Bicyclic heterocycles as mek kinase inhibitors

FIELD: biotechnologies.

SUBSTANCE: invention refers to bicyclic heterocycles of formula I and formula II , in which radicals and symbols have values specified in the formula of the invention. These compounds have inhibiting activity in relation to MEK kinase. The invention also refers to a pharmaceutical composition for treatment of hyperproliferation disease or inflammatory disease, to a method for inhibition of abnormal growth of cells or treatment of hyperproliferation disorders and to a treatment method of inflammatory diseases of a mammal. Besides, the invention refers to use of a pharmaceutical composition for preparation of a medicinal agent for treatment of the above diseases of a mammal.

EFFECT: improving compound application efficiency.

19 cl, 29 ex

 

The present application is an international patent application on which priority is claimed based on provisional application U.S. No. 61/077426, filed July 1, 2008, the contents of which are given here by reference.

The invention relates to the bicyclic heterocycles of formulae I and II, have anticancer activity, and, more specifically, having inhibitory activity against the kinase MEK. The invention relates to compositions and methods used to suppress abnormal cell growth, treatment of hyperproliferative disorders or treatment of inflammatory diseases in a mammal. The invention also relates to methods of using compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

In seeking to understand how Ras transmits intracellular signals growth MAP (mitogen-activated protein) kinase (MAPK) path acts as a key direction between membrane-bound Ras and core. The MAPK path comprises a cascade of phosphorylation events, including three major kinases, namely: Raf, MEK (kinase of the MAP 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 MK2) (Ahn et al., Methods in Enzymology 2001, 332, 417-431). Active MEK then phosphorylates only its known substrates, MAP kinase, ERK1 and 2. Phosphorylation of ERK by MEK occurs on Y204 and T202 for ERK1 and Y185 and T183 for ERK2 (Ahn et al., Methods in Enzymology 2001, 332, 417-431). Phosphorylated ERK dimerizes and then translocases into the nucleus where it accumulates (Khokhlatchev et al., Cell 1998, 93, 605-615). In the nucleus ERK is involved in several important cellular functions, including, but not limited to, nuclear transport, signal transduction, DNA repair, nucleosome Assembly and translocation, 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, which leads to proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res. 1998, 74, 49-139).

There was compelling evidence that genetic mutations and/or overexpression of its protein kinases involved in the pathway MAP kinase, leading to uncontrolled cell proliferation and, ultimately, the formation of tumors, proliferative diseases. For example, some malignant tumors contain mutations that lead to prolonged activation of this pathway due to the continuous production of growth factors. Other mutations can lead to defects in the deactivation of the activated GTP-bound complex of Ras, which again leads to the activation path is Inez MAP. Mutated oncogenic forms of Ras was detected in 50% of cases of malignant tumors of the colon and >90% of cases of malignant tumors of the pancreas, as well as many other types of malignant tumors (Kohl et al., Science 1993, 260, 1834-1837). Recently, skin disease mutations were found in more than 60% of cases of malignant melanoma (Davies, H. Et al., Nature 2002, 417, 949-954). These skin disease mutations lead to constitutive activation of the MAP kinase cascade. Research on primary tumor samples and cell lines also showed constitutive activation or overactivation MAP kinase path in malignant tumors of the pancreas, colon, lung, ovarian and kidney (Hoshino, R. Et al., Oncogene 1999, 18, 813-822).

MEK acts as an attractive therapeutic target in the MAP kinase cascade paths. MEK, at the output of Ras and Raf, is highly specific for the phosphorylation of MAP-kinases; in fact, the only known reason for MEK phosphorylation are the MAP kinases, ERK1 and 2. Inhibition of MEK, as has been shown in several studies, has the potential therapeutic effect. For example, a small molecule MEK inhibitors suppress tumor growth of human that was shown in model devoid of hair mouse xenotransplantation human tumors (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. January 25, 2001) and inhibit the growth of leukemic cells in acute myeloid leukemia (Milella et al., J Clin Invest 2001, 108 (6), 851-859).

Some low molecular weight MEK inhibitors have also been considered, for example, in WO02/06213, WO 03/077855 and WO03/077914. There is still a need for new inhibitors of MEK as an effective and safe therapy for the treatment of a number of proliferative disease conditions, such as conditions associated with hyperactivity of MEK, as well as diseases modulated MEK cascade.

In General, the invention relates to the bicyclic heterocycles of the formula I and II (and/or solvate, hydrates and/or salts)that have anti-tumor and/or anti-inflammatory activity and more specifically, inhibitory activity against MEK kinase. Some of hyperproliferative and inflammatory disorders are characterized by modulating the function of the kinase MEK, for example by mutation or overexpression of proteins. Accordingly, the compounds according to the invention and their compositions are used in the treatment of hyperproliferative disorders such as cancer and/or inflammatory diseases such as rheumatoid arthritis.

where:

Z1represents NR , S, or O;

R1represents H, C1-C3alkyl, CF3, CHF2or cyclopropyl;

R1'represents H, C1-C3alkyl, cyclopropyl, halogen, CF3, CHF2, CN, NRARAor orB;

each RAindependently represents H or C1-C3alkyl;

RBrepresents H or C1-C3alkyl, optionally substituted by one or more Halogens;

Z2represents CR2or N;

Z3represents CR3or N; provided that Z2and Z3at the same time are not both 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 represents

R5represents H or C1-C12alkyl;

X1selected from R11'and-OR11'; when X1is an R11'X1not necessarily 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, -NO2OK what about, -(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;

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

or R11and R12together with the nitrogen atom to which they are attached, form a 3-8-membered saturated, unsaturated or aromatic ring having 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-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-Csub> 6alkyl), -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);

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

W' represents a

whererepresents a

X2represents O, S or NR9;

R7selected 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),-(CR 14R15)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-C12alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heterocyclic, aryl and heteroaryl;

R8selected 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)qOC(=Y')NR11R12, -(CR14R15)qOS(O)2(OR11), -(CR1 R15)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;

R6represents H, halogen, C1-C6alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heteroaryl, heterocyclyl, -OCF3, -NO2, -Si(C1-C6alkyl), -(CR19R20)nNR16R17, -(CR19R20)nOR16or -(CR19R20)nSR16;

each R6'independently represents H, halogen, C1-C6alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heterocyclic, aryl, heteroaryl, CF3, -OCF3, -NO2, -Si(C1-C6alkyl), -(CR19R20)nNR16R17, -(CR19R20)nOR16or -(CR19R20)nSR16; provided that R6and R6'are not both H;

p is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

q is 2 or 3;

where each specified shall lcil, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl in R2, R3, R4, R5, R6, R6', R7, R8, R9, R10, R11, R11', R12, R13, R14and R15independently optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(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) (OR 16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21;

each R16, R17and R18independently represent H, C1-C12alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heterocyclic, aryl or heteroaryl, where these 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(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)NH(C1-C6 alkyl), -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 atom to which they are attached, form a 3-8-membered saturated, unsaturated or aromatic ring having 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/sub> -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 in 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(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);

each Y' independently represents O, NR22or S; and

R22represents H or C1-C12alkyl;

provided that in the formula (I), (i) when Z1represents NR1and Z2represents N, then Y is not a CO2NH2; and (ii) when Z1represents NR1, Z2represents N, R1'represents H, Z3represents CR3where R3represents H, CH3, CF3, CHF2or CH2F,

then Y is not a CO2Et or

The present invention includes a composition (e.g., pharmaceutical composition)containing the compound of the formula I and / or II and/or solvate, hydrates and/or isoli) and media (pharmaceutically acceptable carrier). The present invention also includes a composition (e.g., pharmaceutical composition)containing the compound of the formula I and / or II and/or solvate, hydrates and/or their salts) and media (pharmaceutically acceptable carrier and, in addition, contains a second chemotherapeutic and/or second anti-inflammatory agent. These compositions are used for inhibiting abnormal cell growth or treating the hyperproliferative disorder in a mammal (e.g. human). These compositions can also be used for the treatment of inflammatory diseases in a mammal (e.g. human).

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 II and/or solvate and their salts) or a 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 II and/or solvate and their salts or compositions based on it, which independently or in combination with a second anti-inflammatory agent.

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

Next, the detailed description of some embodiments of the invention, examples of which are illustrated by the structures and formulas. Although the invention is described hereinafter in conjunction with the listed options exercise, you should be aware that they are not intended to limit the invention to these options for implementation. On the contrary, the invention provides for the inclusion of all alternatives, modifications and equivalents, which may be included in the scope of the present invention, as defined in the claims. The person skilled in the art to understanding many ways and products that are similar or equivalent to those described herein, and which could be used in the practical implementation of the present invention. The present invention is not limited in any way by the described methods and products. When one or more of the incorporated references, patents and similar materials differs from or contradicts this application, including but not limited to the above terms, the use of terms, described techniques, or the like, determine what is the application.

The term "alkyl", as used here, refers to saturated linear or branched monovalent hydrocarbon radical consisting of 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 (ISO-Pr, ISO-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (ISO-Bu, ISO-butyl, -CH2CH(CH3)2), 2-butyl (sec-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-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 2CH(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 and the like.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical consisting of from one to twelve carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp2a double bond, where 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=CH2), and the like.

The term "quinil" refers to a linear or branched monovalent hydrocarbon radical consisting of from one 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), and the like.

The terms "carbocycle", "carbocyclic", "carbocyclic ring" and "cycloalkyl" refers to a monovalent non-aromatic, saturated or partially unsaturated Col is in, having 3 to 12 carbon atoms in the form of a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycle having from 7 to 12 atoms can be represented, for example, in the form of bicyclo[4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycle having 9 or 10 ring atoms, can be represented as a bicyclo [5,6] or [6,6] system, or as bridged systems such 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, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl, cyclododecyl and the like.

"Aryl" means a monovalent aromatic hydrocarbon radical of 6-18 carbon atoms, formed by removing one hydrogen atom from a single carbon atom of the initial aromatic ring system. Some of the aryl groups represented in the examples as "Ar". Aryl includes bicyclic radicals containing aromatic ring condensed with a saturated, partially unsaturated ring, or aromatic carbocyclic or geterotsiklicheskikh the ring. Typical aryl groups include, but are not limited to, radicals formed from benzene (phenyl), substituted benzene, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl and the like.

The terms "heterocycle", "heterocyclyl" and "heterocyclic ring" are used herein interchangeably and refer to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) the carbocyclic radical consisting of from 3 to 18 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms are C, where one or more ring atoms are optionally independently substituted by one or more substituents described below. A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and from 1 to 4 heteroatoms selected from N, O and S), or Bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O and S), for example: bicyclo[4,5], [5,5], [5,6] or [6,6] system. The heterocycles described 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 which lastnosti, 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, thiomorpholine, 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. Spiro group is also included in the scope of this definition. Examples of the heterocyclic group, where the ring atoms is substituted by an oxo (=O) groups are pyrimidinones and 1,1-dioxo-thiomorpholine.

The term "heteroaryl" refers to a monovalent aromatic radical with 5 - or 6-membered rings and includes a condensed ring systems (at least one of which is and omatically), 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, benzimidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, triazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properidine.

A heterocycle or heteroaryl group may be attached to carbon (carbon-linked) or nitrogen (nitrogen-linked), which is also possible. As an example, and without limitation, attached to carbon heterocycles or heteroaryl attached in position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5 or 6 pyridazine, in position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5 or 6 pyrazine, in position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, in position 2, 4 or 5 oxazole, imidazole or thiazole, position 3, 4 or 5 isoxazol PI is Azola or isothiazole, in position 2 or 3 of aziridine, in position 2, 3 or 4 azetidine, in position 2, 3, 4, 5, 6, 7 or 8 of a quinoline or position 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

As an example, and without limitation, attached by the nitrogen heterocycles or heteroaryl attached in position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 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 position 9 of carbazole or β-carboline.

The term "halogen" refers to F, Cl, Br or I. Heteroatoms presented in heteroaryl or heterocyclyl include oxylene forms, such as the N+→O-, S(O), and S(O)2.

The terms "treat" and "treatment" refer to both terapevticheskogo treatment and prophylactic or preventative measures, the aim of which is to prevent or moderate (reduce) undesired physiological change or disorder, such as the development or spread of cancer. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, the spread of the disease, stabilizirovannye (i.e. not worsening) state of disease is, delay or slowing of disease progression, improving or weakening of the morbid state, and remission (partial or complete), detected or undetected. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those who are in a state of disease or disorder, as well as those prone to the condition, disease or disorder, or those who need prevention of a condition or disorder.

The phrase "therapeutically effective amount" means an amount of compound according to the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) relaxes, improves or eliminates one or more symptoms of the particular disease, condition or disorder, or (iii) prevents or delays the manifestation of one or more symptoms of the particular disease, condition or disorder described in this document. In the case of cancer, a therapeutically effective quantity of a drug can reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., to restrain to some extent and preferably stop) infiltration of cancer cells into peripheral organs; inhibit (i.e., the counter is tested to some extent and preferably stop) tumor metastasis; to suppress, to some extent, tumor growth; and/or relieve to some extent one or more symptoms associated with cancer. The drug can, to some extent, inhibit growth and/or eliminate existing cancer cells, the drug may be cytostatic and/or cytotoxic agent. For cancer therapy, efficacy can be assessed, for example, by determining the time to disease progression (TTP) and/or determine the reaction rate (RR).

In this application, the terms "abnormal cell growth" and "hyperproliferative disorder" are used interchangeably. Used here, the phrase "abnormal cell growth", unless otherwise specified, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes, for example, the abnormal growth of: (1) tumor cells (tumors)that proliferous by the expression of 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 proliferous using receptor tyrosinekinase; (4) any tumors that proliferous by aberrant serine/threonine kinase activation; and (5) allocatestring and malignant cells of other proliferative diseases, in which there is aberrant activation of the serine/threonine kinase.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. The term "tumor" includes one or more types of cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignant disease. More particular examples of such 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 abdominal cavity, hepatocellular cancer, gastric cancer, including gastroenterology cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colon cancer and rectal cancer, endometrial cancer or uterine cancer, carcinoma of the salivary glands, kidney cancer or renal cancer, prostate cancer, cancer of the vagina, thyroid cancer, hepatocarcinoma, cancer of the anal canal, penhallow carcinoma, acute leukemia, and cancers of the head/brain and neck cancer.

"Chemotherapeutic agent" is a compound used is in the treatment of my cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesilate (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® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodepa, Carbogen, matureup and uredepa; ethylenimines and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylaniline; acetogenins (especially bullatacin, bullatacin); camptothecin (including sinteticheski analogue topotecan); bryostatin; callistemon; CC-1065 (including its sinteticheskie analogues of adozelesin, carzelesin and bizelesin); cryptophycin (in particular, cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including sinteticheskie analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; macrodantin; spongistatin; mutiny, such as chlorambucil, chlornaphazine, chloroformed, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novemberin, fenstein, prednison is in, trofosfamide, uramustine; nitrocefin, such as carmustine, chlorozotocin, fotemustine, lomustin, nimustine and ranimustine; antibiotics such as enediyne antibiotics (for example, calicheamicin, especially calicheamicin gamma lI and calcimining omega Il (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; spiramycin; and neocarzinostatin chromophore and close chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, autralian, azaserine, bleomycin, cathetometer, carubicin, karminomitsin, calcination, chromomycosis, dactinomycin, daunorubicin, demoralizing, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino doxorubicin, cyanomethane doxorubicin, 2-pyrroline doxorubicin and deoxidation), epirubicin, zorubicin, idarubitsin marsellaise, mitomycin, such as mitomycin C, mycofenolate acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, helmitin, radiobeacon, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites 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 analogs, such as Antica is in, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-andrenaline, such as aminoglutethimide, mitotane, trilostane; stimulator Polevoy acid, such as prolinnova acid; Eagleton; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; astroball; bisantrene; edatrexate; defaming; demecolcine; diazinon; alternity; elliptinium acetate; epothilone; etoposide; gallium nitrate; hydroxyurea; lentinan; londini; maytansinoid, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitrean; pentostatin; penomet; pirarubicin; losoxantrone; podofillina acid; 2-acylhydrazides; procarbazine; PSK®polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tinoisamoa acid; creation; 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, for example, TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ (not containing Cremophor), albumin-engineering based on nanoparticles of drugs paclitaxel (American Pharaceutical Partners, Schaumberg, Illinois), and TAXOTERE® (docetaxel; Rhône-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® (gemcitabine); 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; deformational (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

In the definition of "chemotherapeutic agent" also includes: (i) anti-hormonal agents that regulate or inhibit hormone action on tumors such as anti-estrogens and selective modulators of estrogen receptors (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates the production of estrogen in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RTVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flucam is d, nilutamide, bikalutamid, leuprolide and goserelin; as well as troxacitabine (analogue of 1,3-dioxolane nucleoside cytosine); (iv) inhibitors of protein kinase; (v) inhibitors of the lipid kinase; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways involved in aberrant cell proliferation, such as, for example, PKC-alpha, RaIf and H-Ras; (vii) ribozymes such as VEGF inhibitors of gene expression (e.g., ANGIOZYME®) and HER2 inhibitors of gene expression; (viii) vaccines, such as vaccines, gene therapy, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; topoisomerase inhibitor 1, such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above. Other anti-angiogenic agents include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, COX-II (cyclooxygenase II) inhibitors, and inhibitors of VEGF receptor tyrosine kinase. Examples of the used inhibitors of matrix metalloproteinases, which can be used in combination with the present compound/composition described 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 5863949, U.S. patent 5861510 and EP 780386, all of them included in the present the document in its full form links. 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 described in PCT publications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354).

Other examples of chemotherapeutic agents that may be used in combination with the present compounds include inhibitors of PI3K (phosphoinositide-3 kinase), such as those described 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; 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 of which are included in this document in its entirety by reference. Specific examples of these PI3K inhibitors include SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.) and GDC-0941 (PI3K inhibitor, PIramed and Genenetch).

The term "inflammatory disease"as used in this application includes, but is not limited to, rheumatoid arthritis, atherosclerosis, chronic headache, inflammatory bowel disease (including, n is not limited to, Crohn's disease and ulcerative colitis), chronic obstructive pulmonary lung 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 complications of diabetes, fibrous organic disorders in organs such as lungs, liver, kidneys, and inflammatory complications of the cardiovascular system, such as acute coronary syndrome.

"Anti-inflammatory agent is a compound used in the treatment of inflammation. Examples of anti-inflammatory agents include injectable protein therapeutic agents, such as Enbrel®, Remicade®, Humira®, Kineret®. Other examples of anti-inflammatory agents include non-steroidal anti-inflammatory agents (NSAIDs)such as ibuprofen or aspirin (which reduce the buildup and reduce pain); disease-modifying antirheumatoid drugs (DMARDs)such as methotrexate; 5-aminosalicylate (sulfasalazin and do not contain sulfa agents; corticosteroids; immunomodulators such as 6-mercaptopurine ("6-MP"), azathioprine ("AZA"), cyclosporine, and biological response modifiers, such as Remicade.RTM. (infliximab) and Enbrel.RTM. (etanercept); growth factors, firepl the ists; the platelet-derived growth factor, enzyme blockers, such as Arava.RTM. (Leflunomide); and/or chondroprotective agent, such as hyaluronic acid, glucosamine and chondroitin.

Used in this application, the term "prodrug" refers to a precursor or derivative compounds according to the invention, capable of enzymatically or hydrolytically activated or converted into the more active its original form. See, e.g., 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, ester prodrugs, phosphate-containing prodrugs, thiophosphoramide prodrugs, sulfadimidine prodrugs, peptideatlas prodrugs, D-amino acid-modified prodrugs, glycolytically prodrugs, β-lactosidase prodrugs, optionally substituted phenoxyacetamide prodrugs, optionally substituted phenylacetamides prodrugs, 5-fertilizin and other 5-ferritin prodrugs that can be converted into the more active cytotoxic free drug. Examples of cytotoxic drugs that can be converted in about karstenia forms for use in this invention include, but not limited to, compounds according to the invention and a chemotherapeutic agent such as described above.

"Metabolite" is a product that is produced in the body by metabolism of a particular compound or its salts. Metabolites of compounds can be identified using conventional methods known in the field of machinery and their activity can be determined using such tests as described in the present description. Such products can be obtained, for example, oxidation, hydroxylation, recovery, hydrolysis, amidation, desametasone, esterification, deesterification, enzymatic cleavage, and the like, input connections. Accordingly, the invention encompasses metabolites of the compounds according to the invention, including the compounds obtained by the process consisting in contacting compounds of the present invention with a mammal for a period of time sufficient to obtain its metabolic product.

"Liposome" is a small vesicles composed of various types of lipids, phospholipids and/or surfactant that is used for drug delivery (such as MEK inhibitors described herein, and, optionally, a chemotherapeutic drug) to a mammal. Components is liposome usually are Bilaam, like the arrangement of lipids in biological membranes.

Used in this document, the term "packing liner" refers to the instructions, usually invest in industrial available packages of therapeutic products, that contain information about the indications, usage, dosage, introduction, contraindications and/or warnings concerning the use of such therapeutic products.

The term "chiral" refers to molecules, specular reflection which does not coincide with the overlay, while the term "achiral" refers to molecules, flipping, which coincide with the overlay.

The term "stereoisomer" refers to compounds that issues have the same chemical structure, but different orientation of the atoms in space that does not allow them to be vzaimoprevrascheny during rotation around single bonds.

"Diastereoisomer" refers to a stereoisomer with two or more centers of chirality, and whose molecules are not mirror images of one another. Diastereomers have different physical properties such as melting point, boiling points, spectral properties and reactivity. A mixture of diastereoisomers can be separated by using analytical methods high separation, such as crystallization, electrophoresis and chrome is tography.

"Enantiomers" refers to two stereoisomeric compounds, specular reflection which cannot be superimposed on each other.

Stereochemical definitions and conventions used herein generally correspond to the 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 according to the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is assumed that all stereoisomeric forms of the compounds according to the invention, including, but not limited to, the diastereomers, the enantiomers and atropoisomeric, 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. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, where (-) or l means that the connection is levogyrate. The connection to the prefix (+) or d is Pervouralsk. For Dan the Oh chemical structure of these stereoisomers are identical, except that they are mirror images of one another. A specific stereoisomer may also be specified as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mix of enantiomers indicates a racemic mixture or a racemate, which may be formed when stereobitrate or stereospecificity in the reaction or process is missing. The terms "racemic mixture" and "racemate" refers to an equimolar mixture of two enantiomeric samples that do not have optical activity.

The term "tautomer or tautomeric form" refers to the structural isomers of different energy levels, which can vzaimoprevrascheny with a low energy barrier. For example, proton tautomers (also known as prototroph the tautomers) include interconversion via migration of a proton, such as keto-enol and Imin-enamine isomerization. Valence tautomers include vzaimoprevrascheny by moving some of the electrons.

The phrase "pharmaceutically acceptable salt", as used herein, refers to pharmaceutically acceptable organic or inorganic salts of the compounds according to the invention. Examples of salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, KIS the PTA 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, p-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 include the inclusion of other molecules, such as acetate ion, succinate ion, or other counterion. The counterion may be organic or inorganic group which stabilizes the initial connection charge. In addition, pharmaceutically acceptable salt can have more than one charged atom in its structure. For example, when multiply charged atoms are part of a pharmaceutically acceptable salt, it can have multiple counterions. Thus, the pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.

If the connection according to the invention is a base, the desired pharmaceutically acceptable salt may be obtained by any suitable method known in this field, for example, by treatment of the free base near onicescu acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesulfonate acid, phosphoric acid and the like, 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, pyrenoidosa acid, such as glucuronic acid or galacturonic acid, alphahydroxy acid, such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluensulfonate acid or econsultancy acid or the like.

If the connection according to the invention is an acid, the desired pharmaceutically acceptable salt may be obtained in any suitable way, for example, by treatment of 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 and is inoculat, 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" indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that make up the drug, and/or mammals, which are subjected to treatment with this drug.

"MES" refers to an Association or complex of one or more solvent molecules and compounds according to the 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 the complex, where the solvent molecule is water.

The term "protective group" refers to the Deputy, which is typically used to block or protect certain functional groups in the reaction occurring on other functional groups of the compounds. For example, "amino-protective group" is a Vice attached to the amino group that blocks or protects the functional amino group compounds. Suitable amino-protective the group include acetyl, TRIFLUOROACETYL, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, the "hydroxy-protective group" refers to the Deputy hydroxyl group that blocks or protects the hydroxy functional group. Suitable protective groups include acetyl and trialkylsilyl. "Carboxy-protective group" refers to the Deputy carboxyl group that blocks or protects the carboxyl functional group. Well-known carboxy-protective group include phenylsulfonyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluensulfonyl)ethyl, 2-(p-nitrobenzylidene)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. General description of the protective groups and their use, see the review by T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms "compound in this invention", "compounds of the present invention" and "compounds of formula I or II, unless otherwise indicated, include compounds of formula I or II and their stereoisomers, geometric isomers, tautomers, solvate, metabolites, salts (e.g., pharmaceutically acceptable salts and prodrugs. If not stated otherwise, the patterns presented in this document imply the inclusion of compounds that differ only by the presence of one or several the x isotopically enriched atoms. For example, the compounds of formula I or II, where one or more hydrogen atoms replaced by deuterium or tritium, or one or more carbon atoms replaced with13C - or14C-enriched carbon are included in the scope of the present invention.

The present invention relates to the bicyclic heterocycles of the formula I and II, as described above, used as kinase inhibitors, in particular, are used as inhibitors of MEK kinase.

In accordance with the implementation of the present invention, when R3represents -(CR14R15)nC(=O)R11, -(CR14R15)nNR11R12, -(CR14R15)nOR11, -(CR14R15)nSR11, -(CR14R15)nS(O)R11or -(CR14R15)nS(O)2R11; n is 0; and Z1represents O, then the specified R11or R12not represent aryl; when Z1represents O, then R does not represent a CH2-aryl; and all other variables have the meanings indicated in formula I.

In accordance with the implementation of the present invention, compounds have formula I-a (i.e., Z1represents NH, and Z2and Z3represent CH), I-b (i.e., Z1represents NH, Z2represents N and Z3is own the th CH), I-c (i.e., Z1represents NH, Z2represents CH and Z3is a (N), I-d (i.e., Z1represents S, Z2and Z3represent CH), I-e (i.e., Z1represents S, Z2represents N and Z3represents CH), I-f (i.e., Z1is S, Z2represents CH and Z3is a (N), II-a (i.e., Z1represents NH, and Z2and Z3represent CH), II-b (i.e., Z1represents NH, Z2represents N and Z3represents CH), II-c (i.e., Z1represents NH, Z2represents CH and Z3is a (N), II-d (i.e., Z1represents S, Z2and Z3represent CH), II-e (i.e., Z1is S, Z2represents N and Z3represents CH), or II-f (i.e., Z1represents S, Z2represents CH and Z3is a (N); and all other variables have the meanings indicated in formula I or II.

In accordance with the implementation of the present invention, Z2represents CR2and R2represents H, halogen, CF3or C1-C3 alkyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with another implementation of the present invention, Z2represents CR2and R2represents H, methyl, CF3, F or Cl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with another implementation of the present invention, Z2represents CR2and R2represents H, F or Cl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with another implementation of the present invention, Z2represents N; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with the implementation of the present invention, Z3represents CR3and R3represents H, halogen, CF3O-C1-C3alkyl or C1-C3alkyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described in the above.

In accordance with another implementation of the present invention, Z3represents CR3and R3represents H, methyl, CF3, F, OMe, or Cl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with another implementation of the present invention, Z3represents CR3and R3represents H, F, OMe, or Cl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with another implementation of the present invention, Z3represents N; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with the implementation of the present invention, R1represents H, and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with another implementation of the present invention, Z1represents NR1; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above. In d the natives embodiment, R1represents H, and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation of the present invention, Z1represents S; and all other variables have the meanings indicated in formula I or II, or as defined in any of the implementations described above.

In accordance with the implementation of the present invention, R4represents H or C1-C6alkyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation of the present invention, R4represents H or methyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments. In accordance with another implementation of the present invention, R4represents H; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation of the present invention, R5represents H or C1-C6alkyl; and all other variables have the meanings indicated in formula I or I, or as specified in any of the above options accomplishments.

In accordance with another implementation of the present invention, R5represents H or methyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation of the present invention, R5represents H; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation 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)nNR17SO R16, -(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 have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation 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, -(CR9 R20)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 have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation of the present invention, X1is a OR11'where R11'is a 4-6-membered heterocyclyl containing 1 ring nitrogen atom, where the specified heterocyclyl optional is entrusted 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 have the meanings indicated in formula I or II, or as defined in any of the above which of the variants of implementation.

In accordance with another implementation of the present invention, X1represents:

and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation of the present invention, X1represents a

and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation of the present invention, W is aand all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation of the present invention, W represents-OR11'where R11'represents H or C1-C12alkyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation of the present invention, W represents-OR11'where R11'represents H; and all other variables have the meanings indicated in formula I or II, or as defined in any of vysheukazannoe the x variants of implementation.

In accordance with another implementation of the present invention, W represents-OR11'where R11'represents a C1-C6alkyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation of the present invention, W represents-NHSO2R8; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments. In accordance with the implementation of the present invention, R8is cyclopropyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation of the present invention, R6represents halogen, C2-C8quinil, carbocyclic, or-SR16; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation of the present invention, R6represents halogen, C2-C3quinil, C3-carbocycle, or-SR16where R16represents a C1-C2alkyl; and all other variables have the meanings indicated in formula I or II, or as specified in any of the above options accomplishments.

In accordance with another implementation of the present invention, R6represents Br, I, SMe, C3-carbocyclic, or C2quinil; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation of the present invention, R6'represents H, halogen, or C1-C3alkyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation of the present invention, R6'represents H, F, Cl or methyl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with another implementation of the present invention, R6'represents F or Cl; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

In accordance with the implementation of the present invention, p is 1 or 2; and all other variables have the meanings indicated in formula I or II, or as defined in any of the above options accomplishments.

Another in the version of the implementation of the present invention includes compounds described in the examples 5-29 and connections shown below:

The compounds of formula I and II was obtained in accordance with the methods described in the schemes and examples, or by methods known in this field. For example, the compounds of formula I can be obtained according to scheme 1.

Scheme 1

The compounds of formula (VII) can be obtained from intermediates of formula (III) (obtained in accordance with schemes 2, 3 and 5-8 below). The compounds of formula (V) can be obtained from compounds of formula (III) by reacting with aniline of formula (IV) (including appropriate substituents R1), in the presence of a catalyst such as Tris(dibenzylideneacetone)dipalladium(0) or palladium(II) acetate, a base such as potassium phosphate or cesium carbonate, a ligand such as Xantphos or 2-dicyclohexylphosphino-2',6'- (diisopropoxide)biphenyl, in a suitable solvent, such as toluene or DME, at a temperature of from room temperature to a temperature the boiling point of the solvent, or under microwave radiation at temperatures between 70º C to 150 ° C. Alternatively, the compounds of formula (V) can be obtained from compounds of formula (III) by reacting aniline of formula (IV) in the presence of a strong base such as lithium bis(trimethylsilyl)amide, in a solvent which, such as THF, at a temperature of from-78ºC to room temperature. Alternatively, and preferably, when A2represents N, aniline and compound of formula (III) may be subjected to interaction in a solvent such as dioxane or DMF, in the presence of a base such as potassium carbonate, at a temperature from 50ºC to boiling point.

The compounds of formula (VI) can be obtained from compounds of formula (V), where R2 represents a CO2R3 and R3 represents Me, ethyl, other alkyl, by reacting with a base such as sodium hydroxide, in a solvent such as ethanol or methanol, at temperatures from room temperature to the boiling point. When R3 is a CO2tBu, the compounds of formula (VI) can be obtained from compounds of formula (V) by treatment with acid, such as TFU, clean, or in the presence of a solvent, such as DCM, at a temperature from 0ºC up to the boiling point.

Alternatively, when R3 represents Me, can be carried out saponification in non-major conditions, by treatment with a Lewis acid, such as bis(tri-n-botillo)oxide, in a solvent such as toluene, at a temperature from room temperature up to the boiling point.

The compounds of formula (VI) can be subjected to interaction with the functionalized hydroxylamino the formula (VIII) (commercially available or obtained in accordance with scheme 11) or with an amine and a suitable condensing agent, such as O-(7-Aza-benzo-triazole-1-yl)-N,N,N',N'-Tetra-metilamoniu sexafter-phosphate, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or NN'-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, to obtain the compounds formula (VII). Alternatively, the compounds of formula (VII) can be obtained directly from compounds of formula (V) by reacting with an amine or hydroxylamine DΝHR (VIII) in the presence of a strong base, such as bis(trimethylsilyl)amide lithium, in a solvent such as THF, at temperatures from-20ºC to room temperature. Alternatively, the compounds of formula (VII) can be obtained directly from compounds of formula (V) by reacting with an amine or hydroxylamine DΝHR (VIII) in the presence of a Lewis acid such as trimethyl aluminum, in a solvent such as DCM, at a temperature of from room temperature to the boiling point.

In the compounds of the formula (VII), where A1represents Ν, protective groups (ΝPG) can be added and removed at any stage of the synthesis as needed.

The compounds of formula (III), where A1represents NH, N5 and NPG can be obtained in accordance with scheme 2.

Scheme 2

The compounds of formula (IX) can be obtained using the methods described in the literature. The compounds of formula (X) can be obtained from compounds of formula (IX) by reacting with diasterous agent such as sodium nitrite, in the presence of acid, such as acetic acid or tetraphobia acid, and solvent, such as water, at temperatures from-20ºC to 50ºC. The compounds of formula (X) can be protected with a suitable protecting group to obtain the compounds of formula (XIa) and (XIb) by reacting with a suitable sulphonylchloride, such as p-toluensulfonate, or alkylchloride, such as 2-(trimethylsilyl)ethoxymethyl chloride, in the presence of a base such as triethylamine or sodium hydride, in a solvent such as THF or DCM, at a temperature from 0ºC to room temperature. Alternatively, the compounds of formula (X) can be protected by carbamate protecting group such as tert-butyl carbamate, by reacting the compounds of formula (X) with di-tert-butyl dicarbonate in the presence of a tertiary amine base, such as triethylamine, in a solvent such as DCM, at a temperature of about room temperature. Indazols thereof, can be isolated as a mixture of isomers (XIa) and (XIb), as shown.

Alternatively, the compounds of formula (III), where A 1represents NH, NR5 or NPG, can be obtained in accordance with scheme 3.

Scheme 3

Compounds of formulas (XII) and (XVII) may be commercially available or obtained using the methods described in the literature. Compounds of formula (XIII) and (XVIII) can be obtained from compounds of formulas (XII) and (XVII), respectively, by reacting sterically impeded by the strong base, such as diisopropylamide lithium, in a solvent such as THF, at a temperature of from-80ºC to 0ºC, then by blanking familyroom reagent, such as DMF or 1-formylpiperidine. Compounds of formula (XIII) and (XVIII) can be converted into compounds of formula (XIV) and (XIX) by treatment with hydrazine hydrate, pure, or in a solvent such as ethanol or DME, at a temperature of from room temperature to 150 ° C. Alternatively, compounds of formula (XIV) and (XIX) can be obtained from compounds of formula (XIII) and (XVIII) by conversion to an intermediate oxime by reacting with hydroxylamine such as O-methylhydroxylamine, in a solvent such as DME, in the presence of a base such as potassium carbonate, at temperatures from room temperature up to the boiling point. Intermediate oximes can be converted into indazols formulas (XIV) and (XIX) without allocation by treatment with hydrazine hydrate, pure or in the presence of the tvii solvent, such as DME. Compounds of formula (XIV) and (XIX) can be converted into compounds of formula (XVa/XVb), and (settle down under/XXb), using the methods described for the conversion of compounds of formula (X) compounds of formula (XIa) and (XIb). Compounds of formula (XVa/XVb), where X1represents I, Br, can be converted into compounds of formula (XVIa/XVIb), where R2 represents a CO2R3 by a large number of different ways. Most preferably, the compounds of formula (XVIa/XVIb) can be obtained from compounds of formula (XVa/XVb) by exchanging the metal-halogen in the processing of a strong ORGANOMETALLIC base such as n-utility or a Grignard reagent such as isopropyl magnesium iodide, in a solvent such as THF, at a temperature of from-80ºC to 0ºC. Intermediate derivatives argillite or ariline can be converted into compounds of formula (XVIa/XVIb) by clearing the electrophile, such as CO2or methylchloroform. Alternatively, compounds of formula (XVIa/XVIb) can be obtained from compounds of formula (XVa/XVb) by kataliziruemogo transition metal carbonylation using a catalyst such as palladium(II)acetate, a base such as DIPEA, co-catalyst, such as DMAP in a solvent such as methanol, and the source of carbon monoxide, such as Mo(CO)6at a temperature of from 80ºC to boiling point, but, predpochtitel is but using microwave irradiation at a temperature of from about 150ºc to 200ºc is manageable at a pressure of 1-10 bar. Compounds of formula (XVa/XVb), where X1represents I or Br, can be converted into compounds of formula (XVI), where R2 represents CN, by interacting with a metal cyanide, such as cyanide zinc, in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium(0)in a solvent such as DMF, at a temperature from 50ºC to boiling point or using microwave heating at a temperature of from 120ºC to 200ºc is manageable.

The compounds of formula (V), where A1represents NH, NR5, or NPG, can also be obtained in accordance with scheme 4.

Scheme 4

The compounds of formula (XVIII) may be commercially available or obtained using the methods described in the literature. The compounds of formula (XVIII) can be converted into compounds of formula (XXI) by interaction with alcohol, such as methanol (R6= Me), in the presence of acid, such as ammonium chloride, at a temperature of about the boiling point. The compounds of formula (XXI) can be converted into compounds of formula (XXII)using the methods described for the conversion of compounds of formula (III) in the compounds of formula (V) according to scheme 1. The compounds of formula (XXII) can be converted into compounds of formula (XXIII) by interacting with sour is Oh, such as hydrochloric acid, in a solvent such as ether, at a temperature of about room temperature. The compounds of formula (XXIII) can be converted into compounds of formula (XXIV), using the methods described for the conversion of compounds of formula (XVIII) in the compounds of formula (XIX) according to scheme 3.

The compounds of formula (III), where A1represents S and R2 represents a CO2R3 can be obtained in accordance with scheme 5.

Scheme 5

The compounds of formula (XVIII)obtained in accordance with scheme 3, can be converted into compounds of formula (XXVI) by two-stage method. The compounds of formula (XVIII) may be subjected to interaction with bezelmaterial in the presence of a base, such as tert-piperonyl potassium in a solvent such as THF, at a temperature from 0ºC to boiling point. Intermediate thioesters of the formula (XXV) can be converted into compounds of formula (XXVI) by treatment with sulfurylchloride in a solvent such as dichloromethane, followed by interaction with ammonia in a solvent such as a mixture of ethanol/THF. Alternatively, the compounds of formula (XXVI) can be produced from compounds of the formula (XVIII) direct processing of elemental sulfur, ammonia or ammonium hydroxide in a solvent such as DMF or 2-methoxyethanol, at present the AI catalyst, such as methylamine at a temperature from 100ºC to the boiling temperature or at a higher temperature than the boiling temperature (from 150 to 200ºc is manageable), using the reaction autoclave under a pressure of 1-20 bar.

The compounds of formula (XXIX), where A2represents N, can be obtained according to scheme 6.

Scheme 6

Protected aminopyrazole formula (XXVII) can be obtained using the methods described in the literature. The compounds of formula (XXVII) can be subjected to interaction with ether 2-alkoxyethanol acid, such as diethyl ether 2-ethoxymethylenemalonic acid, in the presence of high-boiling solvent such as diphenyl ether, at a temperature of from about 150ºc to 300ºC with obtaining the compounds of formula (XXVIII). The compounds of formula (XXVIII) can be converted into compounds of formula (XXIX) by processing the halogenation agent such as phosphorus oxychloride, clean, or in the presence of a solvent, such as toluene, in the presence or in the absence of a base, such as triethylamine, at a temperature from 50ºC to boiling point.

The compounds of formula XXXIVa and XXXIVb can be obtained in accordance with scheme 7.

Scheme 7

The compounds of formula (XXX) may be commercially available or obtained using the method is, described in the literature. The compounds of formula (XXX) can be converted into compounds of formula (XXXI) by nitrogroup reduction using a catalyst such as Raney Nickel under hydrogen pressure (1-5 bar) in a solvent such as THF, at room temperature. The compounds of formula (XXXII) can be produced from compounds of formula (XXXI) by processing diastereomer agent such as sodium nitrite, in the presence of acid, such as acetic acid or tetraphobia acid, and solvent, such as water, at temperatures from-20ºC to 50ºC. The compounds of formula (XXXII) can be converted into compounds of formula (XXXIII), where PG is a SEM (SEM=2-(trimethylsilyl)ethoxymethyl) by processing the SEM-Cl in the presence of a base such as sodium hydride, in a solvent such as THF, at room temperature. Compounds of formula (XXXIIIa/XXXIIIb) can be converted into compounds of formula (XXXIVa/XXXIVb) by ortho-litrovaya strong base, such as lithium tetramethylpiperidine, in a solvent such as THF, at temperatures from-100ºC to-60ºC, with subsequent quenching of halogenation agent such as iodine or hexachlorethane, at temperatures from-100ºC 0ºC to.

Intermediate compounds of formula XXXVIIa/XXXVIIb can be obtained in accordance with scheme 8.

Scheme 8

Indazols Faure the uly (XXXV) may be commercially available or obtained in accordance with methods, described in the literature. Compounds of formula (XXXVIa/XXXVIb) can be obtained from compounds of formula (XXXV), using the methods described for the conversion of compounds of formula (X) compounds of formula (XIa/XIb), as shown in scheme 2. Compounds of formula (XXXVIa/XXXVIb) can be converted into an acid of formula (XXXVIIa/XXXVIIb) exchanged by lithium-halogen, using a strong ORGANOMETALLIC base such as n-utility, in a solvent such as THF, at temperatures from-100ºC to-60ºC, with posleduyushim damping of the electrophile, such as carbon dioxide at a temperature of from-78ºC to 0ºC. Alternatively, compounds of formula (XXXVIa/XXXVIb) can be converted into compounds of formula (XXXVIIa/XXXVIIb) through formation of an intermediate complex ether, obtained by the interaction of heteroarylboronic carbon monoxide (at a pressure of 1-15 bar) in the presence of a catalyst such as palladium acetate or 1,1'-bis(diphenylphosphino)ferrocene, and a ligand such as triphenylphosphine, and a base, such as sodium acetate, in the presence of alcohol, such as methanol, in a solvent such as DMF or methanol, at a temperature of 80ºC up to 200ºc is manageable.

The compounds of formula II can be obtained in accordance with scheme 9.

Scheme 9

Compounds of formula (XXXIX) can be obtained from intermediates of formula (XXXVIII) (obtained is in accordance with schemes 9 and 10 below). Compounds of formula (XXXIX) can be obtained from compounds of formula (XXXVIII), using the methods described for the conversion of compounds of formula (III) in the compounds of formula (V) according to scheme 1. The compounds of formula (XLI) may be obtained from compounds of formula (XXXIX) and (XL), using the methods described for the conversion of compounds of formulas (V) and (VI) into compounds of formula (VII), as shown in figure 1.

The compounds of formula (XLI), where A1represents NH protective group (NPG), can be added and removed at any stage of the synthesis as needed.

Intermediate compounds of formulae (XLVI) and (XLVII) can be obtained according to scheme 10 below.

Scheme 10

The compounds of formula (XLII) can be subjected to interaction with brainwashin agent such as NBS, in the presence of a radical initiator, such as AIBN, in a solvent such as carbon tetrachloride, at boiling point, with or without activation activation light, obtaining the compounds of formula (XLIII). The compounds of formula (XLIII) can be converted into compounds of formula (XLIV) by treatment with N-oxide, trimethylamine, in the presence of DMSO, a solvent such as DCM, at a temperature from room temperature up to the boiling point. Alternatively, the compounds of formula (XLIV) can be obtained by treating compounds of formula (XLIII)base, such as sodium bicarbonate, in DMSO, at a temperature of about 100ºC. The compounds of formula (XLIV) can be subjected to interaction with bezelmaterial in the presence of a base, such as tert-piperonyl potassium in a solvent such as THF, at a temperature of from-78ºC to-30ºC with obtaining compounds of formula (XLV). Intermediate thioesters of the formula (XLV) can be converted into compounds of formula (XLVI) by treatment with sulfurylchloride in a solvent such as dichloromethane, followed by interaction with ammonia in a solvent mixture such as methanol/THF. Alternatively, the compounds of formula (XLVI) can be obtained from compounds of formula (XLIV) directly by processing elementary sulfur, ammonia or ammonium hydroxide, in a solvent such as DMF or 2-methoxyethanol, in the presence of a catalyst, such as methylamine at a temperature from 100ºC to the boiling temperature or at a higher temperature than the boiling temperature (150-200ºc is manageable) using the reaction autoclave at a pressure of 1-20 bar. The compounds of formula (XLVI) can be converted into compounds of formula (XLVII), using the methods described for the conversion of compounds of formula (III) in the compounds of formula (V) according to scheme 1.

The compounds of formula (I) W'=NHSO2R8or NHSO2NR8R10can be obtained according to scheme 11.

With the EMA 11

The compounds of formula (L) may be commercially available or obtained using the methods described in the literature. The compounds of formula (L) can be subjected to nitration to obtain compounds of formula (LI) by treatment with a mixture of sulfuric and nitric acid at a temperature of <5°C. the compounds of formula (LI) can be converted into compounds of formula (LII) by interacting with orthoformates, such as the trimethyl orthoformate, in the presence of acid, such as p-toluensulfonate acid, in a solvent such as methanol, at a temperature of about the boiling point. The compounds of formula (LII) can be converted into compounds of formula (LIII), using the methods described for the conversion of compounds of formula (III) in the compounds of formula (V) according to scheme 1. The compounds of formula (LIV) can be converted into compounds of formula (LV), using the methods described for the conversion of compounds of formula (XVIII) in the compounds of formula (XIX) according to scheme 3. The compounds of formula (LV) can be converted into compounds of formula (LVI), using the methods described for the conversion of compounds of formula (X) compounds of formula (XIa and XIb) according to scheme 2. Nitro compounds of formula (LVI) can be restored to anilines of formula (LVII), using a reducing agent such as dithionite sodium in a mixture of solvents, such to the to the THF/water/dioxane, when the temperature in the room. Sulfonamides of formula (LVIII) can be obtained from anilines of formula (LVII) by interacting with sulphonylchloride in the presence of a solvent, such as pyridine. The compounds of formula (LIX) can be obtained from compounds of formula (LVIII) under conditions suitable for removal of used protective group. For example, when PG=Boc, the compound of formula (LVIII) can be treated with a strong acid, such as triperoxonane acid, in a solvent such as dichloromethane, at a temperature of about room with obtaining the compounds of formula (LIX).

Hydroxylamine formula (VIIIa) and (VIIIb) can be obtained using the methods described in the literature or synthetically presented in figure 12.

Scheme 12

Primary or secondary alcohols of General formula (LX) can be obtained using the methods described in the literature. The alcohols can be subjected to interaction with N-hydroxyphthalimide using phosphine and condensing reagent such as diethyl azodicarboxylate, to obtain the compounds of General formula (LXI). Compounds of General formula (LXI) may be subjected to removal of the protective groups using hydrazine, methylhydrazine, an acid such as hydrochloric acid, or base, such as aqueous ammonia, obtaining hydroxylamino General the th of formula (VIII-a).

The compounds of formula (VIII-a) can be further modified by reductive amination with 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 ambient temperature to boiling point with getting hydroxylamino General formula (VIII-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, to obtain hydroxylamine General formula (VIII-b).

Alternatively, hydroxylamine formula (VIII-a) can be obtained according to scheme 13.

Scheme 13

Alkylhalogenide formula (LXII) can be subjected to 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 10ºC to 50ºC. The compounds of formula (LXI) can be converted into compounds of formula (VIII-a), using the methods described for the conversion of compounds of formula (LXI) in the compounds of formula (VIII-a) in scheme 12.

Alternatively, the compounds of formula (VIII-a) can be obtained according to scheme 14.

Scheme 14

The compounds of formula (LXII) can be subjected to the interaction of the N-hydroxyphthalimide in the presence of catalytic amounts of a base, such as DIPEA, and a co-catalyst, such as Tetra-butylammonium bromide, in a solvent such as toluene, at a temperature from 50ºC to the boiling temperature to obtain compounds of formula (LXIII). The compounds of formula (LXIII) can be converted into compounds of formula (VIII-a), using the methods described for the conversion of compounds of formula (LXI) in the compounds of formula (VIII-a) in scheme 12.

Anilines of General formula (LXV)used in the reactions of condensation and cross-linking described above, can be obtained using the methods described in the literature or in accordance with the scheme 15.

Scheme 15

Substituted 1-chloro-4-nitrobenzene may be subjected to interaction with the metal R'"MXn, such as cyclopropyl boric acid or hexamethyldisilazane, in a solvent such as xylene, using a catalyst, such as tetrakis(triphenylphosphine)palladium, at a temperature from room temperature up to the boiling temperature to obtain compounds of formula (LXIV). The nitro-group can be recovered using the methods described in the literature, such as the reaction in an atmosphere of hydrogen, at a pressure of from 1 to 5 atmospheres, in the presence of a catalyst such as palladium on what lerude, and in a solvent such as ethanol or ethyl acetate, at room temperature to obtain compounds of formula (LXV).

Alternatively, anilines of the formula (LXVII) can be obtained according to scheme 16.

Scheme 16

4-Bromine or iodine anilines of formula (LXVI) can be subjected to interaction with at least 2 equivalents of a strong metalloorganicheskoi base, such as n-utility, in a solvent such as THF, at temperatures from-100ºC to-20ºC, followed by extinction of intermediate derivatives argillite with an electrophile, such as trimethylsilyl chloride, to obtain the compounds of formula (LXVII).

Note that, when there is a suitable functional group, the compounds of formula (I) or any of the intermediate compounds used in their preparation, can then be converted by one or more standard synthetic methods, using substitution reaction, oxidation, recovery or removal. Specific examples of the introduction of substituents include conventional methods of alkylation, arilirovaniya, heteroarylboronic, acylation, sulfonylamine, halogenation, nitration, formirovanie and binding.

For example, aryl bromide or chloride groups can be converted to arisitide using the Finkelstein reaction, using ICT is CNIC iodide, such as sodium iodide, and a catalyst such as copper iodide, a ligand such as TRANS-N,N'-dimethyl-1,2-cyclohexane diamine, in a solvent such as 1,4-dioxane, and heating the reaction mixture at the boiling point. Aryldialkyl can be converted into arisitide by processing the silane source of iodide such as monochloride iodine, in a solvent such as dichloromethane, with or without using a Lewis acid such as tetrafluoroborate silver, at temperatures from-40ºC up to the boiling point.

In the following example, primary amino (-NH2) group can be alkylated using the recovery method alkylation using an aldehyde or ketone and a borohydride, for example, triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, or an alcohol, such as ethanol, as required, in the presence of acid, such as acetic acid, at ambient temperature. Secondary amino (-NH-) groups can be similarly alkylated using aldehyde.

In the following example, primary amino or secondary amino group can be converted into an amide group (-NHCOR', or-NRCOR') by acylation. The acylation can be accomplished by reacting with a suitable acid chloride acid in the presence of OS is Finance, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reacting with a suitable carboxylic acid in the presence of a suitable condensing agent, such as HATU (O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate), in a suitable solvent such as dichloromethane. Similarly, the amino group can be converted into sulfonamidnuyu group (-NHSO2R', or-NRSO2R') by reacting with a suitable sulphonylchloride in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane. Primary or secondary amino group can be converted to a urea group (-NHCONR'R" or-NRCONR'R") by reacting with an 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 (-NO2) group, for example, by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a carrier, such as carbon in a solvent such as ethyl acetate or an alcohol, e.g. methanol. Alternatively, the conversion may be carried out by a chemical recovery, using, for example, a metal, for example, about the ovo or iron, in the presence of acid, such as hydrochloric acid.

In the following example, amino (-CH2NH2) group 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 carrier such as carbon or Raney Nickel, in a solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, at temperatures from-78ºC to the boiling point of the solvent.

In the following example, amino (-NH2) group can be obtained from the carboxyl group (-CO2H) by conversion into the corresponding acylated (-CON3), rearrangement of kurzius and hydrolysis of the resulting isocyanate (-N=C=O).

The aldehyde group (-CHO) can be converted into an amino group (-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, as required, in the presence of acid, such as acetic acid, at ambient temperature.

In the following example, the aldehyde group can be converted into alkenylphenol group (-CH=CHR') by using the Wittig reaction or Adsw the RT-Emmons, using suitable fosfory or phosphonate in the usual conditions known to a person skilled in the field.

Aldehyde groups can be obtained by recovering the ester groups (such as CO2Et) or nitrile (-CN), using the hydride diisobutylaluminum 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, well-known specialist in this field.

Ester group (-CO2R') can be converted into the corresponding carboxyl group (-CO2H) catalyzed by acid or base hydrolysis, depending on the nature of R. If R is a tert-butyl catalyzed by acid or base hydrolysis can be carried out, 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.

Carboxyl group (-CO2H) can be converted to amides (CONHR' or-CONR'R") by reacting with the appropriate amine in the presence of a suitable condensing agent, such as HATU, in a suitable solvent such as dichloromethane.

In the following example, can be obtained homolo and carboxylic acids, containing in the chain carbon atom (i.e.- CO2H-CH2CO2H) by conversion into the corresponding acid chloride of acid (-COCl), followed by synthesis of the Arndt-Eistert.

In the following example, -OH groups can be formed from the corresponding ether complex (e.g.- CO2R') or aldehyde (-CHO) by restoring, using for example a complex metal hydride such as lithium aluminium hydride in 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, lithium aluminum hydride in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.

The alcohol group can be converted to the deleted group, such as halogen atoms or sulfonyloxy groups, such as alkylsulfonate, for example, tripterocalyx or arylsulfonate, for example p-toluensulfonate the group using conditions known to the person skilled in the art. For example, alcohols can be subjected to interaction thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to obtain the corresponding chloride. Base (e.g. triethylamine) may also order to be used in the reaction.

In another example, an alcohol, phenol or amide groups can be alkylated by binding of 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 carried out by deprotonation using suitable base for example sodium hydride, followed by addition of an alkylating agent, such as alkylhalogenide.

Aromatic halogenated substituents in the compounds may be subjected to the exchange of the halogen-metal by treatment with base, such as lithium base such as n-butyl or tert-butyl lithium, optionally at a low temperature, for example, in the region of -78°C, in a solvent such as tetrahydrofuran, and subsequent damping of the electrophile to introduce a desired substituent. So, for example, formyl group can be introduced using N,N-dimethylformamide as the electrophile. Aromatic halogenated substituents may alternatively be subjected to kataliziruemoi metal (such as palladium or copper) reaction for introduction of, for example, acid, ester, cyano, amide, aryl, heteroaryl, altenloh, akinrinola, thio - or amino substituents. P is Rhodesia ways which can be used include those described Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogenated substituents may also be subjected to nucleophilic substitution with subsequent interaction with a suitable nucleophile such as an amine or alcohol. Mainly, this reaction can be performed at elevated temperature under microwave irradiation.

Compounds of the present invention examined for their ability to inhibit MEK activity and activation (primary research) and their biological effect on the cell growth (secondary research), as described below. Compounds of the present invention, with IC50less than 5 μm (more preferably, less than 0.1 μm, most preferably less than 0.01 μm) in the study of MEK activity of the compounds according to example 1, the IC50less 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 study of MEK activation in 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 the study of cell proliferation in example 3, and/or EC50less than 10 microns (more preferably, less than 1 μm, even more FAV is preferably, less than 0.5 μm, most preferably less than 0.1 μm) in the study of ERK phosphorylation of example 4, use as MEK inhibitors.

The present invention includes a composition (e.g., pharmaceutical composition)containing the compound of the formula I and / or II and/or the MES and/or salt) and the media (pharmaceutically acceptable carrier). The present invention also includes a composition (e.g., pharmaceutical composition)containing the compound of the formula I and / or II and/or solvate and/or their salts) and media (pharmaceutically acceptable carrier, optionally containing auxiliary chemotherapy and/or auxiliary anti-inflammatory agent, for example, such as described herein. These compositions are used for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (e.g. human). These compositions are also used for the treatment of inflammatory diseases in a mammal (e.g. human).

These compounds and compositions are also used for the treatment of autoimmune diseases associated with lesions of the bone, proliferative disorders, infectious diseases, viral diseases, fibrotic diseases or neurodegenerative diseases in a mammal (for example the EP, person). Examples of such diseases/disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retinopathy of prematurity, age related macular degeneration, hemangioma, idiopathic fibrosing alveolitis, rhinitis and atopic dermatitis, kidney disease and renal failure, polycystic disease, congestive heart failure, neurofibromatosis, rejection of transplanted organ, cachexia, stroke, septic shock, heart failure, rejection of transplanted organ, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis B virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV) and Epstein-Barr (EBV). Chronic pain in the context of the present invention, includes, but is not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, gipoterioz, inflammation, arthritis and post-operative pain. Neuropathic pain associated with various conditions, which include, but are not limited to, inflammation, postoperative pain, phantom pain, pain due to burns, gout, trigeminal neuralgia, acute herpetic and post herpetic pain, causalgia, diabetic neuropathy gap plexus neuroma, vasculitis, viral infection, damage by crushing, compression damage, tissue damage, amputation of extremities, arthritis pain and nerve damage between the peripheral nervous system and Central nervous system.

These compounds and compositions are also used for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-kidney disease) in a mammal (e.g. human).

These compounds and compositions are also used for the prevention of implantation of blastocytes in mammals (e.g. humans).

The present invention includes a method of inhibiting abnormal cell growth or treating hyperproliferative disorders in mammals (e.g. humans), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I and / or II and/or its MES and/or salt) or their compositions. The present invention also includes a method of treating inflammatory diseases 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 II and/or its MES and/or salt or composition thereof.

The present invention includes a method of inhibiting abnormal cell growth sludge the treatment of hyperproliferative disorders in a mammal (for example, person), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I and / or II and/or its MES and/or salt or composition thereof, in combination with an additional chemotherapeutic agent such as described herein. The present invention also includes a method of treating inflammatory diseases 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 II and/or its MES and/or salt or composition thereof, in combination with an additional anti-inflammatory agent, such as described in this document.

The present invention includes a method of treating an autoimmune disease, disorder, destructive 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 II and/or its MES and salt or composition thereof, and optionally additionally contain auxiliary therapeutic agent. Examples of such diseases/disorders include, but are not limited to, Diab and diabetic complications, diabetic retinopathy, retinopathy of prematurity, age related macular degeneration, hemangioma, idiopathic fibrosing alveolitis, rhinitis and atopic dermatitis, kidney disease and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, rejection of transplanted organ, cachexia, stroke, septic shock, heart failure, rejection of transplanted organ, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis B virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV) and Epstein-Barr (EBV)

The present invention includes a method of treating pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-kidney 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 II and/or its MES and salt or composition thereof, and optionally additionally contain auxiliary therapeutic agent.

The present invention includes a method of preventing implantation blastocytes in mammals (e.g. humans), including the introduction of a given mammal a therapeutically effective amount is and the compounds of formula I and / or II and/or its MES and salt or composition thereof, and optionally additionally contain auxiliary therapeutic agent.

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

Also suppose that the compounds of the present invention may contribute to the increased susceptibility of abnormal cells to the effects of radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, the present invention additionally relates to a method of sensitization pathological mammalian cells (e.g. human) to treatment with radiation, which includes the introduction of the specified mammal the compounds of formula I and / or II and/or its MES and salt or composition thereof, in an amount which is effective in sensitizing abnormal cells to treatment with radiation.

Introduction compounds of the present invention (hereinafter "the active compound(I)may be carried out by any method that enables delivery of the compounds to the site of action. These methods include oral routes of administration, the intraduodenal route of administration, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), the local way of introduction, inhalation and rectal administration.

The number of active compound for administration will depend on the subject of the treatment, the severity of the disorder or condition, rate of administration, distribution, connection and discretion of the appointing treatment of a doctor. 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 single or fractional doses. For a person weighing 70 kg, the dose may be from about 0.05 to 7 g/day, preferably from about 0.05 to about 2.5 g/day. In some cases, the dose levels below the lower limit in the above limit may be more than adequate, while in other cases it can be used even higher doses without causing harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

The active compound can be used as a standalone therapy or in combination with one or more chemotherapeutic or anti-inflammatory agents, such as described herein. Such joint treatment may be achieved by simultaneous, sequential or separate dosing of the individual components of the treatment.

The pharmaceutical composition may, for example, be in the form suitable for oral administration tablets, capsules, pills, powder, song, slow release, solution, suspension, for parenterally injection as a sterile solution, suspension or emulsion, for topical administration in the form of ointment or cream or for rectal administration in the form of candles. The pharmaceutical composition may be in the form of disposable injection, suitable for single administration of certain doses. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, and so on.

Typical forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. If desirable, such dosage forms can be appropriately buffered.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, fillers and the like. Thus, for oral administration, tablets containing various spare parts of cnie fillers, such as citric acid, can be used in conjunction with various loosening agents such as starch, alginic acid and certain complex silicates, and with condensing agents such as sucrose, gelatin and gum. In addition, for the purposes of tabletting often use lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Can also be used for solid compositions of a similar type in soft and hard filled gelatin capsules. Preferred substances, respectively, include lactose or milk sugar and glycols of high molecular weight. When required aqueous suspensions or elixirs for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring matter or dyes 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 with a certain amount of the active compounds are well known or will be apparent to a person skilled in this field. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

EXAMPLES

Reduction

AIBN Osobistosti amitril

BOC tert-butoxy carbonyl

nBuLi n-utility

CDCl3Deuterated chloroform

CD3OD Deuterated methanol

DCM Dichloromethane

DIAD Aminobutiramida azo, in primary forms

DIPEA Diisopropylethylamine

DMAP (N,N'-dimethyl-4-aminopyridine

DME Dimethyl ether of ethylene glycol

DMF Dimethylformamide

DMSO dimethyl Sulfoxide

Dppf 1,1'-Bis(diphenylphosphino)ferrocene

EDCI l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride

Et3N Triethylamine

Et2O Diethyl ether

HATU O-(7-Asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate

HCl hydrochloric acid

Hyflo® diatomaceous earth

HM-N Isolute ® absorbent diatomaceous earth

HOBt 1-Hydroxybenzotriazole

HPLC high performance liquid chromatography

IMS industrial methyl alcohol

K3PO4rejonowy phosphate potassium

LHMDS bis(trimethylsilyl)amide lithium

MeOH Methanol

NaHCO3Sodium bicarbonate

NH4Cl ammonium Chloride

NaOH sodium Hydroxide

Na2SO4The sodium sulfate

Pd(dppf)Cl2[1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II)

Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

Pd2dba3Tris-(dibenzylideneacetone)dipalladium(0)

Si-PPC-equipped cartridge for flash chromatography on silica gel: Isolute® SPE

Biotage SNAP ® is whether ISCO Redisep®

SCX-2 Isolute ® sorbent silica gel with chemically bound functional group propylsulfonyl acid.

TBME tert-butyl methyl ether

TMEDA Tetramethylethylenediamine

THF Tetrahydrofuran

TFU Triperoxonane acid

TMSCl Trimethylsilane

Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

General terms experimentation

1H NMR spectrum was recorded at ambient temperature using a spectrometer Varian Unity Inova (400 MHz) with sensor triple resonance 5 mm Chemical shifts were expressed in ppm relative to tetramethylsilane. Used the following abbreviations: br=broadened signal, s=singlet, d=doublet, dd=double doublet, t=triplet, q=Quartet, m=multiplet.

Performed the experiments using high-performance liquid chromatography - mass spectrometry (LCMS) to determine retention time (RT) and associated mass ions using one of the following methods.

Method A: Experiments performed on a quadrupole mass spectrometer (Waters Micromass ZQ connected to a Hewlett Packard HP1100 LC detector diode matrix. This system uses a column Higgins Clipeus 5 micron C18 100×3.0 mm and a flow rate of 1 ml/min Initial solvent system was a mixture of 95% water containing 0.1%formic acid (solvent A) and 5% acetonitrile, containing the th of 0.1%formic acid (solvent B), within the first minute, then a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system remained unchanged for another 5 minutes.

Method B: Experiments performed on a quadrupole mass spectrometer Waters Platform LC, connected to a Hewlett Packard HP1100 LC detector diode matrix and 100-position auto sampler using a column Phenomenex Luna C 18(2) 30×4.6 mm and a flow rate of 2 ml/min. and a solvent System was a mixture of 95% water containing 0.1%formic acid (solvent A) and 5% acetonitrile containing 0.1%formic acid (solvent B) for the first 0.50 min, then a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system remained unchanged for a further 0.50 minutes.

Method C: Experiments were performed on a quadrupole mass spectrometer (PE Sciex API 150 EX connected to a Shimadzu LC-10AD, LC detector diode matrix and 225 positional autosampler using column Kromasil C18 50×4.6 mm and a flow rate of 3 ml/min. and a solvent System was a gradient starting with 100% water with 0.05% of TFU (solvent A) and 0% acetonitrile with 0,0375% TFU (solvent B), increasing to 10% solvent A and 90% solvent B for 4 minutes. The final solvent system remained unchanged for a further 0.50 minutes.

Experiments with approx the application of microwave irradiation was performed, using a system of Personal Chemistry Emrys Iniatiator™ or Optimizer™technology, which uses a single-mode resonator and the control of non-stationary fields, both of them provide reproducibility and control. Can be operated at temperatures from 40 to 250ºC, and can be reached pressure up to 20 bar.

EXAMPLE 1 MEK study (the study of MEK activity)

Constitutively activated mutant MEK1 person, expressed in insect cells, was used as source of enzyme activity at a final concentration in kinase research, which is 15 nm.

The study was performed for 30 minutes in the presence of 50 μm ATP, using recombinant GST-ERK1 obtained in E. Coli as substrate. Phosphorylation of the substrate was determined and quantitatively determined using the HTRF reagents supplied by Cisbio. They consist of anti-GST antibody conjugated with allophycocyanin (XL665) and anti-phospho (Thr202/Tyr204) ERK antibody conjugated with Cryptocom europium. They were used with a final concentration of 4 μg/ml and 0.84 μg/ml, respectively. Anti-phospho antibody recognizes ERK1 dual phosphorylated at Thr202 and Tyr204. When both antibodies are associated with ERK1 (that is, when the substrate is phosphorylated), the transfer of energy from cryptate to allophycocyanin occurs after excitation at 340 nm, resulting in radiated fluoresce the tion, that is, in proportion to the amount of phosphorylated substrate. Fluorescence was detected using multilocus fluorimeter.

Compounds were diluted in DMSO before adding to the buffer for the study, and the final concentration of DMSO in the study is 1%.

The value of the IC50was defined as the concentration at which this connection achieves a 50% inhibition in the control sample. The values of the IC50were calculated using the software package XLfit (version 2.0.5).

Specified in the title compounds of examples 5-9, 12-13, 16, 20-23, 25-27 showed the value of the IC50less than 0.1 μm in the study described in example 1. Specified in the title compounds of examples 10-11, 15, 17, and 24 showed the value of the IC50between 0.1 and 0.6 μm in the study described in example 1.

EXAMPLE 2 skin disease research (the study of MEK activation)

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

The study was performed for 30 minutes in the presence of 200 μm ATP, using recombinant GST-MEK1 obtained in E. Coli as substrate. Phosphorylation of the substrate was detected and measured quantitatively using HTRF, and reagents supplied by Cisbio. They consist of anti-GST antibody conjugated with and what Loyalhanna (XL665) and anti-phospho (Ser217/Ser221) MEK antibodies conjugated to Cryptocom europium. Anti-phospho antibody recognizes MEK dual phosphorylated at Ser217 and Ser221 or once phosphorylated at Ser217. When both antibodies are associated with MEK (i.e., when the substrate is phosphorylated), the transfer of energy from cryptate to allophycocyanin occurs after excitation at 340 nm, resulting emitted fluorescence, that is, in proportion to the amount of phosphorylated substrate. Fluorescence was detected using multilocus fluorimeter.

Compounds were diluted in DMSO before adding to the analytical buffer, and the final concentration of DMSO in the study was 1%.

The value of the IC50was defined as the concentration at which this connection achieves a 50% inhibition in the control sample. The values of the IC50calculate, using the software package XLfit (version 2.0.5).

EXAMPLE 3 Study of cell proliferation

Compounds were tested in the study of cell proliferation using the following cell lines:

HCT116 cells of colorectal carcinoma person (ATCC)

A375 cells of malignant human melanoma (ATCC)

Both cell lines were kept in DMEM/F12 (1:1) (Gibco) supplemented with 10% FCS at 37 degrees C in 5% CO2wet camera.

Cells were planted in 96-well tablets with a density of 2000 cells per Lu is ku and after 24 hours they were exhibited in other concentration of the compound in 0,83% DMSO. Cells were grown for a further 72 hours, and to each well was added the same volume of reagent CellTiter-Glo (Promega).

It analyzes cells and generates a luminescent signal proportional to the amount of released ATP (and, consequently, proportional to the number of cells per well), which can be detected using multilocus luminometer.

The value of EC50was determined as the concentration at which this connection achieves a 50% inhibition in the control sample. The values of EC50were calculated using the software package XLfit (version 2.0.5).

In this study, listed in the connection header example 5-7, 9-14, 16-17, 20-22 and 24-27 showed the value EC50less than 0.5 μm in cell line HCT116. Specified in the title compound of example 8 showed EC50less than 0.6 μm in cell line HCT116. Specified in the title compounds of examples 5-12, 14, 16-17 and 20-27 showed the value EC50less than 0.1 μm in cell line A375.

EXAMPLE 4 Study on the basis of phospho-ERK cells

Compounds were tested in cell analysis of phospho-ERK ELISA using the following cell lines:

Cells HCT116 colon carcinoma human (ATCC)

Cells A375 malignant melanoma (ATCC)

Both cell lines are maintained in DMEM/F12 (1:1) (Gibco)with the addition of 10% FCS at 37 degrees C in wet Cam is re with 5% CO 2.

Cells were planted in 96-well tablets with a density of 2000 cells per well and after 24 hours they were exhibited in other concentration of the compound in 0,83% DMSO. Cells were grown for another 2 hours or 24 hours were fixed with formaldehyde (2% final) and permeability.avi methanol. After blocking TBST-3% BSA, fixed cells were incubated with the primary antibody (anti-phospho ERK rabbit) overnight at 4ºC. Cells were incubated with propidium the iodide (fluorescent DNA dye) and the definition of the cellular p-ERK was performed using anti-rabbit secondary antibody conjugated with the fluorescent dye Alexa Fluor 488 (molecular probes). Fluorescence was analyzed using an Acumen Explorer (TTP Labtech), laser scanning microplate of cytometer, and the signal Alexa Fluor 488 were normalized relative to the signal PI (proportional to the number of cells).

The value of EC50was defined as the concentration at which this connection reaches half the value of the signal between the baseline and maximum response. The values of EC50were calculated using the software package XLfit (version 2.0.5).

In this study, listed in the title compounds of examples 5-14, 16-17, 20-22 and 24-27 showed the value EC50less than 0.1 μm in cell line HCT116. Specified in the title compounds of examples 6-12, 14, 17 and 2027 showed the value EC 50less than 0.1 μm in cell line A375.

SYNTHESIS of HYDROXYLAMINO

(S)-1-Aminooxy-propan-2-ol hydrochloride

Stage 1: Ethyl ester of (S)-2-(tert-butyl-dimethyl-silyloxy)-propionic acid,

To a solution of (S)-(-)-ethyllactate time (37.4 g, 0.32 mol) in DCM (200 ml) was added imidazole (25,75 g, 0.38 mol) and TBSCl (50 g, 0.33 mol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and was extracted with DCM (2×50 ml), the combined organic extracts were washed with saturated salt solution, dried (MgSO4) and concentrated in vacuum to obtain specified in the title substance as a colorless oil (100%).1H NMR (CDCl3, 400 MHz) is 4.21 (1H, q, J=6.73 x Hz), 4,14-4,01 (2H, m)of 1.29 (3H, d, J=6,79 Hz)of 1.18 (3H, t, J=7,09 Hz)to 0.80 (9H, s)-0,01 (6H, s).

Stage 2: (S)-2-(tert-butyl-dimethyl-silyloxy)-propan-1-ol

2M solution of LiBH4(2,77 g, 0.13 mol) in THF (60 ml) was added dropwise to a solution of ethyl ester of (S)-2-(tert-butyl-dimethyl-silyloxy)-propionic acid (22,75 g, 0.10 mol) and methanol (5,15 ml, 0.13 mol) in diethyl ether (500 ml) at a temperature of 0ºC. The reaction mixture was stirred at a temperature of 0ºC for 1 hour and then at room temperature for 1.5 hours, then cooled to a temperature of 0ºC and Ostrog what about the extinguished with water. The reaction mixture was filtered and the filtrate was extracted with diethyl ether (2×50 ml), the combined organic extracts were washed with saturated salt solution, dried (MgSO4) and concentrated in vacuum to obtain specified in the title substance as a colorless oil (18.2 g, 97%).1H NMR (CDCl3, 400 MHz) 3,86-of 3.77 (1H, m), 3,45-3,37 (1H, m), 3,31-up 3.22 (1H, m), 1,96-of 1.85 (1H, m)of 1.03 (3H, d, J=6,23 Hz), 0,81 (9H, s)0,00 (6H, s).

Stage 3: 2-[(S)-2-(tert-butyl-dimethyl-silyloxy)-propoxy]isoindole-1,3-dione

To a suspension of (S)-2-(tert-butyl-dimethyl-silyloxy)-propan-1-ol (53,0 g,0.28 mol), N-hydroxyphthalimide (47,0 g, 0.29 mol) and triphenylphosphine (77.9 g, 0.30 mol) in THF (200 ml) at a temperature of 0ºC was added dropwise DIAD (56,8 ml, 0.29 mol). In the process of adding the reagents were dissolved, and the solution was again acquired a red color, gradually turning pale to pale yellow after adding. The reaction mixture was stirred and allowed to warm to room temperature over night. The reaction mixture was concentrated in vacuo and the resulting residue was again dissolved in diethyl ether. The suspension was filtered, and the filtrate was concentrated in vacuum to obtain crude specified in the connection header in the form of oil pale yellow color. The product was used in the next stage without additional purification.

Stage 4: O-[(S)--(tert-butyl-dimethyl-silyloxy)-propyl]hydroxylamine

In a cold solution of crude 2-[(S)-2-(tert-butyl-dimethyl-silyloxy)-propoxy]-isoindole-1,3-dione (0.28 mol) in DCM (200 ml) at a temperature of 0ºC was added methyl hydrazine (14,74 ml, 0.28 mol). The reaction mixture was stirred at a temperature of 0ºC for 30 minutes, then filtered and the filtrate was concentrated in vacuum. The obtained residue was subjected to distillation (so Kip. 108-112°C at a pressure of 2-10 mbar) to obtain specified in the title compounds as colorless oils. (42,63 g, 74% from ethyllactate).1H NMR (CDCl3, 400 MHz) are 5.36 (2H, s), of 3.95 (1H, m), 3,55-to 3.41 (2H, m), was 1.04 (3H, d, J=6,28 Hz), 0,81 (9H, s)0,02 (6H, m).

Stage 5: (S)-1-aminooxy-propan-2-ol hydrochloride

O-[(S)-2-(tert-butyl-dimethyl-silyloxy)-propyl]-hydroxylamine (6,56 g, 31.9 per mmol) was dissolved in IMS (20 ml) and added n HCl (2,79 ml of 33.5 mmol), the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the resulting residue was led from a mixture of IPA/diethyl ether (1:1) to obtain specified in the connection header in the form of a beautiful white needles (3.2 g, 79%).1H NMR (DMSO-d6, 400 MHz) of 10.93 (3H, s), 3,94-of 3.80 (2H, m), of 2.51-2,48 (1H, m), 1,07-of 1.02 (3H, d, J= 6,01 Hz).

Hydrochloride (S)-1-aminocaproyl-2-ol. An alternative way

Stage 1: 2-((S)-2-hydroxy-propoxy)-isoindole-1,3-dione

To a suspension of N-Hydra is ciftligi (250 g, 1.53 mol), toluene (450 ml), tetrabutylammonium bromide (24,7 g, to 76.6 mmol) and (S)-(-)-propylene oxide (214,7 ml of 3.07 mol) was added DIPEA (13.3 ml, to 76.6 mmol). The reaction mixture was heated in nitrogen atmosphere at the boiling temperature for 3 hours. The reaction mixture was concentrated in vacuum to obtain a solid product yellow. The solid product was dissolved in hot ethyl acetate and placed on a layer of flash silica gel (600 g) and the product was suirable diethyl ether (4 l). The ethereal solution was concentrated in vacuum to obtain a solid product, a pale yellow color. The solid product was dissolved in ethyl acetate (150 ml) at a temperature of 75°C was added cyclohexane (300 ml). The solution was left to cool to room temperature with stirring, which caused crystallization from a solution of a solid white product. The crystals were collected by filtration, washed with a mixture of ethyl acetate/hexane (1:2). The solid product was recrystallized using the conditions described previously, to obtain the product in the form of a solid crystalline substance white (233 g, 69%).1H NMR (CDCl3, 400 MHz) 7,89-7,83 (2H, m), 7,81 to 7.75 (2H, m), 4,22 (1H, DD, J=11,5, 2.3 Hz), 4,11-was 4.02 (1H, m), 3,93 (1H, DD, J=11,3, 9,2 Hz), with 3.79 (1H, d, J=3.2 Hz), of 1.18 (3H, d, J=6,4 Hz).

Stage 2: Hydrochloride (S)-1-aminocaproyl-2-ol

A solution of 2-((S)-2-hydroxypropoxy)-isoindole-1,3-dione (20 g, 90,4 mmol) and aqueous hydrochloric acid (150 is l, 6N, 0.9 mol) was stirred at room temperature for 16 hours to obtain a white suspension. The reaction mixture was filtered, and the filtrate was concentrated in vacuum to obtain a solid product is white. The obtained residue was led from the hot mixture of IPA/cyclohexane (10 ml/20 ml), which gave the product, the hydrochloride of (S)-1-aminocaproyl-2-ol in the form of a solid crystalline substance white (7.78 g, 67%).1H NMR (DMSO-d6, 400 MHz) 10,82 (2H, users), 3,92-of 3.78 (3H, m)of 1.06 (3H, d, J=6.2 Hz).

Hydrochloride of 2-aminooxy-2-methyl-propan-1-ol

Stage 1: ethyl ester of 2-(N-Boc-aminooxy)somaclonal acid

To a solution of N-Boc-hydroxylamine (5,2 g, 39,05 mmol) in ethanol (100 ml) was added potassium hydroxide (2,63 g, 46,86 mmol), the mixture was stirred at room temperature until the formation of the solution. Was added ethyl ester 2-bromoisobutyric acid (6,87 ml, 46,9 mmol) and the reaction mixture was heated at the boiling temperature for 18 hours. The reaction mixture was cooled to room temperature, then filtered, and the filtrate was concentrated in vacuum. The obtained oily residue was distributed between water (75 ml) and diethyl ether, and the aqueous fraction was extracted with diethyl ether (2×100 ml). The combined organic extracts were dried (Na2SO4), f is literaly and concentrated in vacuum to obtain specified in the title compound as a clear oil (9.5 g, 99%). LCMS (method C): RT=2,55 min, [M+H]+=248.1H NMR (CDCl3, 400 MHz) 4,20 (kV, 2H), 1,50 (s, 6H), for 1.49 (s, 9H), of 1.30 (t, 3H).

Stage 2: 2-(N-Boc-aminooxy)-2-methylpropan-1-ol

To a solution of ethyl ester of 2-(N-Boc-aminooxy)isobutane acid (2.35 g, 9.5 mmol) in anhydrous ethyl ether (100 ml) at a temperature of 0ºC in an atmosphere of nitrogen was added a 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (17,1 ml, 17 mmol)and the reaction mixture was stirred at a temperature of 0ºC for 5 hours. The reaction mixture was extinguished with water (25 ml) and allowed to warm to room temperature. The suspension was filtered, the residue washed with diethyl ether and the layers were separated. The organic extract was dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the connection header in the form of a solid white color (1,94 g, 99%).1H NMR (CDCl3, 400 MHz) 3,40 (s, 2H), 1,50 (s, 9H), of 1.20 (s, 6H).

Stage 3: hydrochloride 2-aminooxy-2-methyl-propan-1-ol

To a solution of 2-(N-Boc-aminooxy)-2-methylpropan-1-ol (1,94 g of 9.45 mmol) in anhydrous dichloromethane (10 ml) was added 4 M HCl in dioxane (47,3 ml, 200 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue is triturated in ether (3×30 ml) to obtain specified in the connection header in the form of a solid product be the CSOs color (1.10 g, 82 %).1H NMR (DMSO-d6, 400 MHz) 3.58 (s, 2H), 3,48 (s, 2H), of 1.34 (s, 6H).

SYNTHESIS of ANILINES

2-Fluoro-4-trimethylsilyl-phenylamine

Method A. stage 1: (3-fluoro-4-nitrophenyl)-trimethylsilane

4-chloro-2-fluoro-1-nitrobenzene (97,2 g, 0.55 mol) was dissolved in xylene (208 ml) was added hexamethyldisilane (306 g, 2,78 mol). In the mixture for 20 minutes was barbotirovany argon, then was added Pd(PPh3)4(16.2 g, 14 mmol) and the mixture was heated in a continuous current of argon at a temperature of about 150ºc for 1 hour. Then attach a balloon filled with argon, and the mixture was heated at a temperature of about 150ºc for another 60 hours. After cooling, the mixture was diluted with Et2O and filtered through a layer of silica gel in 4 see the Cake on the filter was washed with additional Et2O and the combined organic remains concentrated in vacuum. Purification of the obtained residue using flash chromatography (SiO2, eluent 98:1:1 pentane:CH2Cl2:Et20) was given to 76.7 g specified in the title compound as orange oil, and mixed fractions. Mixed fractions were combined and concentrated, and then distilled (110ºC, 6 mbar) with additional 7.2 g specified in the connection header (only 83.9 g, 71%).1H NMR (DMSO-d6) to 0.30 (9H, s), 7,56 (1H, d, J=8,02 Hz), to 7.67 (1H, DD, J=11,49, 1,14 G is), 8,10 (1H, t, J=7,66 Hz).

Method A. stage 2: 2-fluoro-4-trimethylsilyl-phenylamine

A suspension of 10% of the mass. palladium on carbon (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 reaction mixture was purged with nitrogen five times, then with hydrogen three times. The reaction mixture was then stirred under the hydrogen pressure of 3 bar at room temperature for 4 hours. The reaction mixture then was again purged with nitrogen, then filtered through a layer of cellica Celite®, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain specified in the connection header in the form of butter, light brown (53,0 g, quantitative).1H NMR (CDCl3, 400 MHz) 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, s)of 0.26 (9H, s).

Method B. 2-fluoro-4-trimethylsilyl-phenylamine

To a solution of 4-bromo-2-fluoro-phenylamine (114 g, 0.6 mol) in anhydrous THF (750 ml) in an inert atmosphere at -78°C was added dropwise 1,6M solution BuLi in hexane (1500 ml, 2.4 mol), maintaining the internal temperature below 60ºC. The reaction mixture was treated dropwise TMSCl (256 ml, 2.0 mol), maintaining the internal temperature below 60ºC. The reaction mixture was allowed to warm to 0ºC for 1 hour and poured into ice 2M HCl (approximately 1 liter). The mixture was vigorously stirred for 10 min, then the organic layer is delali, washed with water, then saturated potassium carbonate solution, dried (Na2SO4), filtered and concentrated to obtain specified in the title compound as light brown oil (89 g, 81%).

4-Cyclopropyl-2-fluoro-phenylamine

Stage 1: 3-fluoro-4-nitrophenyloctyl broadcast trifter-methanesulfonic acid

To a solution of 3-fluoro-4-NITROPHENOL (12.5 g, 80 mmol) and anhydride triftormetilfullerenov acid (26,8 ml, 160 mmol) in DCM (300 ml) at a temperature of 0ºC dropwise added triethylamine (44,6 ml, 320 mmol). The reaction mixture was stirred at a temperature of 0ºC for 2 hours, then was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was suppressed by addition of water, and the mixture was extracted with DCM. The organic layer was separated, washed with water and then dried (MgSO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient from 0-40% ethyl acetate in cyclohexane) to obtain the specified 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-the tor-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) was degirolami, and then was heated at a temperature of 90ºC in an argon atmosphere for 2.5 hours. The reaction mixture was left to cool to room temperature, then filtered through a layer of celite Celite®, washed with ethyl acetate. The filtrate was washed (water, saturated brine and then dried (MgSO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-30% ethyl acetate in pentane) to obtain specified in the connection header in the form of a solid product in 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 carbon (200 mg, 10% wt.) in IMS was added a degassed solution of 4-cyclopropyl-2-fluoro-1-nitrobenzene (1.45 g, 8 mmol) in IMS (50 ml), the air was pumped out and the vessel was filled with nitrogen, then was evacuated and filled with hydrogen. The reaction mixture was stirred under the hydrogen pressure of 1 atmosphere at room temperature for 24 hours, then filtered through a layer of celite Celite®, then washed with ethyl acetate. The filtrate was concentrated in vacuum with receipt of the m specified 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, s), 1,83 is 1.75 (1H, m), 0,93-of 0.82 (2H, m), 0,59-of 0.54 (2H, m).

SYNTHESIS of INTERMEDIATE HETEROCYCLIC NUCLEI

Methyl ether 4-chloro-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid and methyl ester of 4-chloro-2-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid

Stage 1: methyl ester of 4-amino-2-chloro-3-methyl-benzoic acid

To a suspension of 4-amino-2-chloro-3-methyl-benzoic acid (0.64 g, of 3.45 mmol) in toluene (10 ml) and methanol (10 ml) at a temperature of 0ºC was added dropwise trimethylsilyldiazomethane (of 3.45 ml, 2 M in hexane, of 6.90 mmol). The reaction mixture was stirred at a temperature of 0ºC for 30 min, during which the reagents were dissolved. The reaction mixture was suppressed by the addition of acetic acid (1 ml), then washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2×10 ml). The combined organic extracts were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum to obtain specified in the connection header in the form of a solid beige color (0.66 g, 96%).1H NMR (CDCl3, 400 MHz) of 2.26 (3H, s), 3,86 (3H, s), 6,55 (1H, d, J=8,8 Hz), 7,60 (1H, d, J=8,8 Hz).

Stage 2: methyl ether 4-chloro-1H-indazol-5-carboxylic acid

To a solution of methyl ester 4-amino-2-chloro-3-methyl-benzoic acid (5.29 g, of 26.5 mmol) in acetic acid (100 ml) was added soliditet (3.9 ml, 29.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then was heated at boiling point for 3 hours. The reaction mixture was concentrated in vacuo and the resulting residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid product is not quite white (of 2.26 g, 40%).1H NMR (CDCl3, 400 MHz) of 3.97 (3 H, s), 7,42 (1H, d, J=8,8 Hz), 7,95 (1H, d, J=8,8 Hz), 8,29 (1H, s).

Stage 3: methyl ether 4-chloro-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid and methyl ester of 4-chloro-2-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid

To a solution of methyl ester 4-chloro-1H-indazol-5-carboxylic acid (1 g, 4,74 mmol) in THF (20 ml) was added p-toluensulfonyl chloride (1.0 g, 5.2 mmol), triethylamine (0.8 ml, 5.7 mmol) and DMAP (catalytic amount). The reaction mixture was stirred at room temperature for 16 hours, during which formed white precipitate. The reaction mixture was diluted with water and extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in VA is uume. The obtained residue was subjected to flash chromatography (SiO2gradient of 0-80% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid product is not quite white (1.51 g, 82%).1H NMR showed that the product was a mixture of 1:1 isomers. LCMS (Method B): RT=as 4.02 min, [M-H]-=363.

Di-tert-butyl ester 4-bromo-indazole-1,5-dicarboxylic acid

Step 1: tert-butyl ether, 2-bromo-4-fluoro-benzoic acid

To a suspension of 2-bromo-4-fluoro-benzoic acid (28.5 g, 0.13 mol) in dichloromethane (500 ml) at room temperature was added oxalyl chloride (11,35 ml, 0.26 mmol)and then DMF (0.05 ml, catalytic amount (ATTENTION! Vigorous gas evolution) and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in DCM (500 ml), then treated with a solution of tert-butanol (28.5 g, 0.26 mol) and pyridine (20.5 g, 0.26 mol). The resulting mixture was stirred at room temperature for 3 days, then diluted with DCM and washed (1M aqueous sodium hydroxide, water, 0,1M aqueous HCl, water), dried (Na2SO4) filtered and concentrated in vacuum to obtain yellow oil. The crude oil was subjected to flash chromatography (Si-PPC, gradient 0 to 20% ethyl acetate in cyclohexane) to the floor is the group specified in the title compounds as colorless oil (15.2 g, 42%).1H NMR (CDCl3, 400 MHz) 7,76-7,73 (1H, m), 7,37 (1H, DD, J=at 8.36, 2,53 Hz), 7,05 (1H, DDD, J=8,70, 7,73, 2,53 Hz)to 1.60 (9H, s).

Step 2: tert-butyl ether, 2-bromo-4-fluoro-3-formyl-benzoic acid

To a solution of tert-butyl methyl ether, 2-bromo-4-fluoro-benzoic acid (10.0 g, 36 mmol) in THF (100 ml) at a temperature of-78ºC under nitrogen atmosphere was added dropwise diisopropylamide lithium (1,8M solution, 20 ml, 36 mmol). The reaction mixture was stirred for 1.25 hours, then was added DMF (10 ml), then was stirred for another 10 minutes, then extinguished acetic acid (3 ml). The products were distributed between ethyl acetate and water, the organic layer was separated, washed with saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuum to obtain yellow oil, which was crystallizability when standing. The crude product is triturated in cyclohexane with obtaining specified in the connection header in the form of solid yellow product (6.8 g, 62%).1H NMR (CDCl3, 400 MHz) 10,38 (1H, s), 7,80-7,73 (1H, m), 7,17 (1H, t, J=a 9.09 Hz), of 1.62 (9H, s).

Step 3: tert-butyl ether 4-bromo-1H-indazol-5-carboxylic acid

Biphasic solution of tert-butyl methyl ether, 2-bromo-4-fluoro-3-formyl-benzoic acid (4,25 g, 14 mmol), DME (25 ml) and hydrazine hydrate (15 ml) was heated at a temperature of 90ºC for 1 hour. After the hladiny products was distributed between ethyl acetate and water, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the connection header in the form of a solid product reddish color (4.1 g, 100%). LCMS (method B) RT=3,63 min, [M + CH3CN + H]+=338/340, [M-H]-=295/297.

Stage 4: di-tert-butyl ester 4-bromo-indazole-1,5-dicarboxylic acid

To a solution of tert-butyl ester 4-bromo-1H-indazol-5-carboxylic acid (3.0 g, 10 mmol) and triethylamine (of 1.53 ml, 11 mmol) in DCM (30 ml) was added di-tert-butyl-dicarbonate (2.4 g, 11 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM, washed (saturated aqueous NaHCO3, water), dried (Na2SO4), filtered and concentrated in vacuum to obtain oil yellow/orange color, which crystallized upon standing. The crude product is triturated in pentane to obtain specified in the connection header in the form of a solid whitish/yellow (1.8 g, 45%).1H NMR (CDCl3, 400 MHz) 8,29 (1H, s), 8,18-8,10 (1H, m), 7,92 (1H, d, J=a total of 8.74 Hz), 1,70 (9H, s), and 1.63 (9H, s).

Tert-butyl ester 4-bromo-benzo[d]isothiazol-5-carboxylic acid

Step 1: tert-butyl ether 4-benzylmethyl-2-bromo-3-formyl-benzoic acid

To a solution of tert-butoxide potassium (318 mg, 2,84 mmol) in THF (20 ml) under nitrogen atmosphere was added bezelmaterial (332 μl, 2,84 mmol) and the mixture was stirred at room temperature for 10 minutes. Added tert-butyl ester 2-bromo-4-fluoro-3-formyl-benzoic acid (860 mg, 2,84 mmol) and stirring was continued for 30 minutes, then reduce saturated aqueous NH4Cl. The products were distributed between ethyl acetate and water, the organic layer was separated, washed with saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the connection header in the form of a solid product in yellow (1,15 g, 100%).1H NMR (CDCl3) 10,57 (1H, s), to 7.61 (1H, d, J=8,44 Hz), 7,40-of 7.25 (6H, m), 4,17 (2H, s)to 1.61 (9H, s).

Step 2: tert-butyl ether 4-bromo-benzo[d]isothiazol-5-carboxylic acid

In cold (0) solution of tert-butyl methyl ether 4-benzylmethyl-2-bromo-3-formyl-benzoic acid (1,15 g, 2.82 mmol) in DCM (15 ml) was added Sulfuryl chloride (453 μl, 5,64 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to the azeotropic distillation with THF (×2) and then was dissolved in THF (7 ml). The resulting solution was cooled to a temperature of 0-5ºC and was added dropwise a solution of ammonia in methanol (2M, 15 ml). Rea is operating and the mixture was stirred cold for 30 minutes, then at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partially dissolved in diethyl ether. The ethereal solution was concentrated in vacuo, and the residue was subjected to flash chromatography (Si-PPC, gradient 0-10% diethyl ether in pentane) to obtain specified in the title compound as a colourless oil (523 mg, 59%).1H NMR (CDCl3) 9,13 (1H, d, J=0,88 Hz), 7,89 (1H, DD, J=at 8.36, 0,97 Hz), 7,83 (1H, d, J=of 8.37 Hz), to 1.61 (9H, s).

7-Fluoro-benzo[d]isothiazol-6-carboxylic acid

Step 1: tert-butyl ether 2,3-debtor-4-methyl-benzoic acid

A mixture of 2,3-debtor-4-methyl-benzoic acid (20,0 g, 116 mmol), di-tert-butyl dicarbonate (of 25.0 g, 116 mmol) and DMAP (2.0 g, 16.4 mmol) in tert-butanol (500 ml) was stirred at 45°C for 5 hours, then concentrated in vacuo. The resulting residue is triturated in Et2O and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was distributed between ethyl acetate and 1M aqueous solution of hydrochloric acid. The organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum to obtain specified in the connection header in the form bestwe the aqueous oil (17.3 g, 65%).1H NMR (CDCl3, 400 MHz) 7,51 (1H, DDD, J=8,3, 6,6, 1.9 Hz), to 6.95 (1H, m), 2,33 (3 H, d, J=2.3 Hz), to 1.59 (9H, s).

Step 2: tert-butyl ether 4-methyl bromide-2,3-debtor-benzoic acid

A solution of tert-butyl methyl ether 2,3-debtor-4-methyl-benzoic acid (17.3 g, 75,9 mmol) and N-bromosuccinimide (13.5 g, 75,9 mmol) in carbon tetrachloride (250 ml) was degirolami for 10 minutes. Added AIBN (1.2 g, to 7.32 mmol) and the reaction mixture was stirred at the boiling temperature for 18 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, TBME in cyclohexane), which gave specified in the title compound as a colourless oil (16.7 g, contaminated with 25% of the original product).1H NMR (CDCl3, 400 MHz) to 7.61 (1H, DDD, J=8,3, 6,4, and 2.1 Hz), 7,18 (1H, DDD, J=8,1, 6,4, 1.8 Hz), 4,49 (2H, d, J=1.3 Hz), to 1.59 (9H, s).

Step 3: tert-butyl ether 2,3-debtor-4-formyl-benzoic acid

To a solution of tert-butyl ether 4-methyl bromide-2,3-debtor-benzoic acid (12.9 g, 42.1 mmol) in DMSO (80 ml) and DCM (40 ml) at a temperature of 0ºC was added N-oxide, trimethylamine (3.4 g, of 45.3 mmol). The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The remainder of the soap is delali between ice water and ethyl acetate. The organic layer was separated and washed twice with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. Received a residue that was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, TBME in cyclohexane), which gave specified in the title compound in the form of solid white (4,34 g, 43%).1H NMR (CDCl3, 400 MHz) 10,38 (1H, d, J=0.8 Hz), 7,71 (1H, dddd, J=7,4, 5,6, and 1.7, 0.8 Hz), 7,63 (1H, DDD, J=7,4, 5,6, 1.5 Hz), to 1.61 (9H, s).

Stage 4: tert-butyl ether 3-benzylmethyl-2-fluoro-4-formyl-benzoic acid

To a solution of tert-butoxide potassium (2.0 g, to 17.9 mmol) in anhydrous THF (80 ml) was added benzyl mercaptan (2,1 ml of 17.9 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then cooled to a temperature of-30ºC. Within 15 minutes, was added dropwise a solution of tert-butyl methyl ether 2,3-debtor-4-formyl-benzoic acid (4,34 g of 17.9 mmol) in anhydrous THF (20 ml) and the resulting mixture was stirred at a temperature of-30ºC for 30 minutes, after which was suppressed by addition of water and was extracted with ethyl acetate. The organic layer was separated, washed with water, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum to obtain specified in the title compound as yellow oil (6.2 g, 100%).1H NMR (CDCl3 , 400 MHz) and 10.20 (1H, d, J=0.6 Hz), to 7.84 (1H, DDD, J=8.0 a, 6,8, 0.7 Hz), to 7.59 (1H, DD, J=8.0 a, and 0.9 Hz), 7,19 (3 H, m), 7,05 (2H, m), 4,07 (2H, s), and 1.63 (9H, s).

Step 5: tert-butyl methyl ether 7-fluoro-benzo[d]isothiazol-6-carboxylic acid

To a solution of tert-butyl methyl ether 3-benzylmethyl-2-fluoro-4-formyl-benzoic acid (6.20 g, to 17.9 mmol) in DCM (100 ml) was added sulfurylchloride (2,9 ml, 35.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The obtained residue was twice subjected to the azeotropic distillation with toluene and then was treated with THF (50 ml). The resulting solution was cooled to a temperature of 0ºC was added a 2M solution of ammonia in methanol (100 ml). The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuum. The obtained residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with water, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The residue was subjected to flash chromatography (Si - PPC, gradient 0% to 10%, Et2O in pentane), which gave specified in the title compound in the form of solid yellow (2,96 g, 65%).1H NMR (CDCl3, 400 MHz) 8,93 (1H, DD, J=4,1, 0.5 Hz), to $ 7.91 (1H, DDD, J=8,3, 5,8, 0.5 Hz), to 7.84 (1H, d, J=8,3 Hz)of 1.64 (9H, s).

tadia 6: 7-fluoro-benzo|d]isothiazol-6-carboxylic acid

To a solution of tert-butyl methyl ether 7-fluoro-benzo[d]isothiazol-6-carboxylic acid (1.0 g, 4.0 mmol) in DCM (10 ml) was added water (0.2 ml) and TFU (10 ml). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuum. The residue was subjected to the azeotropic distillation with toluene to obtain specified in the connection header in the form of a solid product in yellow (788 mg, 100%). LCMS (method B): RT=2,86 min, [M-H]-=196.

SYNTHESIS of VENIAMINOVNA

4-(2-Fluoro-4-iodine-phenylamino)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid

Stage 1: methyl ester of 4-(2-fluoro-4-trimethylsilylmethylamine)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid

Methyl ether 4-chloro-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid and methyl ester of 2-[1-chloro-1-[3-methyl-1-(toluene-4-sulfonyl)-1H-pyrazole-4-yl]-meth-(Z)-ilidene]-but-3-ene acid (1.1 g, 3.0 mmol), 2-fluoro-4-trimethylsilylmethylamine (0,61 g, 3.3 mmol), 2-dicyclohexylphosphino-2'-6'-aminobutiramida biphenyl (0.28 g, of 0.60 mmol), potassium phosphate (0,70 g, 3.3 mmol) and Tris(dibenzylideneacetone)dipalladium (O) (87 mg, 0.15 mmol) suspended in toluene (5 ml) and the resulting mixture was degirolami. The reaction mixture was heated at a temperature of 105ºC for 3 hours. The reaction mixture was suppressed by adding 1M hydrochloric acid, 5 ml) and the resulting mixture was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-100% DCM in cyclohexane) to obtain specified in the connection header in the form of a solid pale brown (0,78 g, 50%). Data1H NMR showed that the product is an individual isomer. LCMS (Method B): RT=5,22 min, [M+H]+=512.

Stage 2: methyl ester of 4-(2-fluoro-4-itfinally)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid

To a solution of methyl ester 4-(2-fluoro-4-trimethylsilylmethylamine)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid (0.56 g, 1.1 mmol) in DCM (3 ml) at a temperature of 0ºC solution was added monochloride iodine in DCM (2.2 ml, 1M, 2.2 mmol). The reaction mixture was stirred at a temperature of 0ºC for 30 minutes. The reaction mixture was suppressed by addition of water (10 ml), then diluted with saturated aqueous sodium thiosulfate (10 ml). The resulting mixture was extracted with ethyl acetate (3×20 ml) and the combined organic fractions were washed with saturated saline (20 ml), dried (MgSO4), then concentrated in vacuo. The obtained residue was subjected to flash chromatography (SiO2gr , diet 0-100% DCM in cyclohexane) to obtain specified in the connection header in the form of a solid light brown color (0.51 g, 83%). LCMS (Method B): RT=4,87 min, [M+H]+=566.

Stage 3: 4-(2-fluoro-4-iodine-phenylamino)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid

To a solution of methyl ester 4-(2-fluoro-4-itfinally)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid (0.51 g, of 0.91 mmol) in toluene (5 ml) was added bis(tributylamine)oxide (0,92 ml, 1.8 mmol) and the reaction mixture was heated at the boiling temperature for 48 hours. The reaction mixture was concentrated in vacuum and the obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-10% methanol in DCM) to obtain specified in the connection header in the form of a solid light brown color (0,46 g, 92%). LCMS (Method B): RT=4,27 min, [M+H]+=552.

4-(2-Fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

Stage 1: ethyl ester of 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

Ethyl ester of 4-chloro-1-(4-methoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (1.8 g, 5.2 mmol) and 2-fluoro-4-stanlin (1.5 g, 6.3 mmol) was dissolved in dioxane (20 ml) and the resulting mixture was stirred at the boiling temperature for 16 hours. The reaction mixture was diluted with water (50 ml) and the aqueous layer was extracted with dichloromethane (3×20 ml). The combined organic fractions of the filter is Vali through a hydrophobic Frit and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-30% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid white color (1.56 g, 56 %). LCMS (Method B): RT=4,78 min, [M+H]+=547.

Stage 2: 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-bl-5-carboxylic acid

To a suspension of ethyl ester of 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (380 mg, 0.71 mmol) in IMS (10 ml) was added an aqueous solution of sodium hydroxide (1,78 ml, 1M, 1.78 mmol). The reaction mixture was heated at 65°C for 2 hours, during which all solids were dissolved. Volatile solvents were removed in vacuum and the resulting solution was acidified to pH ~3 careful addition of aqueous hydrochloric acid (1M), causing precipitate formation. The precipitate was collected by filtration and dried in vacuum at 45°C with obtaining specified in the connection header in a solid brown color (360 mg, 100%). LCMS (Method B): RT=3,84 min, [M+H]+=519.

4-(4-Bromo-2-fluoro-phenylamino)-1H-indazol-5-carboxylic acid

Step 1: di-tert-butyl ester 4-(2-fluoro-4-trimethylsilyl-phenylamino)-indazole-1,5-dicarboxylic acid

A solution of 2-fluoro-4-trimethylsilyl-dryer is lamina (1.2 g, 6.5 mmol) in toluene (20 ml) was added to a mixture of di-tert-butyl ester 4-bromo-indazole-1,5-dicarboxylic acid (2.0 g, 5.0 mmol), Pd2dba3(114 mg, and 2.5 mol%), Xantphos (144 mg, 5 mol%) and trehosnovnogo potassium phosphate (1,49 g, 7 mmol) under nitrogen atmosphere. The mixture was evacuated and filled with nitrogen and then the reaction mixture was heated at a temperature of 90ºC for 18 hours. The cooled reaction mixture was diluted with ethyl acetate, filtered through Celite®and the filtrate was concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, dry put on HM-N, gradient 0-10% ethyl acetate in cyclohexane) to obtain specified in the connection header resin orange (1.9 g, 76%).1H NMR (CDCl3, 400 MHz) there is a 10.03 (1H, s), with 8.05 (1H, d, J=9,03 Hz), EUR 7.57 (1H, DD, J=9,00, or 0.83 Hz), 7,28-to 7.18 (4H, m), by 1.68 (9H, s), and 1.63 (9H, s), and 0.28 (9H, s).

Stage 2: di-tert-butyl ester 4-(4-bromo-2-fluoro-phenylamino)-indazole-1,5-dicarboxylic acid

To a solution of di-tert-butyl ester 4-(2-fluoro-4-trimethylsilyl-phenylamino)-indazole-1,5-dicarboxylic acid (850 mg, 1.7 mmol) in DCM (10 ml) at a temperature of 15 ° C was added dropwise N-bromosuccinimide (303 mg, 1.7 mmol) in solution in DCM (3 ml). The reaction mixture was stirred at a temperature of-15 ° C for 1.25 hours, then was added DCM and the solution was washed (saturated aqueous NaHCO3then water), dried (Na2SO4 ), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-10% ethyl acetate in cyclohexane) to obtain specified in the connection header resin orange (790 mg, 92%). LCMS (method B) RT=5,41 min, [M + CH3CN + Na]+=569/571.

Stage 3: 4-(4-bromo-2-fluoro-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of di-tert-butyl ester 4-(4-bromo-2-forgenerating)-indazole-1,5-dicarboxylic acid (420 mg, 0.83 mmol) in DCM (5 ml) was added TFU (1.2 ml, 16.2 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted with ethyl acetate (2×10 ml). The combined organic extracts were washed with saturated saline (20 ml), dried with MgSO4and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid product is not quite white (232 mg, 80%). LCMS (Method B): RT=3,22 min, [M+H]+=350/352.

4-(2-Fluoro-4-itfinally)-1H-indazol-5-carboxylic acid

Step 1: di-tert-butyl ester 4-(2-FPO is-4-itfinally)-indazole-1,5-dicarboxylic acid

To a solution of di-tert-butyl ester 4-(2-fluoro-4-trimethylsilylmethylamine)-indazole-1,5-dicarboxylic acid (1.07 g, 2.14 mmol) in DCM (10 ml) at a temperature of 0ºC was added monochloride iodine in the form of a solution in DCM (4,2 ml, 1H, 4.2 mmol). The reaction mixture was stirred at a temperature of 0ºC for 20 minutes, then was diluted with saturated aqueous sodium thiosulfate (10 ml) and was extracted with DCM (2×10 ml). The combined organic extracts were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-100% DCM in cyclohexane) to obtain specified in the connection header in the form of a solid pale brown (611 mg, 52%). LCMS (Method B): RT=5,48 min, [M+H]+=554.

Stage 2: 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid

To a solution of di-tert-butyl ester 4-(2-fluoro-4-itfinally)-indazole-1,5-dicarboxylic acid (611 mg, 1.10 mmol) in DCM (5 ml) was added TFU (1.2 ml, 16.2 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted with ethyl acetate (2×10 ml). United organizes the e fraction was washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid product is not quite white (367 mg, 84%). LCMS (Method B): RT=3,23 min, [M+H]+=398.

4-(2-Fluoro-4-methylsulfanyl-phenylamino)-1H-indazol-5-carboxylic acid

Step 1: 2,4-debtor-3-formyl-benzoic acid

A solution of TMEDA (10.5 ml, 70 mmol) in THF (50 ml) was cooled to a temperature of <-80ºC and was treated with second-butyllithium (50 ml, 70 mmol). Was added dropwise a solution of 2,4-diferential acid (5.0 g, of 31.6 mmol) in THF, maintaining the temperature below-80ºC. The reaction mixture was allowed to warm up to the temperature of 75ºC and was treated with DMF (15 ml), the mixture was then allowed to warm up to the temperature 0ºC, then extinguished the reaction mixture with water. The aqueous layer was separated, acidified to pH ~2 (concentrated HCl) and was twice extracted with diethyl ether. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum to obtain yellow oil. The crude product was led from a mixture of cyclohexane/diethyl ether to obtain specified in the connection header in the form of solid yellow product (670 mg, 11%).1H NMR (CDCl3that 400 is Hz) the 10.40 (1H, C)8,31 (1H, DDD, J=8,96, 8,02, between 6.08 Hz), 7,12 (1H, TD, J=a 9.09, 1,42 Hz).

Stage 2: 3-dimethoxymethyl-2,4-debtor-benzoic acid

A mixture of 2,4-debtor-3-formyl-benzoic acid (670 mg, 3.6 mmol) and ammonium chloride (1,15 g, 21.6 mmol) in methanol (20 ml) was heated at boiling temperature for 18 hours. The reaction mixture was concentrated in vacuo, the residue was partially dissolved in ethyl acetate and then filtered. The filtrate was concentrated in vacuum to obtain specified in the connection header in the form of a solid product in yellow (747 mg, 89%yield).1H NMR (DMSO-d6, 400 MHz) of 7.95 (1H, TD, J=8,55, 6,32 Hz), 5,62 (1H, s)to 3.38 (6H, s).

Stage 3: 4-fluoro-2-(2-fluoro-4-methylsulfanyl-phenylamino)-3-formyl-benzoic acid

In cold (-78ºC) solution of 2-fluoro-4-methylsulfanyl-phenyl amine (1.55 g, 9.9 mmol) in THF (15 ml) was added dropwise LHMDS (9,9 ml, 1.0 M solution in hexane 9.9 mmol) in such a way as to maintain the temperature below-65ºC. After stirring for 30 minutes was added dropwise a solution of 3-dimethoxymethyl-2,4-debtor-benzoic acid (700 mg, 3.0 mmol) in THF (15 ml), the mixture was stirred with cooling for 3 hours, then was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was suppressed by adding an aqueous solution of ammonium chloride and the product is distributed between ethyl acetate and water. The aqueous layer was separated and acidified to pH 1 (concentrated HCl) and then was extracted twice with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum. The resulting residue is triturated in diethyl ether to obtain specified in the connection header in the form of solid yellow product (105 mg, 10 %yield).1H NMR (CDCl3, 400 MHz) 10,26-10,23 (2H, m), of 8.04 (1H, DD, J=8,76, of 6.31 Hz), 7.03 is-of 6.96 (2H, m)6,91 (1H, d, J=1,96 Hz), of 6.65 (1H, DD, J=10,02, 8,77 Hz), 2,42 (3H, s).

Stage 4: 4-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-indazol-5-carboxylic acid

To a suspension of 4-fluoro-2-(2-fluoro-4-methylsulfanyl-phenylamino)-3-formyl-benzoic acid (105 mg, 0.32 mmol) in DME (5 ml) was added hydrazine hydrate (5 ml) and the reaction mixture was heated at a temperature of 90ºC for 18 hours. Volatile solvent was removed in vacuum and the residue was acidified with concentrated HCl while cooling. The precipitate was collected by filtration and washed with water to obtain specified in the connection header in the form of solids reddish color (85 mg, 82%). LCMS (Method B) RT3,12 [M+H]+318.

4-(2-Fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

Step 1: tert-butyl ether 4-(2-fluoro-4-trimethylsilyl-phenylamino)benzo[d]isothiazol-5-carboxylic acid

A solution of 2-fluoro-4-trimethylsilyl-phenylamine (340 mg, 1,43 mmol), tert-butyl ester 4-bromo-benzo[d]isothiazol-5-carboxylic acid (449 mg, 1,43 mmol), Pd2dba3(65 mg, 0.07 mmol), Xantphos (83 mg, 0.14 mmol) and trehosnovnogo potassium phosphate (455 mg, 2.14 mmol) in toluene (5 ml) was degirolami and then the reaction mixture was heated at a temperature of 90ºC for 18 hours. The cooled reaction mixture was diluted with ethyl acetate, filtered through Celite®and the filtrate was concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient of 2.5-5% diethyl ether in pentane) to obtain specified in the title compound as a dark oil (465 mg, 78%). LCMS (Method B): RT=5,76 min, [M+H]+=417.

Step 2: tert-butyl ether 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

To a solution of tert-butyl ester 4-(2-fluoro-4-trimethylsilyl-phenylamino)-benzo[d]isothiazol-5-carboxylic acid (416 mg, 1.0 mmol) in DCM (10 ml) at -78°C was added monochloride iodine in the form of a solution in DCM (2.0 ml, 1M, 2.0 mmol). The reaction mixture was stirred at -78°C for 1 hour, then diluted with saturated aqueous sodium thiosulfate and extracted with DCM. The combined organic extracts were washed with saturated salt solution, dried (Na2SO4and koncentrira is whether in vacuum to obtain specified in the title compound as yellow foam (459 mg, 98%). LCMS (Method B): RT=5,32 min, [M+H]+=471.

Stage 3: 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

To a solution of tert-butyl ester 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid (445 mg, 0.95 mmol) in DCM (20 ml) was added water (0.1 ml), the mixture was cooled to a temperature of 0ºC and added TFU (20 ml). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo and the residue was subjected to the azeotropic distillation with toluene (×2) to obtain specified in the connection header in the form of a solid beige color (392 mg, 100%). LCMS (Method B): RT=3,97 min, [M+H]+=415.

7-(2-Fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

Step 1: tert-butyl methyl ether 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of tert-butyl methyl ether 7-fluoro-benzo[d]isothiazol-6-carboxylic acid (1.26 g, 5.0 mmol) and 2-fluoro-4-iodine-phenylamine (1.18 g, 5.0 mmol) in anhydrous THF (25 ml) at -78°C was added 1,0M solution of LHMDS in hexane (10.0 ml, 10.0 mmol) in a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and then was stirred for 30 minutes, after which was suppressed by the addition of saturated aqueous ammonium chloride and was extracted with utilize the atom. The organic layer was separated and washed with water, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, TBME in cyclohexane) to obtain specified in the connection header in the form of a solid product in yellow (717 mg, 30%). LCMS (method B): RT=5,14 min, [M+H]+=471.

Stage 2: 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of tert-butyl ester 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (710 mg and 1.51 mmol) in DCM (5 ml) was added water (0.15 ml) and TFU (5 ml). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The obtained residue was subjected to the azeotropic distillation with toluene to obtain specified in the connection header in the form of a solid product in yellow (571 mg, 91%). LCMS (method B): RT=3,95 min, [M+H]+=415.

7-(4-Bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 4-bromo-2-fluoro-phenylamine (1,05 g of 5.55 mmol) in anhydrous THF (20 ml) at -78°C was added a 1.0 M solution of LHMDS in hexane (of 8.3 ml, 8.3 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 10 minutes and was added dropwise a suspension of 7-fluoro-benzo[d]isothiazol-6-carboxylic acid (547 mg, 2.8 mmol) in anhydrous THF (20 ml). The resulting mixture was stirred at -78°C for 30 min, then the temperature was allowed to rise to room temperature and was stirred for 18 hours, after which it was suppressed by the addition of 1M aqueous HCl (approx. 50 ml) and was extracted with ethyl acetate. The organic layer was separated and washed with water, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0%-10% MeOH in DCM) to obtain specified in the connection header in a solid brown color (584 mg, 58%). LCMS (method B): RT=3,76 min, [M-H]+=365/367.

7-(4-Cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 4-cyclopropyl-2-fluoro-phenylamine (445 mg, to 2.94 mmol) in anhydrous THF (10 ml) at -78°C was added a 1.0 M solution of LHMDS in hexane (4.4 ml, 4.4 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 10 minutes and was added dropwise a suspension of 7-fluoro-benzo[d]isothiazol-6-carboxylic acid (290 mg, about 1.47 mmol) in anhydrous THF (10 ml). The resulting mixture was stirred at -78°C for 30 minutes, then the temperature was allowed to rise to room temperature and was stirred for 18 hours, after which it was suppressed by the addition of 1M aqueous HCl and was extracted with ethyl acetate. The organic layer was separated and washed in the Oh, then with a saturated saline solution, dried (Na2SO4), filtered and evaporated in vacuum. The resulting residue is triturated in diethyl ether to obtain specified in the connection header in a solid brown color (155 mg, 32%). LCMS (method B): RT=3,79 min, [M+H]+=329.

7-(2-Fluoro-4-methylsulfanyl-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 2-fluoro-4-methylsulfanyl-phenylamine (628 mg, 4.0 mmol) in anhydrous THF (15 ml) at -78°C was added 1,0M solution of LHMDS in hexane (6.0 ml, 6.0 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and was added dropwise a suspension of 7-fluoro-benzo[d]isothiazol-6-carboxylic acid (394 mg, 2.0 mmol) in anhydrous THF (15 ml). The resulting mixture was stirred at -78°C for 30 minutes, then the temperature was allowed to rise to room temperature and was stirred for 18 hours, after which it was suppressed by the addition of 1M aqueous HCl (approx. 50 ml) and was extracted with ethyl acetate. The organic layer was separated and washed with water, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%MeOH in DCM) to obtain specified in the connection header in a solid brown color (200 mg, 30%). LCMS (pic is b, B): R T=3,67 min, [M+H]+=335

SYNTHESIS of 5-AMINO-4-ANILINE INDAZOL intermediates

Tert-butyl ester 5-amino-4-(2-fluoro-4-iodine-phenylamino)-indazol-1-carboxylic acid

Step 1: 2,6-debtor-3-nitro-benzaldehyde

To stir 69%nitric acid (6,48 ml, 93,59 mmol), cooled to 5°C, was added dropwise concentrated sulfuric acid (4,16 ml, 78,11 mmol), maintaining the internal temperature below 8°C. After complete addition, stirring was continued for 15 minutes. This mixture was added dropwise to a solution of 2,6-diferentialglea (10 g, 70,37 mmol) in concentrated sulfuric acid (50 ml) maintaining an internal temperature below 10ºC. After complete addition, the mixture was stirred at a temperature of 5ºC for 15 minutes, then was allowed to warm to room temperature over 90 minutes. The reaction mixture was poured into a mixture of ice-water (400 ml) and the formed solid product was stirred for 1 hour. The solid product was collected by filtration, washed with water and dried in vacuum to obtain specified in the connection header (9,27 g, 70%).1H NMR (DMSO-d6, 300 MHz): of 10.21 (1H, t, J=1,02 Hz), charged 8.52 (1H, DDD, J=9,38, 8,60, 5,51 Hz), 7,51 (1H, TD, J=at 9.53, 1,76 Hz).

Stage 2: 2-dimethoxymethyl-1,3-debtor-4-nitrobenzene

A solution of 2,6-debtor-3-nitro-benzaldehyde (9.0 g, 48.1 mmol), monohydrate p-toluensulfonate acid (183 mg, 0,962 mmol), triethylorthoformate (3.5 ml, 32,4 mmol) and methanol (200 ml) was heated at boiling point for 4 hours. The reaction mixture was left to cool to room temperature and then concentrated in vacuum. The obtained residue was dissolved in DCM (250 ml) and washed with a mixture of water (200 ml) and a saturated solution of NaHCO3(50 ml). The organic layer was dried (Na2SO4) and concentrated in vacuum to obtain specified in the connection header (10,83 g, 97%).1H NMR (DMSO-d6, 300 MHz): 8,28 (1H, DDD, J=9,34, 8,48, 5,51 Hz), 7,39 (1H, TD, J=9,34, is 1.81 Hz), to 5.66 (1H, s), 3,40 (6H, s).

Stage 3: (2-dimethoxymethyl-3-fluoro-6-nitrophenyl)-(2-fluoro-4-iodine-phenyl)-amine

To a solution of 2-fluoro-4-iodine-aniline (2.24 g, 9.43 mmol) in anhydrous THF (30 ml) under nitrogen atmosphere was added 1M LHMDS in hexane (18 ml, 1M, 18.0 mmol), maintaining the internal temperature below -65°C. After complete addition, the reaction mixture was stirred for 30 minutes at a temperature of-70ºC. In the reaction mixture was added a solution of 2-dimethoxymethyl-1,3-debtor-4-nitrobenzene (2.0 g, 8,58 mmol) in anhydrous THF (20 ml), maintaining the internal temperature below-68ºC. After complete addition, the reaction mixture was stirred for 30 minutes at a temperature of-70ºC, then Dawa and to warm to room temperature and was stirred for 22 hours. The reaction mixture was extinguished with the help of a saturated aqueous solution of NH4Cl and extracted with ethyl acetate (200 ml). The organic layer was washed with saturated saline solution, dried (Na2SO4), concentrated in vacuo to a minimum volume and triturated in cyclohexane with obtaining specified in the connection header (2,18 g, 56%). LCMS (Method B): RT=4.26 deaths / min, [M-H]-=449.

Stage 4: 6-fluoro-2-(2-fluoro-4-iodine-phenylamino)-3-nitro-benzaldehyde

To a stirred solution of (2-dimethoxymethyl-3-fluoro-6-nitrophenyl)-(2-fluoro-4-iodine-phenyl)-amine (1.0 g, 2.22 mmol) in THF (10 ml) at room temperature was added a solution of 4M HCl. After 2 hours, THF was removed in vacuum and the residue was diluted with water (20 ml), which led to the formation of a precipitate. The solid precipitate was collected by filtration, washed with water and dried in vacuum to obtain specified in the header of the compound (864 mg, 96%). LCMS (Method B): RT=4,06 min, [M-H]-=403.

Stage 5: (2-fluoro-4-iodine-phenyl)-(5-nitro-1H-indazol-4-yl)-amine

To a stirred solution of 6-fluoro-2-(2-fluoro-4-iodine-phenylamino)-3-nitro-benzaldehyde (864 mg, 2.14 mmol) in DME (15 ml) at room temperature was slowly added hydrazine hydrate (10 ml) and the reaction mixture was stirred for 18 hours. The organic solvent was removed in vacuum and the mixture was diluted with water is (50 ml). The formed solid product was collected by filtration, washed with water and dried in vacuum to obtain specified in the connection header (839 mg, 98%). LCMS (Method B): RT=3,61 min, [M+H]+=399.

Step 6: tert-butyl ether 4-(2-fluoro-4-iodine-phenylamino)-5-nitro-indazol-1-carboxylic acid

To a suspension of (2-fluoro-4-iodine-phenyl)-(5-nitro-1H-indazol-4-yl)-amine (839 mg, 2,11 mmol) and triethylamine (0,323 ml, 2.32 mmol) in dichloromethane was added di-tert-butyl dicarbonate (552 mg, 2,53 mmol) and DMF (1 ml), the resulting solution was stirred at room temperature for 2 hours. Was added di-tert-butyl dicarbonate (275 mg, of 1.26 mmol) and DMAP (25 mg, 10 mol%) and the mixture was stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with saturated aqueous NaHCO3(100 ml), then water (100 ml) and then saturated brine (100 ml), then dried (Na2SO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-35% ethyl acetate in cyclohexane) to obtain specified in the connection header (739 mg, 70%). LCMS (Method B): RT=4,57 min, [M-Boc+H]+=399.

Step 7: tert-butyl ether 5-amino-4-(2-fluoro-4-iodine-phenylamino)-indazol-1-carboxylic acid

Suspension of dithionite sodium (978 mg, is 4.21 mmol) and tert-butyl ester 4-(2-fluoro-4-iodine-phenylamino)-5-nitro-is indazol-1-carboxylic acid (700 mg, 1.4 mmol) in water (35 ml) was treated with a mixture of 1:1 THF:dioxane (34 ml), the homogeneous reaction mixture was stirred at room temperature for 4 hours. Adding more dithionite sodium (978 mg, is 4.21 mmol) and stirring continued for 20 hours. The reaction mixture was podslushivaet by adding a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate (150 ml). The organic extract was washed with water, dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the connection header in the form of a solid product in yellow (758 mg, Quant.). LCMS (Method B) RT=4.09 to min, [M+H]+=469.

Tert-butyl ester 5-amino-4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-indazol-1-carboxylic acid

Step 1: 2,6-debtor-4-methoxy-3-nitro-benzaldehyde

To a cold solution (-5ºC) nitric acid (2.7 ml) was added dropwise concentrated sulfuric acid (1.75 ml, 32 mmol), keeping the temperature below 5ºC. The solution was added to a cooled solution of 2,6-debtor-4-methoxy benzaldehyde (5.0 g, 29 mmol) in sulfuric acid (20 ml) over 15 minutes, maintaining the temperature below 5ºC. After stirring at a temperature of 0ºC for 2 hours, the orange solution was poured on ice, the resulting white precipitate was collected potentialtheorie obtaining specified in the connection header in the form of a solid white color (6,33 g, 100%).1H NMR (CDCl3) and 10.20 (1H, t, J=1,17 Hz), 6,69 (1H, DD, J=11,68, 1,93 Hz), a 4.03 (3H, s).

Stage 2: 2-dimethoxymethyl-1,3-debtor-5-methoxy-4-nitrobenzene

A mixture of 2,6-debtor-4-methoxy-3-nitro-benzaldehyde (6.3 g, 29 mmol) in methanol (30 ml) with p-toluensulfonate acid (110 mg, of 0.58 mmol) was heated at boiling temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the connection header in the form of a solid product, pale yellow (6,52 g, 85%).1H NMR (CDCl3) 6,59 (1H, DD, J=11,48, 2,08 Hz), 5,52 (1H, s), 3,93 (3H, s), of 3.45 (6H, s).

Stage 3: (2-dimethoxymethyl-3-fluoro-5-methoxy-6-nitrophenyl)-(2-fluoro-4-iodine-phenyl)-amine

To a cold (-780C) a solution of 2-fluoro-4-iodine-phenylamine (2,97 g, 12.5 mmol) in THF (20 ml) was added dropwise LHMDS (24 ml, 1.0 M solution in hexane 24 mmol), keeping the temperature below-65ºC. After stirring for 30 minutes was added dropwise a solution of 2-dimethoxymethyl-1,3-debtor-5-methoxy-4-nitrobenzene (3.0 g, to 11.4 mmol) in THF (20 ml), the resulting mixture was stirred cold (-78ºC) for 1 hour, then on the Wali to warm to room temperature and was stirred for 18 hours. The reaction mixture was suppressed by adding an aqueous solution of ammonium chloride and was extracted twice with diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuum to obtain a solid product of orange color. The crude orange product triturated in diethyl ether to obtain specified in the connection header in the form of a solid product in yellow (4,2 g, 77%).1H NMR (CDCl3) of 7.36 (1H, DD, J=of 10.09, 1,93 Hz), 7,28-7,17 (2H, m), 6,59 (1H, t, J=8,62 Hz), 6,44 (1H, d, J=11,47 Hz), 5,49 (1H, s), 3,88 (3H, s), 3,39 (6H, s).

Stage 4: 6-fluoro-2-(2-fluoro-4-iodine-phenylamino)-4-methoxy-3-nitro-benzaldehyde

A mixture of (2-dimethoxymethyl-3-fluoro-5-methoxy-6-nitrophenyl)-(2-fluoro-4-iodine-phenyl)-amine (4,2 g, 8,7 mmol) in diethyl ether (70 ml) and 4M HCl (50 ml) was stirred at room temperature for 8 hours. The mixture was extracted with ethyl acetate, the organic extract was washed with water, dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the connection header in the form of solid yellow product (3.1 g, 82%). LCMS (Method B) RT=4,00, no molecular ion.

Stage 5: (2-fluoro-4-iodine-phenyl)-(6-methoxy-5-nitro-1H-indazol-4-yl)-amine

Bi-phase mixture of 6-fluoro-2-(2-fluoro-4-iodine-phenylamino)-4-methoxy-3-nitro-benzo is legido (1.5 g, 3.46 mmol) in hydrazinehydrate (10 ml) and DME (10 ml) was stirred at room temperature for 4 hours, then was heated at a temperature of 50ºC for 3 hours. The reaction mixture was concentrated in vacuo, the residue was treated with water and the resulting solid precipitate was collected by filtration to obtain a solid product of the red/orange color. The solid product was recrystallized from IMS obtaining specified in the connection header in the form of a solid product in yellow (956 mg, 64%). LCMS (Method B) RT=3,62 min, [M+H]+=429 [M-H]-=427.

Step 6: tert-butyl ether 4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-5-nitro-indazol-1-carboxylic acid

A suspension of (2-fluoro-4-iodine-phenyl)-(6-methoxy-5-nitro-1H-indazol-4-yl)-amine (900 mg, 2.1 mmol) in DCM (10 ml) was treated with di-tert-BUTYLCARBAMATE (550 mg, 2.5 mmol) and triethylamine (0,321 ml, 4.6 mmol) and DMF (2 ml). The reaction mixture was stirred for 5 hours at room temperature, then concentrated in vacuo and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with water, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-15% ethyl acetate in cyclohexane) to obtain specified in the title compound in the form of a solid product in yellow (534 mg, 48%).1H NMR (CDCl3) to 7.84 (1H, s), 7,52 (1H, DD, J=9,63, 1.90 GHz), 7,47 (1H, s), 7,43-7,38 (1H, m), 7,29 (1H, d, J=0,78 Hz)6,91 (1H, t, J=8,40 Hz), was 4.02 (3H, s)to 1.70 (9H, s).

Step 7: tert-butyl ether 5-amino-4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-indazol-1-carboxylic acid

Suspension of dithionite sodium (524 mg, of 3.48 mmol) and tert-butyl ester 4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-5-nitro-indazol-1-carboxylic acid (434 mg, 0.87 mmol) in water (10 ml) was treated with a mixture of 1:1 THF:dioxane (10 ml). The homogeneous reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was podslushivaet by adding saturated aqueous sodium hydrogen carbonate solution and then was extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the connection header in the form of solid yellow product (300 mg, 73 %). LCMS (Method B) RT4,16 min, [M+H]+=499 [M-H]-=497.

EXAMPLE 5: (2-hydroxyethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid

Method A. stage 1: (2-vinyloxy-ethoxy)-amide 4-(2-fluoro-4-itfinally)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-iodine-phenylamino)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic sour is s (0,58 g, 1.05 mmol) in DMF (10 ml) was added EDCI (0,22 g, 1.1 mmol), then HOBt (0.16 g, 1.1 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Added O-(2-vinyloxy-ethyl)-hydroxylamine (0.12 g, 1.1 mmol) and DIPEA (0.2 ml, 1.1 mmol) and the reaction mixture was stirred for 16 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml), then aqueous fraction was extracted twice with ethyl acetate (2×10 ml). The combined organic extracts were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid pale brown (439 mg, 66%). LCMS (Method B): RT=4,40 min, [M+H]+=637.

Method A, step 2: (2-hydroxyethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of (2-vinyloxy-ethoxy)-amide 4-(2-fluoro-4-itfinally)-1-(toluene-4-sulfonyl)-1H-indazol-5-carboxylic acid (200 mg, 0.31 mmol) in methanol (3 ml) was added hydrochloric acid (1 ml, 1N) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resulting residue dissolve the Yali in TFU (2 ml). The reaction mixture was heated at a temperature of 65ºC for 3 hours, then at a temperature of 50ºC for 16 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2×10 ml). The combined organic fractions were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to obremenitve preparative HPLC (gradient 10-95% acetonitrile/water+0,1%formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The obtained product was dissolved in ethyl acetate (5 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The aqueous fraction was extracted twice with ethyl acetate (2×10 ml) and the combined organic fractions were washed with saturated saline (20 ml), dried with MgSO4and concentrated in vacuum to obtain specified in the connection header in the form of a solid white (14 mg, 10%). LCMS (Method A): RT=8,31 min, [M+H]+=457.1H NMR (DMSO-d6, 400 MHz): 13,19 (1H, s), 11,60 (1H, s), to 9.93 (1H, s), 7,66 (1H, DD, J=10,31, 1,93 Hz), 7,46 (1H, d, J=8,70 Hz), 7,42 (1H, d, J=8,56 Hz), 7.23 percent (1H, s), 7,01 (1H, d, J=8,77 Hz)6,91 (1H, t, J=8,64 Hz), and 4.68 (1H, ), 3,85 (2H, t, J=4,92 Hz), 3,60-to 3.52 (2H, m).

Method B, step 1: (2-vinyloxyethoxy)-amide 4-(2-fluoro-4-itfinal the Mino)-1H-indazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (2.14 g, of 5.39 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (668 mg, of 6.50 mmol) in DMF (50 ml) was added EDCI (1,14 g, to 5.93 mmol), HOBt (0,80 g, to 5.93 mmol) and DIPEA (1 ml, to 5.93 mmol). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (30 ml), washed with saturated aqueous sodium hydrogen carbonate (300 ml) and the aqueous fraction was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with saturated brine (30 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid product, pale yellow (1.85 g, 71%). LCMS (Method B): RT=3,52 min, [M-H]-=481.

Method B, step 2: (2-hydroxyethoxy)-amide 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid

To a solution of (2-vinyloxyethoxy)-amide 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (1.85 g, of 3.84 mmol) in methanol (40 ml) was added hydrochloric acid (3 ml, 1N, 3 mmol). The reaction mixture was stirred at room temperature for 1 hour, during which formed off-white solid OS the dock. The reaction mixture was concentrated in vacuo and the residue triturated in hot methanol/water (10 ml, 1:1). The product was collected by filtration and dried in vacuum to obtain specified in the connection header in the form of a solid product is not quite white (1.26 g, 72%). LCMS (Method A): RT=8,28 min, [M+H]+=457.1H NMR (DMSO-d6): 13,20 (1H, s), of 11.61 (1H, s), to 9.93 (1H, s), 7,66 (1H, DD, J=10,32, of 1.95 Hz), 7,46 (1H, d, J=8,81 Hz), 7,42 (1H, DD, J=8,49, of 1.84 Hz), 7,24 (1H, s), 7,01 (1H, d, J=8,78 Hz)6,91 (1H, t, J=8,65 Hz), and 4.68 (1H, s), of 3.85 (2H, DD, J=5,41, 4,48 Hz), of 3.56 (2H, t, J=4,85 Hz).

EXAMPLE 6: (2-hydroxyethoxy)-amide 4-(2-fluoro-4-itfinally)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

Stage 1: (2-vinyloxyethoxy)-amide 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (360 mg, 0.71 mmol), O-(2-vinyloxyethyl)-hydroxylamine (79 mg, 0.77 mmol), HOBt (103 mg, 0.77 mmol), EDCI (147 mg, 0.77 mmol) and DIPEA (130 μl, 0.77 mmol) was dissolved in DMF (10 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2×10 ml). Joint the United organic fraction was washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid product in yellow (346 mg, 81%). LCMS (Method B): RT=4,08 min, [M+H]+=604.

Stage 2: (2-hydroxyethoxy)-amide 4-(2-fluoro-4-itfinally)-1H-pyrazolo[3,4-b]pyridine 5-carboxylic acid

(2 Vinyloxyethoxy)-amide 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (346 mg, or 0.57 mmol) was dissolved in TFU (5 ml) and the reaction mixture was heated at 65°C for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2×10 ml). The combined organic extracts were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-10% methanol in DCM) to obtain specified in the connection header in the form of solid yellow product (75 mg, 30%). LCMS (Method A): RT=6,67 min, [M+H]+=458.1H NMR (DMSO-d6, 400 MHz) 13,51 (1H, s), 11,75 (1H, s), 10,38 (1H, s), to 8.45 (1H, s), 7,80 (1H, DD, J=9,67, to 1.86 Hz), of 7.64-of 7.60 (1H, m), 7,30-7,21 (1H, m), 6,74 (1H, s), 4,71 (1H, s), 3,90 (2H, t, J=4,95 Hz), 3,61-,56 (3H, m).

EXAMPLE 7: ((S)-2-hydroxypropoxy)-amide 4-(2-fluoro-4-itfinally)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

Stage 1: ((S)-2-hydroxypropoxy)-amide 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

To a solution of 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (728 mg, 1.4 mmol), HOBt (228 mg, 1.7 mmol) and EDCI (323 mg, 1.7 mmol) in DMF (15 ml) was added a solution of hydrochloride (S)-1-aminocaproyl-2-ol (200 mg, 1.5 mmol) and DIPEA (596 μl, 3.5 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 3 hours, then was diluted with water (30 ml) and the aqueous layer was extracted with dichloromethane (3×20 ml). The combined organic extracts were filtered through a hydrophobic Frit and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of solid cream-colored product (500 mg, 60%). LCMS (Method B): RT=3,23 min, [M+H]+=592.

Stage 2: ((S)-2-hydroxypropoxy)-amide 4-(2-fluoro-4-itfinally)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

((S)-2-hydroxypropoxy)-amide 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (500 mg, 0.85 mmol) rest rely in TFU (5 ml) and the resulting mixture was heated at a temperature of 65ºC for 3 hours, then concentrated in vacuo. The obtained residue was dissolved in dichloromethane (10 ml) and methanol (2 ml), and then vigorously stirred saturated aqueous sodium bicarbonate (20 ml) for 2 hours. The aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic fractions were filtered through a hydrophobic Frit, then concentrated in vacuo. The obtained residue was purified using a reversible-phase HPLC (gradient 10-95% methanol/water+0,1%formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm) to obtain specified in the connection header in the form of a solid white color (106 mg, 27%). LCMS (Method A): RT=7,19 min, [M+H]+=472.1H NMR (DMSO-d6, 400 MHz) 13,51 (1H, s), 10,37 (1H, s), to 8.45 (1H, s), 7,80 (1H, DD, J=9,68, 1.89 Hz), 7,63-of 7.60 (1H, m), 7,25 (1H, t, J=8,42 Hz), 6,74 (1H, s), 3,88-3,81 (1H, m), of 3.73 at 3.69 (2H, m)of 1.05 (3H, d, J=6,34 Hz).

EXAMPLE 8: (2-hydroxy-1,1-dimethylmethoxy)-amide 4-(2-fluoro-4-itfinally)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

Stage 1: (2-hydroxy-1,1-dimethylmethoxy)-amide 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b|pyridine-5-carboxylic acid

To a solution of 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (737 mg, 1.4 mmol), HOBt (231 mg, 1.7 mmol) and EDCI (327 mg, 1.7 mmol) in DMF (15 ml) was added a solution of the hydrochloride of 2-amino the si-2-methyl-propan-1-ol (280 mg, 2.0 mmol) and DIPEA (603 μl, 3.6 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 3 days, then was diluted with water (30 ml) and the aqueous layer was extracted with dichloromethane (3×20 ml). The combined organic fractions were filtered through a hydrophobic Frit and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of solid yellow product (420 mg, 49%). LCMS (Method B): RT=3,47 min, [M+H]+=606.

Stage 2: (2-hydroxy-1,1-dimethylmethoxy)amide 4-(2-fluoro-4-itfinally)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

(2-Hydroxy-1,1-dimethylmethoxy)-amide 4-(2-fluoro-4-itfinally)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (420 mg, 0.69 mmol) was dissolved in TFU (5 ml) and the reaction mixture was heated at a temperature of 65ºC for 3 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in dichloromethane (10 ml) and methanol (2 ml), then washed with saturated aqueous sodium bicarbonate (3×10 ml). The aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic extracts were filtered through a hydrophobic Frit, then concentrated in vacuo. The obtained residue was purified using reversible phase HPLC (gradient 10-95% methanol/the ode of+0.1%formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm) to obtain specified in the connection header in the form of a solid white (21 mg, 11%). LCMS (Method A): RT=7,71 min, [M+H]+=486.1H NMR (DMSO-d6, 400 MHz) 13,53 (1H, s), 11,20 (1H, s), 10,15 (1H, s), 8,49 (1H, s), 7,80 (1H, d, J=9,68 Hz), 7,63 (1H, d, J=scored 8.38 Hz), 7,25 (1H, t, J=scored 8.38 Hz), 6,70 (1H, s)and 4.65 (1H, s)of 1.17 (6H, s).

EXAMPLE 9: ((R)-2,3-dihydroxy-propoxy)-amide 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid

Stage 1: ((R)-2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)amide 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (150 mg, 0.38 mmol) and O-((R)-2,2-dimethyl-[l,3]dioxolane-4-ylmethyl)-hydroxylamine (83 mg, or 0.57 mmol) in DMF (4 ml) was added EDCI (80 mg, 0.42 mmol), HOBt (56 mg, 0.42 mmol) and DIPEA (70 μl, 0.42 mmol). The reaction mixture was stirred at room temperature for 3.5 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2×10 ml). The combined organic extracts were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-10% methane is in DCM) to obtain the specified title compound in the form of a solid product, pale yellow (135 mg, 68%). LCMS (Method B): RT=3,45 min, [M+H]+=527.

Stage 2: ((R)-2,3-dihydroxy-propoxy)-amide 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid

To a solution of ((R)-2,2-dimethyl-[l,3]dioxolane-4-ylethoxy)-amide 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (135 mg, 0.26 mmol) in methanol (4 ml) was added hydrochloric acid in dioxane (2 ml, 4h, 8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-10% methanol in DCM) to obtain the specified title compound in the form of a solid product is not quite white (94 mg, 75%). LCMS (Method A): RT=to 7.67 min, [M+H]+=487.1H NMR (DMSO-d6, 400 MHz) 13,20 (1H, s), 11,67 (1H, s), 9,94 (1H, s), 7,66 (1H, DD, J=10.30 a.m., with 1.92 Hz), 7,47 (1H, d, J=8,79 Hz), 7,45-7,41 (1H, m), 7,22 (1H, s), 7,01 (1H, d, J=8,78 Hz), 6,92 (1H, t, J=8,64 Hz), 3,92-of 3.85 (1H, m), 3,76-to 3.58 (2H, m), 3,41-and 3.31 (2H, m).

EXAMPLE 10: (2-hydroxy-ethoxy)-amide 4-(4-bromo-2-fluoro-phenylamino)-1H-indazol-5-carboxylic acid

Stage 1: (2-vinyloxy-ethoxy)-amide 4-(4-bromo-2-forgenerating)-1H-indazol-5-carboxylic acid

To a solution of 4-(4-bromo-2-forgenerating)-1H-indazol-5-carboxylic acid (115 mg, 0.33 mmol) and 0-(2-vinyloxy-ethyl)-hydroxylamine (51 mg, 0.49 mmol) in DMF (3 ml) was added EDCI (69 mg, 0.36 mmol), HOBt (49 mg, 0.6 mmol) and DIPEA (61 μl, 0.36 mmol). The reaction mixture was stirred at room temperature for 4 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2×10 ml). The combined organic extracts were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-10% methanol in DCM) to obtain the specified title compound in the form of a solid product, pale yellow (96 mg, 67%). LCMS (Method B): Rτ=3,43 min, [M-H]-=433/435.

Stage 2: (2-hydroxy-ethoxy)-amide 4-(4-bromo-2-fluoro-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of (2-vinyloxy-ethoxy)-amide 4-(4-bromo-2-forgenerating)-1H-indazol-5-carboxylic acid (96 mg, 0.22 mmol) in methanol (5 ml) was added hydrochloric acid (1 ml, 1N, 1 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo. The obtained residue was dissolved in methanol (2 ml) was added a few drops of water, which caused the formation of a precipitate. The product was collected by filtration and dried in vacuum to obtain specified in the connection header product solid not quite white(50 mg, 55%). LCMS (Method A): RT=7,99 min, [M+H]+=409/411.1H NMR (DMSO-d6, 400 MHz) 13,20 (1H, s), of 11.61 (1H, s), for 9.95 (1H, s), 7,58 (1H, DD, J=10,48, 2,24 Hz), 7,47 (1H, d, J=8,77 Hz), 7,29 (1H, DDD, J=8,60, 2,21, of 1.05 Hz), 7.23 percent (1H, s), was 7.08 (1H, t, J=8,81 Hz), 7,01 (1H, d, J=8,81 Hz), 4,68 (1H, s), 3,86 (2H, t, J=4,95 Hz), of 3.56 (3H, s).

EXAMPLE 11: ((S)-2-hydroxy-propoxy)-amide 4-(4-bromo-2-fluoro-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of 4-(4-bromo-2-forgenerating)-1H-indazol-5-carboxylic acid (115 mg, 0.33 mmol) and hydrochloride (S)-1-aminooxy-propan-2-ol (63 mg, 0.49 mmol) in DMF (3 ml) was added EDCI (69 mg, 0.36 mmol), HOBt (49 mg, 0.36 mmol) and DIPEA (150 μl, 0.85 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction was extracted twice with ethyl acetate (2×10 ml). The combined organic fractions were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum. The obtained residue was subjected to preparative reversed-phase HPLC (10-90% acetonitrile/water with 0.1%formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The obtained product was dissolved in ethyl acetate (5 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The aqueous fraction was extracted with dvaid is by ethyl acetate (2×10 ml) and the combined organic layers were washed with saturated saline (20 ml), dried (MgSO4) and concentrated in vacuum to obtain specified in the connection header in the form of a solid white (61 mg, 44%). LCMS (Method A): RT=8,45 min, [M+H]+=423/425.1H NMR (DMSO-d6, 400 MHz) 13,21 (1H, s), 11,63 (1H, s), for 9.90 (1H, s), 7,58 (1H, DD, J=10,47, 2,24 Hz), 7,46 (1H, d, J=8,75 Hz), 7,29 (1H, DDD, J=8,59, 2,19, 1,06 Hz), 7.23 percent (1H, s), was 7.08 (1H, t, J=8,80 Hz), 7,02 (1H, d, J=8,78 Hz), 4,77 (1H, d, J= 4,15 Hz), 3,84-of 3.78 (1H, m), 3,70-3,61 (2H, m)of 1.03 (3H, d, J=6,33 Hz).

EXAMPLE 12: (2-hydroxy-ethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

Stage 1: (2-vinyloxy-ethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid (240 mg, of 0.58 mmol) in THF (6 ml) was added DIPEA (396 μl, 2.34 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (119 mg, 1.15 mmol), HOBt (156 mg, 1.15 mmol) and EDCI (221 mg, 1.15 mmol), then the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resulting residue was distributed between ethyl acetate and water. The organic extract was washed with saturated aqueous sodium bicarbonate solution, then with water, dried (Na2SO4) and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-10% methanol in DCM) with the doctrine stated in the title compound (258 mg, 89%). LCMS (Method B): RT=3,83 min, [M+H]+=500.

Stage 2: (2-hydroxy-ethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

To a suspension of (2-vinyloxy-ethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid (258 mg, 0.52 mmol) in methanol (10 ml) was added hydrochloric acid (1.0 ml, 1M solution, 1.0 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate and saturated aqueous NaHCO3. The organic layer was separated and washed with water, then with saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-SPE, gradient 0-100% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of a solid white color (140 mg, 57%). LCMS (Method A): RT=9,72 min, [M+H]+=474.1H NMR (CD3OD, 400 MHz) to 8.57 (1H, s), 7,71 (1H, d, J=8.53 Hz), 7,69-to 7.61 (1H, m), 7,51 (1H, DD, J=10,43, 1,94 Hz), 7,33 (1H, d, J=8.54 in Hz), to 6.67 (1H, t, J=8,63 Hz)to 3.92 (2H, t, J=4,60 Hz), 3,70 (2H, t, J=4,60 Hz).

Example 13: (2-hydroxy-ethoxy)-amide 4-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-indazol-5-carboxylic acid

Stage 1: (2-vinyloxy-ethoxy)-amide 4-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-methylsulfanyl)-1H-indazol-5-carboxylic acid (85 mg, 0,268 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (33 mg, 0.32 mmol) in DMF (10 ml) was added EDCI (66 mg, 0.32 mmol), HOBt (47 mg, 0.32 mmol) and DIPEA (68 μl, 0.40 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate, then with water, dried (Na2SO4), filtered and concentrated in vacuum. The obtained solid product was subjected to flash chromatography (Si-PPC, gradient of 0-75% ethyl acetate in DCM) to obtain specified in the connection header in the form of a solid reddish-brown (45 mg, 42%). LCMS (Method A): RT=3,40 min, [M+H]+=403.

Stage 2: (2-hydroxy-ethoxy)-amide 4-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-indazol-5-carboxylic acid

A solution of (2-vinyloxy-ethoxy)-amide 4-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-indazol-5-carboxylic acid (45 mg, 0,112 mmol) in methanol (5 ml) was treated with hydrochloric acid (1M, 0,225 ml, 0.22 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in methanol and to this solution was added water, which caused a precipitate, which was filtered. The filtrate was extracted twice atilas what tatom, the combined extracts were dried (Na2SO4), filtered and concentrated in vacuum. The crude product was combined with the previously precipitated solid residue was subjected to flash chromatography (Si-PPC, gradient 0-10% methanol in DCM) to give the solid product. The solid product is triturated in diethyl ether to obtain a solid product pale reddish-brown (23 mg, 55%). LCMS (Method A) RT7,79 [M+H]+377.1H NMR (MeOD, 400 MHz): 7,52-7,44 (1H, m), 7,21-to 7.09 (3H, m), 7,06 (1H, DD, J=to 8.41, 2,08 Hz), 6,93 (1H, d, J=8,88 Hz), of 4.54 (1H, s), as 4.02-3,98 (2H, m in), 3.75 (2H, DD, J=5,28, of 4.05 Hz), 2,48 (3H, s).

EXAMPLE 14: ethoxy-amide 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (100 mg, 0,252 mmol) in DMF (3 ml) were added hydrochloride O-ethylhydroxylamine (37 mg, 0,378 mmol), HOBt (37 mg, 0,277 mmol) and EDCI (53 mg, 0,277 mmol). The reaction mixture was stirred at room temperature for 1 hour, then was added DIPEA (91 μl, 0,529 mmol) and the reaction mixture was stirred at room temperature for 18 hours. In the reaction mixture was added an additional amount, as at the beginning of the reaction, O-ethyl hydroxylamine hydrochloride, HOBt, EDCI and DIPEA and the stirring continued for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate, the solid product, dropped in the mixture, was filtered, washed with water to obtain specified in the title compound (41 mg, 37%). LCMS (Method A): RT=9,65 min, [M+H]+=441.1H NMR (DMSO-d6, 400 MHz): 13,19 (1H, s), 11,51 (1H, s), becomes 9.97 (1H, s), 7,66 (1H, DD, J=10,35, of 1.95 Hz), 7,46 (1H, d, J=8,78 Hz), 7,42 (1H, DD, J=of 8.47, of 1.84 Hz), 7,25 (1H, s), 7,02 (1H, d, J=8,76 Hz)6,91 (1H, t, J=8,66 Hz), 3,86 (2H,, kV, J=? 7.04 baby mortality Hz)and 1.15 (3H, t, J=7.03 is Hz).

EXAMPLE 15: (tetrahydro-Piran-4-yloxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (100 mg, 0,252 mmol) in DMF (3 ml) was added O-(tetrahydro-Piran-4-yl)-hydroxylamine (44 mg, 0,378 mmol), HOBt (37 mg, 0,277 mmol), EDCI (53 mg, 0,277 mmol) and DIPEA (92 μl, 0,529 mmol). The reaction mixture was stirred at room temperature for 70 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate, then with water, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 30-100% ethyl acetate in cyclohexane). The obtained solid product was washed in methanol, the solid product was filtered, washed with methanol to obtain specified in the title compound (33 mg, 26%). LCMS (Method A): RT=9,27 min, [M+H]+=497.1H NMR (DMSO-d6, 400 MHz): 13,19 (1H, s), 11,44 (1H, s), 9,87 (1H,s), the 7.65 (1H, DD, J=10,36, of 1.95 Hz), of 7.48 (1H, d, J=8,77 Hz), 7,44-7,38 (1H, m), 7,28 (1H, s), 7,03 (1H, d, J=8,75 Hz), 6.89 in (1H, t, J=8,66 Hz), was 4.02-3,93 (1H, m), 3,84 is 3.76 (2H, m), 3,36 of 3.28 (2H, m), 1,88-of 1.81 (2H, m,)and 1.51 (2H, dddd, J=12,96, 9,42, 8,75, 4,11 Hz).

EXAMPLE 16: cyclopropylmethoxy-amide 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (70 mg, 0,176 mmol) and O-cyclopropylmethoxy (23 mg, 0.21 mmol) in DMF (3 ml) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μl, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate, then with water, dried (Na2SO4), filtered and concentrated in vacuum. The obtained solid product was ground in a solution of hot methanol/water/NaHCO3the solid product was filtered, washed with water to obtain specified in the connection header in the form of a solid pale pink color (24 mg, 29%). LCMS (Method A): RT=10,42 min, [M+H]+=467.1H NMR (DMSO-d6, 400 MHz) 13,17 (1H, s), to 7.64 (1H, DD, J=10,37, of 1.95 Hz), of 7.48 (1H, d, J=8,76 Hz), 7,42-7,37 (1H, m), 7,26 (1H, d, J=0.95 Hz), 7,01 (1H, DD, J=8,76, 0,99 Hz), 6.87 in (1H, t, J=8,66 Hz), 3,62 (2H, d, J=7,13 Hz), 1,08-1,00 (1H, m), and 0.50 to 0.44 (2H, m), 0,23-0,17 (2H, m).

EXAMPLE 17: methoxime 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic KIS is the notes

To a solution of 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (70 mg, 0,176 mmol) and O-methyl-hydroxylamine (19 mg, 0.21 mmol) in DMF (2 ml) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μl, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate, then with water, dried (Na2SO4), filtered and concentrated in vacuum. The obtained solid product was ground in a solution of hot methanol/water/NaHCO3the solid product was filtered, washed with water to obtain specified in the connection header in the form of a solid pale pink color (33 mg, 44%). LCMS (Method A): RT=a 9.09 min, [M+H]+=427.1H NMR (DMSO-d6, 400 MHz) 13,20 (1H, s), are 11.62 (1H, s), 9,99 (1H, s), 7,66 (1H, DD, J=10,33, 1,94 Hz), 7,46-7,40 (2H, m), 7.23 percent (1H, s), 7,01 (1H, d, J=8,78 Hz), 6,92 (1H, t, J=8,66 Hz)to 3.64 (3 H, s).

EXAMPLE 18: methoxy-methyl-amide 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (70 mg, 0,176 mmol) and N-O-dimethyl-hydroxylamine (21 mg, 0.21 mmol) in DMF (3 ml) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μl, 0.42 mmol). The reaction mixture was stirred at room temperature for the of 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate, then with water, dried (Na2SO4), filtered and concentrated in vacuo and then subjected to the azeotropic distillation with diethyl ether to obtain foam pale-reddish-brown (35 mg, 45%). LCMS (Method A): RT=9,63 min, [M+H]+=441.1H NMR (DMSO-d6, 400 MHz) 13,16 (1H, s), of 8.25 (1H, s), to 7.59-7,51 (2H, m), 7,34-7,28 (2H, m), 7,14 (1H, d, J=8,55 Hz), of 6.71 (1H, t, J=8,73 Hz)to 3.38 (3H, s), 3,10 (3H, s).

EXAMPLE 19: [4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-yl]-(3-hydroxy-azetidin-1-yl)-methanon

To a solution of 4-(2-fluoro-4-itfinally)-1H-indazol-5-carboxylic acid (70 mg, 0,176 mmol) and hydrochloride 3-hydroxyazetidine (23 mg, 0.21 mmol) in DMF (1 ml) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μl, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate, then with water, dried (Na2SO4), filtered and concentrated in vacuum. The resulting residue is triturated in cyclohexane with obtaining specified in the connection header in the form of a solid product pale reddish (39 mg, 49%). LCMS (Method A): RT=8,23 min, [M+H]+=453.1H NMR (DMSO-d6, 400 MHz) 13,17 (1H, s), of 9.55 (1H, is), 7,63 (1H, DD, J=10,47, 1,94 Hz), 7,41-7,37 (1H, m), 7,37 (1H, s), 7,32 (1H, d, J=8,69 Hz), 7,05-7,00 (1H, m), 6,92-PC 6.82 (1H, m), 5,67 (1H, d, J=6,13 Hz), of 4.44-4,37 (1H, m), 4,24 (2H, users), 3,83 (2H, users).

EXAMPLE 20: ((S)-2-hydroxy-propoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid (150 mg, 0,362 mmol), diisopropylethylamine (0.25 ml, 1,45 mmol), HOBt (98 mg, 0,724 mmol) and (S)-1-aminooxy-propan-2-ol (92 mg, 0,724 mmol in DMF (2 ml) was added EDCI (139 mg, 0,724 mmol). The reaction mixture was stirred for 16 hours at room temperature, diluted with ethyl acetate, and washed with water, saturated aqueous sodium bicarbonate, then saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 30%-80% EtOAc in cyclohexane), which gave specified in the title compound as a solid product (45 mg, 26%). LCMS (method A): RT=10,26 min, [M+H]+=488.1H NMR (DMSO-d6, 400 MHz) 11,72 (1H, s), which 9.22 (1H, s), 8,69 (1H, s), 7,86-7,81 (1H, m), of 7.64-of 7.55 (2H, m), 7,30 (1H, DD, J=of 8.47 and 1.83 Hz), 6,63 (1H, t, J=8,72 Hz), to 4.73 (1H, s), 3,76-3,68 (1H, m), 3,53 (2H, d, J=5,78 Hz), 0,99 (3H, d, J=6,33 Hz).

EXAMPLE 21: ((R)-2,3-dihydroxy-propoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

One hundred who ia 1: ((R)-2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

To a solution of 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid (250 mg, 0,604 mmol), diisopropylethylamine (0,42 ml, 2,42 mmol), HOBt (163 mg, 0,1,21 mmol) and O-((R)-2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-hydroxylamine (178 mg, 1,21 mmol) in DMF (2 ml) was added EDCI (232 mg, to 1.21 mmol). The reaction mixture was stirred for 16 hours at room temperature, diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, then saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0%-50% EtOAc in cyclohexane), which gave specified in the title compound as a solid product (142 mg, 43%). LCMS (method B): RT=3,92 min, [M+H]+=544.

Stage 2: ((R)-2,3-dihydroxy-propoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid

To a solution of ((R)-2,2-dimethyl-[l,3]dioxolane-4-ylethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid (142 mg, 0,261 mmol) in MeOH (2 ml) was added 4M solution of HCl in dioxane (2 ml). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The obtained residue was treated with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, in the Doubs, then with a saturated saline solution, dried (Na2SO4), filtered and concentrated in vacuum. The resulting residue is triturated in a mixture of ethyl acetate/cyclohexane gave specified in the title compound as a solid product (73 mg, 56%). LCMS (method A): RT=8,97 min, [M+H]+=504.1H NMR (DMSO-d6, 400 MHz) 11,78 (1H, s), 9.28 are (1H, s)8,64 (1H, s), to 7.84 (1H, DD, J=8,48, 0,92 Hz), of 7.64-EUR 7.57 (2H, m), 7,31 (1H, DD, J=of 8.47 and 1.83 Hz), of 6.65 (1H, t, J=8,71 Hz), 4,80 (1H, s), of 4.54 (1H, s), 3,80 (1H, t, J=6,46 Hz), 3,68-3,61 (2H, m), 3,32 (2H, s).

EXAMPLE 22: ((R)-2,3-dihydroxy-propoxy)-amide 7-(2-fluoro-4-methylsulfanyl-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

Stage 1: ((R)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-amide 7-(2-fluoro-4-methylsulfanyl-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 7-(2-fluoro-4-methylsulfanyl-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (200 mg, of 0.60 mmol) and diisopropylethylamine (0,31 ml of 1.80 mmol) in DMF (2 ml) was added O-((R)-2,2-dimethyl-[l,3]dioxolane-4-ylmethyl)-hydroxylamine (176 mg, 1.20 mmol), EDCI (230 mg, 1.20 mmol) and HOBt (162 mg, 1.20 mmol). The reaction mixture was stirred for 18 hours at room temperature, and then was diluted with ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 50%-100%, Et2O in pentane), which gave specified in the title compound as yellow oil (171 mg, 61%). LCMS (method B): RT=3,85 min, [M+H]+=464.

Stage 2: ((R)-2,3-dihydroxy-propoxy)-amide 7-(2-fluoro-4-methylsulfanyl-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of ((R)-2,2-dimethyl-[l,3]dioxolane-4-ylethoxy)-amide 7-(2-fluoro-4-methylsulfanyl-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (170 mg, of 0.37 mmol) in MeOH (2 ml) was added 1,0M aqueous solution of hydrochloric acid (0,80 ml). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was treated with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0%-100% MeOH in DCM)gave specified in the title compound in the form of solid yellow product (42 mg, 26%). LCMS (Method A): RT=8,80 min, [M+H]+=478.1H NMR (CD3OD) 8,81 (1H, s), 7,63-7,56 (2H, m), 7,12? 7.04 baby mortality (3H, m), 4,10-Android 4.04 (1H, m), 3,98-3,86 (2H, m), 3,64-3,55 (2H, m)of 2.50 (3H, s).

EXAMPLE 23: ((R)-2,3-dihydroxy-propoxy)-amide 7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

Stage 1: ((R)-2,3-dihydroxy-propoxy)-amide 7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (155 mg, 0.47 mmol) and diisopropylethylamine (0.10 ml, 0.61 mmol) in DMF (5 ml) was added O-((R)-2,2-dimethyl-[l,3]dioxolane-4-ylmethyl)-hydroxylamine (97 mg, 0.66 mmol), EDCI (117 mg, 0.61 mmol) and HOBt (83 mg, 0.61 mmol). The reaction mixture was stirred for 2 hours at room temperature, diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, then saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was treated with MeOH (10 ml) was added a 4.0 M solution of hydrochloric acid in dioxane (1.0 ml). The reaction mixture was stirred at room temperature for 1 h, then was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The obtained residue was subjected to reversed phase HPLC (Gemini 5 micron C18250×21,20 mm column with 0.1%formic acid, gradient acetonitrile/water, 15-95%, the ramp time 20 minutes), which gave specified in the title compound in the form of a solid product W is logo color (115 mg, 59%). LCMS (method A): RT=9,02 min, [M+H]+=418.1H NMR (DMSO-d6, 400 MHz) 9,98 (1H, s), 8,97 (1H, s), 7,72 (1H, s), to 7.61 (1H, d, J=8.35 Hz), 7,09-of 6.90 (3H, m), of 3.95 (1H, DD, J=9,94, 3,81 Hz), with 3.79 (2H, d, J=16,92 Hz), 3,40 (2H, d, J=5,46 Hz), 2,03-of 1.94 (1H, m), 1,03 is-0.97 (2H, m,), 0,77 is 0.71 (2H, m).

EXAMPLE 24: ((R)-2,3-dihydroxy-propoxy)-amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

Stage 1: ((R)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 7-(4-bromo-2-fluorescent-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (584 mg, of 1.59 mmol) and diisopropylethylamine (of 0.82 ml, 4.77 mmol) in DMF (6 ml) was added O-((R)-2,2-dimethyl-[l,3]dioxolane-4-ylmethyl)-hydroxylamine (468 mg, 3,18 mmol), EDCI (611 mg, 3,18 mmol) and HOBt (430 mg, 3,18 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, then saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 50%-100%, TBME in cyclohexane), which gave specified in the title compound as yellow oil (370 mg, 47%). LCMS (method B): RT=3,96 min, [M+H]+=496/498.

Stage 2: ((R)-2,3-dihydroxy-propoxy)amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of ((R)-2,2-dimethyl-[l,3]dioxolane-4-ylethoxy)-amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (370 mg, 0.75 mmol) in MeOH (4 ml) was added 1,0M aqueous solution of hydrochloric acid (1.50 ml). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The obtained residue was treated with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, MeOH in DCM)gave specified in the title compound as yellow solid product color (242 mg, 71%). LCMS (method A): RT=8,80 min, [M+H]+=456/458.1H NMR (CD3OD, 400 MHz) 8,87 (1H, s), 7,76-of 7.70 (1H, m), to 7.61 (1H, d, J=at 8.36 Hz), 7,42 and 7.36 (1H, m), 7,30-of 7.25 (1H, m), to 6.95 (1H, t, J=8,66 Hz)4,06 (1H, DD, J=10,08, 3.55 Hz), 3.96 points-a 3.83 (2H, m), 3,64-of 3.54 (2H, m).

EXAMPLE 25: (2-hydroxy-ethoxy)-amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

Stage 1: (2-vinyloxyethoxy)-amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (210 mg, or 0.57 mmol) and diisopropylethylamine (0,29 ml, 1,71 mmol) in DMF (2 ml) was added O-(2-Winnie the hydroxy-ethyl)-hydroxylamine (117 mg, to 1.14 mmol), EDCI (220 mg, to 1.14 mmol) and HOBt (154 mg, to 1.14 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, then saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0%-100%, TBME in cyclohexane), which gave specified in the title compound as yellow oil (95 mg, 37%). LCMS (method B): RT=3,90 min, [M+H]+=452/454.

Stage 2: (2-hydroxy-ethoxy)-amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of (2-vinyloxy-ethoxy)-amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (95 mg, 0.21 mmol) in MeOH (4 ml) was added 1,0M aqueous solution of hydrochloric acid (0,42 ml). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The obtained residue was treated with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0%-100% ethyl acetate in DCM), which gave specified in the title compound in the form of a solid product is altago colors (62 mg, 70%). LCMS (method A): RT=9,51 min, [M+H]+=426/428.1H NMR (CDCl3,400 MHz) 9,37 (1H, s), cent to 8.85 (1H, s), 8,76 (1H, s), 7,51 (1H, d, J=8,40 Hz), the 7.43 (1H, d, J=8,40 Hz), 7,34-7,29 (1H, m), 7,28 (1H, d, J=8,75 Hz), 7,02 (1H, t, J=8,46 Hz), 4,10 (2H, t, J=4.09 to Hz), 3,91 (1H, s), of 3.80 (2H, s).

EXAMPLE 26; (2-hydroxy-ethoxy)-amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

Stage 1: (2-vinyloxy-ethoxy)-amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (328 mg, of 0.79 mmol) and diisopropylethylamine (0,41 ml, is 2.37 mmol) in DMF (2 ml) was added O-(2-vinyloxy-ethyl)-hydroxylamine (163 mg, was 1.58 mmol), EDCI (303 mg, was 1.58 mmol) and HOBt (213 mg, was 1.58 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate and washed with water, then saturated aqueous sodium bicarbonate, then saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0%-100%, TBME in cyclohexane), which gave specified in the title compound as yellow foam (194 mg, 49%). LCMS (method B): RT=3,99 min, [M+H]+=500.

Stage 2: (2-hydroxy-ethoxy)-amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic to the slots

To a solution of (2-vinyloxy-ethoxy)-amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (187 mg, and 0.37 mmol) in MeOH (4 ml) was added a 1.0 M aqueous solution of hydrochloric acid (0.75 ml). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The obtained residue was treated with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%ethyl acetate in DCM), which gave specified in the title compound in the form of solid yellow product (128 mg, 72%). LCMS (method A): RT=9,81 min, [M+H]+=474.1H NMR (CDCl3, 400 MHz) was 9.33 (1H, s), 8,86 (1H, s), 8,77 (1H, s), 7,55-7,40 (4H, m), at 6.84 (1H, t, J=8,30 Hz), 4,10 (2H, t, J=4,16 Hz), 3,91 (1H, t, J=6,45 Hz), 3,80 (2H, t, J=4,55 Hz).

EXAMPLE 27; ((R)-2,3-dihydroxy-propoxy)amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

Stage 1: ((R)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (377 mg, of 0.91 mmol) and diisopropylethylamine (of 0.47 ml, 2,73 mmol) in DMF (4 ml) was added O-((R)-2,2-dime the Il-[l,3]dioxolane-4-ylmethyl)-hydroxylamine (268 mg, 1.82 mmol), EDCI (349 mg, 1.82 mmol) and HOBt (246 mg, 1.82 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, then saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%TBME in cyclohexane), which gave specified in the title compound in the form of solid yellow product (266 mg, 54%). LCMS (method B): RT=4,04 min, [M+H]+=544.

Stage 2: ((R)-2,3-dihydroxy-propoxy)amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid

To a solution of ((R)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid (263 mg, 0.48 mmol) in MeOH (10 ml) was added a 1.0 M aqueous solution of hydrochloric acid (0,97 ml). The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The obtained residue was treated with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated salt solution, dried (Na2SO4), filtered and evaporated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%ethyl acetate in DCM), which gave specified the title compound in the form of solid yellow product (127 mg, 53%). LCMS (method A): RT=9,05 min, [M+H]+=504.1H NMR (CD3OD, 400 MHz) 8,88 (1H, s), 7,74 (1H, d, J=at 8.36 Hz), to 7.61 (1H, d, J=8.35 Hz), 7,53 (1H, DD, J=10,01, 1,93 Hz), 7,44 (1H, DDD, J=at 8.36, 1,93, 1,06 Hz), 6,76 (1H, t, J=8.53 Hz), of 4.05 (1H, DD, J=there is a 10.03, 3,50 Hz), 3.96 points-a 3.83 (2H, m), 3,63-to 3.52 (2H, m).

EXAMPLE 28: [4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-yl]-amide cyclopropanemethanol acid

Step 1: tert-butyl ether 5-cyclopropanemethylamine-4-(2-fluoro-4-iodine-phenylamino)-indazol-1-carboxylic acid

To a solution of tert-butyl ester 5-amino-4-(2-fluoro-4-iodine-phenylamino)-indazol-1-carboxylic acid (200 mg, 0.43 mmol) in pyridine (2 ml) was added cyclopropanesulfonyl chloride (0,218 ml, 2.14 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated, washed with saturated saline, then was dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was subjected to flash chromatography (Si-PPC, gradient 10-35% ethyl acetate in cyclohexane) to obtain the specified title compound (206 mg, 84%). LCMS (Method B): RT=4,17 min, [MH]+= 573.

Stage 2: [4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-yl]-amide cyclopropanemethanol acid

To a solution of tert-butyl EPE is a 5-cyclopropanemethylamine-4-(2-fluoro-4-iodine-phenylamino)-indazol-1-carboxylic acid (206 mg, 0.36 mmol) in DCM (8 ml) was added TFU (1 ml) and the reaction mixture was stirred at room temperature for 2 hours. Added additional amount TFU (1 ml) and stirring continued for 1 hour, then the reaction mixture was concentrated in vacuo and the residue was subjected to the azeotropic distillation with DCM, methanol and then DCM. The resulting residue is triturated in diethyl ether, the solid product was filtered and dried in vacuum at 40ºC with obtaining specified in the connection header in the form of solid yellow product (83 mg, 49%). LCMS (Method A): RT=there is a 10.03 [M+H]+=437,1H NMR (DMSO-d6, 400 MHz): 13,14 (1H, s), 9,07 (1H, s), 7,80 (1H, s), EUR 7.57 (1H, DD, J=10,84, a 1.96 Hz), 7,39 (1H, s), 7,31 (1H, d, J=a total of 8.74 Hz), 7,25-7,20 (2H, m), of 6.45 (1H, t, J=8,84 Hz), 2,40 of-2.32 (1H, m), 0.75 to 0,62 (4H, m)-0,05 (1H, t, J=3,33 Hz).

EXAMPLE 29; [4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-1H-indazol-5-yl]-amide cyclopropanemethanol acid

Step 1: tert-butyl ether 5-cyclopropanemethylamine-4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-indazol-1-carboxylic acid

To a solution of tert-butyl ester 5-amino-4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-indazol-1-carboxylic acid (200 mg, 0,401 mmol) in pyridine (2 ml) was added cyclopropanesulfonyl chloride (281 mg, 2.0 mmol) and the reaction mixture was stirred at room temperature for 18 chaison the mixture was treated with water and was extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuo to obtain an oily residue. The residue was subjected to flash chromatography (Si-PPC, gradient 0 to 25% ethyl acetate in cyclohexane) to obtain specified in the connection header in the form of foam is not quite white (217 mg, 89%). LCMS (Method B) RT=4,16 min, [M+H]+=603.

Stage 2: [4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-1H-indazol-5-yl]-amide cyclopropanemethanol acid

A solution of tert-butyl ester 5-cyclopropanemethylamine-4-(2-fluoro-4-iodine-phenylamino)-6-methoxy-indazol-1-carboxylic acid (217 mg, 0.36 mmol) in DCM (5 ml) was treated with TFU (2 ml) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated in Dyatlovo live with obtaining specified in the connection header in the form of a solid product is not quite white (102 mg, 52 %). LCMS (method A): RT=10,17 [M+H]+=503.1H NMR (DMSO-d6, 400 MHz): 12,92 (1H, s), 8,72 (1H, s), 7,60-7,52 (2H, m), 7,34-7,24 (2H, m), of 6.71 (1H, s), 6,53 (1H, t, J=8,80 Hz), of 3.84 (3H, s), 2,53 is 2.46 (1H, m), 0,84-to 0.73 (2H, m), 0,72-0,66 (2H, m).

1. The compound of formula I and II:

or its pharmaceutically acceptable salt, where:
Z1represents NR1or S;
R1represents H;
R1'our opinion is t H a;
Z2represents CR2or N;
Z3represents CR3;
R2and R3represent H;
R4represents N or C1-C6alkyl;
Y W represents-C(O)-;
W represents
R5represents H or C1-C12alkyl;
X1selected from R11'and-OR11';
R11represents H, C1-C12alkyl or tetrahydropyran-4-yl;
or R11'and R5together with the nitrogen to which they are attached, represent azetidin, substituted hydroxyl group;
R6represents halogen, C3-C5cycloalkyl or -(CR19R20)nSR16;
R6'is a halogen;
p is 1;
n is 0, 1, 2 or 3;
the specified alkyl, R11'optionally substituted -(CR19R20)nOR16or R21;
R16represents H or C1-C12alkyl;
R19and R20represent H;
R21represents a C3-C5-cycloalkyl.

2. The compound according to claim 1, where Z2represents N and Z3represents CR3.

3. The compound according to claim 1, where Z2represents CR2and Z3represents CR3.

4. The compound according to claim 2 or 3, where Z1is NR 1.

5. The compound according to claim 2 or 3, where Z1represents S.

6. The compound according to claim 4, where X1chosen from:


7. The connection according to claim 6, where R6selected from halogen, -SR16C3-C4carbocycle.

8. The connection according to claim 7, where R6represents I, Br, -SMe, C3carbocyclic.

9. The connection of claim 8, where R6'represents F or Cl.

10. The connection according to claim 7, where R4represents H or methyl.

11. The connection of claim 10, where R4represents H.

12. The connection of claim 10, where R5represents H or methyl.

13. The connection section 12, where R5represents H.

14. The compound according to claim 1, selected from the group consisting of
(2 hydroxyethoxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid;
(2 hydroxyethoxy)-amide 4-(2-fluoro-4-ilfenomeno)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid;
((S)-2-hydroxypropoxy)-amide 4-(2-fluoro-4-ilfenomeno)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid;
(2-hydroxy-1,1-dimethylmethoxy)-amide 4-(2-fluoro-4-ilfenomeno)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid;
((R)-2,3-dihydroxy-propoxy)-amide 4-(2-fluoro-4-ilfenomeno)-1H-indazol-5-carboxylic acid;
(2 hydroxyethoxy)-amide 4-(4-bromo-2-fluoro-phenylamino)-1H-indazol-5-carboxylic what Islami;
((S)-2-hydroxypropoxy)-amide 4-(4-bromo-2-fluoro-phenylamino)-1H-indazol-5-carboxylic acid;
(2 hydroxyethoxy)-amide-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid;
(2 hydroxyethoxy)-amide 4-(2-fluoro-4-methylsulfonylamino)-1H-indazol-5-carboxylic acid;
toxemia 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid;
(tetrahydropyran-4-yloxy)-amide 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid;
cyclopropylmethoxy 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid;
methoxyamine 4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-carboxylic acid;
[4-(2-fluoro-4-iodine-phenylamino)-1H-indazol-5-yl]-(3-hydroxy-azetidin-1-yl)-methanone;
4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid ((S)-2-hydroxypropoxy)-amide;
((R)-2,3-dihydroxypropane)amide 4-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-5-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 7-(2-fluoro-4-methylsulfonylamino)-benzo[d]isothiazol-6-carboxylic acid;
((R)-2,3-dihydroxy-propoxy)amide 7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid;
(2 hydroxyethoxy)amide 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazol-6-carboxylic acid;
(2 hydroxyethoxy)amide 7-(2-fluoro-4-itfinally is)benzo[d]isothiazol-6-carboxylic acid; and
((R)-2,3-dihydroxypropane)amide 7-(2-fluoro-4-iodine-phenylamino)-benzo[d]isothiazol-6-carboxylic acid; or
its pharmaceutically acceptable salt.

15. Pharmaceutical composition for treating hyperproliferative disorders or inflammatory diseases in a mammal containing a therapeutically effective amount of a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier.

16. Method of inhibiting abnormal cell growth or treating a hyperproliferative disorders in a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition according to item 15.

17. A method of treating inflammatory disease in a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition according to item 15.

18. The use of the pharmaceutical composition according to item 15 in the preparation of a medicine for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal.

19. The use of the pharmaceutical composition according to item 15 in the preparation of medicines for the treatment of inflammatory diseases in a mammal.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

Antiviral compounds // 2505540

FIELD: biotechnologies.

SUBSTANCE: invention pertains to new compounds that have the properties of HCV virus replication inhibitor. In expression I: , A1 is C6aryl, substituted by -X1-R7; X1 is -S-; R7 is C6aryl, not necessarily substituted by one RA; Z1 is -N(RB)-; each of W1 and W2 is N; R1 is hydrogen; R3 and R4 together with carbon atoms, to which they are connected, form 6-member heterocyclic ring containing N as heteroatom, where 6-member heterocyclic ring is not necessary substituted by one RA; A2 represents C6aryl or 5-member heterocyclyl containing N as heteroatom; R2 represents -N(Rb)C(O)C(R5R6)N(R8)-T-Rd, or -LK-B; R6 and R8 together with atoms, to which they are connected, form 5-member heterocyclic ring; the values of radicals RA, R5, T, RC, RD, RD' and RD", LK, B are given in the invention's expression. Invention also pertains to pharmaceutical composition containing the said compounds, method for inhibiting HCV virus replication, method for HCV infection curing and method for obtaining the said compounds.

EFFECT: improving compound application efficiency.

25 cl, 6 tbl, 18 ex

Antiviral compounds // 2505539

FIELD: chemistry.

SUBSTANCE: in formula III:

,

each of X1 and X2 is independently selected from a bond, -CH2-, -O- or -S- and at least one of X1 and X2 is selected from -CH2-, -O- or -S-; each of R7 and R8 is independently selected from hydrogen or C6aryl, optionally substituted with one or more Ra and at least one of R7 and R8 is selected from C6aryl, optionally substituted with one or more Ra; each of Z1 and Z2 is selected from -N(RB)-, each of W1, W2, W3, W4, W5, W6, W7 and W8 is independently selected from N or C(Rd), where Rd in each case is selected from hydrogen; each of R1, R2, R9, R11, R12, R14, R15 and R16 in each case is independently selected from hydrogen or Ra; each of m and n is 0; Ra in each case is independently selected from halogen, hydroxy group, amino group, -LA and -Ls-Re; La in each case is selected from C1-C6-alkyl; values of radicals T, Rb, Rb', Re are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, a method of inhibiting HCV replication, a method of treating HCV infection and a method of producing said compounds.

EFFECT: high efficiency of using compounds.

7 cl, 6 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of novel pyrrolopyrazine derivatives of formula , where variables Q and R are as defined in the claim, which inhibit JAK and SYK.

EFFECT: high effectiveness when treating autoimmune and inflammatory diseases.

11 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to 7-benzoyl-8-hydroxy-6-phenyl-9-(3-phenyl-2-quinoxalinyl)-10H-pyrido[1,2-a]quinoxalin-10-one of formula (1)

EFFECT: obtaining a novel compound which can be used in medicine as a drug having analgesic activity.

3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel imidazopyridine or imidazopyrimidine derivatives of formula (I) and to pharmaceutically acceptable salts and esters thereof, where A is N or C(R6); R1 is hydrogen, lower alkyl; R2 is halogen, C(O)NR7R8 or C(O)OR9; R3 is hydrogen, NR10R11; R4 is hydrogen, lower alkyl; R5 is phenyl or thiazolyl or pyridine, which can be substituted with one substitute independently selected from a group consisting of halogen; R6 is hydrogen, halogen, CN, C3-C6cycloalkyl; R7 and R8 are independently selected from a group consisting of hydrogen, lower alkyl, lower alkoxy-lower alkyl, fluoro-lower alkyl, C3-C6cycloalkyl, N(H,lower alkyl)-lower alkyl, hydroxy- lower alkyl, hydroxy-lower alkoxy- lower alkyl, N(lower alkyl2)C(O)- lower alkyl, lower alkoxy, hydroxy-lower alkyl-oxetanyl- lower alkyl, oxo-tetrahydrofuranyl, tetrahydrofuranyl-lower alkyl, hydroxy-fluoro-lower alkyl, tetrahydrofuranyl, phenyl and thiazolyl or pyridine, or R7 and R8 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of pyrrolidinyl, azetidinyl, morpholinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, 3,4-dihydro- 1H-pyrrolo[1,2-a]pyrazinyl, 2-oxa-6-aza-spiro[3.3]heptyl, 5,6-dihydro- 8H-imidazo[1,2-a]pyrazinyl, [1,4]oxazepanyl, piperazinyl, thiomorpholinyl and 2-oxa-5-aza-bicyclo[2.2.1]heptyl, where the heterocyclyl is optionally substituted with 1 or 2 substitutes independently selected from a group consisting of halogen, lower alkyl, lower alkyl-C(O), lower alkoxy-lower alkyl, oxo, hydroxy, hydroxy-lower alkyl, N(lower alkyl2); R9 is lower alkyl; R10 and R11 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of piperidinyl, morpholinyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treating said pathological conditions and use of the compound of formula (I).

EFFECT: obtaining novel imidazopyridine or imidazopyrimidine derivatives which are PDE10A inhibitors.

24 cl, 94 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to pyrazolo[3,4-b]pyridine compounds and a method for production thereof. Described are 2-(6-aryl-4-aroyl-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-oxo-N-arylacetamides of formula ,

where Ar1=Ph, C6H4Me-4; Ar2=Ph, C6H4Me-4, C6H4Br-4, and a method for production thereof by boiling 1-aryl-4,5-diaroyl-1H-pyrrole-2,3-diones with 5-amino-3-methyl-1-phenyl-1H-pyrazole in a medium of inert aprotic solvent.

EFFECT: obtaining novel compounds which can be used as primary products for synthesis of novel heterocyclic systems and in pharmacology as potential medicinal agents with analgesic activity.

4 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted 4-aminocyclohexane derivatives of general formula I: where: R1 and R2 independently denote C1-3-alkyl, H or R1 and R2 together with an N tom form a (CH2)3, (CH2)4 ring; R3 optionally denotes a phenyl or thienyl linked through a C1-3-alkyl chain, each unsubstituted; or an unsubstituted C1-6-alkyl; R4 denotes indole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, optionally mono- or multi-substituted with a substitute selected from a group comprising F, CI, Br, CN, CH3, C2H5,' NH2, tert-butyl, Si(ethyl)3, Si(methyl)2(tert-butyl), SO2CH3, SO2-phenyl, C(O)CH3, NO2, SH, CF3, OCF3, OH, OCH3, OC2H5, N(CH3)2; in form of a racemate; enantiomers, diastereomers, mixtures of enantiomers or diastereomers or separately an enantiomer or diastereomers; bases and/or salts of physiologically compatible acids or cations; as well as a drug based on compounds I for treating neuropathic pain.

EFFECT: improved properties.

14 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of formula I: or salts thereof, where: A1 denotes hydrogen, CN, CI, F, Br, OMe, (1-4C alkyl) or cyclopropyl; A2 denotes hydrogen, Cl, Br, F, (1-4C alkyl) or cyclopropyl; W denotes -C(=O)NR1- or -NR2C(=O)-; each of R1 and R2 denotes hydrogen or methyl; L denotes a chemical bond, -(CR3R4)n-(CRaRb)m-(CR5R6)-*, (2-4C)alkenylene, -O(1-4C alkyl)-*, -(1-4C alkyl)-O-*, -(1-4C alkyl)-S-*, (3-6C)cycloalkylene or hetCyc1, where the symbol "*" indicates the binding position of G, under the condition that if W denotes -C(=O)NR2-, then L is not -(CH=CH)-; m equals 0, 1 or 2; n equals 0 or 1; Ra and Rb are independently selected from hydrogen and (1-4C alkyl); R3 denotes hydrogen, (1-4C alkyl) or CH2OH; R4 denotes hydrogen or methyl; R5 denotes hydrogen, (1-4C alkyl), OH, -O(1-4C alkyl) or F; R6 denotes hydrogen, F or methyl; or R5 and R6 together with the carbon atom with which they are bonded form a cyclopropyl ring, hetCyc1 denotes a group of formula where t equals 1 or 2 and p equals 0 or 1, and the symbol "*" indicates the position of binding with G; G denotes Ar1, Ar2, naphthyl, benzo-condensed (5-6C)cycloalkyl ring, optionally substituted with one or more substitutes independently selected from Cl and OMe, benzo-condensed 5-6-member heterocyclic ring with 1-2 heteroatoms independently selected from O and N, (3-6C)cycloalkyl ring, optionally substituted with one or more substitutes independently selected from (1-4C)alkyl, oxaspirononanyl ring or t-butyl; Ar1 denotes phenyl, optionally substituted with one or more substitutes independently selected from F, Cl, Br, CF3, (1-4C)alkyl, OH, -O(1-4C alkyl), -S(1-3C alkyl), -SCF3, cyclopropyl, -CH2N(1-3C alkyl)2, -O-(2-3C)fluoroalkyl, -O-(1-3C)difluoroalkyl-O-(1-3C)trifluoroalkyl, -OCH2(cyclopropyl) and (3-4C)alkynyl; Ar2 denotes phenyl, substituted with Ar3, -O-Ar4, hetAr1 or -O-hetAr2, where Ar2 is further optionally substituted with one or more substitutes independently selected from F, O or CF3; Ar3 denotes phenyl, optionally substituted with one or more substitutes independently selected from F, CI, Br and (1-4C alkyl); Ar4 denotes phenyl, optionally substituted with one or more substitutes independently selected from F, CI, Br and (1-4C alkyl); hetAr1 denotes a 6-member heteroaryl with 1-2 nitrogen atoms, optionally substituted with one or more substitutes independently selected from (1-4C alkyl); hetAr2 denotes a 6-member heteroaryl with 1-2 nitrogen atoms, optionally substituted with one or more substitutes independently selected from (1-4C alkyl) and CF3; R7a, R7 and R8 each independently denotes hydrogen or methyl; R9 denotes hydrogen, methyl, fluorine or NO2; and R10 denotes hydrogen, methyl or fluorine; where A1, A2, W, L, G, R7a, R7b, R8, R9 and R10 assume values given in the description, which are DP2 receptor modulators which are effective in treating immunological diseases.

EFFECT: inventions relate to a method of producing compounds of formula 1, a pharmaceutical composition based on said compounds and a method of treatment.

30 cl, 1 tbl, 239 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel quinazolina derivatives, which have benzofurane substituent of formula: in which each of R1, R2, R5, R8, R9 and R10 represent H, R3 and R4 similarly represent alkoxy or methoxyethoxy group; R6 represents alkyl; R7 represents-C(O)NRaRb, and each of Ra and Rb independently represents H, alkyl, ethyl, substituted with diethylaminogroup, C3-C6cycloalkyl, or Ra and Rb together form cycloalkyl; Z represents N; X represents O, S or NR, where R represents H or alkyl.

EFFECT: invention relates to pharmaceutical composition, inhibiting KDR, based on said compounds, method of treating associated with angiogenesis disorder, representing cancer, age-related macular degeneration or chronic inflammatory disease, and method of inhibiting activity of growth factor of vessel endothelium.

18 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I and formula IV wherein the radical values are such as specified in cl. 1 and 4 of the patent claim, as well as to their therapeutically acceptable salts. Besides, the invention refers to a composition for treating cancer on the basis of the compounds of formula I, to using the compounds of formula I for preparing the therapeutic agent for treating cancer, as well as to using it for treating cancer.

EFFECT: there are prepared and described the new compounds which inhibit anti-apoptotic Bcl-2 and Bcl-x protein activity.

17 cl, 481 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new uracil derivatives possessing human dUTPase inhibitory activity. In formula (I) n is equal to an integer 1 to 3; X member a bond, an oxygen atom, a sulphur atom, an alkenyl group containing 2 to 6 carbon atoms, a bivalent aromatic hydrocarbon group containing 6 to 14 carbon atoms, or a bivalent 5-7-merous saturated or unsaturated heterocyclic group containing 1 nitrogen or sulphur atom; Y means a bond or a linear or branched alkylene group containing 1 to 8 carbon atoms optionally having a cycloalkylydene structure containing 3 to 6 carbon atoms on one carbon atom; and Z means -SO2NR1R2 or -NR3SO2-R4, wherein R4 means an aromatic hydrocarbon group containing 6 to 14 carbon atoms which is optionally substituted by 1-2 substitutes, or an unsaturated 5-7-member heterocyclic group containing 1 nitrogen or sulphur atom which is optionally substituted by 1-2 halogen atoms; the radical values R1, R2 and the substitutes of the group R4 are presented in the patent claim.

EFFECT: invention relates to a pharmaceutical compositions comprising said compounds, to a human dUTPase inhibitor and a method of treating a human dUTPase-associated disease.

10 cl, 85 tbl, 179 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a method for preparing an immobilised 1,2-benzisothiazolin-3-one complex, an antimicrobial composition containing it and to using the above composition as an antimicrobial agent. The immobilised 1,2-benzisothiazolin-3-one is prepared by heating 1,2-benzisothiazolin-3-one and zinc chloride brought to the boiling point with partial condensation in C1-C4 alcohol to prepare a solution to be cooled and added with the immobilising effective amount of zinc oxide. The prepared mixture is brought to the boiling point with partial condensation, cooled to room temperature and filtered to prepare the immobilised 1,2 - benzisothiazolin-3-one/zinc oxide complex.

EFFECT: declared inventions provide producing the antimicrobial immobilised 1,2 - benzisothiazolin-3-one/zinc oxide complexes applicable as preserving agents due to their wash-out resistance.

12 cl, 4 dwg, 2 tbl, 22 ex

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