Azaindolizines and methods for preparing them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel azoindolizines or pharmaceutically acceptable salts thereof having Mek-kinase inhibitory activity in formula : ZA means CRA; RA means H or halogen; each of R1, R2 and R3 means H; W means: , each R4 and R5 means H; X1 represents -OR7; each R7 means C2-C12-hydroxyalkyl, 2,3-dihydroxypropyl, C2-C3-alkenoxyC1-C6-alkoxy, (2,2-dimethyl-[1,3]dioxalan-4-yl)-methyl or piperidinyl; X4 means: R6 means halogen or -SR16; R6 means halogen; p is equal to 1; R16 means C1-C12-alkyl.

EFFECT: invention relates to a pharmaceutical compositions containing these compounds, to a method of inhibiting the abnormal cell growth and the use of the compounds for preparing a drug preparation for inhibiting the abnormal cell growth.

9 cl, 10 ex

 

Cross-reference to related applications

This application claims priority based on provisional application for U.S. patent number 61/015942, filed December 21, 2007, the contents of which in its entirety is included in this description by reference.

The technical field to which the invention relates.

The present invention relates to azaindolizines with anticancer activity and, more specifically, to azaindolizines that inhibit the activity of MEK kinase. The present 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.

Background of invention

In the quest to understand how Ras transmits extracellular signals to growth, the path of the MAR(mitogen-activated protein)kinase (MARK) appears as a very important path between related Ras membrane and the nucleus. The way MARK covers a cascade of phosphorylation events, including three key kinases, namely Raf, MEK (kinase MAR-kinase) and ERK (MAP-kinase). Active, GTP-bound Ras leads to activation and indirect phosphorylation of Raf-kinase. Then Raf phosphorylates MEK and MEK on two serine residues (S218 and S222 for MAC and S222 and S226 for MAC) (Ahn et. al., Methods in Enzymology, 2001, 332, 417-431). Activated MEK then phosphorylates t is like its known substrates, MAR-kinases, ERK1 and ERK2. ERK - phosphorylation by MEK occurs Y204 and T202 in the case of ERK1 and Y185 and T183 if 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, Assembly, and translocation of nucleosomes and the processing and translation of mRNA (Ahn et. al., Molecular Cell, 2000, 6, 1343-1354). Everywhere, treatment of cells with growth factors leads to activation of ERK1 and ERK2, which results in proliferation and, in some cases, the differentiation (Lewis et. al., Adv. Cancer Res., 1998, 74, 49-139).

It was conclusively proven that genetic mutations and/or overexpression of its protein kinases involved in the path MAR-kinase, leading to uncontrolled cell proliferation and, ultimately, to the formation of tumors in proliferative diseases. For example, some cancer include mutations that result in continuous activation of this pathway due to the continuous production of growth factors. Other mutations can lead to defects in the deactivation of the activated complex of GTP-bound Ras, again leading to activation path MAR-kinase. Mutated oncogenic forms of Ras calc the us in the case of 50% of cancers of the colon and > 90% of cancers of the pancreas, as well as many other types of cancer (Kohl et. al., Science, 1993, 260, 1834-1837). Recently a skin disease mutations identified in the case of more than 60%, malignant melanoma (Davies H., et. al., Nature, 2002, 417, 949-954). These mutations in skin disease result in constitutive active cascade MAR-kinase. Studying samples of primary tumors and cell lines also indicate a constitutive or an overactive path MAR-kinase in cancer of the pancreas, colon, lung, ovary and kidney (R. Hoshino, et. al., Oncogene, 1999, 18, 813-822).

MEK appears as an attractive therapeutic target in case the path MAR-kinase cascade. MEK below Ras and Raf during transcription, is a very specific phosphorylation MAR-kinase; indeed, the only known substrates for phosphorylation of MEK are MAR-kinases, ERK1 and ERK2. It was shown that inhibition of MEK brings potential therapeutic benefit in some studies. For example, it is shown that small molecule inhibitors of MEK inhibit the growth of human tumor xenografts "Nude" mice (Sebolt-Leopold et. al., Nature Medicine, 1999, 5 (7), 810-816); Trachet et. al., AACR, 6-10 April, 2002, abstract No. 5426; Tecle, H., IBC 2.sup.nd International Conference of Protein Kinases, 9-10 September, 2002), block static allodynia in animals (WO 01/05390 published 25 January the OC 2001) and inhibit the growth of cells in acute myeloid leukemia (Milella et. al., J. Clin. Invest., 2001, 108 (6), 851-859).

Some small molecule inhibitors of MEK was also discussed, for example, in WO 02/06213, WO 03/077855 and WO 03/077914. However, there is a need for new inhibitors of MEK as an effective and safe therapeutic agents for the treatment of a variety of statuses proliferative diseases, such as conditions associated with hyperactivity of MEK, as well as diseases modulated by the MEK cascade.

Summary of the invention

This invention generally relates to azaindolizines formula I-a or I-b (and/or their solvate, hydrates and/or salts) with anticancer and/or anti-inflammatory activity and more specifically with inhibiting MEK-kinase activity. Some of hyperproliferative and inflammatory disorders are characterized by a modulation function MEK kinase, for example, by mutations or overexpression of proteins. Therefore, compounds according to this invention and containing compositions suitable for the treatment of hyperproliferative disorders such as cancer and/or inflammatory diseases such as rheumatoid arthritis.

where

ZAmean CRAor N;

RAmeans N, CF3, halogen, C1-C6-alkyl or CN;

each of R1, R2and R3independently mean H, C1-C6-lkyl, halogen, CN, CF3, -(CR19R20)nNR16R17, -OR16, -SR16or-C(=O)NR16R17;

W means:

or

R4and R5independently denote N or C1-C12-alkyl;

X1selected from R7and-OR7; when X1means R7then X1(i.e., R7), optional, together with R5and the nitrogen atom to which they are bound, form a 4-7-membered saturated or unsaturated cycle having 0-2 additional heteroatoms selected from O, S and N, where the specified cycle is optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)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 R16;

each R7independently mean H, C1-C12-alkyl, C2-C8alkenyl,2-C8-quinil, carbocyclic, heterocyclic, aryl or heteroaryl;

X4means:

R6means H, halogen, C1-C6-alkyl, C2-C8alkenyl,2-C8-quinil, carbocyclic, heteroaryl, heterocyclyl, -OCF3, -NO2, -Si(C1-C6-alkyl), -(CR19R20)nNR16R17, -(CR19R20)nOR16or -(CR19R20)nSR16;

R6'means H, halogen, C1-C6-alkyl, carbocyclic, CF3, -OCF3, -NO2, -Si(C1-C6-alkyl), -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nSR16With 2-C8alkenyl,2-C8-quinil, heterocyclyl, aryl or heteroaryl;

p denotes 0, 1, 2 or 3;

each n independently is 0, 1, 2 or 3;

where each specified alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl R1, R2, R3, R4, R5, R6, R6', R7and RAindependently optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6-alkyl), -(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)n/sub> S(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 R16;

each R16, R17and R18independently mean H, C1-C12-alkyl, C2-C8alkenyl,2-C8-quinil, carbocyclic, heterocyclic, aryl or heteroaryl where the specified alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl or heteroaryl optionally substituted by one or more groups selected from halogen, CN, -OCF3, CF3, -NO2With1-C6-alkyl, -OH, -SH, -O(C1-C6-alkyl), -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)2, -SO2(C1-C6-alkyl), -CO2H, -CO2(C1-C6-alkyl), -C(O)NH2-C(O)NH(C1-C6-alkyl), -C(O)N(C1-C6-alkyl)2, -N(C1-C6-alkyl)C(O)(C1-C6-alkyl), -NHC(O)(C1-C6-alkyl), -NHSO2(C1-C6-alkyl), -N(C1-C6-alkyl)SO2(C1-C6-alkyl), -SO2NH2, -SO2NH(C1-C6-alkyl), -SO2N(C1-C6-alkyl)sub> 2, -OC(O)NH2, -OC(O)NH(C1-C6-alkyl), -OC(O)N(C1-C6-alkyl)2, -OC(O)O(C1-C6-alkyl), -NHC(O)NH(C1-C6-alkyl), -NHC(O)N(C1-C6-alkyl)2, -N(C1-C6-alkyl)C(O)NH(C1-C6-alkyl), -N(C1-C6-alkyl)C(O)N(C1-C6-alkyl)2, -NHC(O)NH(C1-C6-alkyl), -NHC(O)N(C1-C6-alkyl)2, -NHC(O)O(C1-C6-alkyl) and-N(C1-C6-alkyl)C(O)O(C1-C6-alkyl);

or R16and R17together with the nitrogen atom to which they are attached, form a 3-8-membered saturated, unsaturated or aromatic cycle having 0-2 heteroatoms selected from O, S and N, where the specified cycle is optionally substituted by one or more groups selected from halogen, CN, -OCF3, CF3, -NO2With1-C6-alkyl, -OH, -SH, -O(C1-C6-alkyl), -S(C1-C6-alkyl), -NH2, -NH(C1-C6-alkyl), -N(C1-C6-alkyl)2, -SO2(C1-C6-alkyl), -CO2H, -CO2(C1-C6-alkyl), -C(O)NH2-C(O)NH(C1-C6-alkyl), -C(O)N(C1-C6-alkyl)2, -N(C1-C6-alkyl)C(O)(C1-C6-alkyl), -NHC(O)(C1-C6-alkyl), -NHSO2(C1-C6-alkyl), -N(C1-C6-alkyl)SO2(C1-C6and the Qila), -SO2NH2, -SO2NH(C1-C6-alkyl), -SO2N(C1-C6-alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C6-alkyl), -OC(O)N(C1-C6-alkyl)2, -OC(O)O(C1-C6-alkyl), -NHC(O)NH(C1-C6-alkyl), -NHC(O)N(C1-C6-alkyl)2, -N(C1-C6-alkyl)C(O)NH(C1-C6-alkyl), -N(C1-C6-alkyl)C(O)N(C1-C6-alkyl)2, -NHC(O)NH(C1-C6-alkyl), -NHC(O)N(C1-C6-alkyl)2, -NHC(O)O(C1-C6-alkyl) and-N(C1-C6-alkyl)C(O)O(C1-C6-alkyl);

R19and R20independently selected from H, C1-C12-alkyl, -(CH2)n-aryl, -(CH2)n-carbocycle, -(CH2)n-heterocyclyl and -(CH2)n-heteroaryl;

each Y' independently denotes O, NR21or S; and

R21means N or C1-C12-alkyl.

The present invention relates to compositions (e.g., pharmaceutical compositions)containing the compound of formula I-a or I-b (and/or its solvate, hydrates and/or salts) and a carrier (a pharmaceutically acceptable carrier). The present invention also relates to compositions (e.g., pharmaceutical composition)containing the compound of formula I-a or I-b (and/or its solvate, hydrates and/or salts) and a carrier (a pharmaceutically priemel the range of the carrier), optionally containing a second chemotherapeutic agent and/or the second anti-inflammatory agent. Compositions according to the present invention are suitable for inhibiting abnormal cell growth or treating hyperproliferative disorders in a mammal (e.g. human). Compositions according to the present invention is also suitable for the treatment of inflammatory diseases in a mammal (e.g. human).

The present invention relates to 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-a or I-b (and/or its solvate or salt) or containing compositions, individually or in combination with a second chemotherapeutic agent.

The present invention relates to 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-a or I-b (and/or its solvate or salt) or containing compositions, individually or in combination with a second anti-inflammatory agent.

The present invention relates to a method of using compounds according to the ACLs of the present invention for in vitro in situ and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions.

Detailed description of typical embodiments of the

Following is a detailed description of some embodiments of the present invention, examples of which are illustrated with accompanying structures and formulas. Although this invention will be described in conjunction with the above embodiments, it should be clear that this invention is not limited to these embodiments. On the contrary, imply that the invention covers all alternatives, modifications and equivalents that may be included in the scope of the present invention, as indicated in the claims. A qualified specialist in this field there are many methods and materials similar or equivalent to those described herein, which can be used when implementing the present invention. The present invention is in no way limited to the methods and materials. When one or more of the incorporated literature, patents, and similar materials differs from this proposal or contradicts this application, including, but not limited to defined terms, use of terms, described techniques, or the like, it is monitored in real the application.

Definition

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

The term "alkenyl" refers to a monovalent hydrocarbon radical with a linear or branched chain, with two to twelve carbon atoms, at least one site of unsaturation, i.e. a carbon-carbon sp2is a 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=CH2and so on

The term "quinil" refers to a monovalent hydrocarbon radical with a linear or branched chain, with two to twelve carbon atoms, 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, -CH2With≡CH), etc.

The terms "carbocycle", "carbocyclic", "carbocyclic cycle" and "cycloalkyl" refers to a monovalent non-aromatic, saturated or actiono unsaturated cycle, having 3-12 carbon atoms, in the form of a monocycle, or 7-12 carbon atoms, in the form of Bicycle. Bicyclic carbocycle having 7-12 carbon atoms, can be classified, for example, as a bicyclo[4,5]-, [5,5]-, [5,6]- or [6,6]system, and bicyclic carbocycle having 9 or 10 atoms of the cycle, can be classified as a bicyclo[5,6]or [6,6]system, or as a system with bridge bond, 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, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl, cyclododecyl etc.

The term "aryl" means a monovalent aromatic hydrocarbon radical with 6 to 18 carbon atoms obtained by removing one hydrogen atom from a single carbon atom of the original aromatic cyclic system. Some of the aryl groups represented in the form of typical structures as "Ar". Aryl includes bicyclic radicals containing aromatic cycle, condensed with a saturated, partially unsaturated or aromatic cycle by carbocycle or heterocycle. Typical aryl groups include, but are not limited to, radicals, the origin is adamie from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl etc.

The terms "heterocycle", "heterocyclyl" and "heterocyclic cycle interchangeably used in this description, and they refer to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in a loop) the carbocyclic radical with 3-18 atoms of the cycle in which at least one atom of the cycle is a heteroatom selected from a nitrogen atom, oxygen and sulfur, and the remaining atoms of the cycle mean carbon atoms, where one or more atoms of the cycle independently optionally substituted by one or more substituents described below. A heterocycle may be a monocycle having 3-7 members cycle (2-6 carbon atoms and 1-4 heteroatoms selected from N, O, P and S), or bicyclo with 7-10 members cycle (4-9 carbon atoms and 1-6 heteroatoms selected from N, O, P 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 the present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960), 82: 5566. The term "heterocyclyl" also includes radicals, where the radicals heterocycle condensed with a saturated, partially unsaturated cycle or arene is to ensure carbocycle or heterocycle. Examples of heterocycles 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, pyrazolidine, imidazoline, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes and azabicyclo[2.2.2]hexanal. Spiro-residues are also included in the scope of this definition. Examples of the heterocyclic group, where the atoms of the cycle is replaced by oxopropyl (=O)are pyrimidinones and 1,1-dioxothiazolidine.

The term "heteroaryl" refers to a monovalent aromatic radical with 5 - or 6-membered cycle, and includes a condensed cyclic system (at least one of which is aromatic) 5-18 atoms, containing one or more heteroatoms independently selected from nitrogen atom, oxygen and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridine), imidazolyl, imidazopyridines, pyrimidinyl (including the traveler, 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.

Heterocyclic or heteroaryl group may be attached to carbon (carbon-linked) or nitrogen (nitrogen-linked), where this is possible. As an example, and without limitation, carbon-linked heterocycles or heteroaryl linked 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, thiofuran, thiophene, pyrrole or tetrahydropyrrole, in position 2, 4 or 5 oxazole, imidazole or thiazole, position 3, 4 or 5 isoxazol, pyrazole 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, nitrogen-linked heterocycles or heteroaryl with whom are closely linked 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 in position 9 carbazole or β-carboline.

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

The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures where necessary to prevent or slow down (lessen 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, relieving symptoms, reducing the spread of disease, stabilized (i.e. not worsening) the status of the disease, delay or reduction in the development of the disease, reducing the intensity or temporary relief of disease status and remission (full or partial), or detected or not detected. The term "treatment" can also mean prolonged survival, compared with WA is Emim survival, if you do not receive treatment. Patients with need of treatment include those already with the condition or violation, as well as those prone to have the condition or violation, or such, which should be prevented by the condition or violation.

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, reduces the intensity or eliminates one or more symptoms of a particular disease, condition or violation, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or violation described in this description. In the case of cancer, a therapeutically effective quantity of a drug may decrease the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or alleviate to some extent one or more symptoms associated with cancer. To a certain extent and, drug may prevent growth and/or kill existing cancer cells, and this tool may be cytostatic and/or cytotoxic. In the case of cancer therapy, efficacy can be determined, for example, by assessing the time to disease progression (TTP) and/or determine the speed of response (RR).

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

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. "Tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or malignant lymphoma. More particular examples of such cancers include squamous cancer cells (for example, cancer of the squamous epithelial cells), 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 peritoneum, hepatocellular cancer, cancer of the stomach or stomach, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, carcinoma of the salivary gland, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, carcinoma of the penis, acute leukemia, and cancers of the head/brain and neck.

"Chemotherapeutic agent" is a compound suitable for the treatment of cancer ill the deposits. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), sutent (SU11248, Pfizer), letrozole (FEMARA®, Novartis), machinemessiah (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), 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 sulphonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodepa, carboquone, matureup and uredepa; ethylenimines and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylaniline; acetogenins (especially bullatacin, bullatacin); camptothecin (including the synthetic analogue topotecan); bryostatin; callistemon; CC-1065 (including its synthetic analogues of adozelesin, carzelesin and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and SW-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; chlormethine, such as chlorambucil, chlornaphazine, chlorpropamide, estramustine, ifosfamide, mechlorethamine, mejorescasinosenespanol, melphalan, novemberin, finestein, prednimustine, trofosfamide, brazilein; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustin, nimustine and ranimustine; antibiotics such as antibiotics type enediyne (for example, calicheamicin, especially calicheamicin-gamma and calicheamicin-omega (Angew Chem. Intl. Ed. Engl. (1994), 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; spiramycin; and, neocarzinostatin-chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, autralian, azaserine, bleomycin, actinomycin, carubicin, karminomitsin, calcination, chromomycin, dactinomycin, daunorubicin, demoralizing, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morphosyntactical, cyanomethaemoglobin, 2-pyrrolidinecarbonyl and deoxidation), epirubicin, zorubicin, idarubitsin, marsellaise, mitomycin, such as mitomycin C, mycofenolate acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, colomycin, radiobeacon, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); analogs of folic acid, such as deeperin, methotrexate, peripherin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, timipre, tioguanin; pyrimidine analogues such as unit ants the Tabin, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone-propionate, epitiostanol, mepitiostane, testolactone; antiadrenergic tools such as aminoglutethimide, mitotane, trilostane; filler folic acid, such as prolinnova acid; Eagleton; aldophosphamide; aminolevulinic acid; eniluracil; amsacrine; astroball; bisantrene; edatrexate; defaming; demecolcine; diazinon; alternity; liptini-acetate; epothilone, etoposide; gallium nitrate; hydroxyurea; lentinan; londini; maytansinoid, such as mitanin 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; triaziquone; 2,2',2"-trihlortrietilamin; trichothecenes (especially T-2-toxin, verrucarin And, roridin and unguided); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; Galitsin; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoid, such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ (does not contain cremophor), formulations of paclitaxel in the form associated with the Alba is another nanoparticles of paclitaxel (American Pharmaceutical 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 items.

Also in the definition of "chemotherapeutic agent" includes: (i) antihormone tools that regulate or inhibit hormone action on tumors such as antiestrogens and selective modulators of estrogen receptor (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifenside), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and FARESTON® (toremifene); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates the production of estrogen in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (magistralata), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flute the ID, nilutamide, bikalutamid, leuprolide, goserelin; and troxacitabine (analogue 1,3-dioxolane-nucleoside cytosine); (iv) inhibitors of protein kinases; (v) inhibitors lietkynes; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways involved in aberrant cell proliferation, such as, for example, RKS-alpha, Ralf and H-Ras; (vii) ribozymes such as inhibitors of the expression of VEGF (e.g., ANGIOZYME®) and inhibitors of HER2 expression; (viii) vaccines such as vaccines for gene therapy, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; topoisomerase inhibitor 1, such as LURTOTECAN®; ABARELIX® rmRH; (ix) antiangiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above funds. Other antiangiogenic tools include inhibitors of MMP-2 (matrix metalloproteinase 2)inhibitors, MMP-9 (matrix metalloproteinase 9)inhibitors SOH-II (cyclooxygenase II) inhibitors of VEGF-receptor tyrosine kinase. Examples of suitable inhibitors of matrix metalloproteinases, which can be used in combination with the compounds according to the present invention and/or compositions according to the present invention (such as any one of the compounds specified in the headers of examples 5-10), described in International applications WO 96/33172, WO 96/2753, 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, in EP 945864, in U.S. patent 5863949, in U.S. patent 5861510 and EP 780386, all of which are included in this description in its entirety by reference. 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 of WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1 ipropose)hinzelin (AZD2171; example 240 from WO 00/47212), vatalanib (RTK; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds such as compounds described in International PCT publications under the numbers WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354).

Other examples of chemotherapeutic agents that can be used in combination with the compounds according to the present invention (such as any one of these headers compounds of examples 5-10) include inhibitors of PI3K (phosphoinositide-3-kinase), such as described in the footsteps of Yaguchi et. al., (2006), Jour. of the Nat. Cancer Inst., 98(8): 545-556; in U.S. patent 7173029; U.S. patent 7037915; U.S. patent 6608056; U.S. patent 6608053; U.S. patent 6838457; U.S. patent 6770641; U.S. patent 6653320; U.S. patent 6403588; U.S. patent 2008/0242665; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; U.S. patent 2004/092561; WO 2004/007491; WO 2004/006916; WO 2003/037886; U.S. patent 2003/149074; WO 2003/035618; WO 2003/034997; U.S. patent 2003/158212; EP 1417976; patent, Is As 2004/053946; JP 2001247477; JP 08175990; JP 08176070; U.S. patent 6703414 and WO 97/15658, all of which are included in this description in its entirety by reference. Specific examples of such inhibitors include PI3K SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (a PI3K inhibitor, Exelixis, Inc.) and GDC-0941 (PI3K inhibitor, Genentech, Inc.).

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

"Anti-inflammatory agent" means a compound suitable for the treatment of inflammation. Examples of anti-inflammatory drugs include injectable protein therapeutic agents, such as Enbrel®, Remicade®, Humira®, Kineret®. Other examples of anti-inflammatory drugs include asteroid who's anti-inflammatory drugs (NSAIDs), such as ibuprofen or aspirin (to reduce swelling and relieve pain); Antirheumatic drugs, disease modifying (DMARDs)such as methotrexate; 5-aminosalicylate (sulfasalazin and not containing sulfur funds); corticosteroids; immunomodulators such as 6-mercaptopurine ("6-MP"), azathioprine ("AZA"), cyclosporine, and biological response modifiers, such as Remicade.RTM. (infliximab) and Enbrel.RTM. (etanercept); fibroblast growth factors; growth factors, platelet; blockers of enzymes, such as Arava.RTM. (Leflunomide); and/or cartilage protective agent, such as hyaluronic acid, glucosamine and chondroitin.

The term "prodrug", as used in this application refers to a precursor or derivative compounds according to this invention, which is capable of enzymatically or hydrolytically activated or become more active in its original form. See, for example, Wilman, "Prodrugs in Cancer Chemotherapy", Biochemical Society Transactions, 14, pp. 375-382, 615thMeeting 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 according to the invention include, but are not limited to, those containing ester prodrugs, phosphate-containing prodrugs, thiophosphoramide prodrugs, sulfadimidine prodrugs, peptideatlas is alacarte, modified D-amino acid prodrugs, glycosylated prodrugs containing β-lactam prodrugs, optionally substituted prodrugs containing phenoxyacetamide, optionally substituted prodrugs containing phenylacetamide, 5-fortitudinous and other 5-ptoluidine prodrugs, which can evolve into a more active recitations drug. Examples of cytotoxic drugs that can be derivationally education proletarienne forms for use according to this invention, include, but are not limited to, compounds according to this invention and a chemotherapeutic drug, such as described above.

"Metabolite" is a product resulting from the metabolism of a particular compound or its salts in the body. Metabolites of compounds can be identified using standard techniques known in the field, and their activity determined using tests such as, for example, described in this description. Such products can be obtained, for example, as a result of oxidation, hydroxylation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic cleavage, and the like, input connections. Accordingly, this invention relates is the metabolites of the compounds according to this invention, including compounds produced by a process comprising contacting compounds according to this invention with a mammal for a period of time sufficient for the formation of its metabolic product.

"Liposome" is a small membrane vesicle (vesicles), including various types of lipids, phospholipids and/or surfactant which is suitable for delivery of a drug (such as MEK inhibitors described herein, and, optionally, a chemotherapeutic agent) to a mammal. The components of the liposomes, as a rule, arranged in a double-layer formation, similar to the lipid bilayer of biological membranes.

The term "instructions for use", as used herein, refers to the instructions, usually invest in industrial packaging of therapeutic drugs, which 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 which have the property of incompatibility with its mirror image, while the term "achiral" refers to molecules that are compatible with its mirror reflection.

The term "stereoisomer" refers to the connection of eniam, which have the same chemical structure and connectivity of atoms, but differ in the arrangement of these atoms relative to each other in space, and cannot carry out reciprocal transformation for the rotation around the simple relations.

The term "diastereoisomer" refers to a stereoisomer with two or more centers of chirality, and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. A mixture of diastereoisomers can be separated using analytical methods with a high degree of separation, such as crystallization, electrophoresis and chromatography.

The term "enantiomers" refers to two stereoisomers of the compounds, which are incompatible mirror reflection of each other.

Stereochemical definitions and conventions used in this description, usually according to 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 this invention may include asymmetric or chiral centers and therefore exist in different stereoisomeric forms. Assume that all stereoisomeric forms of the joint is in accordance with this 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 are capable of rotation in the plane of plane-polarized light. When 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(s) centre(s). The prefixes d and l or (+) and (-), used to indicate the sign of the rotation of the connection in the plane of plane-polarized light where the prefix is (-) or 1 meaning that the compound is levogyrate. The connection to the prefix (+) or d is Pervouralsk. For a given chemical structure, these stereoisomers are identical, except when they are mirror images of each other. Individual stereoisomer can also be viewed as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. The mixture of enantiomers in a ratio of 50:50 is considered as a racemic mixture or a racemate, which(th) can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refers to an equimolar mixture of two enantiomers, N. the having optical activity.

The term "tautomer or tautomeric form" refers to the structural isomers with different energies, which are interconvertible due to the low energy barrier. For example, proton tautomers isomerism (also known as prototroph the tautomers) include interconversion due to the migration of a proton, such as keto-enol and imino-Tamina isomerization. The tautomers with valence isomerism (valence tautomers) include interconversion by reallocating some of the electrons.

The phrase "pharmaceutically acceptable salt", as used in this context, refers to pharmaceutically acceptable organic or inorganic salts of the compounds according to this invention. Examples of salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannat, Pantothenate, bitartrate, ascorbate, succinate, maleate, getitemat, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate "mesilate", aconsultant, bansilalpet, p-toluensulfonate, pamoate (i.e., 1,1'-Methylenebis(2-hydroxy-3-aftout), alkali metal salts (e.g. sodium and potassium), salts of alkaline earth metals (e.g. magnesium), and ammonium salt. To farmaci is almost acceptable salt, you can add another molecule, such as acetate ion, succinate ion, or other counterion. The counterion may be any organic or inorganic "fragment", which stabilizes the charge of the original connection. In addition, pharmaceutically acceptable salt can have more than one charged atom in its structure. When multiply charged atoms are part of a pharmaceutically acceptable salt, it can have many counterions. Consequently, the pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.

If the connection according to this invention is a base, the desired pharmaceutically acceptable salt may be obtained using any suitable method available in this area, for example, by treating the free base of an inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesulfonate acid, phosphoric acid, etc. or organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, paranoidly acid, such as glucuronic acid or galacturonic acid, alpha-hydro is sigilata, 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, a sulfonic acid such as p-toluensulfonate acid or econsultancy acid, or the like

If the connection according to this invention is an acid, the desired pharmaceutically acceptable salt may be obtained using any suitable technique, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkali earth metal hydroxide, or the like, Illustrative examples of suitable salts include, but are not limited to, organic salts, resulting from the use of amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The phrase "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients included in the finished dosage form, and/or mlekovita is m, which when subjected to treatment.

The term "MES" refers to an Association or complex of one or more solvent molecules and compounds according to this 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 a water.

The term "protective group" refers to the Deputy, which, as a rule, blocks or protects the individual functionality, at that time, how the interaction with other functional groups of the compounds. For example, "aminosidine group" represents a Deputy, attached to the amino group, to block or protect the functional amino group in the compound. Suitable aminosidine groups include acetyl, TRIFLUOROACETYL, tert-butoxycarbonyl (VOS), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hidroxizina group" refers to the Deputy hydroxyl group that blocks or protects the hydroxyl functionality. Suitable protective groups include acetyl and trialkylsilyl. "Carboxyamide group" refers to the Deputy carboxyl group that blocks or protects the carboxyl f is nctionality. Normal carboxyamide group include phenylsulfonyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluensulfonyl)ethyl, 2-(p-nitrobenzylidene)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl etc. In relation to General descriptions of protective groups and their use, refer to the manual T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms "compound according to the invention", "compounds according to the present invention", "compounds of formula I-a or I-b", "azaindolizines and azaindolizines formula I-a or I-b", except as otherwise indicated, include compounds/azaindolizines formula I-a or I-b, and their stereoisomers, geometric isomers, tautomers, solvate, metabolites, salts (e.g., pharmaceutically acceptable salts and prodrugs.

The present invention relates to azaindolizines formula I-a or I-b, as described above, are suitable as inhibitors of kinases, especially suitable as inhibitors of MEK kinase. The present invention relates to compounds of formula II-a or II-b (i.e., ZAmean CRAand all other variables have the meanings as indicated in the case of formula I-a or I-b.

In one embodiment of the present invention, R1means H, halogen, CN, CF3With1-C6-alkyl, -NR16R17, -OR16or-SR16; there are all the other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b.

In another embodiment of the present invention, R1denotes H, Cl, Br, F, CN, CF3, CHF2, methyl, ethyl, -NH2, -NH(CH3), -N(CH3)2, -OH or-OCH3; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b.

In another embodiment of the present invention, R1denotes H, Cl, F, CF3or methyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b.

In another embodiment of the present invention, R1means H or F; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b.

In one embodiment of the present invention, R2means H, halogen, CN, CF3With1-C6-alkyl, -NR16R17, -OR16or-SR16; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R2denotes H, Cl, F, CN, CF3, CHF2, methyl, ethyl, -NH2, -NH(CH3), -N(CH3)2, -OH or-OCH3; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R2denotes H, Cl,F, CF3or methyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R2means H; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, R3means H, halogen, CN, CF3With1-C6-alkyl, -NR16R17, -OR16or-SR16; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R3denotes H, Cl, F, CN, CF3, CHF2, methyl, -NH2, -NH(CH3), -N(CH3)2, -OH or-OCH3; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R3denotes H, Cl, F, CF3or methyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R3means H; and all other variables they are the only values as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, RAdenotes H, halogen or CF3; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, RAdenotes H, F or Cl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, R4means N or C1-C6is alkyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R4means H or methyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R4means H; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, R5means N or C1- 6is alkyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R5means H or methyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R5means H; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R5means methyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, X1means OR7; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, X1means OR7where R7means N or C1-C12-alkyl (for example, C1-C6-alkyl), substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19 20)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 R16; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, X1 means OR7where R7means heterocyclyl (e.g., 4-6-membered heterocyclyl), optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')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)nC(=Y')NR 16R17and R16; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, X1means OR7where R7means 4-6-membered heterocyclyl having 1 nitrogen atom in the cycle where the specified heterocyclyl optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(R 19R20)nS(O)2NR16R17, -(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R16; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, X1means:

;

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, X1means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, X1means R7; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, X1means R7where R7means N or C1-C12-alkyl (for example, C1-C6-alkyl), Zam is placed one or more groups, independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6-alkyl), -(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 R16; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or IIb or as defined in any one of the embodiments, above.

In another embodiment of the present invention, X1means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R5mean N and X1means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R5means N, RAmeans N, and X1means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, X1means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R5means methyl, and X1means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as specified in any od the ohms of the embodiments, above.

In one embodiment of the present invention, X1means R7and X1(i.e., R7together with R5and the nitrogen atom to which they are linked, form a 4-to 5-membered saturated cycle having 0-2 additional heteroatoms selected from O, S and N, where the specified cycle is optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17, -(CR19R20 nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R16; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, W means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, W means-OR7where R7means N or C1-C12is alkyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, W means-OR7where R7means H; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, W means-OR7where R7means1-C6is alkyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b or as specified in the yubom one of the embodiments, above.

In one embodiment of the present invention, R6means halogen, C2-C8-quinil, carbocyclic or-SR16; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, R6means halogen, C2-C3-quinil,3-carbocyclic or-SR16where R16means1-C2is alkyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, R6'denotes H, halogen or1-C3is alkyl; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In one embodiment of the present invention, p is 1 or 2; and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described above.

In another embodiment of the present invention, X4means:

and all other variables have the meanings as indicated in the case of formulas I-a, I-b, II-a or II-b, or as defined in any one of the embodiments described the data above.

Another embodiment of the present invention relates to the compounds described in examples 5-10, and the following compounds:

Obtaining compounds of formula I-a or I-b

Azaindolizines formula I-a or I-b receive in accordance with the techniques described below in the schemes and in the examples or by methods known in this field. The initial substance and various intermediate products can be obtained from commercial sources, derived from commercially available compounds or obtained using well-known methods of synthesis (for example, described in WO 02/06213, WO 03/077855 and WO 03/077914).

For example, azaindolizines formula (II-a) can be obtained using the synthesis pathway, shown in schemes 1 and 2.

Scheme 1

Anilines of formula (IV) (including relevant substituents R1) can be obtained commercially or obtained in accordance with methods described in the literature. The compounds of formula (VI) can be obtained from anilines of formula (IV) by entering into interaction with the acid chlorides of the acids of formula (V), in the presence of a base, such as triethylamine, and a catalyst, such as DMAP in a solvent such as DMF. The compounds of formula (VI) can be converted into compounds of formula (VIII) by entering into interaction with alkylhalogenide formula (VII), in risotti Foundation, such as potassium hydroxide, in a solvent such as ethanol. The compounds of formula (IX) can be obtained from compounds of formula (VIII) by treatment with phosphorus oxychloride in a solvent such as toluene, at a temperature from 50°C to the boiling temperature under reflux.

The compounds of formula (X) can be obtained from compounds of formula (IX) by entering into interaction with a base such as sodium hydroxide, in a solvent such as methanol, ethanol or dioxane, at temperatures from room temperature to the boiling temperature under reflux. Alternatively, the compounds of formula (X) can be obtained from compounds of formula (IX) by treatment with a Lewis acid, such as tribromide boron, in a solvent such as dichloromethane, at a temperature from -78°C to the boiling temperature under reflux.

The compounds of formula (X) may be introduced in the interaction with the functionalized hydroxylamine of the formula (XII) (commercially available or obtained in accordance with scheme 3) or with an amine, and a suitable binding agent such as O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium-hexaphosphate, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or N,N'-dicyclohexylcarbodiimide, in the presence of N-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base, such as diisopropylethylamine is or triethylamine, in an inert solvent, such as tetrahydrofuran, N,N-dimethylformamide or dichloromethane, at about room temperature, to obtain the compounds of formula (XI). Alternatively, the compounds of formula (XI) can directly be obtained from compounds of formula (IX) by introducing them into interaction with an amine or hydroxylamine DNHR, in the presence of a Lewis acid such as trimethylaluminum in a solvent such as DCM, at a temperature of from room temperature to the boiling temperature under reflux.

Alternatively, the compounds of formula (IX) can be obtained according to scheme 2.

Scheme 2

Chloromethylpyridine formula (VII) can be entered into interaction with the ether tsianuksusnogo acid, such as methyl ether tsianuksusnogo acid, in the presence of a base such as sodium hydride, in a solvent such as THF, at a temperature from 0°C to the boiling temperature under reflux, to obtain the compounds of formula (XV). The compounds of formula (XVI) can be obtained from compounds of formula (XV) by treatment with acid, such as triperoxonane acid, neat or in a solvent such as dioxane, at temperatures from 50°C to the boiling temperature under reflux, or using microwave radiation at a temperature of from 90°to 180°C. With the organisations of the formula (IX) can be obtained from compounds of formula (XVI) by introducing them into interaction with arylhalides or aritifical (including appropriate substituents R1), in the presence of a catalyst such as Tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, a base such as potassium phosphate, tert-piperonyl sodium, 1,8-diazabicyclo[5.4.1]undec-7-ene or cesium carbonate, ligand, such as 9,9'-dimethyl-4,5-bis(diphenylphosphino)xanthene, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',6'-(dimethoxy)biphenyl or tributylphosphine, in a suitable solvent, such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at temperatures from room temperature to the boiling point of the solvent, or under microwave irradiation at a temperature of from 70°to 150°C. Compounds of formula (IX) can be converted into compounds of formula (XI), using the methodology presented in figure 1.

Hydroxylamine formula (XII) can be obtained using the techniques described in the literature, or the path of synthesis, is shown in figure 3.

Scheme 3

Primary or secondary alcohols of General formula (XX) can be obtained using the methods described in the literature. They can be introduced in the interaction with the N-hydroxyphthalimide, when using phosphine and binding reagent, such as diethylazodicarboxylate, to obtain the compounds of General formula (XXI). With compounds of General formula (XXI) can remove protection using the hydrazine or methylhydrazine, obtaining hydroxylamino General formula (XII-a). The compounds of formula (XII-a) can optionally be 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 the boiling temperature under reflux. In addition, the compounds of formula (XII-a) can optionally be modified by alkylation with alkylhalogenide, in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, getting hydroxylamine General formula (XII-b).

You should take into account that when you have the appropriate functional group, the compounds of formula (I) or any of the intermediates used for their production, optionally derivateservlet using one or more standard methods of synthesis, using substitution, oxidation, recovery or cleavage reaction. Methods specific substitution include standard alkylation, atilirovanie, heteroarylboronic, acylation, sulfonylamine, halogenation, nitridation, formirovanie and binding.

For example, groups of arilbred or artilharia can be turned into arisitide, is using the Finkelstein reaction, using a source of iodide such as sodium iodide, and a catalyst such as copper iodide, a ligand such as TRANS-N,N'-dimethyl-1,2-cyclohexanediamine, in a solvent such as 1,4-dioxane, and heating the reaction mixture up to the boiling temperature under reflux. Aryldialkyl can be turned into arisitide by processing silane using a 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 a temperature from -40°C up to the boiling temperature under reflux.

In an additional example, a primary amino group (-NH2) you can alkilirovanii by way of restorative alkylation using an aldehyde or ketone and borohydride, such as triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as halogenated hydrocarbon such as 1,2-dichloroethane, or an alcohol, such as ethanol, when necessary, in the presence of acid, such as acetic acid, approximately at ambient temperature. Secondary amino group (-NH-) can similarly be alkilirovanii using aldehyde.

In an additional example, primary or secondary amino group can be converted into amide group (-NHCOR', or-NRCOR') by acylation. Acylation can the be achieved by introducing into engagement with the corresponding acid chloride acid, in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by introducing into engagement with the corresponding carboxylic acid, in the presence of a suitable coupling agent such as HATU (O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine), in a suitable solvent such as dichloromethane. Similarly, the amino group can be converted into sulfonamidnuyu group (-NHSO2R' or-NR"SO2R') by entering into interaction with the corresponding 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 into a urea group (-NHCONR'R" or-NRCONR'R") by entering into interaction with the appropriate isocyanate in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane.

Amine (-NH2) can be obtained by restoring the nitro group (-NO2), for example, by catalytic hydrogenation using for example hydrogen in the presence of a catalyst based on a metal, such as palladium on a carrier, such as charcoal, in a solvent such as ethyl acetate or an alcohol, e.g. methanol. Alternatively, the transformation can be done by chemical recovery, and the uses, for example, metal, such as tin or iron, in the presence of acid, such as hydrochloric acid.

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

In an additional example, an amino group (-NH2) can be obtained from carboxylic acid groups (-CO2N) by transformation into the corresponding acylated (-CON3), rearrangement of kurzius and hydrolysis of the resulting isocyanate (-N=C=O).

Aldehyde group (-Cho) can be converted into the 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, when necessary, in the presence of acid, such as acetic acid, approximately, when the ambient temperature.

In an additional example, the aldehyde group can be converted into alkene is global group (-CH=CHR') by the reaction of the Wittig or Wadsworth-Emmons, using the corresponding phosphorane or phosphonate, under standard conditions known to a qualified specialist in this field.

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

Ester group (-CO2R') can be converted into the corresponding acid group (-CO2N) by hydrolysis catalyzed by acid or base, depending on the nature of R. If R is tert-butyl, can be achieved hydrolysis catalyzed by acid, for example, by treatment with organic acids, such as triperoxonane acid, in an aqueous solvent, or by treatment with inorganic acids such as hydrochloric acid, in an aqueous solvent.

Carboxyl group (-CO2N) can be transformed into amides (CONHR' or-CONR'R") by entering into interaction with the appropriate amine, in the presence of a suitable coupling agent such as HATU, in a suitable solvent such as dichloromethane.

In a further example, ka is oil acid can be homological one carbon atom (i.e., from-CO2N-CH2CO2N) by conversion into the corresponding acid chloride of acid (-COCl), with subsequent synthesis of the Arndt - Eistert.

In a further example, the group-IT can be obtained from the corresponding esters (for example, -CO2R') or aldehydes (-Cho) by restoring, using for example a complex metal hydride, such as sociallyengaged, diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol. Alternatively, the alcohol can be obtained by restoring the appropriate acid (-CO2N), using, for example, sociallyengaged, in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.

The alcohol group can be turned into a deleted group, such as halogen atoms or sulfonyloxy, such as alkylsulfonate, for example, tripterocalyx, or arylsulfonate, for example, p-toluensulfonate, using conditions known to a qualified specialist in this field. For example, alcohol can enter into interaction with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to obtain the corresponding chloride. Base (e.g. triethylamine) can also be used for interaction.

In another when the ore, 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, such as triphenylphosphine and an activator such as diethyl-, aminobutiramida or diethylazodicarboxylate. Alternatively, alkylation can be achieved by deprotonation using suitable base for example sodium hydride, followed by the subsequent addition of an alkylating agent, such as alkylhalogenide.

Halogenations substituents in the compounds can be subjected to the exchange of the halogen-metal by treatment with base, such as lithium base such as n-utility or tert-utility, optionally at a low temperature, for example, approximately -78°C, in a solvent such as tetrahydrofuran, and then to recover with the help of the electrophile to introduce the desired substituent. Thus, for example, formyl group can be entered by using N,N-dimethylformamide as the electrophile. Halogenations substituents can, alternatively, be subjected to the reactions catalyzed by metal (such as palladium or copper)for injection, for example, acid, ester, cyano, amide, aryl, heteroaryl, alkenyl, etkinlik, thio - or aminosalicyclic. Suitable methods, to the which you can use include described Heck, Suzuki, Stille, Buchwald or Hartwig. Halogenations deputies also can be subjected to nucleophilic substitution with subsequent introduction into interaction with an appropriate nucleophile such as an amine or alcohol. Mainly, this interaction can be performed at elevated temperature, in the presence of microwave radiation.

Compounds according to the present invention were tested for their ability to inhibition of MEK activity and activation (primary analysis) and in relation to their biological effects on growing cells (secondary analysis), as described below. Compounds according to the present invention, with IC50less than 5 μm (more preferably, less than 0.1 μm, most preferably less than 0.01 μm) according to the analysis of the activity of MEK in accordance with 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) according to the analysis of activation of MEK in accordance with 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) according to the analysis of cell proliferation in accordance with example 3, and/or EC50less than 10 microns (more FAV is preferably, less than 1 μm, even more preferably less than 0.5 μm, most preferably less than 0.1 μm) according to the analysis of phosphorylation of ERK in accordance with example 4, are suitable as inhibitors of MEK.

The present invention relates to compositions (e.g., pharmaceutical composition)containing the compound of formula I-a or I-b (and/or its solvate, and/or salts thereof) and a carrier (a pharmaceutically acceptable carrier). The present invention also relates to compositions (e.g., pharmaceutical composition)containing the compound of formula I-a or I-b (and/or its solvate, and/or salts thereof) and a carrier (a pharmaceutically acceptable carrier), further comprising a second chemotherapeutic agent and/or the second anti-inflammatory agent, such as the means described in this description. Compositions according to the present invention are suitable for inhibiting abnormal cell growth or treating hyperproliferative disorders in a mammal (e.g. human). Compositions according to the present invention is also suitable for the treatment of inflammatory diseases in a mammal (e.g. human).

Compounds according to the present invention (such as any one of these headers compounds of examples 5-10) and the composition is also suitable for the treatment of autoimmune diseases, destructive bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (e.g. human). Examples of such diseases/disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retrolental fibroplasia associated with age macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis, and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, rejection of an organ transplant, cachexia, shock, septic shock, heart failure, rejection of an organ transplant, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis (B) (HBV), human papilloma virus human (HPV), cytomegalovirus (CMV) and Epstein-Barr (EBV). Chronic pain, for the purposes of the present invention, includes, but is not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, hypothyroidism, inflammation, arthritis, and post-operative pain. Neuropathic pain is associated with numerous conditions which include, but are not limited to, inflammation, postoperative pain, pain "fan who Ohm limb", the pain from the burn, gout, trigeminal neuralgia, acute herpetic and post herpetic pain, causalgia, diabetic neuropathy, avulsion nerve plexus, neuroma, vasculitis, viral infection, ruptured, constructionno damage, tissue damage, amputation of extremities, arthritis pain and damage to the nerves between the peripheral nervous system and Central nervous system.

Compounds according to the present invention (such as any one of these headers compounds of examples 5-10) and the composition is also suitable for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-kidney disease) in a mammal (e.g. human).

Compounds according to the present invention (such as any one of these headers compounds of examples 5-10) and the composition is also suitable to prevent implantation of blastocytes in a mammal (e.g. human).

The present invention relates to a method of inhibiting abnormal cell growth or a method of treatment of hyperproliferative disorders in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I-a or I-b (and/or its solvate, and/or its salts) or containing composition. is also related to the present invention is a method of treating inflammatory disease in a mammal (for example, person), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I-a or I-b (and/or solvate and/or its salts) or containing composition.

The present invention relates to 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-a or I-b (and/or its solvate, and/or its salts) or containing compositions, in combination with a second chemotherapeutic agent, such as the means described in this description. The present invention also relates to 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-a or I-b (and/or its solvate, and/or its salts) or containing compositions, in combination with a second anti-inflammatory agent, such as the means described in this specification.

The present invention relates to a method of treatment of autoimmune diseases, destructive bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegen Arutyunova disease in a mammal (for example, person), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I-a or I-b (and/or solvate and/or its salts) or containing composition and additionally not necessarily including the introduction of a second therapeutic agent. Examples of such diseases/disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retrolental fibroplasia associated with age macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis, and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, rejection of an organ transplant, cachexia, shock, septic shock, heart failure, rejection of an organ transplant, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis (B) (HBV), human papilloma virus human (HPV), cytomegalovirus (CMV) and Epstein-Barr (EBV).

The present invention relates to 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 to the icesta the compounds of formula I-a or I-b (and/or its solvate, and/or its salts) or containing composition and additionally not necessarily including the introduction of a second therapeutic agent.

The present invention relates to a method of preventing implantation blastocytes in the case of a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I-a or I-b (and/or its solvate, and/or its salts) or containing composition and additionally not necessarily including the introduction of a second therapeutic agent.

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

Also suppose that the compounds according to the present invention can make abnormal cells more sensitive to treatment with radiation for purposes of destruction of such cells and/or inhibiting the growth of such cells. Accordingly, the invention additionally relates to a method of sensitizing abnormal cells in a mammal (e.g. human) in relation to the radiation treatment, which includes an introduction to the specified mammal a certain amount of the compounds of formula I-a or I-b (and/or its solvate, and its salts) yesteraday his compositions, moreover, this quantity is effective in sensitizing abnormal cells to treatment with radiation.

Introduction compounds according to the present invention (hereinafter, "active(s) connection(s)") can be effective in any way in which it is possible to deliver compounds to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular introduction or infusion), local injection, inhalation and rectal administration.

Enter the number of active connections depends on the subject, which they were treated, the severity of the violation or condition, rate of administration, the nature of the compound and the discretion of the attending physician. However, the effective dose is in the range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day, in single or divided doses. For a person weighing 70 kg, this amount is from about 0.05 to 7 g/day, preferably from about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the above range may be more than adequate, while in other cases it can be used even higher doses without causing any l the Bo 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 monotherapy or in combination with one or more chemotherapeutic or anti-inflammatory drugs, such as described in this description. This combined treatment can be carried out by simultaneous, sequential or separate dosing of the individual components of the treatment.

Pharmaceutical composition, for example, may be in a form suitable for oral administration in the form of tablets, capsules, pills, powder, finished dosage formulations with delayed release, solution, suspension, for parenteral 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 a suppository. The pharmaceutical composition may be in the form of standard dosage forms, suitable for a single administration of precise dosages. The pharmaceutical composition includes a standard pharmaceutical carrier or excipient and the connection according to this invention as the active ingredient. In addition, the composition may include other therapeutic or pharmaceutical agents, carriers, adjuvants, etc.

Model forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, such as aqueous solutions of propylene glycol or dextrose. Such dosage forms can be suitably buffered, if desired.

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, excipients, etc. So, for oral administration, tablets containing various excipients such as citric acid, can be used in conjunction with various dezinfeciruyuhimi agents such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and gum Arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, are often suitable for tabletting purposes. Solid compositions of a similar type can also be used in soft and hard-filled drug gelatin capsules. Preferred substances, therefore, include lactose or milk sugar, and glycols of high molecular weight. When peroral the th introduction of the desired aqueous suspensions or elixirs, active connection in this case can be combined with various sweetening or flavoring agents, dyes or coloring substances, and, if desired, emulsifiers or suspendresume agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of obtaining various pharmaceutical compositions with a specific number of active compounds known or apparent to the skilled in this field. For example, see, Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

EXAMPLES

Abbreviations

DCMDichloromethane
DIPEAdiisopropylethylamine
DMAP4-dimethylaminopyridine
DMF (DMF)dimethylformamide
EDCI1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
HClhydrochloric acid
HOBt1-hydroxybenzotriazole
IMSindustrial is methylated spirits
MeonMethanol
NCSN-chlorosuccinimide
RTroom temperature

General experimental conditions

1H-NMR spectra were recorded at ambient temperature using a spectrometer Varian Unity Inova (400 MHz) with a triple resonance probe 5 mm Chemical shifts are expressed in ppm (millionths), tetramethylsilane. Use the following abbreviations: user. = - broadened signal, s = singlet, d = doublet, DD = double doublet, t = triplet, q = Quartet, m = multiplet.

Experiments using high-performance liquid chromatography - mass spectrometry (LCMS) to determine retention times (RT) and associated mass ions is carried out using one of the following methods.

Method a: Experiments carried out using a quadrupole mass spectrometer (Waters Micromass ZQ connected to a Hewlett Packard HP1100 LC detector diode matrix. In the case of this system using a column Higgins Clipeus, C18, 5 μm, 100×3.0 mm, and a flow rate of 1 ml/min, the Initial solvent system consists of 95% water containing 0.1% formic acid (solvent A)and 5% acetonitrile containing 1% formic acid, (the solvent), in the first minute, then a gradient up to 5% solvent a and 95% solvent B, in the next 14 minutes. The final solvent system is held constant over the next 5 minutes.

Method: the Experiments osushestvliayut when using a quadrupole mass spectrometer Waters Platform LC, connected to a Hewlett Packard HP1100 LC detector with diode array and 100-position sampler, using a column Phenomenex Luna C18(2)30×4.6 mm, and a flow rate of 2 ml/min. and a solvent System consists of 95% water containing 0.1% formic acid (solvent A)and 5% acetonitrile containing 0.1% formic acid (solvent B), in the first of 0.50 minutes, then the gradient until 5% solvent a and 95% solvent B, in the next 4 minutes. The final solvent system is kept constant during the following 0.50 minutes.

Experiments using microwave radiation is carried out using a Personal Chemistry Emrys Iniatiator™ or Optimizer™, which used a single-mode resonator and dynamic field setting (tuning), both of them have the function of reproduction and control. You can reach the temperature of 40-250aboutAnd you can reach pressures up to 20 bar.

Example 1

Analysis of MEK (analysis activity MEK)

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

The analysis was carried out for 30 minutes in the presence of 50 μm ATP, using recombinant GST-ERK1 produced in E. coli as substrate. Phosphorylation of the substrate were detected and quantitatively determined using HTRF-reagents manufactured by Cisbio. They consist of antibodies against GST conjugated to allophycocyanin (XL665), and antibodies against phospho(Thr202/Tyr204)-ERK (anti-phospho-antibody)conjugated to Cryptocom europium. These antibodies were used at a final concentration of 4 μg/ml and 0.84 μg/ml, respectively. Anti-phospho-antibody recognizes ERK1, doubly phosphorylated at Thr202 and Tyr204. When both antibodies are associated with ERK1 (that is, when the substrate is phosphorylated), is the transfer of energy from cryptate to allophycocyanin after excitation at 340 nm, resulting in imitiruemogo fluorescence, which is proportional to the amount of biogas produced phosphorylated substrate. Fluorescence was detected using a multichannel fluorometer.

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

IC50was defined as the concentration at which this connection causes Inga is the funding by 50% relative to control. The values of the IC50calculated using XLfit software (version 2.0.5).

Specified in the headers of the compounds of examples 5-6 and 8-10 showed IC50less than 0.5 μm, in the case of the analysis described in example 1.

Example 2

Analysis of skin disease analysis of activation of MEK)

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

The analysis was carried out for 30 minutes in the presence of 200 μm ATP, using recombinant GST-MEK1 produced in E. coli as substrate. Phosphorylation of the substrate were detected and quantitatively determined using HTRF-reagents manufactured by Cisbio. They consist of antibodies against GST conjugated to allophycocyanin (XL665), and antibodies against phospho(Ser217/Ser221)-MEK (anti-phospho-antibody)conjugated to Cryptocom europium. Anti-phospho-antibody recognizes MEK, doubly phosphorylated at Ser217 and Ser221 or once phosphorylated at Ser217. When both antibodies are associated with MEK (i.e., when the substrate is phosphorylated), is the transfer of energy from cryptate to allophycocyanin after excitation at 340 nm, resulting in imitiruemogo fluorescence, which is proportional to the amount of biogas produced phosphorylated substrate. Fluorescence was detected using a multichannel flu is Rymer.

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

IC50was defined as the concentration at which this compound causes an inhibition of 50% compared to control. The values of the IC50calculated using XLfit software (version 2.0.5).

Example 3

Analysis in relation to cell proliferation

Compounds were tested by analysis of cell proliferation using the following cell lines:

NST human colorectal carcinoma (ATSS)

A human malignant melanoma (ATSS)

Both cell lines are maintained in DMEM/F12 (1:1) (Gibco), supplemented with 10% fetal calf serum, at 37°C in an incubator with a humid atmosphere with 5% CO2.

Cells were planted in 96-well tablets and 2000 cells/well and after 24 hours they were subjected to various concentrations of compounds from 0.83% DMSO. Cells were cultured in the next 72 hours, and to each well was added the same volume of reagent CellTiter-Glo (Promega). He analyzes cells and generates a luminescent signal proportional to the amount of released ATP (and, hence, proportional to the number of cells per well), which can be detected using a multichannel luminometer.

EU 50was defined as the concentration at which this compound causes an inhibition of 50% compared to control. The values of the IC50calculated using XLfit software (version 2.0.5).

In this analysis, listed in the headers of the compounds of examples 5-6 and 8-9 showed EU50less than 11.5 μm, in the case of both cell lines.

Example 4

Cell based analysis of phospho-ERK

Compounds were tested by cell based enzyme-linked immunosorbent assay (ELISA) phospho-ERK, using the following cell lines:

NST human colorectal carcinoma (ATSS)

A human malignant melanoma (ATSS)

Both cell lines are maintained in DMEM/F12 (1:1) (Gibco), supplemented with 10% fetal calf serum, at 37°C in an incubator with a humid atmosphere with 5% CO2.

Cells were planted in 96-well tablets and 2000 cells/well and after 24 hours they were subjected to various concentrations of compounds from 0.83% DMSO. Cells were cultured in the next 2 hours or 24 hours, fixed with formaldehyde (final 2%) and "impregnated" with methanol. After blocking with TBST-3% BSA, fixed cells were incubated with the primary antibody (rabbit against phospho-ERK) over night at 4°C. the Cells were incubated with propidium the iodide (fluorescent DNA dye) and was carried out by detection of the cellular p-ERK, 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 cytometer for microplates, and the signal Alexa Fluor 488 was normalized to PI signal (proportional to the number of cells).

EU50was defined as the concentration at which this connection leads to half the signal path between the baseline and maximum response. Values EU50calculated using XLfit software (version 2.0.5).

In this analysis, listed in the headers of the compounds of examples 5-6 and 8-9 showed EU50less than 1 μm, in the case of both cell lines.

Ethyl ester of N-(2-fluoro-4-itfeel)malonovoi acid

To a solution of 2-fluoro-4-iodoaniline (15,1 g of 63.7 mmol), triethylamine (8,9 ml of 63.7 mmol) and DMAP (100 mg, 0.8 mmol) in DMF (45 ml) add ethylmalonate (9.8 ml, to 76.4 mmol). The reaction mixture is heated at 60°C for 2 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (30 ml), washed with water (20 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The obtained OST is OK subjected to flash chromatography (SiO 2the gradient of 20-30% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solid white (19.5 g, yield 87%).

LCMS (method B): RT= 3,43 min, M+N+= 352.

Ethyl ester of N-(2-fluoro-4-itfeel)-2-pyrimidine-4-ylmethylamino acid

Ethyl ester of N-(2-fluoro-4-itfeel)malonovoi acid (20.5 g, 58,4 mmol), 4-chloromethylpyridine (5.0 g, for 38.9 mmol) and potassium hydroxide (3.28 g, for 58.4 mmol) was dissolved in IMS (200 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (30 ml), washed with water (20 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2gradient of 10-40% ethyl acetate in cyclohexane)to give specified in the title compound in the form of not-quite-white solid (6.9 g, yield 39%).

LCMS (method B): RT= 3,29 min, M+N+= 444.

Ethyl ester of 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of ethyl ester of N-(2-fluoro-4-itfeel)-2-pyrimidine-4-ylmethylamino acid (4 g, 9,02 mm is l) in toluene (120 ml) is added phosphorus oxychloride (V) (4,2 ml, 45,1 mmol). The reaction mixture is refluxed for 16 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (30 ml), washed with saturated aqueous sodium bicarbonate solution (20 ml)and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2gradient of 0-40% ethyl acetate in cyclohexane)to give a solid dark brown color. This solid is triturated in diethyl ether (10 ml), getting mentioned in the title compound in the form of a solid light brown color (0,63 g, yield 16%).

LCMS (method B): RT= 3,95 min, M+N+= 426.

7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of ethyl ester of 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (230 mg, 0.54 mmol) in a mixture of dioxane (2 ml) and water (1 ml) add monohydrate of lithium hydroxide (45 mg, at 1.08 mmol). The reaction mixture is heated at 60°C for 1 hour. Added dropwise an aqueous solution of hydrochloric acid (1 M solution) to achieve pH ~5, which causes the formation of sludge. The reaction mixture AHP crystal growth is litrovuyu and the solid residue is washed with ethyl acetate (5 ml), getting listed in the title compound in the form of not-quite-white solid (67 mg, yield 31%).

LCMS (method B): RT= 3,22 min, M+N+= 398.

Methyl ester of N-(2-fluoro-4-methylsulfinylphenyl)malonovoi acid

To a solution of 2-fluoro-4-methylsulfonylamino (13 g, 82,7 mmol), triethylamine (9.3 ml, and 86.8 mmol) and DMAP (100 mg, 0.8 mmol) in DMF (50 ml) add methylmalonate (11.5 ml, 82,7 mmol). The reaction mixture is heated at 60°C for 2 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (30 ml), washed with water (20 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2the gradient of 10-30% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solid white (15,4 g, yield 72%).

LCMS (method B): RT= 2,94 min, M+N+= 258.

Methyl ester of N-(2-fluoro-4-methylsulfinylphenyl)-2-pyrimidine-4-ylmethylamino acid

Methyl ester of N-(2-fluoro-4-methylsulfinylphenyl)-malonovoi acid (15,4 g to 59.9 mmol), 4-chloromethylpyridine (5,13 g, and 39.9 mmol) and potassium hydroxide (3,36 g, 59,9 IMO is b) was dissolved in IMS (150 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (30 ml), washed with water (20 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane)to give specified in the title compound in the form of not-quite-white solid (4.9 g, yield 23%).

LCMS (method B): RT= 3,02 min, M+N+= 350.

Methyl ester of 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of methyl ester of N-(2-fluoro-4-methylsulfinylphenyl)-2-pyrimidine-4-ylmethylamino acid (2 g, 5,72 mmol) and diisopropylethylamine (2,9 ml, and 17.2 mmol) in dioxane (30 ml) is added phosphorus oxychloride (V) (2.7 ml, 28.6 mmol) and the reaction mixture is refluxed for 1 hour. The reaction mixture is cooled to a temperature of 0°C and quenched with water (10 ml). The reaction mixture was diluted with saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organic fractions washed with saturated is olivem solution dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2the gradient of 10-20% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solid light brown color (0,80 g, yield 42%).

LCMS (method B): RT= 3,70 min, M+N+= 332.

7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of methyl ester 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (635 mg, 1.9 mmol) in dioxane (8 ml) and water (2.5 ml) is added monohydrate of lithium hydroxide (161 mg, 3.8 mmol). The reaction mixture is stirred at a temperature of 55°C for 2 hours, then cooled to room temperature. Added dropwise an aqueous solution of hydrochloric acid (1 M solution) to achieve a pH of ~3. The reaction mixture is extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo, obtaining mentioned in the title compound in the form of a solid dark brown color (600 mg, yield 99%).

LCMS (method B): RT= 3,20 min, M+N+= 318.

Methyl ester of 5-chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

RA is Toru methyl ester 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (576 mg, of 1.40 mmol) in DCM (10 ml) was added NCS (206 mg, 1.54 mmol)and the reaction mixture is refluxed for 3 hours. Add NCS (37 mg, 0.28 mmol) and the reaction mixture is refluxed for 2 hours. The reaction mixture was diluted with water and the product extracted with DCM (3 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2gradient of 0-40% ethyl acetate in cyclohexane)to give specified in the title compound in the form of not-quite-white solid (300 mg, yield 48%).

LCMS (method B): RT= 4,11 min, M+N+= 446.

5-Chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of methyl ester 5-chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (300 mg, 0.67 mmol) in DCM (6 ml) add tribromide boron (0,65 ml, 6.7 mmol). The reaction mixture is refluxed for 1 hour. The reaction mixture is cooled to a temperature of 0°C and carefully quenched by adding water (5 ml). The reaction mixture was diluted aqueous solution of hydrochloric acid (2 ml, 1 M solution) and extracted with ethyl acetate (3 x 10 ml). The combined organic fractions washed with nassen the m salt solution, dried (MgSO4) and concentrated in vacuo, obtaining the product in a solid dark brown color (335 mg, yield 115%).

LCMS (method B): RT= to 3.58 min, M+N+= 432.

Example 5

(2 Hydroxyethoxy)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

Stage 1: (2-Vinyloxyethoxy)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

7-(2-Fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (67 mg, 0.18 mmol), O-(2-vinyloxyethyl)hydroxylamine (18 mg, 0.18 mmol), HOBt (26 mg, 0,19 mmol), EDCI hydrochloride (37 mg, 0,19 mmol) and DIPEA (31 μl, 0.18 mmol) suspended in DMF (3 ml). The reaction mixture was stirred at room temperature for 16 hours, during which the reagents are dissolved. The reaction mixture was concentrated in vacuo, the obtained residue is dissolved in ethyl acetate (10 ml), washed with aqueous saturated sodium bicarbonate solution (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane)to give specified in the title compound in the form of TV is Gogo substances in yellow (54 mg, yield 65%).

LCMS (method B): RT= 3,38 min, M+N+= 483.

Stage 2: (2-Hydroxyethoxy)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of (2-vinyloxyethoxy)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (54 mg, 0.11 mmol) in IMS (3 ml) is added an aqueous solution of hydrochloric acid (0.5 ml, 1 M solution, 0.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The product is triturated in a mixture of Meon/diethyl ether, obtaining mentioned in the title compound in the form of a solid light brown color (20 mg, yield 39%).

1H-NMR (d6-DMSO, 400 MHz) made 11.32 (1H, s), 8,69 (1H, s), 7,98 (1H, s), 7,49 (1H, DD, J=11,0, 2.0 Hz), 7,40 (2H, s), 7.18 in-7,14 (1H, m), 6,74 (1H, s), of 5.92 (1H, t, J=8,8 Hz)and 4.65 (1H, t, J=5.6 Hz in), 3.75 (2H, t, J=5.0 Hz), of 3.46 (2H, q, J=5.0 Hz).

LCMS (method A): RT= 8,14 min, M+N+= 457.

Example 6

((R)-2,3-Dihydroxypropane)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

7-(2-Fluoro-4-is adreniline)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (90 mg, 0.23 mmol), O-((R)-2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)hydroxylamine (35 mg, 0.23 mmol), HOBt (35 mg, 0.26 mmol), EDCI hydrochloride (50 mg, 0.26 mmol) and DIPEA (40 μl, 0.23 mmol) dissolved in DMF (3 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml)and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is dissolved in a solution of hydrogen chloride in dioxane (2 ml, 4 M solution) and stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo and the resulting residue is subjected to reverse-phase HPLC (gradient: 20% to 80% acetonitrile/water with 0.1% formic acid column Phenominex gemini PhC6, 5 micron, 250×20 mm). The product is dissolved in ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo, obtaining specified in the title compound in the form of solid yellow t the ETA (22 mg, yield 20%).

NMR (d6-DMSO, 400 MHz) is 11.39 (1H, s), 8,68 (1H, s), to 7.99 (1H, s), 7,49 (1H, DD, J=10,9, 1.8 Hz), 7,41 (2H, s), 7,14-7,17 (1H, m), 6,74 (1H, s), of 5.92 (1H, t, J=8,9 Hz), 4.80 to 4.81 (1H, m), 4,53 (1H, s), 3,80 (1H, DD, J=of 9.6 and 3.6 Hz), 3,56-3,66 (2H, m).

LCMS (method A): RT= EUR 7.57 min, M+N+= 487.

Example 7

(Piperidine-4-yloxy)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

Step 1: tert-Butyl ether 4-{[7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carbonyl]aminooxy}-piperidine-1-carboxylic acid

7-(2-Fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (190 mg, 0.48 mmol), tert-butyl ester 4-aminoantipyrine-1-carboxylic acid (154 mg, to 0.72 mmol), HOBt (106 mg, of 0.79 mmol), EDCI hydrochloride (150 mg, 0.79, which mmol) and DIPEA (120 μl, to 0.72 mmol) suspended in DMF (5 ml). The reaction mixture was stirred at room temperature for 1 hour, during which the reagents are dissolved. The reaction mixture was concentrated in vacuo, the obtained residue is dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography the raffia (SiO 2, gradient 0-100% ethyl acetate in cyclohexane)to give specified in the title compound in the form of a solid brown color (180 mg, yield 65%).

LCMS (method B): RT= 3,69 min, M+N+-tBu = 540 (100%), M+N+-Boc = 496 (95%).

Stage 2: (piperidine-4-yloxy)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

tert-Butyl ether 4-{[7-(2-fluoro-4-ilfenomeno)-pyrrolo[1,2-C]pyrimidine-6-carbonyl]aminooxy}piperidine-1-carboxylic acid (180 mg, 0.30 mmol) is dissolved in a solution of hydrogen chloride in dioxane (1 ml, 4 M solution). The reaction mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo. The resulting residue is subjected to reverse-phase HPLC (gradient: 10-60% acetonitrile/water with 0.1% formic acid column Phenominex gemini PhC6, 5 micron, 250×20 mm). The product is dissolved in ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo, obtaining mentioned in the title compound in the form of a solid yellow (37 mg, yield 25%).

1H-NMR (DMSO-d6): 8,73 (1H, s), 7,92 (1H, s), 7,49 (1H, DD, J=10,98, with 1.92 Hz), 7,41-7,38 (2H, m), 7,16-7,13 (1H, m), 6,72 (1H, d, J=0,92 Hz), to 5.93 (1H, t, J=8,Hz), 3,72-3,62 (1H, m), 2,87 (2H, dt, J=12,72, 4,49 Hz), 2,41-2,31 (2H, m), 1,67 (2H, dt, J=12,84, 4,01 Hz), 1.32 to to 1.21 (2H, m).

LCMS (method A): RT= 6,17 min, M+N+= 496.

Example 8

((R)-2,3-Dihydroxypropane)amide 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

Stage 1: ((R)-2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)-amide 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]-pyrimidine-6-carboxylic acid

7-(2-Fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (287 mg, 0.90 mmol), O-((R)-2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)hydroxylamine (133 mg, 0.90 mmol), HOBt (135 mg, 0,99 mmol), EDCI hydrochloride (191 mg, 0,99 mmol) and DIPEA (169 μl, 0,99 mmol) dissolved in DMF (5 ml). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2the gradient of 30-100% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solids brown is Veta (246 mg, yield 61%).

LCMS (method B): RT= 3.28 minutes, M+N+= 447.

Stage 2: ((R)-2,3-Dihydroxypropane)amide 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of ((R)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-amide 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (246 mg, 0,56 mmol) in methanol (1 ml) add a solution of hydrogen chloride in dioxane (1 ml, 4 M solution, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate solution (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2, gradient 0-10% DCM in methanol)to give a solid light brown color. This solid is triturated in acetonitrile (3 ml), getting mentioned in the title compound in the form of a solid beige color (100 mg, yield 45%).

1H-NMR (DMSO-d6): 11,38 (1H, s)8,64 (1H, t, J=1.0 Hz), 7,86 (1H, s), 7,41-7,39 (2H, m), to 7.15 (1H, DD, J=12,09, 2,09 Hz), 6,82-6,79 (1H, m), of 6.73 (1H, s), the 6.06 (1H, t, J=8,82 Hz), 4,82 (1H, s), a 4.53 (1H, s), 3,80 (1H, DD, J=9,68, 3,51 Hz), 3,67 is 3.57 (2H, m), 3,31-3,24 (2H, m).

(SMe coincides with the solvent is m).

LCMS (method A): RT= 7,14 min, M+N+= 407.

Example 9

(2 Hydroxyethoxy)amide 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

Stage 1: (2-Vinyloxyethoxy)amide 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

7-(2-Fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (200 mg, to 0.63 mmol), O-(2-vinyloxyethyl)hydroxylamine (106 mg, 0.69 mmol), HOBt (94 mg, 0.69 mmol), EDCI hydrochloride (132 mg, 0.69 mmol) and DIPEA (118 μl, 0.69 mmol) dissolved in DMF (5 ml). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solids brown (139 mg, yield 55%).

LCMS (method B): RT= 3,35 min, M+N+= 403.

Stage 2: (2-Hydroxyethoxy)amide 7-(2-fluoro-4-metals is lifealtering)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of (2-vinyloxyethoxy)amide 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid in IMS add an aqueous solution of hydrochloric acid (4 n solution, 0.5 ml). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 times 5 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2, gradient 0-10% DCM in methanol), receiving specified in the title compound in the form of not-quite-white solid (73 mg, yield 56%).

1H-NMR (DMSO-d6): to 11.31 (1H, s), 8,65 (1H, s), a 7.85 (1H, s), 7,42-7,37 (2H, m), to 7.15 (1H, DD, J=12,10, 2,09 Hz), 6,82-6,79 (1H, m), of 6.73 (1H, s), the 6.06 (1H, t, J=8,82 Hz), of 4.66 (1H, in), 3.75 (2H, DD, J=5,34, 4,47 Hz), of 3.46 (2H, t, J=4,82 Hz), a 2.36 (3H, s).

LCMS (method A): RT= 7,35 min, M+N+= 377.

Example 10

((R)-2,3-Dihydroxypropane)amide 5-chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

Stage 1: ((R)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)amide 5-chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

5-Chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (145 mg, 0.34 mmol), O-((R)-2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)hydroxylamine (50 mg, 0.34 mmol), HOBt (50 mg, and 0.37 mmol), EDCI hydrochloride (71 mg, and 0.37 mmol) and DIPEA (63 μl, of 0.37 mmol) dissolved in DMF (3 ml). The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2gradient of 25-100% ethyl acetate in cyclohexane)to give specified in the title compound in the form of solids brown (57 mg, yield 25%).

LCMS (method B): RT= 3,63 min, M+N+= 561.

Stage 2: ((R)-2,3-Dihydroxypropane)amide 5-chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid

To a solution of ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 5-chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid (57 mg, 0.1 mmol) in methanol (1 ml) add a solution of hydrogen chloride in dioxane (1 ml, 4 M solution, 4 mmol). The reaction mixture was stirred at whom atoi temperature for 1 hour, then diluted with ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate solution (10 ml) and the aqueous fraction extracted twice with ethyl acetate (2 x 10 ml). The combined organic fractions washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM)to give a solid light brown color. This solid is triturated in acetonitrile (3 ml), receiving specified in the title compound in the form of not-quite-white solid (13 mg, yield 45%).

1H-NMR (CH3OH-d4): a total of 8.74 (1H, d, J=l,57 Hz), 7,49 (1H, d, J=6,61 Hz), 7,42 (1H, DD, J=10,78, 1,91 Hz), 7,38 (1H, DD, J=6,61, 1,58 Hz), 7,21 (1H, DDD, J=8,48, 1,90, 1,11 Hz), 6,14 (1H, t, J=8,76 Hz), 3,89-of 3.80 (1H, m), 3,79-3,71 (2H, m,), 3,56-of 3.42 (2H, m).

LCMS (method A): RT= 7,70 min, M+N+= 521.

1. The compound of formula I-and

and its pharmaceutically acceptable salts,
where ZAmean CRA;
RAmeans H or halogen;
each of R1, R2and R3means N;
W means:

each R4and R5means N;
X1represents-OR7;
each R7means2-C12-hydroxyalkyl, 2,3-dihydroxypropyl,2-C3-alkenones1-C6-al is hydroxy, (2,2-dimethyl-[1,3]dioxolan-4-yl)-methyl or piperidinyl; X4means:

R6means halogen or-SR16;
R6means halogen;
p is 1;
R16means1-C12-alkyl.

2. The compound according to claim 1, where RAdenotes H, F or Cl.

3. The compound according to claim 2, where X1choose from:


4. The compound according to claim 3, where X4choose from:

5. The compound according to claim 1, where the compound is chosen from the group containing:
(2 hydroxyethoxy)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid;
(piperidine-4-yloxy)amide 7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 7-(2-fluoro-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid;
(2 hydroxyethoxy)amide 7-(2-what Thor-4-methylsulfonylamino)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 5-chloro-7-(2-fluoro-4-ilfenomeno)pyrrolo[1,2-C]pyrimidine-6-carboxylic acid;
or its pharmaceutically acceptable salt.

6. The pharmaceutical composition inhibiting the activity of Mek kinase-containing compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. Method of inhibiting abnormal cell growth, comprising the administration to a mammal a therapeutically effective amount of the pharmaceutical composition according to claim 6.

8. The use of compounds according to any one of claims 1 to 5 for inhibiting abnormal cell growth.

9. The use of compounds according to any one of claims 1 to 5 for the preparation of medicinal products intended for inhibiting abnormal cell growth.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new tetracyclic compounds of general formula (I), wherein is a single or double bond; no bonds or a single bond; or V means N; T and X as shown in structure fragments above; U and W independently mean C or N with one of them shall be N; R3, R4, R5 and R6 - H; Rv is absent; Ru and Rw are independently absent or mean (C1-12)alkyl; Y =N-OR1 or NP'1, wherein R1 - H, (C1-12)alkyl optionally substituted by phenyl, phenyloxy, carboxy, (C1-12)alkoxy, (C1-12)alkoxycarbonyl, or (C2-12)alkenyl; R'1 is phenyl, or pharmaceutically acceptable salts thereof, or diastereomers thereof, or regioisomers thereof, or: mixtures thereof, a pharmaceutical composition containing them, and specific compounds for cysteine protease inhibition.

EFFECT: compounds may be used in medicine in treating cancer, neurodegenerative diseases, inflammatory disorders, cardiovascular diseases, etc.

8 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new pyrimidine substituted macrocyclic compounds of genral formula (I) , wherein A= -C(=O)OR1 or -C(=O)-NH-SO2-R2; R1 = H or C1-6alkyl; R2 = phenyl, thienyl, C3-7cycloalkyl optionally substituted by C1-6alkyl; X = N or CH; E = NR5; R5 = H or C1-6alkyl; n = 4 or 5; R7=H, C1-6alkyl, C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy; R8 =C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy, morpholino or -NRaRb, wherein Ra and Rb independently mean H or C1-6alkyl; R9 = Rq = H; or their pharmaceutically acceptable addition salts, or stereoisomers, and pharmaceutical compositions containing them.

EFFECT: compounds are inhibitors of HCV NS3 serine protease and can find application in treating chronic hepatic disorders, particularly chronic hepatitis.

10 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to producing new 5,8,9,10-tetrahydropyrimido[4,5-d]azocine derivatives having triflate, secondary and tertiary amino groups in the 4th position of general formula specified below. In general structural formula: 2-12 2 X=OTf (Tf means triflate), X means NR1R22 related to the groups 3-12

.

The method consists in the fact that 6-isopropyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one reacts with methyl propyolate in methanol at room temperature to produce methyl 8-isopropyl-4-oxo-2-phenyl-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (1). Thereafter, the prepared compound reacts with triftalane hydride in dichloromethane in the presence of pyridine at t°=-10°C; it is recovered and purified with by means of column chromatography to prepare methyl 8-isopropyl-2-phenyl-4-{[(trifluoromethyl)sulphonyl]oxy}-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (2); then the solution I mmole of the prepared product (2) in absolute dioxide is added with 2 mmole of K2CO3 and 1.5 mmole of appropriate amine. After being boiled for two hours and removing the solvent, respective 4-amino substituted 5,8,9,10-tetrahydropyrimido[4,5-d]azocine of formula 3-12 is prepared. The method is directed to prepare the products in the form of white or yellow powder, or in the form of drying oil.

EFFECT: after the primary screening, the compounds appeared to be acetyl- and butyrylcholin esterase inhibitors and can find application as scaffolds in searching the preparations for treating neurodegenerative diseases.

10 ex

FIELD: medicine, pharmaceutics.

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

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

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them.

EFFECT: invention also refers to a method for preparing the compounds of formula (I), the based pharmaceutical compounds, to the use of said compounds for preparing said drug preparation for treating or preventing anxiety, epilepsy, sleep disorders, including insomnia, as well as for inducing a sedative-hypnotic effect, anaesthesia and muscular relaxation.

23 cl, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (VIII):

X represents NR7; Y represents O or N-(CH2)nR19; n is equal to 1 or 2; m is equal to 1 or 2; R1 represents H or C1-6alkyl; R2 independently represents H, C1-6alkyl or C5-6cycloalkyl; each of R4 and R4 independently represents H or C1-6alkyl; or R4 and R4 together form spiro-C3-6cycloalkyl group; R19 represents H, C1-6alkyl, C6aryl or C3cycloalkyl group; R6 represents OR8 ; and each of R7 and R8 independently represents H or C1-6alkyl. The invention also refers to compounds of formula VI, VII, a pharmaceutical composition containing said compounds, and a method of treating a proliferative disease, such as cancer.

EFFECT: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a PLK1 kinase inhibitor.

24 cl, 8 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new monophosphate salt of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide which may be used for treating a disease responding to protein kinase activity inhibition. The method for preparing the monophosphate salt of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide involves the reaction of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide in the form of a free base with phosphoric acid in methanol. Also, the invention refers to a pharmaceutical composition containing: (a) a therapeutically effective amount of the monophosphate salt of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide; and (b) at least one pharmaceutically acceptable carrier, a diluent, an excipient, as well as to the use of the therapeutically effective amount of the monophosphate salt of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide in preparing a drug preparation for treating a disease responding to protein kinase activity inhibition.

EFFECT: preparing the composition for treating a disease responding to protein kinase activity inhibition.

4 cl, 8 dwg, 17 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a Raf-kinase inhibitor that is a solid form A of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[(1]imidazole-2-amine hydrate, a pharmaceutical composition containing a solid form A, and the use thereof for treating cancer.

EFFECT: preparing the composition for treating cancer.

21 cl, 48 dwg, 16 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely oncology and may be used for treating multiple myeloma in a patient recurrent after bortezomib or refractory therapy. That is ensured by administering a VEGF antagonist representing a VEGF antibody (bevacizumab). What is also presented is a method of treating multiple myeloma recurrent after alkylating agent therapy.

EFFECT: group of inventions provides the effectiveness of the VEGF antibody for suppression of bortezomin sensitive and/or resistant tumours.

48 cl, 10 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science, and aims at treating viral diseases in animals. What is declared is a composition for treating viral diseases in animals, containing two subtypes of vertebrate recombinant interferon mixed in equal molar proportions.

EFFECT: use of the declared composition enables ensuring the substantial increase of the therapeutic effect of recombinant interferons and minimising the potential adverse effects associated with their use.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an antiproliferative agent for treating benign hyperplasia of prostate (BHP). The antiproliferative agent for treating benign hyperplasia of prostate based on herbal raw materials represents terrestrial peat lipids prepared by grinding terrestrial peat in a planetary ball mill or a ball mill, extracting ground peat in mixed ethanol and chloroform, filtering, evaporating and drying in the specific environment.

EFFECT: agent enables extending the range of herbal products on the basis of domestic herbal raw materials effective in treating BHP.

3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an anticancer drug containing a combination of 1-(3-C-ethinyl-β-D-ribopentifuranosyl)cytosine or its salt, and carboplatin. The invention also refers to the use of this combination for preparing the anticancer agent, a method of treating cancer which comprises administering the combination to the patient, and a method of enhancing the anticancer effect of carboplatin.

EFFECT: combination of 1-(3-C-ethinyl-β-D-ribopentifuranosyl)cytosine or its salt, and carboplatin provides the enhanced anticancer effect and the reduced unfavourable effects.

8 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. There are presented versions of a CD20 modified antibody or its antigen-binding fragment. Each version is characterised by the fact that it comprises a variable region of a light chain and a variable region of a heavy chain and induces a higher level of apoptosis as compared with B-Lyl murine antibody. There are presented versions of the compositions to enhance the effector functions. One of such compositions contains antibodies wherein at least 20% of the Fc oligosaccharides are bisectional and non-fucosylated, whereas the other one contains antibodies wherein at least 50% of the oligosaccharides are non-fucosylated. Also, there are described: versions of a host cell to produce the antibodies, an expression vector, as well as the versions of the coding polynucleotides, a method for producing the antibodies in a cell and using the antibodies for preparing a drug for treating disorders treated by B-cells depletion.

EFFECT: use of the inventions provides the antibodies with the improved therapeutic properties, including with higher Fc receptor binding and enhanced effector function that can be find application in treating tumors.

36 cl, 3 ex, 9 tbl, 26 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to virology, and concerns the Newcastle disease virus strain. The characterised strain NDV/Mallard/Adigeya/8/2008 is recovered from a dead duck, and deposited in the Collection of Cultures of the State Research Centre for Virology and Biotechnology "Vector" under registration number No. V-512.

EFFECT: presented strain may be used to study the oncolytic properties and mechanisms, and to develop the anticancer candidate preparations based thereon.

9 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to combinations of peptides in each case with the same sequence length (SEQL) which can be prepared in a stable reproducible quality and quantity of a mixture (A) containing a number of x amino acid with protected acid groups or a number of z peptides with the acid groups protected by the protective groups and the activated amino groups, with the amino acids in the mixture (A) found in a specific molar ratio, and a mixture (B), containing a number of y amino acids with the amino groups protected by the protective groups, with a molar ratio of the amino acids of the mixture (B) being the same as the molar ratio of the amino acids of the mixture (A), and the number x=y, and x is a figure from 11 to 18.

EFFECT: new combinations of the peptides are presented.

13 cl, 2 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula 1a: , wherein Q1 and Q2, each separately and independently is specified in a group consisting of N and C-Z6, provided both Q1 and Q2 are not C-Z6 simultaneously; E1 represents phenyl, and wherein the cycle E1 is substituted by one or more residues R16, and wherein the cycle E1 is substituted by one or more residues R18; wherein A is specified in a group consisting of phenyl or pyrazolyl; G1 means pyrazolyl; the cycle A is substituted in any substituted position by one residue A1, wherein A1 is specified in a group consisting of A2 and A3; A2 and A3 are those as specified in cl.1 of the patent claim, the cycle A is optionally substituted by one or more residues R2; X2 represents a direct bond wherein E1 is independently bound to the group NR3 in formula 1a; X3 represents -O-; V and V2 represent H2, and VI is independently specified in a group consisting of H2 or O; each Z2 is independently and separately specified in a group consisting of hydrogen, C1-C6-alkyl; each Z3 is independently and separately specified in a group consisting of H, C1-C6-alkyl, branched C3-C7-alkyl and - (CH2)nN(R4)2; each Z4 represents H; each Z6 is independently and separately specified in a group consisting of H, C1-C6-alkyl, branched C3-C7-alkyl, hydroxyl, hydroxy-C3-C6-alkyl, branched hydroxy-C2-C6-alkyl-, (R3)2N-, (R4)2N-, -N(R3)C(O)R8, C(O)N(R4)2, halogen, -(CH2)nG1 and -R17; each R2 is specified in a group consisting of C1-C6-alkyl and branched C3-C8-alkyl; each R3 represents H; each R4 represents H, C1-C6-alkyl or branched C3-C7-alkyl; each R8 is independently and separately specified in a group consisting of C1-C6-alkyl and branched C3-C7-alkyl; each R16 is independently and separately specified in a group consisting of C1-C6-alkyl, branched C3-C7-alkyl, halogen and a cyano group; each R17 represents pyrazolyl; wherein R17 may be additionally substituted by one or more residues Z2 or Z3; R18 represents hydrogen; and n is equal to 0-6; p is equal to 1-4; q is equal to 2-6; r is equal to 0 or 1; t is equal to 1-3, v is equal to 1 or 2. Besides, the invention describes a method for modulation of wild-type kinase activity, a pharmaceutical composition for treating hyperproliferative diseases in cancer in mammals; there are also described methods of treating cancer in a patient.

EFFECT: there are prepared and described new compounds which can find the application in modulation of kinase activity.

20 cl, 56 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical compositions for local application. Claimed compositions include sildenafil, minoxidil, testosterone, or alprostadil, euphyllin, yohimbine, or sildenafil, minoxidil, yohimbine as active agents respectively. Claimed compositions also contain hydrogenated lecithins in combination with cholesterol, emulsifying agent, preservative and demineralised water in specified weight ratios.

EFFECT: group of inventions ensures fast penetration through skin and complex therapy of erectile dysfunction taking into account impact on psychogenic and endocrine factors.

3 cl, 4 tbl, 7 ex

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