
R1'represents H;
Z2represents CR2;
Z3represents CR3or N;
R2and R3independently selected from H, halogen;
R4represents H;
Y W represents-C(O)-;
W representsor
R5represents H;
X1selected from R11'and-OR11';
each R11'independently represents H, C1-C2alkyl, C2-C8alkenyl;
X4represents a

R6represents H, halogen, cyclopropyl or -(CR19R20)n-SR16;
R6'represents H, halogen;
p represents 0, 1, 2 or 3;
n represents 0, 1 or 2;
where each specified alkyl in R11'independently substituted with one or two groups independently selected from halogen, -(CR19R20)nOR16and R21 ;
each R16independently represents H, C1-C12alkyl;
R19and R20independently selected from H, C1-C8of alkyl;
R21is cyclopropyl.

2. The compound according to claim 1, where Z3represents CR3.

3. The compound according to claim 2, where R2represents H, Cl or F.

4. The compound according to claim 2, where R3represents H, Cl or F.

5. The compound according to claim 2, where Y is W-C(O), W is a X1-N(R5)and X1choose from

6. The compound according to claim 2, where Y is W-C(O), W is a X1-N(R5)and X1choose from

7. The compound according to claim 5 or 6, where X is chosen from

8. The compound according to claim 1, where the specified connection selected from the group consisting of:
(2 Hydroxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid;
((R)-2,3-Dihydroxypropane)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid;
((S)-2-Hydroxypropoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid;
(2 Hydroxyethoxy)amide 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid;
((S)-2-Hydroxypropoxy)amide 5-(4-bromo-2-forgenerating)imidazo[1,5-a]pyridine-6-carbon is Oh acid;
((S)-2-Hydroxypropoxy)amide 5-(4-bromo-2-forgenerating)-8-torymidae[1,5-a]pyridine-6-carboxylic acid;
(2 Hydroxyethoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid;
((R)-2,3-Dihydroxypropane)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid;
((S)-2-Hydroxypropoxy)amide 8-fluoro-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid;
(2 Hydroxyethoxy)amide 5-(2-permituserenvironment)imidazo[1,5-a]pyridine-6-carboxylic acid;
(2 Hydroxyethoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid;
((S)-2-Hydroxypropoxy)amide 5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxylic acid;
(2 Hydroxyethoxy)amide 5-(4-cyclopropyl-2-forgenerating)imidazo[1,5-a]pyridine-6-carboxylic acid;
(R)-N-(2,3-Dihydroxypropane)-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide;
N-Ethoxy-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide;
N-(Cyclopropylmethoxy)-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyrazin-6-carboxamide;
5-(2-Fluoro-4-iodoaniline)-N-methylimidazo[1,5-a]pyrazin-6-carboxamide;
5-(4-Bromo-2-forgenerating)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyrazin-6-carboxamide;
(S)-5-(4-Bromo-2-forgenerating)-N-(2-hydroxypropoxy)imidazo[1,5-a]pyrazin-6-carboxamide;
(R)-5-(4-Bromo-2-tortenelem the but)-N-(2,3-dihydroxypropane)imidazo[1,5-a]pyrazin-6-carboxamide;
5-(4-Bromo-2-forgenerating)-N-(cyclopropylmethoxy)imidazo[1,5-a]pyrazin-6-carboxamide; or its pharmaceutically acceptable salt.

9. Pharmaceutical composition for treating hyperproliferative disorders in a mammal, comprising a compound according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

10. Method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition according to claim 9.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula:

in which: X represents one of the following groups: - a phenyl group optionally substituted by one or more groups, optionally selected from one of the following atoms and groups: halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, NRaRb, R1 represents hydrogen atom, halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, amino, the group NRcRd; with the alkyl and alkoxy groups being optionally substituted by one or more halogens, hydroxy, amino or (C1-C6)alkoxy, R2 represents one of the following groups: -hydrogen atom, - (C1-C6)alkyl group optionally substituted by one or more groups optionally substituted by hydroxy, halogen, amino, the group NRaRb, the phenyl group, the - (C1-C3)alkoxygroup optionally substituted by one or more groups independently selected from hydroxy, halogen, amino, the group NRaRb, - (C3-C7)cycloalkyl((C1-C6)alkyl, - (C3-C7)cycloalkyl(C1-C6)alkoxy, -(C2-C6)alkenyl, - (C2-C6)alkinyl, - the group -CO-R5,- the group -CO-NR6R7,- the group -CO-O-R8,- the group -NR9-CO-R10,- the group -NR11R12,- halogen atom,- the cyanogroup,- the phenyl group optionally substituted by one or more groups optionally selected from the following atoms and groups: halogen, (C1-C6)alkoxy, NRaRb, -CO-R5, -CO-NR6R7, -CO-O-R8, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkyl group optionally substituted by one or more hydroxy groups or NRaRb R3 represents hydrogen atom, (C1-C6)alkyl, (C1-C6)alkoxy or halogen atom, R4 represents hydrogen atom, (C1-C4)alkyl, (C1-C4)alkoxy or fluorine atom, R5 represents hydrogen atom, the phenyl group or (C1-C6)alkyl, R6 and R7, the same or different represents hydrogen atom or (C1-C6)alkyl, or together with nitrogen atom forms a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S,R8 represents (C1-C6)alkyl, R9 and R10, the same or different, represent hydrogen atom or (C1-C6)alkyl, R11 and R12, the same or different, represent (C1-C6)alkyl, or together with nitrogen atom form a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S, Ra and Rb independently represent hydrogen atom, (C1-C6)alkyl or together with nitrogen atom form a 4-7-member cycle, Rc represent hydrogen atom, and Rd represents (C1-C6)alkyl and at least one of the substitutes R1, R2, R3 and R4 are different from hydrogen; and when R3 means methyl, X is unsubstituted; when R1 means methyl, X is unsubstituted; when R2 means chlorine, X is other than parafluorophenyl; in the form of a base or an acid addition salt. The invention also refers to the compounds selected from the group, to a drug, to a pharmaceutical composition, as well as to application of the compounds of formula (I) by any of cl. 1-4.

EFFECT: preparing new biologically active compounds for treating or preventing the diseases associated with nuclear receptor NOT.

13 cl, 18 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel synthesis of 11H-indolo[2,3-c]quinoline derivatives of formula I, which can be used in synthesis of novel preparations for pharmaceutical purposes. In the method of producing 11H-indolo[2,3-c]quinoline derivatives of general formula I

indexRR1R2НННIbClННIcClОСН3ОСН3IdСН3ННIeНОСН3Н

, the corresponding 4-[2-(2-nitrophenyl)-1H-indol-3-yl]-but-3-en-2-ones II are boiled in acetic acid in the presence of twenty-fold molar excess of carbonyl iron for 5 minutes.

EFFECT: method widens the range of obtained products and simplifies the process owing to use of other initial compounds and conditions.

1 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered an agent showing properties of a cognitive function activator representing 1,3-dimethyl-5-(pyridyl-4-amino)methylene-barbituric acid

and an agent of the same purpose, 4-amino-1-(3-nitro-2-oxo-1-phenyl-1,2-dihydronaphthiridinyl)pyridinium chloride -versions.

EFFECT: high biological activity in scopolamine amnesia of the offered agents is presented.

2 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of bicyclic imdazo-3-lylamines of general formula and corresponding physiologically transportable salts thereof, where A1 denotes a nitrogen atom or a C-R1a-group, A2 denotes a nitrogen atom or a C-R1b-group, A3 denotes a C-R1c-group, A4 denotes a nitrogen atom or a C-R1d-group, R1a, R1b, R1c, R1d independently denote hydrogen, halogen, -C(=O)-OR12, -OR16, a straight or branched, saturated, unsubstituted or halogen-tri-substituted C1-10-aliphatic residue, or an unsubstituted phenyl residue which can be bonded through a straight or branched C1-5-alkylene group, or R1b and R1c or R1c and R1d together with a C-C-bridge bonded to them optionally form an unsubstituted annelated phenyl residue, R2 and R3 independently denote hydrogen, -C(=O)-R2b, (CH2)q -C(=O)-R21, where q equals 1, -(CH2)r- C(=O)-O-R22, where r equals 1, a straight or branched, saturated unsubstituted C1-16-aliphatic residue, saturated, unsubstituted C4-8-cycloaliphatic residue which can be bonded through a straight or branched C1-5-alkylene group, or an unsubstituted or at least mono-substituted phenyl or heteroaryl residue which can be bonded through a straight or branched C1-5-alkylene group, or R2 and R3 together with the nitrogen atom with which they are bonded to as a ring member form a saturated heterocycloaliphatic residue which is piperidine or pyrrolidine, R12, R16, R20, R21 and R22 independently denote hydrogen, straight or branched, saturated C1-4-aliphatic residue or an unsubstituted or at least mono-substituted phenyl residue, which can be bonded through a straight or branched C1-5-alkylene group, M1 denotes a phenyl or heteroaryl residue which can be substituted with an additional substitute which is methyl or -CH2-CN, M2 denotes an unsubstituted or at least mono-substituted phenyl or heteroaryl residue, wherein the heteroaryl is selected from a group consisting of the following residues: furyl (furanyl), thienyl (thiophenyl), imidazolyl, thiazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl and quinolyl, the expression "at least mono-substituted" in association with "phenyl" or "heteroaryl" relates to a phenyl or heteroaryl residue which can be substituted with 1 or 2 substitutes independently selected from a group comprising halogen, , -CN, -NO2, -OH, -NH2, -CH2-NH2, -C(=O)-OH, C1-C5alkyl, -CH2-O-C1-C5alkyl, -C2-C5alkenyl, -S-C1-C5alkyl, -O-C1-C5alkyl, -CF3, -O-CF3, -NH-C1-C5alkyl, -N-(C1-C5alkyl)2, -C(=O)-O-C1-C5alkyl, -C(=O)-H, -C(=O)-C1-C5alkyl, -NH-S(=O)2-C1-C5alkyl, -NH-C(O)-C1-C5alkyl, -S(=O)2-NH2,-S(=O)2-NH-C1-C5alkyl, -CH2OH, -C(=O)-NH2, -Si(phenyl)2[C1-C5alkyl], (1,3)-dioxolanyl, phenyl and pyrrolyl. The invention also relates to methods of producing compounds of formula I, a medicinal agent based on compounds of formula I, use of compounds of formula I to prepare the medicinal agent.

EFFECT: obtaining novel derivatives of bicyclic imidazo-3-ylamines of general formula I, used to regulate the mGluR5-receptor.

30 cl, 3 tbl, 365 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of general formula: [1], where R1 denotes an optionally substituted C2-C12 alkyl, aryl or heterocyclic group which can be a mono- or bicyclic 5-11-member radical, where the heteroatoms can be nitrogen, oxygen or sulphur; X1 denotes C2-C4 an alkylene group; X2 denotes a bond; X3 denotes a group of general formula NR3 or CR4R5NR3 (where R3 denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group) and R4 and R5 are identical or different, and each denotes a hydrogen atom or a lower alkyl group or bond; X4 denotes a lower alkylene or lower alkenylene or lower alkynylene group, which can be substituted with one or more oxo groups or a bond; X5 denotes a sulphur atom or bond; Y1 denotes an optionally substituted divalent 4-, 5- or 6-member alicyclic hydrocarbon residue or an optionally subsituted divalent 5- or 6-member alicyclic amine residue, where the heteroatoms can be nitrogen or oxygen; Z1, Z2, Z3, Z4, Z5 and Z6 are identical or different, and each denotes a nitrogen atom or a group of general formula CR7 (where R7 denotes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted amino group, or an amino group substituted with one or more C1-6 alkyl groups, a lower alkyl group, a cycloalkyl, a lower alkoxy group or a monocyclic 5-member heterocyclic group which can be substituted with one or more halogen atoms, where the heteroatoms can be nitrogen, acid or sulphur or a group of general formula Q1CO2R10 (where R10 denotes a carboxyl-protective group and Q1 denotes a lower alkenylene group), provided that at least one of Z3, Z4, Z5 and Z6 denotes a nitrogen atom, or salt thereof. The invention also describes an antimicrobial agent based on said compound.

EFFECT: novel compounds which can be used as antimicrobial agents are obtained and described.

25 cl, 176 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula:

in which: X represents one of the following groups: - a phenyl group optionally substituted by one or more groups, optionally selected from one of the following atoms and groups: halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, NRaRb, R1 represents hydrogen atom, halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, amino, the group NRcRd; with the alkyl and alkoxy groups being optionally substituted by one or more halogens, hydroxy, amino or (C1-C6)alkoxy, R2 represents one of the following groups: -hydrogen atom, - (C1-C6)alkyl group optionally substituted by one or more groups optionally substituted by hydroxy, halogen, amino, the group NRaRb, the phenyl group, the - (C1-C3)alkoxygroup optionally substituted by one or more groups independently selected from hydroxy, halogen, amino, the group NRaRb, - (C3-C7)cycloalkyl((C1-C6)alkyl, - (C3-C7)cycloalkyl(C1-C6)alkoxy, -(C2-C6)alkenyl, - (C2-C6)alkinyl, - the group -CO-R5,- the group -CO-NR6R7,- the group -CO-O-R8,- the group -NR9-CO-R10,- the group -NR11R12,- halogen atom,- the cyanogroup,- the phenyl group optionally substituted by one or more groups optionally selected from the following atoms and groups: halogen, (C1-C6)alkoxy, NRaRb, -CO-R5, -CO-NR6R7, -CO-O-R8, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkyl group optionally substituted by one or more hydroxy groups or NRaRb R3 represents hydrogen atom, (C1-C6)alkyl, (C1-C6)alkoxy or halogen atom, R4 represents hydrogen atom, (C1-C4)alkyl, (C1-C4)alkoxy or fluorine atom, R5 represents hydrogen atom, the phenyl group or (C1-C6)alkyl, R6 and R7, the same or different represents hydrogen atom or (C1-C6)alkyl, or together with nitrogen atom forms a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S,R8 represents (C1-C6)alkyl, R9 and R10, the same or different, represent hydrogen atom or (C1-C6)alkyl, R11 and R12, the same or different, represent (C1-C6)alkyl, or together with nitrogen atom form a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S, Ra and Rb independently represent hydrogen atom, (C1-C6)alkyl or together with nitrogen atom form a 4-7-member cycle, Rc represent hydrogen atom, and Rd represents (C1-C6)alkyl and at least one of the substitutes R1, R2, R3 and R4 are different from hydrogen; and when R3 means methyl, X is unsubstituted; when R1 means methyl, X is unsubstituted; when R2 means chlorine, X is other than parafluorophenyl; in the form of a base or an acid addition salt. The invention also refers to the compounds selected from the group, to a drug, to a pharmaceutical composition, as well as to application of the compounds of formula (I) by any of cl. 1-4.

EFFECT: preparing new biologically active compounds for treating or preventing the diseases associated with nuclear receptor NOT.

13 cl, 18 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound 4-(1-(4-(4-methoxyphenylthio)-2,5-dioxo-2,5-dihydro-1H-pyrro-3-yl)-1H-indol-3-yl)butyl carbamimidothioate (the compound "ЛХТА-1833") which can be used in therapy of colon cancer, breast cancer, melanoma, leucosis.

EFFECT: preparing the new compounds for treating cancer.

2 cl, 2 tbl, 3 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 4-arylcumarine derivatives and a based drug which can be used for treating tumours of general formula

, where A means a group , where CnHm represents residual fatty acids of saturate and olefin series, n represents number 13, 15 or 17, m represents number 27, 31 or 33, while R1, R2, R3 represent hydrogen atoms and/or methoxygroup OCH3. The drug contains said 4-arylcumarine derivatives contained in liposomes containing phosphatidylcholine, phosphatidylinositol and lipid oligopolysaccharide.

EFFECT: there are prepared the new oncology compounds and the new drug showing lesser systemic toxicity and greater membrane affinity.

12 cl, 9 ex, 1 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to composition for prevention and treatment of cancer. Pharmaceutical composition for prevention and treatment of cancer, which contains one or more components selected from group, consisting of cell line obtained from Taxus cambium or procambium with specified characteristics. Functional food product for prevention or improvement of state in case of cancer, which contains one or more components selected from group, consisting of cell line obtained from Taxus cambium or procambium with specified characteristics.

EFFECT: composition and product efficiently induce death of cancer cells, have minimal side effects.

11 cl, 22 dwg, 4 tbl, 8 ex

Kinase inhibitors // 2440352

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula : a pharmaceutically acceptable salt or solvate thereof, having Syk kinase inhibiting properties. The invention also relates to a pharmaceutical composition containing said compound, methods of treating diseases whose development is aided by c-kit receptor activity, such as arthritis, rheumatoid arthritis, tumours, mantle cell lymphoma, as well as a method of inhibiting angiogenesis.

EFFECT: improved method.

13 cl, 4 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology, and can be used for treatment of ovarian cancer recurrences. For this purpose combined courses of subtotal body irradiation (STBI) and chemical therapy (CT) are carried out. STBI is performed with field of diaphragm dome to feet in single dose 0.1 Gy to course dose 1 Gy. CT is carried out immediately after STBI. After each combined course of STBI and CT additionally, after 1-1.5 months course of CT is carried out. After that, after 1-1.5 months entire course of treatment (STBI+CT+CT) is repeated until remission is achieved or total STBI dose not higher than 4 Gy. If after achievement of total STBI dose - 4 Gy, there is no remission, only CT is continued with 1-2 month intervals between courses. All CT courses, performed in the process of treatment are performed with medications from group of taxanes and platinum derivatives.

EFFECT: method ensures increase of remission cases and duration of recurrence-free period in patients due to enhance of cytostatic action onto tumour cells as a result of introduction into treatment scheme of additional courses of chemical therapy between combined courses of STBI and CT, as well as due to reduction of intervals between therapy courses.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, photodynamic therapy of tumours. Photosensitiser (PS), in particular radachlorine is added to nanoparticles of emulsion of perfluorocarbons (PFC), consisting of perfluorodecalin and perfluoromethylcyclohexylpiperidine, stabilised with proxanol 268 solution. Emulsion of PFC with PS is added to stem cells of bone marrow (SCBM), in particular, autologic. Their joined cultivation is carried out, after which SCBM is introduced to subject with malignant tumour, in particular breast tumour. Zone of tumour growth is subjected to impact by light irradiation in dose sufficient for complete or partial tumour destruction. Subject can be represented by a mammal, in particular, human being.

EFFECT: method ensures targeted impact, complete or partial tumour regress, excludes systemic phototoxic injuries.

6 cl, 3 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical composition for injection targeted local application which involves a sterile suspension of platinum complex (OC-6-43)-bis(acetato)-(1-adamantilamino)ammine-dichloroplatinum (IV) (LA-12) in a pharmaceutically acceptable hydrophilic or hydrophobic injection liquid phase with 100% of platinum complex particles sizing less than 250 mcm.

EFFECT: invention provides preparing the sterile platinum complex suspension LA-12 suitable for injection application and containing a sufficient therapeutically effective amount of the complex.

13 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology and concerns early diagnosis of postradiation myocardial damage in patients suffering lung cancer at the stages of combination treatment by examining a morphofunctional myocardial status. It involves gated myocardial 99mTc-MIBI SPECT described by two diagnostic criteria: myocardial perfusion values and left ventricular contractility. The criteria are evaluated fivefold: prior to treatment, after 2 courses of neoadjuvant chemotherapy and after 1, 6 and 12 months following a radical surgery with intraoperative radiation therapy. The derived values are compared with the reference values prior to treatment, and if observing a persistent decrease, postradiation myocardial damage is diagnosed.

EFFECT: technique provides adequate assessment of the progression myocardial status, higher diagnostic accuracy and reliability of early postradiation myocardial damages - up to one year prior to treatment in the given group of patients with lung of cancer having an initial considerable risk of development of a cardiac pathology.

1 ex, 1 app, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula:

in which: X represents one of the following groups: - a phenyl group optionally substituted by one or more groups, optionally selected from one of the following atoms and groups: halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, NRaRb, R1 represents hydrogen atom, halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, amino, the group NRcRd; with the alkyl and alkoxy groups being optionally substituted by one or more halogens, hydroxy, amino or (C1-C6)alkoxy, R2 represents one of the following groups: -hydrogen atom, - (C1-C6)alkyl group optionally substituted by one or more groups optionally substituted by hydroxy, halogen, amino, the group NRaRb, the phenyl group, the - (C1-C3)alkoxygroup optionally substituted by one or more groups independently selected from hydroxy, halogen, amino, the group NRaRb, - (C3-C7)cycloalkyl((C1-C6)alkyl, - (C3-C7)cycloalkyl(C1-C6)alkoxy, -(C2-C6)alkenyl, - (C2-C6)alkinyl, - the group -CO-R5,- the group -CO-NR6R7,- the group -CO-O-R8,- the group -NR9-CO-R10,- the group -NR11R12,- halogen atom,- the cyanogroup,- the phenyl group optionally substituted by one or more groups optionally selected from the following atoms and groups: halogen, (C1-C6)alkoxy, NRaRb, -CO-R5, -CO-NR6R7, -CO-O-R8, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkyl group optionally substituted by one or more hydroxy groups or NRaRb R3 represents hydrogen atom, (C1-C6)alkyl, (C1-C6)alkoxy or halogen atom, R4 represents hydrogen atom, (C1-C4)alkyl, (C1-C4)alkoxy or fluorine atom, R5 represents hydrogen atom, the phenyl group or (C1-C6)alkyl, R6 and R7, the same or different represents hydrogen atom or (C1-C6)alkyl, or together with nitrogen atom forms a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S,R8 represents (C1-C6)alkyl, R9 and R10, the same or different, represent hydrogen atom or (C1-C6)alkyl, R11 and R12, the same or different, represent (C1-C6)alkyl, or together with nitrogen atom form a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S, Ra and Rb independently represent hydrogen atom, (C1-C6)alkyl or together with nitrogen atom form a 4-7-member cycle, Rc represent hydrogen atom, and Rd represents (C1-C6)alkyl and at least one of the substitutes R1, R2, R3 and R4 are different from hydrogen; and when R3 means methyl, X is unsubstituted; when R1 means methyl, X is unsubstituted; when R2 means chlorine, X is other than parafluorophenyl; in the form of a base or an acid addition salt. The invention also refers to the compounds selected from the group, to a drug, to a pharmaceutical composition, as well as to application of the compounds of formula (I) by any of cl. 1-4.

EFFECT: preparing new biologically active compounds for treating or preventing the diseases associated with nuclear receptor NOT.

13 cl, 18 ex, 2 tbl

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